信息编号11333101至11333150间共50条。
☉ 11333101:Cause of V pattern strabismus in craniosynostosis: a case report
Jules Stein Eye Institute, 100 Stein Plaza, UCLA Los Angeles, CA, USA Keywords: craniosynostosis; extraocular muscle pulleys; heterotopic extraocular muscle; strabismus Strabismus is a common association in patients with craniosynostosis or craniofacial dysostosis (60–70%).1–3 V pattern exotropia is the most common ocular motility problem. Various theories have been proposed to explain the cause of the V pattern and surgical attempts to correct it with weakening procedures of the inferior oblique have been disappointing.2,3 This is a case report of one child with this disorder who underwent orbital computed tomography (CT) scans and had a marked improvement of the V pattern following strabismus surgery based on the CT findings. CASE REPORT This child with craniosynostosis had undergone six previous cranial surgeries. She had three strabismus surgical procedures including anterior transpositions of the inferior obliques in an attempt to correct a large V pattern. She presented to us with a chin up position, V pattern exotropia (60 prism dioptres), over-elevation in adduction, limitation of depression in adduction, and incomitant hypertropias in side gazes (fig 1). Objective fundus excyclotorsion was noted. Figure 1 Preoperative V pattern exotropia, over-elevation in adduction, under-depression in adduction in both eyes. Orbital imaging demonstrated that all extraocular muscles in each eye were present, normal in size and shape but anatomically displaced. The extraocular muscles in the left eye were rotated clockwise and in the right eye were rotated counterclockwise (fig 2). Ineffectiveness of inferior oblique weakening procedures and the presence of muscle heterotopy led us to consider that the over-elevation in adduction was most likely related to the anatomical displacement of the rectus muscles. Figure 2 Preoperative coronal views on CT scan of both orbits showing evidence of rectus muscle heterotopy. A vertical line joining the centre of the belly of the vertical rectus muscles shows the relative temporal displacement of the superior rectus muscle compared to the nasal displacement of the inferior rectus muscle. A horizontal line joining the centre of the belly of the horizontal rectus muscles shows the relative inferior displacement of the lateral rectus muscle compared to superior displacement of the medial rectus muscle. Surgical exploration confirmed muscle heterotopy. The lateral recti were found slanting inferiorly (fig 3). Repositioning of the lateral recti superiorly to a more horizontal position and suturing the superior border of the muscle belly to the adjacent sclera about 18 mm from the limbus using a non-absorbable suture was the first surgical procedure performed by us on this patient. This led to some improvement of the V pattern. This was followed by recession and nasal repositioning of the superior recti suturing the nasal border of the muscle belly to the adjacent sclera about 18 mm from the limbus using a non-absorbable suture. This achieved good alignment in the primary position and eliminated the anomalous chin up position, markedly reduced the V pattern, eliminated the over-elevation in adduction, and improved depression in adduction (fig 4). Figure 3 Intraoperative photograph. The left eye is adducted with a muscle hook placed under the lateral rectus muscle (LR). The lower line highlights the downward slanting of the left lateral rectus muscle. A curved ruler is used to show the normal horizontal path of the lateral rectus muscle. Figure 4 Postoperative clinical pictures showing improvement in V pattern exotropia with improvement in versions in adduction. COMMENT V pattern strabismus in craniosynostosis may be related to anatomical malposition of the rectus muscles. This may be documented by orbital imaging, which could also aid in planning the surgical approach. In these cases the overelevation in adduction and under depression in adduction may be due to the anatomical displacement of the rectus muscles.2 References Coats DK, Paysse EA, Stager DR. Surgical management of V-pattern strabismus and oblique dysfunction in craniofacial dysostosis. JAAPOS 2000;4:338–42. Clark RA, Miller JM, Rosenbaum AL, et al. Heterotopic muscle pulleys or oblique muscle dysfunction? JAAPOS 1998;2:17–25. Limon de Brown , Monasterio FO, Feldman MS. Strabismus in plagiocephaly. J Pediatr Ophthalmol Strabismus 1998;25:180–90....查看详细 (4514字节)

☉ 11333102:Bilateral ischaemic optic neuropathy and stroke after multiple bee stings
1 University of Houston University Eye Institute, Houston, TX, USA 2 University of Texas Medical Branch, Galveston, TX, USA Keywords: bee sting; stroke; optic neuropathy; hemianopia Despite the common occurrence of insect stings and local and systemic allergic reactions,1 there are few reports of optic neuropathy or stroke following bee or wasp stings and, to our knowledge, there has been no report of both cerebral infarction and optic neuropathy occurring in the same patient after such an event. We report on a middle aged woman who sustained both a stroke and ischaemic optic neuropathy after multiple bee stings. CASE REPORT A 57 year old white woman reported being stung by 30–40 bees, identified as Africanised honey (killer) bees, in the back of her neck, head, right eye, face, and right arm. She was treated with intravenous antihistamines and antiemetics at a local emergency room and released. Two days later, the patient experienced a severe headache with nausea and vomiting and noticed a left homonymous visual field loss. She went to see her primary doctor and while there became unresponsive, leading to hospitalisation. Head computed tomography (CT) showed a right occipital ischaemic infarct. Shortly thereafter, the patient experienced acute nausea and vomiting with neck rigidity and was readmitted. A head CT scan and brain magnetic resonance image (MRI)/magnetic resonance angiography (MRA) were performed showing a large right temporo-occipital haemorrhagic infarct (fig 1A, B). An ocular examination revealed best corrected visual acuity (BCVA) of 20/20-1 right eye and 20/30-2 left eye at distance and 20/20 right eye and 20/200 left eye at near, with left homonymous hemianopia, a left inferior altitudinal defect, and bilateral arcuate defects (fig 1C) with bilateral haemorrhagic disc oedema. Figure 1 MRI (A), MRA (B), and Humphrey 30-2 visual fields (C) of our patient. Past medical and surgical history are significant only for controlled arterial hypertension and pseudophakia. Neuro-ophthalmic examination 5 weeks after her sting episode showed BCVA of 20/15 right eye and 20/25 left eye at distance and 20/20 right eye and 20/30+1 at near. Amsler grid and automated perimetry showed a left homonymous hemianopic defect with a right inferior arcuate defect and a left inferior altitudinal defect. Pupil examination showed isocoria with a 0.3–0.6 log unit relative afferent pupillary defect in the left eye. Motility was unremarkable, as was anterior segment both eyes. Intraocular pressures were 20 mm Hg right eye and 18 mm Hg left eye. Funduscopic examination showed bilateral disc oedema with pallid swelling superiorly and temporally in both eyes and peripapillary haemorrhage and cotton wool spots in both eyes consistent with anterior ischaemic optic neuropathy (AION). Both maculas were unremarkable without exudative changes. Both retinas were flat with normal vasculature out to the periphery. Three months after the sting event, the patient reported some improvement of peripheral vision, and repeat visual fields improved slightly inferiorly but were otherwise unchanged. Both optic discs were now flat and showed superior temporal pallor with corresponding nerve fibre layer dropout. COMMENT In their literature review of five cases and report of two additional cases of optic neuropathy occurring after bee and wasp sting, Maltzman, et al2 describe common characteristics, such as acute to subacute onset of symptoms, moderate to severe visual loss followed by significant recovery (except in one case of a sting directly to the eye); oedematous and haemorrhagic optic discs, and central or caecocentral scotomas. Although our patient had subacute vision loss associated with haemorrhagic disc oedema, her case differs because of minimal recovery of vision and altitudinal visual loss consistent with an ischaemic neuropathy, rather than a transient optic neuritis. Seven cases of wasp and bee sting associated cerebral infarction were found in the literature.3–9 Reported neurological complications included seizure, hemiparesis, aphasia, apraxia, dysarthria, ataxia, and coma, none of which were experienced by our patient. None of these patients had a full eye examination, although in one patient8 a right homonymous superior quadrantanopia was demonstrated (table 1). Table 1 Reports of cerebral hypoxia and infarction following bee/wasp sting The pathophysiology explaining the associated stroke is unknown. Hypotension caused by anaphylaxis may certainly induce cerebral and optic nerve ischaemia; however, this was not documented in our case. Similar to acute myocardial infarction after hymenoptera stings, it has been suggested that vasoconstriction secondary to mediators released after the sting, aggravated by exogenous adrenaline, and platelet aggregation also contribute to cerebral ischaemia.8 Bee venom itself contains histamine, thromboxane, leucotrienes, and other vasoactive and inflammatory mediators. In our patient, we postulate that the systemic immune mediated reaction to the bee sting caused vasoconstriction and a prothrombotic state with subsequent ischaemia leading to both the stroke and AION. In addition, a neuropharmacological (sympathetic) mechanism of endothelial permeability involving the cerebral vasculature with a concurrent systemic thrombogenic or immune response has also been postulated.5,6 References Ewan PW. ABC of allergies: venom allergy. BMJ 1998;316:1365–8. Maltzman JS, Lee AG, Miller NR. Optic neuropathy occurring after bee and wasp sting. Ophthalmology 2000;107:193–5. Day JM. Death due to cerebral infarction after wasp stings. Arch Neurol 1962;7:184–6. Starr JC, Brasher GW. Wasp sting anaphylaxis with cerebral infarction. Ann Allergy 1977;39:431–3. Riggs JE, Ketonen LM, Bodensteiner JB, et al. Wasp sting-associated cerebral infarction: a role for cerebrovascular sympathetic innervation. Clin Neuropharmacol 1993;16:362–5. Riggs JE, Ketonen LM, Wymer JP, et al. Acute and delayed cerebral infarction after wasp sting anaphylaxis. Clin Neuropharmacol 1994;17:384–8. Speach DP, Wong TM, Cattarin JA, et al. Hypoxic brain injury with motor apraxia following an anaphylactic reaction to hymenoptera venom. Brain Injury 1998;12:239–44. Crawley F , Schon F, Brown MM. Cerebral infarction: a rare complication of wasp sting. J Neurol Neurosurg Psychiatry 1999;66:550–1. Bhat R , Bhat KR, Pais R, et al. Bilateral haemorrhagic cerebellar infarction following honeybee sting. J Assoc Physicians India 2002;50:721–2....查看详细 (6671字节)
☉ 11333103:Prevention and Control of Meningococcal Disease: Recommendations for Use of Meningococcal Vaccines in Pediatric Patients
ABSTRACT Two peaks in the incidence of invasive meningococcal disease (IMD) occur in pediatric patients: infants younger than 1 year and adolescents 15 to 18 years of age. Although the incidence of IMD is highest in infants, the case-fatality rate is highest in adolescents (20%). Epidemiologic studies also have demonstrated increased risk of IMD among college freshman living in dormitories compared with other college students and similarly aged persons in the general population. At least 75% of cases of IMD in 11- to 18-year-olds are caused by serogroups A, C, Y, and W-135; thus, IMD potentially is preventable by immunization with quadrivalent meningococcal vaccines. Meningococcal A, C, Y, W-135 conjugate vaccine (MCV4) was licensed in 2005 for use in people 11 to 55 years of age. On the basis of data indicating increased risk of meningococcal disease and fatality among certain adolescents and college students, the American Academy of Pediatrics recommends administration of MCV4 to young adolescents (at the 11- to 12-year visit), students entering high school or 15-year-olds, and college freshmen who will be living in dormitories. For pediatric patients 11 years and older who are at increased risk of meningococcal disease, MCV4 also is recommended. The purposes of this statement are to provide the rationale for routine use of MCV4 in adolescents and to update recommendations for use of the meningococcal polysaccharide vaccine in pediatric patients. Key Words: meningococcal disease Abbreviations: IMD, invasive meningococcal disease CDC, Centers for Disease Control and Prevention AAP, American Academy of Pediatrics MPSV4, tetravalent meningococcal (A, C, Y, W-135) polysaccharide vaccine FDA, Food and Drug Administration MCV4, tetravalent meningococcal (A, C, Y, W-135) conjugate vaccine SBA, serum bactericidal activity rSBA, serum bactericidal assay using baby rabbit serum GMT, geometric mean titer Td, adult-type diphtheria and tetanus toxoids OMP, outer membrane protein BACKGROUND INFORMATION Each year, 1400 to 3000 cases of invasive meningococcal disease (IMD) occur in the United States, reflecting the 5- to 7-year cycles in incidence.1 Although the annual incidence of IMD is relatively low, ranging from 0.5 to 1.1 per 100000 population (Centers for Disease Control and Prevention [CDC]), case-fatality rates and sequelae among survivors are appreciable. Death occurs in 10% to 14% of cases, and significant sequelae including limb or digit amputation, skin scarring, neurologic disabilities, and hearing loss occur in 11% to 19% of cases.2 Although only a portion of these cases present clinically as meningitis, Neisseria meningitidis has become the leading cause of bacterial meningitis in children after the dramatic reductions in the incidence of Streptococcus pneumoniae and Haemophilus influenzae type b infections achieved after introduction of conjugate vaccines for these pathogens. The incidence of IMD in pediatric patients has 2 peaks. The highest incidence of meningococcal disease is in infants younger than 12 months, but a second, lower peak occurs during adolescence.2 Adolescents 15 years or older are more likely than infants and children to have meningococcemia without meningitis (40% vs 20%, respectively), shock at presentation (69% vs 27%, respectively), and a fatal outcome (22.5% vs 4.6%, respectively).3 Not surprisingly then, adolescents have the highest case-fatality rate (estimated at 20%) of any age group. Survivors at any age are at risk of permanent sequelae. The American Academy of Pediatrics (AAP) previously recommended tetravalent meningococcal (A, C, Y, W-135) polysaccharide vaccine (MSPV4 [Menomune-A/C/Y/W-135; Sanofi Pasteur, Swiftwater, PA]) for use in certain high-risk children and adolescents, including travelers to countries with epidemic or hyperendemic meningococcal disease, for people who have certain medical conditions (terminal complement component deficiencies and anatomic or functional asplenia), and for control of meningococcal disease outbreaks attributable to strains in the vaccine.4 Previous AAP guidelines for college freshmen have emphasized education about meningococcal disease and the availability of a meningococcal vaccine without recommending routine use of meningococcal polysaccharide vaccine.5 The new tetravalent meningococcal (A, C, Y, W-135) conjugate vaccine (MCV4 [Menactra; Sanofi Pasteur]), licensed by the Food and Drug Administration (FDA) on January 14, 2005, for use in people 11 to 55 years of age, should become an important addition to existing meningococcal disease–preventive measures. This statement provides the recommendations of the AAP for prevention and control of meningococcal disease in pediatric patients through immunization with MPSV4 as well as the new MCV4. More detailed information regarding contemporary epidemiology of IMD, evaluation and management of suspected outbreaks of IMD, cost-effectiveness analyses for meningococcal vaccines, and recommendations for use of meningococcal vaccines and chemoprophylaxis in adults can be found in the statement of the Advisory Committee on Immunization Practices of the CDC.2 EPIDEMIOLOGY OF IMD The overall case-fatality rate of IMD in children and adults in the United States is 10% to 14%.2 From 1991 to 2002, the highest incidence of IMD in the United States (9.2 per 100000) was among infants younger than 1 year (Fig 1); the rate among adolescents 11 to 19 years of age (1.2 per 100000) also was higher than that for the general population. Thirty-eight percent of IMD cases were observed in infants and children younger than 11 years, but adolescents had the highest case-fatality rate (20%). Certain patients are at increased risk of IMD, including patients with deficiency of the terminal complement pathway (C5-C9) or C3 and patients with anatomic or functional asplenia (ie, sickle cell disease). Healthy children also can be at increased risk of meningococcal disease if they are traveling to or living in areas outside the United States where IMD is hyperendemic or epidemic or if they are involved in a confirmed outbreak. In the United States, more than 98% of cases of IMD in children and adults are sporadic, but since 1991, the frequency of localized outbreaks has increased, especially in schools.6 The proportion of meningococcal disease caused by serogroup Y has increased from 2% in 1989–19917 to 37% in 1997–2002.2 Currently, serogroups B, C, and Y are the major causes of IMD in the United States, each being responsible for approximately one third of all cases. The proportion of cases caused by each serogroup varies by age group; more than half of cases among infants younger than 1 year are caused by serogroup B, for which no vaccine is licensed or available in the United States.8 Seventy-five percent of all cases of meningococcal disease in people 11 to 18 years of age are caused by serogroups (A, C, Y, or W-135) included in currently available vaccines.2 The incidence of IMD caused by these vaccine-preventable serotypes peaks in people 18 years of age (1.8 per 100000), is beginning to increase substantially at 15 years of age, and decreases by 19 years of age (Fig 2). Three studies conducted in the United States address the risk of meningococcal disease among college students.9–11 Each study demonstrated that the risk of meningococcal disease was higher in college students who reside in dormitories than in other college students. The earliest of these reports described a low overall incidence of meningococcal disease in college students (1 per 100000 population per year), but IMD occurred 9 to 23 times more frequently in students residing in dormitories than in students residing in other types of accommodations.11 In the second study, which was a retrospective, cohort investigation conducted in Maryland for the period of 1992–1997, the overall incidence of IMD in college students was similar to the incidence in the US population of people the same age (1.74 vs 1.44 per 100000, respectively), but rates were significantly higher among students living in dormitories compared with students living off campus (3.2 vs 0.96 per 100000; P = .05).10 Finally, US surveillance data from the 1998–1999 school year suggested that the overall rate of meningococcal disease among undergraduate college students was lower than the rate among people 18 to 23 years of age who were not enrolled in college (Table 1; 0.7 vs 1.5 per 100000, respectively). Among the 600000 freshmen who lived in dormitories during this period, the rate (5.1 per 100000) was higher than any age group in the population other than children younger than 2 years but lower than the threshold of 10 per 100000 recommended for initiating meningococcal immunization campaigns.9 Although ample data define the risk for IMD among certain college students, there are no studies among adolescents in living circumstances that may be similar to college dormitories (boarding schools, "sleep-away" camps, etc). In the absence of data establishing increased risk, adolescents in these circumstances should be immunized only if they fall into a recommended group by age or underlying medical condition. In 2000, the Advisory Committee on Immunization Practices and AAP Committee on Infectious Diseases1,5 concluded that college students who live in dormitories are at increased risk of meningococcal disease relative to other people their age. They recommended that college students and their parents be informed by health care professionals of the risks of meningococcal disease and potential benefits of immunization with MPSV4, that college and university health services facilitate implementation of educational programs concerning meningococcal disease and availability of immunization services, and that the vaccine be made available to those requesting immunization. As of August 2004, 31 states have adopted legislation requiring colleges to provide information on risks of meningococcal disease to matriculating students and students residing on campus. Eleven of those states mandate immunization of students living on campus unless an immunization waiver is provided. MENINGOCOCCAL VACCINES There are 2 meningococcal vaccines licensed for use in children and adults. Menomune-A/C/Y/W-135 (MPSV4) was licensed in 1981 for use in children older than 2 years as well as adults and has been recommended by the AAP for use in these children only if they are at increased risk of meningococcal disease.4 Menactra (MCV4) was licensed in 2005 for use in children 11 years and older and adults through 55 years of age. Currently, MCV4 is being considered for licensure by the FDA for use in children 2 to 10 years of age. Meningococcal Polysaccharide Vaccine Vaccine Composition and Administration Each dose of MPSV4 consists of 50 μg each of the 4 (A, C, Y, and W-135) purified meningococcal capsular polysaccharides. MPSV4 (Menomune-A/C/Y/W-135) is available in single-dose (0.5-mL) and multiple-dose (5-mL) vials. MPSV4 is administered subcutaneously as a single 0.5-mL dose. MPSV4 can be administered concomitantly with other vaccines at different anatomic sites.12,13 Protective concentrations of antibodies usually are achieved within 7 to 10 days of immunization.14 Immunogenicity and Efficacy MPSV4 (Menomune-A/C/Y/W-135) was licensed in the United States in 1981 on the basis of safety and immunogenicity data. Immunogenicity of this vaccine was compared with immunogenicity of an existing bivalent A and C meningococcal polysaccharide vaccine, which had demonstrated 97% efficacy against serogroup A and 90% efficacy against serogroup C meningococcal disease in military recruits.15 The immunologic criterion used for licensing was an increase in serum bactericidal activity (SBA) of fourfold or greater in 90% of adults 3 to 4 weeks after immunization. The immunogenicity and efficacy of serogroup A and C meningococcal polysaccharide vaccines are established. Serogroup A polysaccharide vaccine induces antibodies in some children as young as 3 months of age, although an immune response comparable to that in adults is not achieved until 4 to 5 years of age; serogroup C polysaccharide vaccine is poorly immunogenic in children younger than 24 months. Serogroup A and C polysaccharide vaccines have demonstrated estimated clinical efficacies of more than 85% in school-aged children and adults and are useful in controlling outbreaks.16,17 Serogroup Y and W-135 polysaccharide vaccines are safe and immunogenic in children older than 2 years and adults, and although clinical efficacy has not been documented, immunization with these polysaccharide vaccines induces high titers of serum bactericidal antibodies, a correlate of protection. The antibody responses to each of the 4 polysaccharides in the tetravalent polysaccharide vaccine are serogroup-specific and independent. Serogroup C polysaccharide vaccine can cause immunologic hyporesponsiveness (reduced antibody response after reimmunization with the same polysaccharide antigen), but the biological significance of this observation is unclear.18 Duration of Protection In children 2 to 5 years of age, measurable concentrations of antibodies against group A and C polysaccharides decrease substantially during the first 3 years after a single dose of vaccine.19 Although vaccine-induced protection likely persists in school-aged children and adults for at least 3 years, the efficacy of the group A vaccine administered to children younger than 5 years may decrease markedly within this period of time. In one study, group A vaccine efficacy in children immunized at younger than 4 years decreased from more than 90% to less than 10%; in children given vaccine at older than 4 years of age, vaccine efficacy was 67% 3 years later.20 Precautions and Contraindications MPSV4 has been used extensively in mass-immunization programs as well as in the military and among international travelers. Adverse reactions to MPSV4 generally are mild; the most frequent reaction is pain and redness at the injection site lasting for 1 or 2 days. Estimates of the incidence of such local reactions have varied, ranging from 4% to 56%. Transient fever occurs in up to 5% of vaccine recipients in some studies but is less common in older children and adults. Most studies report the rate of systemic allergic reactions (eg, urticaria, wheezing, and rash) as 0.0 to 0.1 per 100000 vaccine doses.21 Anaphylaxis has been documented in less than 0.1 per 100000 vaccine doses.22 Meningococcal Conjugate Vaccines Theoretic Advantage of MCV4 Bacterial polysaccharides, including those comprising the capsule of N meningitidis, are T-cell–independent antigens. T-cell–independent antigens do not elicit a memory response. They stimulate mature B lymphocytes but not T lymphocytes, thus inducing a response that is neither long lasting nor characterized by anamnestic response after subsequent challenge with the same polysaccharide antigen.23 Meningococcal polysaccharide vaccines, therefore, have several inherent limitations. Meningococcal polysaccharide vaccines do not confer long-lasting immunity and do not elicit a sustainable reduction of nasopharyngeal carriage of N meningitidis to result in herd immunity.24 Conjugation (covalent coupling) of polysaccharide to a protein carrier that contains T-cell epitopes changes the expression of the immune response to the polysaccharide from T-cell independent to T-cell dependent, resulting in an improved primary response to the polysaccharide and a strong anamnestic response at reexposure.25 Both conjugate H influenzae type b and conjugate S pneumoniae vaccines introduced for mass infant immunization in the United States in 1990 and 2000, respectively, have been successful in reducing the incidence of disease caused by serotypes contained in the vaccines.1 In addition, both vaccines decrease asymptomatic carriage of the respective bacteria, thus protecting unimmunized individuals through a herd-immunity effect.1 Meningococcal Serogroup C Conjugate Vaccine in the United Kingdom In November 1999, 3 monovalent serogroup C conjugate vaccines were introduced in the United Kingdom during a national immunization campaign. A routine 3-dose infant immunization series began at the same time as a mass catch-up campaign targeting all children between 12 months and 17 years of age.26 By 2001–2002, vaccine coverage in the United Kingdom was estimated at 80% in infants, 84% in toddlers, 76% in preschoolers, and 87% in school-aged children.27 Effectiveness of the meningococcal group C conjugate vaccines within the first year of immunization ranged from 88% to 98% in different age groups.28 Because the vaccine campaign was initiated in 1999, duration of protection data are not yet available. However, effectiveness among infants who received 3 doses of vaccine at 2, 3, and 4 months of age decreased by 81% after only 1 year.28 Although the number of cases remains low, likely in part because of vaccine-induced herd immunity, this study raises important questions about the meningococcal vaccine schedule and the need for a booster dose in infants. Carriage rates of group C meningococci in the United Kingdom decreased by 66% during the campaign; incidence of IMD decreased by 67% in unimmunized children 1 to 17 years of age, demonstrating the ability of the conjugate vaccine to elicit herd immunity.27 Vaccine Composition and Administration MCV4 is a tetravalent meningococcal conjugate vaccine (Menactra) that contains capsular polysaccharides from serogroups A, C, Y, and W-135 (4 μg each) conjugated to 48 μg of diphtheria toxoid. MCV4 is available only in single-dose (0.5-mL) vials; vaccine is administered as a single 0.5-mL dose. Protective concentrations of antibodies are achieved within 8 days of immunization. Immunologic Correlates of Protection Studies in military recruits conducted in the United States in the 1960s demonstrated that naturally acquired bactericidal antibodies measured by SBA confer protection from IMD. SBA titers of 1:4 using human serum as an exogenous complement source (hSBA) are considered to be the correlate of protection against serogroup C meningococcal disease.29 This correlate of protection was used in the recent licensure of monovalent serogroup C meningococcal conjugate vaccines in the United Kingdom without the requirement for clinical efficacy trials.30 However, immunogenicity data supporting the use of these conjugate vaccines were generated by a serum bactericidal assay using baby rabbit serum (rSBA), rather than human serum, as an exogenous complement source. Additional evaluation of rSBA threshold values were performed by using vaccine efficacy estimates from postlicensure surveillance in the United Kingdom. Postlicensure surveillance data suggested that an rSBA 4 weeks after immunization of 1:8 was most consistent with the observed protective effect.31 On the basis of these efficacy estimates, rSBA titers of <1:8 were proposed to be predictive of susceptibility to IMD. The proportion of responders in various clinical trials of meningococcal C conjugate vaccines and on the group C seroprevalence study conducted before introduction of group C conjugate vaccines also provide evidence that rSBA titers of 1:8 correlate with short-term protection.32 There exist little or no similar data linking immune response to efficacy for serogroups A, Y, or W-135. MCV4 was licensed on the basis of demonstrated noninferiority to MPSV4 for immunogenicity and safety. MPSV4 had been licensed on the basis of efficacy against serogroup A and C meningococcal disease in military recruits.33 The primary criterion in determining immunogenic noninferiority of MCV4 to MPSV4 was the percentage of adolescents and adults who had an increase in SBA of fourfold or greater after receiving MCV4 compared with the percentage of those after MPSV4 was used. However, for licensure of MCV4, an rSBA of 1:128 was considered as "protective," because it would not only predict short-term but also long-term clinical efficacy. Immunogenicity A randomized, controlled trial compared the immunogenicity of MCV4 and MPSV4 in adolescents 11 to 18 years of age 28 days after immunization. A similar percentage of subjects achieved at least a fourfold increase in rSBA titers in the MCV4 and MPSV groups (Table 2). The percentage of adolescents with at least a fourfold increase in rSBA was highest for serogroup W-135 (96.7% for MCV4; 95.3% for MPSV4) and lowest for serogroup Y (81.8% for MCV4; 80.1% for MPSV4). The percentage of subjects achieving an rSBA geometric mean titer (GMT) of 1:128 was higher than 98% for all meningococcal serogroups in both MCV4 and MPSV4 recipients.34 Duration of Protection and Reimmunization Unlike MPSV4, the duration of protection after MCV4 is not known but is expected to be longer than 3 years; additional studies will be needed to confirm this. More data are anticipated to become available within the next 5 years to guide recommendations regarding reimmunization for people who were immunized previously with MCV4. Reimmunization with MCV4 is indicated for adolescents 11 years and older previously immunized with MPSV4 if they remain at high risk of IMD (eg, people residing in areas in which disease is epidemic). In children 2 to 10 years of age immunized with MPSV4, antibody concentrations decrease rapidly over 2 to 3 years. If indications continue to exist for immunization, use of MCV4 may be considered within 3 to 5 years if adolescents are 11 years or older.4 To date, the only data concerning reimmunization with MCV4 come from a study in which 76 adolescents previously immunized with MCV4 and 77 adolescents previously immunized with MPSV4 were compared with 88 age-matched vaccine-naive adolescents.34 rSBA was measured in sera from these adolescents before (day 0) and 8 and 28 days after immunization with MCV4 (Table 3). Adolescents initially immunized with MCV4 had higher rSBA GMT before reimmunization than adolescents initially immunized with MPSV4; this difference reached statistical significance for serogroup A (P < .001) and W-135 (P < .001) but not for serogroups C and Y. In addition, a higher percentage of adolescents initially immunized with MCV4 had protective rSBA titers of 1:128 compared with adolescents initially immunized with MPSV4 (Table 3). Vaccine-naive adolescents had low rSBA before immunization compared with adolescents who had received MCV4 or MPSV4 previously. Response to reimmunization with MCV4 also was assessed by determining the percentage of adolescents initially immunized with MCV4 or MPSV4 with rSBA titers of 1:128 before (day 0) and 8 and 28 days after administration of MCV4 and with vaccine-naive controls. All adolescents in each of the 3 groups achieved rSBA titers of 1:128 28 days after MCV4 (Table 3). Subjects initially primed with MCV4 achieved higher rSBA GMTs compared with vaccine-naive controls for all serogroups except serogroup A. Concomitant Administration of MCV4 and Other Vaccines Among adolescents 11 to 18 years of age, a randomized, controlled trial evaluated the immunogenicity and safety of MCV4 administered concomitantly with tetanus and diphtheria toxoids absorbed for adult use (Td; Sanofi Pasteur) versus Td administered concomitantly with placebo and then MCV4 administered 28 days later. Concomitant administration of Td and MCV4 did not adversely affect immune response to antigens in either vaccine.34 When MCV4 and Td were administered concomitantly, antibody response to diphtheria antigen 28 days after immunization was greater (diphtheria GMT: 120.9 IU/mL) than when Td and MCV4 were administered sequentially 28 days apart (diphtheria GMT: 8.4 IU/mL 28 days after Td dose). Safety Among adolescents 11 to 18 years of age, safety of administering MCV4 and MPSV4 was assessed in 2 randomized, controlled trials.34 The percentage of subjects reporting systemic adverse events was similar in both groups (Table 4). Approximately half of the adolescents experienced at least 1 systemic adverse reaction, but less than 5% experienced at least 1 severe systemic reaction. Fever was reported by 3.4% to 5.1% of adolescents who received MCV4 and by 2.5% to 3.0% of adolescents who received MPSV4, a difference that was not significant. Local adverse reactions were more common among adolescents who received MCV4 than among adolescents who received MPSV4 (Table 5). Of adolescents who received MCV4, 13.1% to 16.9% reported pain that limited movement in the arm of injection, compared with 2.6% to 3.9% of adolescents who received MPSV4. These differences in frequency of local reactions could be attributable in part to different methods of administering the 2 vaccines (MCV4 is administered intramuscularly; MPSV4 is administered subcutaneously). The frequency of local adverse reactions reported after MCV4 administration was similar to that reported after Td administration, which, like MCV4, is given intramuscularly.34 Precautions and Contraindications Immunization with MCV4 is contraindicated among people known to have hypersensitivity to any component of the vaccine, including diphtheria toxoid, and to dry, natural rubber latex, which is used in the vial stopper. Serious adverse events are rare in later allergic persons given vaccines from vials with rubber stoppers. Any adverse effect suspected to be associated with MCV4 vaccine should be reported to the Vaccine Adverse Events Reporting System (more information can be obtained by calling 800-822-7967 or by accessing the Web site at www.vaers.org). Cost of Meningococcal Vaccines Whether universal immunization of adolescents with tetravalent A, C, Y, W-135 meningococcal vaccine would result in a net cost or a net savings to society depends on IMD incidence, which varies by year, the rates of death or permanent sequelae, and the cost of immunization. A recent study from the CDC suggests that universal immunization of adolescents would be cost-effective.35 However, variations in the epidemiology of and outcomes from IMD by region make it impossible to generate a precise estimate of the cost benefit. If, as expected, universal adolescent immunization with MCV4 becomes a reality in the next few years, more precise estimates should become available. The total cost of immunizing a single adolescent with MCV4 includes direct and indirect costs. The direct costs include supplies (eg, vaccine [MCV4 = $82.00 and MPSV4 = $86.10 per dose], syringe with needle), personnel, and administrative expenses. Public and private insurers should be responsible for payment of costs for MCV4. MCV4 is included in the Vaccines for Children program. For private insurers, avoiding financial responsibility by transferring this to intermediate risk-bearing entities (eg, independent practice associations or other physician groups), individual physicians, or college health services will result in adolescents not being immunized in a timely fashion. Physicians incur significant administrative expenses when ensuring that adolescents are immunized with recommended vaccines in a timely fashion, including explaining risk and benefits of immunization to adolescents and parents; ordering, purchasing, storing, and administering the vaccine; recording immunizations in records; and other activities. Physicians should receive reimbursement for expenses associated with each vaccine administration. FUTURE NEEDS MCV4 has been licensed on the basis of safety and short-term immunogenicity data in adolescents. Several postmarketing studies are planned, including a study to evaluate the duration of antibody responses in participants who received a single dose of MCV4 vaccine or MPSV4 vaccine 5 and 10 years earlier and a study to evaluate safety and immunogenicity when MCV4 is given concomitantly with tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine. However, vaccine effectiveness and herd immunity based on the ability of MCV4 to alter transmission patterns cannot be predicted from immunogenicity data alone. Information on MCV4 effectiveness, duration of protection, and herd-immunity effects obtained from MCV4 evaluation studies will be indispensable in guiding prevention policies and formulating recommendations for immunization in other age groups. MCV4 and other meningococcal conjugate vaccines may be licensed in the United States in the near future for use in other age groups, including children 2 to 10 years of age and infants. Such vaccines are undergoing clinical trials and are likely to be more immunogenic in infants and young children compared with MPSV4, which currently is the only meningococcal vaccine licensed in the United States for use in young children. Because meningococcal serogroup B capsular polysaccharide is poorly immunogenic in humans, vaccine development has focused on common surface proteins, including the outer membrane proteins (OMPs) of specific epidemic strains.36 OMP vaccines have shown good efficacy in older children and adults, but efficacy in infants and young children, in whom rates of disease are highest, has not been demonstrated. In addition, the variability in OMP strains causing endemic disease likely will limit their usefulness in the United States.37 Because of the potential limitations of these vaccines, other new approaches to meningococcal serogroup B vaccines are being pursued. With the recent sequencing of the serogroup B meningococcal genome, several new genes encoding putative membrane proteins have been identified, suggesting potential new targets for serogroup B vaccines. The availability of new meningococcal conjugate vaccines as well as the pursuit of new vaccine strategies should lead to substantial improvements in control and prevention of meningococcal disease in the United States and globally. Although the signs and symptoms of IMD frequently are nonspecific, increasing awareness of meningococcal disease can result in people seeking medical care earlier and improved clinical outcome. In addition, educating adolescents and their parents about the benefits of receiving MCV4 is critical to prevention of a substantial number of cases of IMD. However, parents and adolescents must understand that MCV4 will not prevent all meningococcal disease, and at least 25% of cases in adolescents are caused by serogroup B.1 Educating the general public about the benefits of being immunized with MCV4 may foster increased immunization coverage rates for adolescents and substantially decrease the burden of meningococcal disease in the United States. RATIONALE FOR MENINGOCOCCAL VACCINE RECOMMENDATIONS MCV4 offers advantages over MPSV4. First, it demonstrates a T-cell–dependent characteristic so that children given a second dose have an anamnestic or booster response not found after a second dose of MPSV4. Second, the elevated rSBA 3 years after MCV4 but not after MPSV4 immunization in adolescents suggests a longer duration of immunity than with MPSV4. Third, the experience in the United Kingdom with the monovalent meningococcal serogroup C conjugate vaccine demonstrating a reduction in nasopharyngeal carriage of that serogroup in immunized infants and children as well as herd immunity affecting nonimmunized children suggests that MCV4 also will have similar effects, although data will be necessary to demonstrate these characteristics. Finally, MCV4 should induce antibodies against most strains causing IMD among adolescents 11 years or older. Because the initial supply of MCV4 will be limited for the next 2 to 3 years, initially only 2 cohorts can be recommended to be immunized routinely. The first cohort, young adolescents at the 11- to 12-year visit, was selected because this is the age at which a booster dose of Td already is recommended and when well visits to the pediatrician are more likely to occur than in older adolescents.2 The AAP also emphasizes the importance of more pediatric patients of this age having well visits for preventive services other than immunization. A recommendation to immunize all 11- to 12-year-olds, therefore, not only is more likely to be feasible compared with older adolescents but also should be associated with enhancing the importance of the young adolescent visit. The second cohort, entering high school students or 15-year-olds, whichever comes first, was chosen on the basis of 2 factors: the peak IMD incidence and routine medical visits by adolescents 13 years and older. The peak incidence of disease occurs after 15 years of age, but less than 20% of adolescents 16 to 18 years of age have routine medical visits to pediatricians. Some states already have high school entry laws requiring certain vaccines. Once MCV4 supply is abundant, routine immunization of all adolescents likely will be recommended. Also, within 3 years, information on duration of immunity and need for reimmunization, if any, should become available. To date, the vaccine uptake by adolescents suggests that pediatricians should do everything possible to use other medical visits (eg, sports or camp preparticipation physical examinations or evaluations for minor illnesses such as upper respiratory tract infections) to ensure that recommended vaccines are administered. RECOMMENDATIONS Two cohorts of adolescents should be immunized routinely with MCV4: (1) young adolescents at the 11- to 12-year visit; and (2) adolescents at high school entry or 15 years of age, whichever comes first (both evidence grade I [see the Appendix ]). Within 3 years, the goal will be routine immunization of all adolescents with MCV4 beginning at 11 years of age. Adolescents should visit a health care professional at 11 to 12 years of age, when immunization status and other preventive services can be addressed. Subsequent annual visits throughout adolescence also are recommended. Entering college students who plan to live in dormitories should be immunized with MCV4 routinely (evidence grade II-2). People at increased risk of meningococcal disease should be immunized with MCV4 if they are at least 11 years of age, including adolescents who have a terminal complement deficiency or adolescents who have anatomic or functional asplenia (evidence grade II-3); or adolescents who travel to or reside in countries in which N meningitidis is hyperendemic or epidemic (CDC Travelers' Health Hotline 877-FYI-TRIP or online at www.cdc.gov/travel) (evidence grade II-3). Because people with HIV infection are likely to be at higher risk of meningococcal disease, although not to the extent that they are at risk of invasive S pneumoniae infection, they may elect to be immunized with MCV4 if they are at least 11 years of age. Children 2 to 10 years of age at increased risk of meningococcal disease (see recommendations 3 and 4) should be immunized with MPSV4, because MCV4 is not yet licensed for use in these children. People who wish to decrease their risk of meningococcal disease may elect to receive MCV4 if they are 11 years or older. For control of meningococcal outbreaks caused by vaccine-preventable serogroups (A, C, Y, or W-135), MPSV4 or MCV4 should be used for people 11 years or older (evidence grade II-2). MCV4 is preferred, but MPSV4 is acceptable. For children 2 to 10 years of age, MPSV4 should be used. Immunization with MCV4 may be indicated for adolescents previously immunized with MPSV4. These people should be considered for reimmunization 3 to 5 years after receiving MPSV4 if they remain at increased risk of meningococcal disease. Public and private insurers should be responsible for payment of costs of MCV4, its administration to adolescents for whom MCV4 is recommended, and administrative costs involved in providing vaccines to high-risk people. COMMITTEE ON INFECTIOUS DISEASES, 2004–2005 Margaret B. Rennels, MD, Chairperson H. Cody Meissner, MD, Vice Chairperson Carol J Baker, MD Robert S. Baltimore, MD Joseph A. Bocchini, Jr, MD John S. Bradley, MD Penelope H. Dennehy, MD Robert W. Frenck, Jr, MD Caroline B. Hall, MD Sarah S. Long, MD Julia A. McMillan, MD Keith R. Powell, MD Lorry G. Rubin, MD LIAISONS Richard D. Clover, MD American Academy of Family Physicians Steven Cochi, MD Centers for Disease Control and Prevention Joanne Embree, MD Canadian Paediatric Society Marc A. Fischer, MD Centers for Disease Control and Prevention Benjamin Schwartz, MD National Vaccine Program Office Mamodikoe Makhene, MD National Institutes of Health Douglas Pratt, MD Food and Drug Administration Jeffrey R. Starke, MD American Thoracic Society Jack Swanson, MD Practice Action Group EX OFFICIO Larry K. Pickering Red Book Editor CONSULTANT Edgar O. Ledbetter, MD STAFF Alison Siwek, MPH APPENDIX. US Preventive Services Task Force Rating System of Quality of Scientific Evidence38 FOOTNOTES Lead author REFERENCES Centers for Disease Prevention and Control. Prevention and control of meningococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2000;49(RR-7) :1 –10 Bilukha OO, Rosenstein N; Centers for Disease Control and Prevention. Prevention and control of meningococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. 2005;54(RR-7) :1 –21 Harrison LH, Pass MA, Mendelsohn AB, et al. Invasive meningococcal disease in adolescents and young adults. JAMA. 2001;286 :694 –699 American Academy of Pediatrics. Meningococcal infections. In: Pickering LK, ed. Red Book: 2003 Report of the Committee on Infections Diseases. 26th ed. Elk Grove Village, IL: American Academy of Pediatrics. 2003;430 –436 American Academy of Pediatrics, Committee on Infectious Diseases. Meningococcal disease prevention and control strategies for practice-based physicians (addendum: recommendations for college students). Pediatrics. 2000;106 :1500 –1504 Jackson LA, Schuchat A, Reeves MW, Wenger JD. Serogroup C meningococcal outbreaks in the United States. An emerging threat. JAMA. 1995;273 :383 –389 Jackson LA, Wenger JD. Laboratory-based surveillance for meningococcal disease in selected areas, United States, 1989–1991. MMWR CDC Surveill Summ. 1993;42(2) :21 –30 Rosenstein NE, Perkins BA, Stephens DS, et al. The changing epidemiology of meningococcal disease in the United States, 1992–1996. J Infect Dis. 1999;180 :1894 –1901 Bruce MG, Rosenstein NE, Capparella JM, Shutt KA, Perkins BA, Collins M. Risk factors for meningococcal disease in college students. JAMA. 2001;286 :688 –693 Harrison LH, Dwyer DM, Maples CT, Billmann L. Risk of meningococcal infection in college students. JAMA. 1999;281 :1906 –1910 Froeschle J. Meningococcal disease in college students. Clin Infect Dis. 1999;29 :215 –216 Centers for Disease Control and Prevention. Control and prevention of meningococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 1997;46(RR-5) :1 –51 Centers for Disease Control and Prevention. General recommendations on immunization. Recommendations of the Advisory Committee on Immunization Practices (ACIP) and the American Academy of Family Physicians (AAFP). MMWR Recomm Rep. 2002;51(RR-2) :1 –35 Borrow R, Southern J, Andrews N, et al. Comparison of antibody kinetics following meningococcal serogroup C conjugate vaccine between healthy adults previously vaccinated with meningococcal A/C polysaccharide vaccine and vaccine-naive controls. Vaccine. 2001;19 :3043 –3050 Artenstein MS, Gold R, Zimmerly JG, Wyle FA, Schneider H, Harkins C. Prevention of meningococcal disease by group C polysaccharide vaccine. N Engl J Med. 1970;282 :417 –420 Rosenstein N, Levine O, Taylor J, et al. Efficacy of meningococcal vaccine and barriers to vaccination. JAMA. 1998;279 :435 –439 Cochi SL, Markowitz L, Joshi DD, et al. Control of epidemic group A meningococcal meningitis in Nepal. Int J Epidemiol. 1987;16 :91 –97 MacDonald NE, Halperin SA, Law BJ, Forrest B, Danzig LE, Granoff DM. Induction of immunologic memory by conjugates vs plain meningococcal C polysaccharide vaccine in toddlers: a randomized controlled trial. JAMA. 1998;280 :1685 –1689 Lepow ML, Goldschneider I, Gold R, Randolph M, Gotschlich EC. Persistence of antibody following immunization of children with groups A and C meningococcal polysaccharide vaccines. Pediatrics. 1977;60 :673 –680 Reingold AL, Broome CV, Hightower AW, et al. Age-specific differences in duration of clinical protection after vaccination with meningococcal polysaccharide A vaccine. Lancet. 1995;2(8447) :114 –118 Yergeau A, Alain L, Pless R, Robert Y. Adverse events temporally associated with meningococcal vaccines. CMAJ. 1996;154 :503 –507 Roberts J, Bryett K. Incidence of reactions to meningococcal A and C vaccine among U.K. schoolchildren. Public Health. 1988;102 :471 –476 Stein KE. Thymus-independent and thymus-dependent responses to polysaccharide antigens. J Infect Dis. 1992;165(suppl) :S49 –S52 Hassan-King MK, Wall RA, Greenwood BM. Meningococcal carriage, meningococcal disease and vaccination. J Infect. 1988;16 :55 –59 Frasch CE. Regulatory perspectives in vaccine licensure. In: Ellis RW, Granoff DM, eds. Development and Clinical Uses of Haemophilus influenzae Type b Conjugate Vaccines. New York, NY: Marcel Dekker; 1994:435 –453 Salisbury D. Introduction of a conjugate meningococcal type C vaccine programme in the UK. J Paediatr Child Health. 2001;37 :S34 –S36 Ramsay ME, Andrews NJ, Trotter CL, Kaczmarski E, Miller EB. Herd immunity from meningococcal serogroup C conjugate vaccination in England: database analysis. BMJ. 2003;326 :365 –366 Trotter CL, Andrews NJ, Kaczmarski EB, Miller E, Ramsay ME. Effectiveness of meningococcal serogroup C conjugate vaccine 4 years after introduction. Lancet. 2004;364 :365 –367 Goldschneider I, Gotschlich EC, Artenstein MS. Human immunity to the meningococcus: I. The role of humoral antibodies. J Exp Med. 1969;129 :1307 –1326 Miller E, Salisbury D, Ramsay M. Planning, registration, and implementation of an immunisation campaign against meningococcal serogroup C disease in the UK: a success story. Vaccine. 2001;20(suppl 1) :S58 –S67 Andrews N, Borrow R, Miller E. Validation of serological correlate of protection for meningococcal C conjugate vaccine by using efficacy estimates from postlicensure surveillance in England. Clin Diagn Lab Immunol. 2003;10 :780 –786 Jodar L, Griffiths E, Feavers I. Scientific challenges for the quality control and production of group C meningococcal conjugate vaccines. Vaccine. 2004;22 :1047 –1053 Sippel JE. Meningococci. Crit Rev Microbiol. 1981;8 :267 –302 Shephard CW, Ortega-Sanchez IR, Scott RD II, Rosenstein NE, ABCs Team. Cost-effectiveness of conjugate meningococcal vaccination strategies in the United States. Pediatrics. 2005;115 :1220 –1232 Bjune G, Hoiby EA, Gronnesby JK, et al. Effect of outer membrane vesicle vaccine against group B meningococcal disease in Norway. Lancet. 1991;338 :1093 –1096 Tondella ML, Popovic T, Rosenstein NE, et al. Distribution of Neisseria meningitidis serogroup B serosubtypes and serotypes circulating in the United States. The Active Bacterial Core Surveillance Team. J Clin Microbiol. 2000;38 :3323 –3328 US Preventive Services Task Force. Appendix A: task force ratings. In: Guide to Clinical Preventive Services. 2nd ed. Alexandria, VA: International Medical Publishing; 1996:861 –865...查看详细 (44217字节)

☉ 11333104:The use of magnetic resonance imaging in the diagnosis of suspected giant cell arteritis
1 Birmingham and Midland Eye Centre, Dudley Road, Birmingham B18 7QU, UK 2 Sandwell and West Birmingham Hospitals NHS Trust, City Hospital, Birmingham, UK 3 Queen Elizabeth Hospital, University Hospitals Birmingham, NHS Trust, Birmingham, UK Keywords: magnetic resonance imaging; giant cell arteritis Giant cell arteritis (GCA) is a vasculitis of unknown origin that has a predisposition for the cranial arteries in the elderly. It has potentially devastating visually complications and produces a broad range of symptoms and signs that mimic many other medical and surgical conditions. Blood tests reflect the underlying inflammatory process, yet the erythrocyte sedimentation rate (ESR) may be normal in 8% of patients with biopsy proved GCA.1 Nevertheless, making a definitive diagnosis has importance therapeutically as patients are committed to a lengthy oral corticosteroid regimen. Non-invasive techniques, such as colour Doppler or duplex ultrasonography, have been studied in an attempt to improve patient preselection for temporal artery biopsy (TAB).2,3 Magnetic resonance imaging (MRI) has been shown to improve the diagnosis of early Takayasu arteritis.4 More recently several case reports have described the diagnostic potential of MR angiography and gadolinium contrast MRI in demonstrating the vessel changes of GCA.5,6 We compared the ability of MRI to detect changes in the temporal arteries with TAB in patients clinically suspected of having GCA. METHODS AND RESULTS A prospective, pilot, single masked study of seven female patients (age range 60–88 years, mean 76 years) with suspected giant cell arteritis, and two age matched healthy controls was undertaken. Local research ethical approval and informed written consent were obtained. All patients underwent a standard clinical examination including a detailed history and clinical examination. Investigations included ESR and C reactive protein (CRP). Each patient was given a GCA criteria "score" based on the 1990 ACR (American College of Rheumatology) classification7 (Table 1). Within 48 hours of presentation patients underwent a unilateral temporal artery MRI scan on a 1.5T scanner using a surface coil and small field of view. T1 and T2 weighted images perpendicular to the temporal artery and a time of flight sequence were obtained. The MRI visualised the location of the temporal artery that was subsequently biopsied in a standard manner within 24 hours of the scan. Two healthy age matched controls also underwent a medical assessment, ESR and CRP, and an MRI as detailed above, but a TAB was not performed. The MRI scans were reported by an independent, masked neuroradiologist. Table 1 1990 American College of Rheumatology criteria for the classification of giant cell (temporal) arteritis (traditional format) Each patient’s ACR criteria "score" and the results of the MRI scan and TAB are shown in Table 2. The finding of three out of five ACR criteria is associated with a 94% sensitivity and 91% specificity for the diagnosis of GCA.7 There were two positive and one equivocal TAB result from the seven patients, but no positive MRI findings were identified. However, when using the ACR criteria as "gold standard," there were two true negative MRI scan results compared with three false negative scan results. The two remaining MRI scans were described as equivocal, in comparison with the ACR criteria—one patient was positive for GCA and the other patient’s ACR criteria "score" was negative for GCA. From the data the negative predictive values of MRI scanning and TAB for GCA were 40% and 50%, respectively. Of the five patients who showed a prompt response to oral corticosteroid, the MRI scan was negative in four and equivocal in the other. Table 2 Summary of results COMMENT Although our study sample was small our findings suggest that MRI scanning was unable to distinguish between a normal and an affected artery. We conclude that there is no potential for the use of MRI scanning without contrast enhancement in the evaluation of patients with suspected GCA. References Hayreh SS, Podhajsky PA, Raman R, et al. Giant cell arteritis: validity and reliability of various diagnostic criteria. Am J Ophthalmol 1997;123:285–96. Schmidt WA, Kraft HE, Vorpahl K, et al. Color duplex ultrasonography in the diagnosis of temporal arteritis. New Engl J Med 1997;337:1336–42. Wenkel H , Michelson G. Correlation of ultrasound biomicroscopy with histological findings in diagnosis of giant cell arteritis. Klin Monatsbl Augenheilkd 1997;210:48–52. Tanigawa K , Eguchi K, Kitamura Y, et al. Magnetic resonance imaging detection of aortic and pulmonary artery wall thickening in the acute stage of Takayasu arteritis: improvement of clinical and radiologic findings after steroid therapy. Arthritis Rheum 1992;35:476–80. Mitomo T , Funyu T, Takahashi Y, et al. Giant cell arteritis and magnetic resonance angiography. Arthritis Rheum 1998;41:1702. Anders HJ, Sigl T, Sander A, et al. Gadolinium contrast magnetic resonance imaging of the temporal artery in giant cell arteritis. J Rheumatol 1999;26:2287–8. Hunder GG, Bloch DA, Michel BA, et al. The Americal College of Rheumatology 1990 criteria for the classification of giant cell arteritis. Arthritis Rheum 1990;33:1122–8....查看详细 (5381字节)
☉ 11333105:Effects of trypan blue on cell viability and gene expression in human retinal pigment epithelial cells
1 Department of Ophthalmology, Hong Kong Sanatorium and Hospital, Hong Kong, People’s Republic of China 2 Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, People’s Republic of China ABSTRACT Aim: To evaluate the effects of trypan blue on cell viability and gene expression in human retinal pigment epithelial (RPE) cells. Methods: Three concentrations (0.06 mg/ml, 0.6 mg/ml, and 4 mg/ml) of trypan blue were applied to human ARPE19 cells for 1 minute. Cell viability was measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. RPE cells were sampled daily for 6 consecutive days to assess the effects of trypan blue on cell viability. The effects of trypan blue on the expression of apoptosis related and cell cycle arrest gene expressions including c-fos, c-jun, p53, and p21 were performed using reverse transcription-polymerase chain reaction and immunostaining. Results: The MTT assay showed a concentration dependent suppression effect of trypan blue on cell viability, with higher reduction in the 0.6 mg/ml and 4 mg/ml trypan blue treated groups. No significant change in the expression of c-fos and c-jun was found with all three concentrations of trypan blue. An increase in p53 expression was found in the 4 mg/ml trypan blue treated group at 10–30 minutes after trypan blue application. Immunostaining showed a mild, albeit insignificant, increase of p53 expression in the RPE cells. No significant increase in p21 expression was observed in the 0.06 mg/ml trypan blue treated group but there were significant increases in p21 expression in both the 0.6 mg/ml (p = 0.032) and the 4 mg/ml (p = 0.025) treated groups. Conclusions: Trypan blue may lead to toxicity on cultured RPE cells as indicated by the reduction in cell viability and changes in the expression of apoptosis related and cell cycle arrest genes at higher concentrations. The application of 0.06 mg/ml trypan blue for 1 minute appeared to have no significant effect on cultured RPE. Abbreviations: ERM, epiretinal membrane; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; ILM, internal limiting membrane; MTT assay, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay; PBS, phosphate buffered saline; RPE, retinal pigment epithelium Keywords: trypan blue; cell viability; gene expression; apoptosis; toxicity Trypan blue is a vital stain that has been used as an intraoperative stain to facilitate anterior segment surgery, particularly in the staining of the anterior capsule in white mature cataract.1–3 Recently, trypan blue has also been shown to be an useful intraoperative agent for improving the visualisation of peripheral epiretinal membrane (ERM) in patients with proliferative vitreoretinopathy, as well as macular ERM and retinal internal limiting membrane (ILM) in cases of macular pucker and idiopathic macular hole.4–9 Improved visualisation is particularly important for thin, cellophane type of ERM, since this can enhance complete removal of the ERM to maximise the long term outcome by minimising ERM recurrence. Previous studies have demonstrated the safety of intravitreal trypan blue in rabbit eyes as well as in retinal pigment epithelium (RPE) cell culture.10,11 It has been shown that the application of up to 3 mg/ml trypan blue for 5 minutes appeared to have no toxic effect on cultured RPE cells in terms of cell viability.11 However, intravitreal injection of 2 mg/ml trypan blue was found to cause marked damage to the inferior retina in rabbit eyes after the presence of intravitreal trypan blue for 4 weeks.10 This response is concentration dependent as no evidence of retinal toxicity was found in the rabbit eyes at 0.6 mg/ml trypan blue, but toxicity was found at concentration of 2 mg/ml. However, it remained uncertain whether this concentration dependent toxicity of trypan blue on the cultured RPE cells was present as a previous study showed no evidence of toxicity at concentrations between 0.6 mg/ml to 3 mg/ml.11 In these previous studies, the expressions of gene and various proteins associated with cell toxicity were not investigated. Moreover, serial measurements were not performed to investigate the time dependent toxicity effect of trypan blue. Investigating the potential retinal toxicity associated with intraocular dye is important as recent study has suggested potential adverse visual outcome in macular hole surgery with indocyanine green assisted ILM removal.12 Adequate testing should therefore be performed before the routine use of intraocular dye.13 The aim of this study was to investigate the effects of various concentrations of trypan blue on the viability of cultured human RPE cells. In addition to cell viability, the expressions of various apoptosis related and cell cycle related genes were also evaluated in order to provide a more comprehensive profile of the toxicity of trypan blue on cultured human RPE cells. MATERIALS AND METHODS Cell culture Human ARPE19 cells were obtained from the American Type Culture Collection (Manassas, VA, USA) and grown in a 1:1 (vol/vol) mixture of Dulbecco’s modified Eagle’s and Ham’s F12 medium (DF, Gibco, Rockville, MA, USA) containing 3 mM L-glutamine (Gibco), 10% fetal bovine serum (Gibco), and antibiotics (100 units/ml penicillin G and 100 mg/ml streptomycin sulfate, Gibco). RPE cells within five passages were grown to 70% confluence before the application of trypan blue dye. Drug treatment ARPE19 cell monolayers were washed twice with 0.01M phosphate buffered saline (PBS, Gibco) and placed in three concentrations of trypan blue (0.06 mg/ml, 0.6 mg/ml, and 4 mg/ml). The lower two concentrations of 0.06 mg/ml and 0.6 mg/ml trypan blue were prepared using the stock trypan blue solution of 4 mg/ml concentration (T8154, Sigma, St Louis, MO, USA) and diluted using appropriate volume of 0.01M PBS as the solvent. The osmolarity of PBS, and trypan blue solutions of 0.06 mg/ml, 0.6 mg/ml, and 4 mg/ml concentrations were measured as 280 mOsM, 282 mOsM, 284 mOsM, and 296 mOsM, respectively using the Wescor 5500 Vapour Pressure Osmometer. Trypan blue solution was given to the cultured cells for 1 minute with a loading area of 200 μl/cm2. The control sample did not contain any dye. After washing twice with PBS, the cells were placed in fresh culture medium containing antibiotics (200 units/ml penicillin G and 200 mg/ml streptomycin sulfate, Gibco) and incubated at 37°C with 5% CO2 balanced with air. Cell viability assay ARPE19 cells (5x104 cells) were seeded onto 24 well plates and treated with trypan blue as described above. A cell viability assay was performed every 24 hours using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The cells were washed with PBS and 0.5 mg/ml MTT in serum free medium was added to the culture and incubated at 37°C for 3 hours. Formazan extraction was performed with isopropanol and the quantity determined colorimetrically by using a spectrophotometer (NanoDrop, Rockland, DE, USA) at 570 nm with the correction of interference at 690 nm. For each group, four individual samples were collected and measured. The effects of trypan blue on ARPE19 cell viability was determined daily for 6 consecutive days after the initial trypan blue application. The results were expressed as units of absorbance of MTT at 570 nm. As each group originated from a single pool of cells, the changes in absorbance reflect the changes in the total numbers of viable cells of the same population over time and in relation to concentrations of trypan blue used. The difference in absorbance between the control and trypan blue treated groups were analysed to determine the cell viability. The percentage of viability in the presence of trypan blue was calculated by dividing the absorbance reading of cells under different trypan blue concentrations by the absorbance reading of cells under normal growth (assumed 100% viability on day 0) without trypan blue. Gene expression, PCR, and immunochemistry Samples of ARPE19 cells were collected at 0, 10, 20, 40, 50, 90, and 120 minutes after the application of trypan blue for RNA isolation. Total RNA was extracted using a RNeasy Kit (Qiagen, CA, USA). Cells were put to lysis buffer containing 1% ?-mecaptoethanol (Sigma, St Louis, MO, USA), and passed through a QIAShredder column (Qiagen) and the total RNA was obtained following the supplier’s protocol. Reverse transcription was performed on 500 ng of total RNA using 10 ng/ml random primers and SuperScript enzyme (Gibco). cDNA corresponding to 5, 10, 15, and 20 ng of total RNA was amplified with primers specific for glyceraldehyde-3-phosphate dehydrogenase (GAPDH) for 25 cycles. Linear range of amplification was determined by plotting the amount of cDNA used in PCR against the optical density of products. Standardised cDNAs corresponding to 10 ng of total RNA were amplified using the following primer pairs: GAPDH: up: 5'-gaa ggt gaa ggt cgg agt–3'; down: 5'-gaa gat ggt gat ggg att tc–3'. c-fos: up: 5'-aga cag acc aac tag aag atg a-3'; down: 5'-agc tct gtg gcc atg ggc ccc-3'. c-jun: up: 5'-gtg acg gac tgt tct atg act g-3'; down: 5'-ggg ggt cgg cgt ggt ggt gat g-3'. p53: up: 5'-ttg ccg tcc caa gca atg gat ga-3'; down: 5'-tct ggg aag gga cag aag atg ac-3'. The amplification products were then separated on 2% agarose gel, stained with 0.5 μg/ml ethidium bromide and the band intensity was quantified. The optical density of each reaction was normalised against that of GAPDH. For the immunochemistry, ARPE19 cells were grown on glass surface precoated with 0.1% bovine serum albumin (Sigma), 10 ng/ml fibronectin (Gibco), and 10 ng/ml laminin (Gibco). Cell samples were harvested 24 hours after the application of trypan blue and fixed with 3% paraformaldehyde pH 7.40 in 20 mM HBSS-HEPES buffer (Sigma). The fixative was then diluted to 0.5% and fixed for 30 minutes at room temperature. After antigen retrieval using 50 mM NH4Cl in PBS for 30 minutes on ice, the samples were blocked with 10% fetal bovine serum (FBS) in PBS for 20 minutes on ice to remove the non-specificities. The cell samples were then incubated with antibodies against p53 and p21 proteins (Santa Cruz, CA, USA). Staining was detected by immunofluorescence (secondary antibodies from Amersham, UK and nuclear counterstaining with DAPI from Sigma) or avidin-biotin complex method (Vector Lab, CA, USA) and observed under fluorescent and light microscopes (Zeiss, Germany). The number of positively stained cells was counted in a total of five optical fields of 200 μm in diameter each. The mean number of positively stained cells was calculated and compared with the control without trypan blue stain. RESULTS Cell viability assay The effect of trypan blue on the viability of ARPE19 cells was suppressive and this effect was concentration dependent (fig 1A, B). At 0.06 mg/ml trypan blue, the percentage of viable cells was reduced to 42% compared with the trypan blue free control group on day 1 and 2. By day 6, the percentage of viable cells recovered to a level similar to the control group. The level of absorbance in the 0.06 mg/ml trypan blue treated group was not statistically significant when compared with the control group except on day 5. Higher concentrations of trypan blue at 0.6 mg/ml and 4 mg/ml showed a more prominent reduction in the viability of ARPE19. The difference in the level of absorbance compared with the control was statistically significant on day 1–3 in the 0.6 mg/ml trypan blue treated group and all time intervals in the 4 mg/ml trypan blue treated group. The percentage of viable cells was reduced to around 35% compared with the control group on days 1 and 2 when the cells were being treated with trypan blue at 0.6 mg/ml and 0.4 mg/ml (fig 1B). On day 6, the percentage of viable cells in the 0.6 mg/ml trypan blue group had recovered to around 90% of the control level whereas the 4 mg/ml group had recovered to 76%. Figure 1 (A) MTT assay showing the proliferation of ARPE19 cells after the application of three concentrations of trypan blue (Tb) compared with control. Greater reduction in cell viability was found with higher concentration of trypan blue. (B) Trypan blue toxicity was expressed as the ratio of viable cells against control. There was a concentration dependent reduction in cell viability caused by trypan blue. Reduction in the percentage of viable cells was most marked in the first 2 days after application of trypan blue. Gene expression The expression of apoptosis related gene of the ARPE19 cells in response to trypan blue was investigated. For the control sample and all concentrations of trypan blue, no significant difference in the level of expression for GAPDH in 10 ng of total RNA was detected (fig 2). There were also no significant changes in the RNA expression levels of c-fos and c-jun at various concentrations of trypan blue throughout the 120 minutes of trypan blue application compared with control (fig 3A, B). There was an increase in p53 expression in the 4 mg/ml trypan blue treated group between 10–30 minutes following the initial administration of trypan blue (fig 3C). The p53 expression increased by 1.35 times to that of the control. Figure 2 PCR signal intensities of c-fos, c-jun, and p53 in ARPE19 cells treated with different concentrations of trypan blue: (A) control; (B) 0.06 mg/ml; (C) 0.6 mg/ml, and (D) 4 mg/ml. Samples were collected at 0, 10, 20, 30, 40, 50, 90, and 120 minutes. The intensities were compared against that of the GAPDH. Figure 3 Quantification of PCR signal intensities of (A) c-fos, (B) c-jun, and (C) p53 in ARPE19 after the application of trypan blue (Tb) compared with control. No significant increase in expression of c-fos or c-jun was found. For the 4 mg/ml trypan blue treated group, there was an increase in the expression of p53 from 10–30 minutes following trypan blue application. Further gene expression studies for p53 and p21 proteins were conducted using immunochemistry. Most of the cells displayed positive staining for p21 and p53 proteins after overnight incubation with 10–6M camptothecin, which served as the positive control. For the expression of p53 proteins on immunostaining, a mild increase in the intensity of staining at all the concentrations of trypan blue was observed (fig 4A). However, the change in the level of expression was not statistically significant. For the immunostaining of p21 proteins, significant increases in the number of stained cells were found at higher concentrations of 0.6 mg/ml and 4 mg/ml trypan blue treated groups compared with the control (Mann-Whitney U test, p = 0.032 and p = 0.025 respectively) (fig 4B). There was also a mild increase in the level of p21 protein expression for the 0.06 mg/ml trypan blue treated group but the difference was not statistically significant (Mann-Whitney U test, p = 0.157). Figure 4 Immunofluorescence of (A) p53 and (B) p21. No significant difference in the number of cells stained positive for p53 was observed for various concentrations of trypan blue. Significant increase in the number of p21 positively stained cells was observed in 0.6 mg/ml and 4 mg/ml trypan blue treated groups. DISCUSSION In this study, we utilised the MTT assay to determine the effects of various concentrations of trypan blue on the viability of cultured RPE cells. It was found that there was a concentration dependent effect of trypan blue on the cell viability of RPE cells, with higher reductions in the viability of the RPE cells at higher concentrations of trypan blue (0.6 mg/ml and 4 mg/ml). The effect of trypan blue on decreased RPE cell viability appeared to be transient and was more marked within the first 2 days after the application of trypan blue at all three concentrations. At 6 days after the application of trypan blue, a significant reduction in cell viability was only limited to the 4 mg/ml trypan blue treated group and no significant change was observed in the groups treated with lower concentrations (0.06 mg/ml and 0.6 mg/ml). Previous studies have evaluated the toxicity of trypan blue on rabbit retina and on cultured RPE cells.10,11 Veckeneer et al10 reported the lack of retinal toxicity, both histologically and electrophysiologically, in rabbit eyes 4 weeks after intravitreal injection of 0.6 mg/ml trypan blue. However, at a higher concentration of 2 mg/ml trypan blue, light and electron microscopy revealed damaged photoreceptors and marked retinal layer disorganisation in the inferior retina. The finding suggested that a lower concentration of trypan blue should be used in vitreoretinal surgery. In another study on the effects of trypan blue on culture RPE cells, no evidence of increased cell death at concentrations of up to 3 mg/ml after 5 minutes was found.11 This is contrary to our results that with the application of trypan blue for 1 minute, reductions in cell viability of the 0.6 mg/ml and 4 mg/ml trypan blue treated groups were observed. One of the reasons is the difference in the concentrations of trypan blue used in the two experiments, as limited toxicity of trypan blue on RPE cell was found at a lower concentration of 0.06 mg/ml. Another reason for the lack of cell toxicity caused by trypan blue in the previous study may be because of the timing of the cell viability measurement. In the study by Stalmans et al cell viability was measured using live/dead fluorescent kit with a confocal microscope after 30 minutes of incubation.11 Serial measurements of cell viability in our study allowed the monitoring of cell viability at various time points. This is important since the effect of trypan blue on cell culture is time dependent and the reduction in cell viability caused by trypan blue may not be detected if the samples were measured too early or too late. The short incubation time in previous study, therefore, might not have reflected the true toxicity of trypan blue on the RPE cells.11 Cellular response to stresses and toxic agents may involve the expressions of genes that have roles in cell regulation and transformation.14 Various transcriptions factors are involved in the expression of apoptosis associated genes such as p53, c-fos, and c-jun.15,16 In this study, PCR and immunostaining were used to evaluate the gene expressions of various apoptosis related and cell cycle related genes. Results from the PCR on the level of expressions for c-fos and c-jun showed no significant change within the first 2 hours after application of the three concentrations of trypan blue. At the highest concentration of 4 mg/ml of trypan blue, there was an increased expression of p53 at 10–30 minutes after the application of trypan blue compared with control. Immunostaining of p53 of the RPE cells also showed an increased number of positively stained cells at all three concentrations of trypan blue compared with control but the level did not reach statistical significance. For the p21 expression, significant increase in number of cells with p21 expression was found at all three concentrations of trypan blue compared with control. The p21 protein is an inhibitor of cyclin dependent kinases and can arrest cells in the G0-G1 phase.17,18 The increase in p21 in ARPE19 cells caused by trypan blue may imply the arrest of cell cycle progression or induction of transient arrest in the G1 phase, making room for DNA repair and therefore the cell growth is retarded. This is supported by the cell viability study using MTT since the reduction of cell viability is most marked in the first 2 days after the application of trypan blue and the reduction of cell viability is less significant on day 6. In summary, a concentration dependent reduction in cultured RPE cell viability may occur after the application of trypan blue. No significant changes in the expressions of c-fos and c-jun were observed. However, increased p53 expression was found at the highest concentration of 4 mg/ml trypan blue treated group. There was also a significant increase in the expression of p21 protein at all concentrations of trypan blue as demonstrated in the RPE cells using immunofluorescence. Since the commercially available trypan blue for intraocular use contains trypan blue at concentrations of 0.6 mg/ml or higher, our findings suggest that the concentration to be used clinically may need to be lowered in order to prevent possible toxicity to the RPE or other cells. Moreover, in order to minimise the concentration dependent toxicity associated with trypan blue, partial fluid-air exchange performed before injection of trypan blue may be potentially harmful as this may increase the local concentration of the dye. Further in vivo and in vitro studies of intraocular dyes are warranted. REFERENCES Melles GR, de Waard PW, Pameyer JH, et al. Trypan blue capsule staining to visualize the capsulorhexis in cataract surgery. J Cataract Refract Surg 1999;25:7–9. Bhartiya P , Sharma N, Ray M, et al. Trypan blue assisted phacoemulsification in corneal opacities. Br J Ophthalmol 2002;86:857–9. Ermis SS, Ozturk F, Inan UU. Comparing the efficacy and safety of phacoemulsification in white mature and other types of senile cataracts. Br J Ophthalmol 2003;87:1356–9. Feron EJ, Veckeneer M, Parys-Van Ginderdeuren R, et al. Trypan blue staining of epiretinal membranes in proliferative vitreoretinopathy. Arch Ophthalmol 2002;120:141–4. Stalmans P , Feron EJ, Parys-Van Ginderdeuren R, et al. Double vital staining using trypan blue and infracyanine green in macular pucker surgery. Br J Ophthalmol 2003;87:713–16. Kwok AK, Lai TY, Li WW, et al. Trypan blue and indocyanine green assisted epiretinal membrane surgery: clinical and histopathological studies. Eye. advance online publication, 5 March 2004; doi: 10, 1038/sj. eye. 6701359. Li K , Wong D, Hiscott P, et al. Trypan blue staining of internal limiting membrane and epiretinal membrane during vitrectomy: visual results and histopathological findings. Br J Ophthalmol 2003;87:216–19. Teba FA, Mohr A, Eckardt C, et al. Trypan blue staining in vitreoretinal surgery. Ophthalmology 2003;110:2409–12. Perrier M , Sebag M. Trypan blue-assisted peeling of the internal limiting membrane during macular hole surgery. Am J Ophthalmol 2003;135:903–5. Veckeneer M , van Overdam K, Monzer J, et al. Ocular toxicity study of trypan blue injected into the vitreous cavity of rabbit eyes. Graefes Arch Clin Exp Ophthalmol 2001;239:698–704. Stalmans P , Van Aken EH, Melles G, et al. Trypan blue not toxic for retinal pigment epithelium in vitro. Am J Ophthalmol 2003;135:234–6. Ando F , Sasano K, Ohba N, et al. Anatomic and visual outcomes after indocyanine green-assisted peeling of retinal internal limiting membrane in idiopathic macular hole surgery. Am J Ophthalmol 2004;137:609–14. Sebag J . Indocyanine green-assisted macular hole surgery: too pioneering? Am J Ophthalmol 2004;137:744–6. Yonish-Rouach E , Deguin V, Zaitchouk T, et al. Transcriptional activation plays a role in the induction of apoptosis by transiently transfected wild-type p53. Oncogene 1995;11:2197–205. Isoherranen K , Westermarck J, Kahari VM, et al. Differential regulation of AP-1 family members by UV irradiation in vitro and in vivo. Cell Signal 1998;10:191–5. Chao C , Saito S, Kang J, et al. p53 transcriptional activity is essential for p53-dependent apoptosis following DNA damage. EMBO J 2000;19:3967–75. Vogelstein B , Lane D, Levine AJ. Surfing the p53 network. Nature 2000;408:307–10. Sherr CJ, Roberts JM. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 1999;13:1501–2....查看详细 (23974字节)

☉ 11333106:Medicaid Policy Statement
ABSTRACT Medicaid is a vital safety net for children that must be maintained. It is the largest single insurer of children, yet millions of children who are eligible remain unenrolled. Every effort should be made to implement expanded eligibility and streamlined enrollment procedures. Early and Periodic Screening, Diagnosis, and Treatment (EPSDT) benefits should be maintained for all eligible children. On average, Medicaid covers 30% of a pediatrician's patients, yet inadequate reimbursement affects children's access to care. States should increase reimbursement to at least parity with Medicare. Key Words: Medicaid EPSDT Medicaid managed care eligibility equal access Abbreviations: AAP, American Academy of Pediatrics SCHIP, State Children's Health Insurance Program EPSDT, Early and Periodic Screening, Diagnosis, and Treatment CMS, Centers for Medicare and Medicaid Services INTRODUCTION Every child, regardless of health status, requires health insurance. Research has consistently shown the important role that health coverage plays in children's access to and use of health care services and attainment of positive health outcomes.1 Medicaid is a vital component of the American health and social safety net, particularly for low-income children and children with special health care needs.2 The entitlement to Medicaid should be protected to ensure the health and well-being of millions of children. The American Academy of Pediatrics (AAP) recognizes the achievements of the Medicaid program in improving access to health care services for infants, children, adolescents, and young adults, hereafter referred to as children. The Medicaid program provides documented improvement in health care access, preventive visits, and having a usual source of care, resulting in improved health care outcomes and overall health status of children.3–5 The AAP and its members have made a strong commitment to the Medicaid program. In general, pediatricians serve more Medicaid patients than do other primary care physicians.6,7 On average, 30% of a pediatrician's patients are covered by Medicaid,8 illustrating the commitment of pediatricians to ensure that Medicaid-insured children have access to a medical home.9 The 1990s brought significant progress in expanding health care coverage for children younger than 21 years through Medicaid expansions and the creation of the State Children's Health Insurance Program (SCHIP). In 2000, annual Medicaid enrollment reached 24.2 million or 30.7% of infants, children, and adolescents younger than 21 years.10 This enrollment represents an 8% increase in the proportion of children covered by Medicaid since 1993.11 Between 2000 and 2002, Medicaid and SCHIP covered an additional 3.4 million children and kept the proportion of uninsured children constant (below 12%) even as employment-based coverage continued to drop.12 Still, an estimated 9.2 million children 0 through 18 years of age were uninsured in 2002, of whom 4.1 million were eligible for Medicaid, 2.4 million were eligible for SCHIP programs, and 2.8 million were not eligible for either program.10 With the recent economic downturn, however, state and federal budget deficits threaten to undo gains just when demand for these programs is increasing. Not since World War II have states faced worse financial crises. States are confronting difficult decisions: whether to bypass entitled eligibility, limit outreach, restrict or eliminate benefits, cut provider payments, or alter policy through waivers. In 2003, all 50 states implemented cost-containment strategies, most of which were directed at adults.13 Because parental insurance is a predictor of children's insurance status, decreasing the eligibility of adults will have a predictable negative effect on children's coverage. In the future, children are likely to be more affected by state Medicaid budget shortfalls. At the federal level, major program reforms are also under consideration, including allowing states more flexibility in changing Medicaid rules and regulations without waivers, altering eligibility requirements, cutting benefits to optional Medicaid eligibility groups, implementing cost sharing, and offering capped funding allotments or block grants for acute and long-term care. Although children through 20 years of age represent 54% of all Medicaid enrollees, they account for only 23.5% of all Medicaid expenditures.10 The demographic trend toward more elderly individuals requiring Medicaid long-term care support creates significant pressure on federal and state governments to contain costs. Consequently, state and federal cost-containment strategies targeting children are not likely to yield significant savings and, in fact, may result in far greater state expenditures. Costs do not disappear when children are cut from or drop out of the Medicaid program as a result of cost-containment strategies. States may experience higher expenditures in areas such as primary clinics in public health departments, increased utilization of emergency departments, and an increase in the number of preventable hospitalizations. Other costs, which are more difficult to quantify, such as school absences for children and missed work for parents when children are sick as well as the adverse consequences of delayed treatment, are also likely.14 The AAP, therefore, continues to maintain its strong support for the Medicaid program and offers a series of recommendations to support continued improvements. The following recommendations apply to all Medicaid programs, including fee-for-service, managed care, and prepaid programs unless otherwise specified. ELIGIBILITY The AAP recommends that states implement the following eligibility provisions to ensure coverage of all children eligible for Medicaid under federal legislation. Maintain, or preferably extend, coverage under regular Medicaid and Medicaid-SCHIP programs to cover children up to a higher family income level. Expand coverage of all low-income adolescents through 21 years of age. Continue to take advantage of the flexibility provided by federal law to disregard certain income, assets, and resources so that eligibility levels for children are higher. Maintain Medicaid eligibility, coverage, and access for children with special health care needs through home- and community-based services waivers and Katie Beckett programs. Adopt and maintain presumptive Medicaid eligibility policies for children who are presumed eligible for Medicaid on the basis of income to enroll temporarily and receive services, similar to the option available for pregnant women. Streamline the eligibility determination process to simplify child enrollment and retention and to decrease administrative costs.15 Ensure that a redetermination of eligibility be made before disenrolling any children from Medicaid because of changes in their eligibility for cash assistance under the Temporary Assistance for Needy Families (TANF) program or the Supplemental Security Income (SSI) program. Ensure that children who are removed from their homes by the state and placed in the foster care system are immediately enrolled in Medicaid. Congress should pass the Family Opportunity Act, which would permit a Medicaid buy-in option for families with children who have chronic disabling conditions and who are not Medicaid eligible. Implement the Medicaid option to cover youth exiting foster care on or after their 18th birthday. Implement continuous Medicaid eligibility for children through 21 years of age with screening or evaluation only once during a 12-month period. OUTREACH, ENROLLMENT, AND RETENTION The AAP recommends that states continue their important work to strengthen outreach, enrollment, and retention to ensure that all potentially eligible Medicaid recipients are enrolled in the program. Eliminate means testing, enrollment caps, waiting lists, and requirements that applicants be uninsured for a period of time before enrollment in Medicaid programs. Maintain or increase outreach efforts to reach families whose children are potentially eligible for Medicaid but not enrolled, including but not limited to legal immigrants, SCHIP-eligible children whose family income has changed, and privately insured children in low-income families. Accept applications by mail, by phone, and online, replicating effective strategies of automatic enrollment piloted in Covering Kids initiatives.16 Continue to expand the use of multiple enrollment sites and "express-lane" eligibility determination, including hospitals, birth certificate clerks' offices, primary care offices, health care centers, emergency departments, urgent care centers, child care centers, Head Start programs, Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) programs, schools, child care resources and referral agencies, and places of worship. Extend automatic enrollment in Medicaid for children in families deemed eligible for Temporary Assistance for Needy Families, Supplemental Nutrition Program for Women, Infants, and Children, and food stamps.17 Coordinate Medicaid and SCHIP outreach and universal enrollment processes, including the use of common application forms that are short and written in easily understood language and translated into multiple languages. Encourage and provide incentives for collaboration among enrollment entities, health care professionals, and health plans to improve effective communication and coordination to enroll eligible families and retain participating children. Establish federal policy to prevent denial of citizenship because of previous receipt of Medicaid and any other health services. BENEFITS AND COST SHARING Medicaid benefits vary by state.18 The AAP recommends that Medicaid continue to offer all eligible children the Early and Periodic Screening, Diagnosis, and Treatment (EPSDT) benefit and all other mandatory and optional benefits. In addition: Clearly specify the full scope of pediatric Medicaid benefits, including EPSDT, in consumer brochures, state plan documents, and managed care contracts. States should also inform families about Medicaid benefits excluded from managed care contracts and educate them on how to access these carved-out but covered services. Encourage states to ensure that EPSDT, in combination with other mandatory and optional benefits, covers the benefits outlined in the AAP policy statement "Scope of Health Care Benefits for Newborns, Infants, Children, Adolescents, and Young Adults Through Age 21 Years."19 Ensure that states' EPSDT periodicity schedules are consistent with the AAP periodicity schedule in "Recommendations for Preventive Pediatric Health Care"20 and Bright Futures21 and that immunization schedules are consistent with the recommended childhood and adolescent immunization schedule published annually by the AAP, the Advisory Committee on Immunization Practices, and the American Academy of Family Physicians.22 Ensure that states' medical necessity definitions, consistent with EPSDT policy, are included in all consumer brochures, state plan documents, and managed care contracts. When making medical necessity determinations, state Medicaid agencies should consider whether health interventions for children assist in achieving, maintaining, or restoring health and functional capacity; are appropriate for age and developmental status; and will take into account the specific needs of the child.23 Encourage states to offer the full scope of pediatric Medicaid benefits, including EPSDT, for children under Section 1115 demonstration waivers and Health Insurance Flexibility and Accountability waivers. Promote parity of behavioral health benefits with medical benefits in insurance plans.19 Maintain the policy prohibiting cost sharing on all Medicaid benefits for children, particularly preventive services. MANAGED CARE In recent decades, fiscal and policy considerations have encouraged the use of managed health care delivery models for Medicaid programs. At present, nearly 52.2% of Medicaid beneficiaries receive their health care services through managed care plans.24 The AAP recommends implementing the following safeguards to ensure that the federal government (through its policies) and states (through contracting with health plans, managed care organizations, primary care case management programs, and behavioral health plans) meet the health care needs of children. Ensure that every effort is made by states for Medicaid beneficiaries to make timely and informed selections of managed care organizations and primary care clinicians. This effort includes providing sufficient education and support to consumers, such as face-to-face counselors to provide information on how to choose a health plan, how to access primary care and referral services and out-of-pocket plan benefits, and how to use appeal and grievance procedures. Provide educational materials for families that are culturally sensitive and written at literacy levels and in languages used by Medicaid recipients. Quality-performance data should also be available from states and meaningful to Medicaid consumers. Consumer-education efforts must address the lack of resources, information, and training that prevents many consumers from being involved in advisory and oversight bodies.25 For Medicaid participants who do not choose and must be assigned to a managed care organization, use practical criteria to assign them, including current and previous relationships with primary care and specialty clinicians, location of clinicians, assignment of other family or household members, cultural and linguistic preferences, choices by other members in the service area, and capacity of managed care organizations to provide special care or services appropriate for children. Pediatricians should be considered primary care clinicians (not subspecialists), eligible to have children assigned to them in all default enrollment systems and state-based enrollment broker options. Every effort should be made to allow Medicaid patients to remain with their medical home. Include in the provider network of all managed care organizations and fee-for-service programs26 sufficient numbers of appropriately trained and board-eligible or board-certified providers of pediatric care, including primary, medical subspecialty, surgical specialty, and psychiatric pediatric care, or provide a network outside the plan. Physicians and other licensed providers of developmental, behavioral, and substance-abuse services should be accessible or available by referral from the primary care clinician to provide medically necessary services without restrictions from the managed care organization. In addition, Medicaid-eligible children should have access to children's mental health and substance-abuse services, oral health care, social work services, developmental evaluation services, occupational therapy services, physical therapy services, speech therapy and language services, school-linked clinic services, and other necessary public health services. The network should also include hospitals that specialize in the care of children in both inpatient and outpatient settings. In determining network adequacy, states should base determinations on the number of Medicaid providers accepting all new Medicaid patients. With federal support, states should offer incentives for managed care organizations, fee-for-service programs, and primary care case management programs to identify children with special health care needs and offer plan providers enhanced payments for providing a medical home, including family education, practice-based care coordination, and transition to adult care, for these children. Require state coordination of care between Title V agencies and mental health agencies that serve Medicaid managed care beneficiaries. Encourage states to implement special planning and oversight of the use of managed care for children with special health care needs, including children in foster care and children with mental health conditions. This should cover benefit specifications for specialty or chronic care services, composition of pediatric provider networks, policies for flexible service authorization, care coordination, quality-performance measures for preventive care delivery for children with various types of chronic conditions, family participation, pediatric risk-adjustment mechanisms, and other financial incentives for high-quality care. Encourage states to select managed care organizations on the basis of their ability or demonstrated readiness to provide Medicaid-eligible children with quality care based on the use of quality-performance measures. Also, managed care organizations should be selected on the basis of their abilities to complement and coordinate services with existing maternal and child health programs to ensure maximum health benefits to families. Streamline Medicaid administrative processes to create a minimal paperwork burden for physicians. ACCESS TO PEDIATRIC SERVICES The AAP recommends that the Centers for Medicare and Medicaid Services (CMS) and states focus new attention on the availability of and access to a wide range of pediatric services. For all families with children, encourage the availability of medical homes that include access to primary care pediatricians, pediatric medical subspecialists, pediatric surgical specialists, developmental and behavioral service providers, care coordinators, and hospitals with appropriate pediatric expertise. Efforts should be made by state Medicaid agencies and managed care organizations to maintain established relationships of children with their primary care and specialty pediatricians to avoid disruptions in the continuity of care. Ensure that behavioral health panels include mental health professionals with adequate training and experience in caring for children and adolescents. Support the "prudent-layperson" standardand oppose copayments for emergency care to allow timely access to emergency services. Provide pediatric-appropriate medication formularies to provide quality care. Support ongoing research to monitor the Medicaid participation rates of primary care and specialty pediatricians and to evaluate other aspects of access to and quality of care for children under Medicaid. FINANCING AND REIMBURSEMENT The AAP recommends that the CMS and state Medicaid agencies reexamine their reimbursement policies that are woefully inadequate for physicians who care for children. Adequate Medicaid reimbursement is necessary to achieve access. Low payment, capitation, and paperwork concerns all relate to low Medicaid participation by primary care office–based pediatricians, pediatric medical subspecialists and pediatric surgical specialists, mental health providers, and dentists.27 State policy makers should address these 3 factors to ensure sufficient primary care physician capacity to appropriately serve children enrolled in Medicaid. States must pay primary care pediatricians and pediatric medical subspecialists and pediatric surgical specialists adequately so they can continue to provide and improve quality care for low-income children. Federal and state policy makers and private managed care administrators should ensure appropriate levels of reimbursement and payment rates. All states should regularly review Medicaid reimbursement rates and raise them to at least parity with Medicare. Health care for children is relatively inexpensive when compared with that for adults. Moreover, cutting state funding for Medicaid means losing significant federal matching funds. Failure to invest adequately in the health of children today could have serious consequences for the populations of tomorrow.28 The AAP recommends that policy makers: Increase the Federal Medical Assistance Percentage as necessary to provide critical fiscal relief to states and to maintain disproportionate share hospital payments. Oppose the conversion of Medicaid financing to an annual allotment or block grant program with a fixed budget and oppose caps on federal Medicaid spending. Enforce the federal equal-access provision requiring that state plans for medical assistance ensure that payments are "sufficient to enlist enough providers so that care and services are available under the plan at least to the extent that such care and services are available to the general population in the geographic area."29 Strong evidence demonstrates that adequate reimbursement is a prerequisite for states to comply with federal law. Require all states to increase Medicaid reimbursement rates to at least parity with Medicare. Require all states to establish a process to review and update Medicaid provider payment rates on an annual basis. Adjust payments for case-mix differences based on chronic conditions, a pediatric diagnostic classification system, or other risk-adjustment mechanism. Because pediatric risk-adjustment techniques are not well developed, contract provisions should be included to address carved-out services, outlier payment, reinsurance or shared-risk arrangements for individual children, and aggregate plan loss or profits. All financing mechanisms should be sufficient to adequately fund the overall costs of caring for children eligible for Medicaid and should provide adequate reimbursement to physicians caring for these patients. New financing approaches should be piloted and evaluated with an analysis of the effect on children, their families, and their pediatricians before broad implementation. When states raise capitation rates, they should ensure funds are used by health plans to improve access, quality, and reimbursement of health services. Eliminate barriers to pediatricians' reimbursement for the behavioral health services that they legitimately provide within their scope of skills as general pediatricians. Provide Medicaid reimbursement for pediatrician-directed care coordination of children with special health care needs. Provide Medicaid reimbursement for observation, rapid-treatment, and 23-hour units, day medicine services, and necessary interhospital transport services. Adjust Medicaid reimbursement, including capitation payments, or create contingency funds to account for advances in pediatric care, including but not limited to new vaccines and new technologies. Timely adjustments to coverage and capitation rates reflecting these medical advances should be included in all state managed care contracts. Adopt health plan reimbursement levels that value services to children. Encourage the CMS to obligate states contracting with managed care organizations to disclose their physician-payment methodologies and rates (whether fee-for-service or capitated) for each child eligibility group on an annual basis. The CMS should require states to make nonproprietary information easily available on request. The adequacy of Medicaid payments should be based on the true costs of delivering care and not on the commercial market rate, which may be inadequate. Initiate a process to modify the resource-based relative-value scale for children to correct inequities pertaining to pediatrics. In particular, a system for the ongoing evaluation of expenses for practice overhead, including expenses specific to pediatrics, should be implemented. Establish a National Medicaid Payment Advisory Commission and a national Medicaid utilization database with AAP representation to address the many child health services payment issues within the Medicaid program. Encourage states to offer a provider-relations committee to address reimbursement issues. Explore innovative methods to establish trust funds to support graduate medical education relevant to the provision of care for Medicaid participants and to ensure a qualified pediatric workforce. Require the federal government to provide reimbursement for trained interpreter services for patients with limited English proficiency to decrease errors in medical interpretation and potential adverse clinical consequences.30 QUALITY-IMPROVEMENT ACTIVITIES The AAP recommends enhancing state Medicaid quality-improvement activities for children, including those with special health care needs, in collaboration with state AAP chapters. Implement quality-performance measures by states that address access to care, utilization, effectiveness, and satisfaction related to preventive, primary, acute, and chronic care for children. Such performance measures should be consistent with current pediatric practice parameters of the AAP. Establish appropriate incentives from federal and state programs so that Medicaid plans and providers deliver high-quality services. Ensure uniform and consistent EPSDT reporting with minimal paperwork burden on providers and a review process and compliance plan that is conducted by persons specifically trained in and practicing pediatrics. Educational and nonpunitive programs should be implemented to ensure effective and uniform EPSDT. Conduct the Consumer Assessment of Health Plan Survey for a representative sample of children enrolled in state Medicaid programs, especially children with special health care needs, and the screener for parents of children with special health care needs. The Agency for Healthcare Research and Quality (AHRQ) and the National Committee for Quality Assurance should include pediatricians in updating the survey and the Health Employer Data and Information System (HEDIS). The AHRQ and other agencies should include pediatricians in establishing new quality-performance measures affecting children. Federal and state agencies should work with the AAP to develop programs to improve the quality of pediatric care as well as tools and measures to monitor changes, especially in the provision of medical homes for children with special health care needs. States should update meaningful provider-assessment and -certification activities, including peer review, provider credentialing, medical record reviews, and timely analysis and reporting of findings to providers, plans, and beneficiaries. Encourage Medicaid programs to partner with other state agencies such as Title V offices to support practice-level improvements in pediatric care, especially in providing a medical home for children with special health care needs. States should monitor enrollment patterns and reasons for enrollment changes to ensure that managed care organizations do not encourage "high-cost" persons to switch to other plans and do not underserve Medicaid beneficiaries. States should implement general administrative-review processes to ensure that managed care organizations and behavioral health organizations are qualified and available. States should provide timely, linguistically appropriate, and meaningful results of quality-related activities to beneficiaries to facilitate their participation in health care decision-making. Committee on Child Health Financing, 2003–2004 Thomas K. McInerny, MD, Chairperson Charles J. Barone, II, MD Jeffrey M. Brown, MD, MPH Richard Lander, MD John R. Meurer, MD, MBA Richard Y. Mitsunaga, MD Mark S. Reuben, MD Steven E. Wegner, MD, JD Mark J. Werner, MD, CPE Consultant Margaret McManus, MHS Staff Jean Davis, MPP FOOTNOTES Section 1915(c) of the Social Security Act allows federal Medicaid matching payments to be used for certain long-term care services that would otherwise not qualify. These home- and community-based services may be provided to Medicaid beneficiaries who, but for the provision of these services, would require the level of care provided in a hospital or nursing facility of an intermediate care facility. Section 1902(e)(3) of the Social Security Act, 42 USC 1396a(e)(3), allows states to provide Medicaid coverage to disabled children receiving medical care at home who would qualify for Medicaid if they were institutionalized. Section 1115 of the Social Security Act (42 USC 1315) allows states to waive compliance with any provision of Medicaid, in addition to other federal programs authorized by the Act, for any experimental, pilot, or demonstration project that would promote the objectives of the Medicaid program. A Health Insurance Flexibility and Accountability waiver allows states to cut benefit packages and increase cost sharing. Section 4704 (b)(2)(C) of the Balanced Budget Act of 1997 (Public Law 105-33) defines the prudent-layperson standard as "a medical condition manifesting itself by acute symptoms of sufficient severity (including severe pain) such that a prudent layperson, who possess an average knowledge of health and medicine, could reasonably expect the absence of immediate medical attention to result in placing the health of the individual (or, with respect to a pregnant woman, the health of the woman or her unborn child) in serious jeopardy, serious impairment to bodily functions, or serious dysfunction of any bodily organ or part." Lead author REFERENCES Lewit EM, Bennett C, Behrman RE. Health insurance for children: analysis and recommendations. Future Child.2003; 13 :5 –29 Children Now. California Report Card 2002. Oakland, CA: Children Now;2002 Grumbach K, Hart LG, Mertz E, Coffman J, Palazzo L. Who is caring for the underserved A comparison of primary care physicians and nonphysician clinicians in California and Washington. Ann Fam Med.2003; 1 :97 –104 Perloff JD, Kletke PR, Fossett JW, Banks S. Medicaid participation among urban primary care physicians. Med Care.1997; 35 :142 –157 American Academy of Pediatrics, Medical Home Initiatives for Children With Special Needs Project Advisory Committee. The medical home. Pediatrics.2002; 110 :184 –186 American Academy of Pediatrics, Division of Health Policy Research. FY 1993 Medicaid State Reports. Elk Grove Village, IL: American Academy of Pediatrics;1994 Fairbrother G, Dutton MJ, Bachrach D, Newell KA, Boozang P, Cooper R. Costs of enrolling children in Medicaid and SCHIP. Health Aff (Millwood).2004; 23 :237 –243 American Academy of Pediatrics, Committee on Child Health Financing. Scope of health care benefits for newborns, infants, children, adolescents, and young adults through age 21 years. Pediatrics.1997; 100 :1040 –1041 American Academy of Pediatrics, Committee on Practice and Ambulatory Medicine. Recommendations for preventive pediatric health care. Pediatrics.2000; 105 :645 –646 Green M, Palfrey JS, eds. Bright Futures: Guidelines for Health Supervision of Infants, Children and Adolescents. 2nd ed. Arlington, VA: National Center for Education in Maternal and Child Health; 2000 American Academy of Pediatrics, Committee on Infectious Diseases, Advisory Committee on Immunization Practices, American Academy of Family Physicians. Recommended childhood and adolescent immunization schedule—United States, July–December 2004. Pediatrics.2004; 113 :1448 –1450 Berman S. A pediatric perspective on medical necessity. Arch Pediatr Adolesc Med.1997; 151 :858 –859 Molnar C. Addressing challenges, creating opportunities: fostering consumer participation in Medicaid and Children's Health Insurance managed care programs. J Ambul Care Manage.2001; 24 :61 –67 Skaggs D, Clemens SM, Vitale MG, Femino JD, Kay RM. Access toorthopedic care for children with Medicaid versus private insurance in California. Pediatrics.2001; 107 :1405 –1408 Berman S, Dolins J, Tang SF, Yudkowsky B. Factors that influence the willingness of private primary care pediatricians to accept more Medicaid patients. Pediatrics.2002; 110 :239 –248 Freed GL, Fant K. The impact of the "aging of America" on children. Health Aff (Millwood).2004; 23 :168 –174 Omnibus Budget Reconciliation Act of 1989 (Pub L No. 101-239), 1396a(a)(30)(A) Flores G, Laws MB, Mayo SJ, et al. Errors in medical interpretation and their potential clinical consequences in pediatric encounters. Pediatrics.2003; 111 :6 –14...查看详细 (32558字节)
☉ 11333107:The evaluation of a humidifying device for vitreoretinal surgery
1 Department of Ophthalmology, Auckland, New Zealand 2 Fisher and Paykel HealthCare Division, Auckland, New Zealand ABSTRACT Aim: To study the feasibility of humidifying air during vitreoretinal surgery and measure the water content of air before and after intraocular transit. Methods: The absolute water content of air was measured in a series of six eyes undergoing fluid-air exchange during macular hole surgery. Infrared absorption spectroscopy was used to determine the water content of the air infusing and exiting each eye. After baseline measurements for each eye were recorded, a second fluid-air exchange was performed and the effect of humidifying the air infusion was documented.The humidifying device used in this study was a prototype adapted from a commercially available respiratory humidifier and enables humidified air to be delivered at a controlled temperature. Results: The water content of air increased following intraocular transit, implying dehydration occurs from the intraocular surfaces. For a standard airline infusion the mean increase in water content of air egressing from an eye was 13.4 mg/l. Humidifying the air reduced the rate of water loss by nearly 90%. Conclusions: Significant water losses can occur from eyes undergoing fluid-air exchange. Humidifying the infused air can substantially reduce the dehydrating effect during an air exchange. This outcome may have a beneficial effect in reducing cataract formation and visual field defects associated with macular hole surgery. Keywords: dehydration injury; fluid-air exchange; humidity; macular hole Fluid-air exchange during vitreoretinal surgery is used frequently as a tool for retinal re-attachment. The surface tension of air in an aqueous environment is such that subretinal fluid can be hydraulically removed as air is pumped into the eye. While this manoeuvre is usually simple and effective, complications of fluid-air exchange are well known and may lead to cataract and retinal injury.1,2 One of the mechanisms that may be important in causing damage arises as a consequence of dehydration of the intraocular surfaces.3 We have previously reported on the parameters governing water vapour in air and report herein the results of humidifying air in vitreoretinal surgery.4 METHODS Study aims We sought to quantify the loss of water content occurring from six eyes undergoing macular hole surgery during fluid gas exchange using ambient air. We consequently sought to demonstrate the ability of a prototype humidifier for vitreoretinal surgery to produce highly humidified air for infusion and to determine if humidification of infusion air reduces water loss from the eye during fluid-air exchange. In one patient the infusion line became blocked during the change to humidified air. This single data set was excluded from analysis. The dehydration effects of the partially humidified air on the intraocular interfaces can be determined from Dalton’s law of evaporation which states: the rate of evaporation is related to the vapour pressure deficit at the fluid-air interface and a "wind function."5,6 The latter function describes the flow velocity and wind pattern over the water source while the former term defines the difference in partial pressure of water vapour in air when saturated (which is temperature dependent) and that of the delivered gas; in this case, air. Dalton’s law of evaporation can be expressed in the following form: E = f(u)*(es – ea) Where f(u) is called the "wind function" and es = saturation vapour pressure ea = vapour pressure in the air. In order to calculate an absolute value for the rate of evaporation, it is necessary to derive a wind function describing the complex fluid flow dynamics within the eye. This value is not yet determined. However, it can be shown mathematically that Dalton’s law can also be used to define the differential change in the rate of evaporation between ambient room air and humidified air, without requiring the wind function. Accordingly the percentage change in the rate of evaporation for the six eyes under the two conditions described was calculated.5,6 Equipment used Absolute water content (absolute humidity, mg/l) was measured using an infrared hygrometer, which provides for real time readings (Fisher and Paykel Healthcare, Auckland, New Zealand). This device determines the water content of air by measuring the absorption spectra in the infrared portion of the electromagnetic spectrum and comparing with a known standard. The accuracy of the hygrometer is plus or minus 1 mg/l. The importance of measuring absolute as opposed to relative humidity of an air sample means the effect of temperature and ambient pressure can be ignored and has been previously discussed.4 The highly humidified air used during the fluid-air exchange was achieved using the Fisher & Paykel MR820 humidifier. This is a prototype device adapted from a commercially available respiratory humidifier and enables humidified air to be delivered at a controlled temperature. Sterilisation of this unit was achieved by gamma irradiation and meets both the ISO 11137 and the BS/EN 552 standards (respectively, International Organisation for Standardisation and National Standard Body of the United Kingdom) Technique Measurements were made in a series of six eyes undergoing fluid-air exchange during macular hole surgery. After baseline measurements were recorded for each eye with ambient air, the eye was then refilled with balanced salt solution (Alcon, Fort Worth, TX, USA) and a second fluid-air exchange was performed. The air infusion pressure was maintained at 26 mm Hg for the duration of the surgery. The water content was measured 5 minutes after the completion of the initial air exchange and again some 5 minutes after the infused air was humidified. The infrared hygrometer was used to determine absolute humidity of the following: Ambient air Air exiting from the six eyes during standard fluid-air exchange performed with ambient air Air delivered to five eyes via the MR820 humidifier Air exiting from five eyes during fluid-air exchange conducted using humidified air Ethics approval and informed consent was obtained from all patients. Additional studies on the sites and extent of heat loss, together with measurements of water content of humidified air were conducted under controlled conditions in the laboratory. RESULTS The mean water content of the filtered air in the standard infusion line was 8.2 mg/l (range 8–10 mg/l). Conversely the humidified air, heated to 37°C in the MR820 humidifier had a mean water content of 40.4 mg/l (range 40–40.6 mg/l) as measured immediately after leaving the heating coil used to raise the ambient temperature of the infused air (just before connecting to three way tap and 20 gauge infusion line). However cooling and condensation of the water vapour occurred in the unheated portion of the humidified air line (that is, the 20 gauge infusion connecting between the three way tap and the eye). The heat losses were subsequently documented in the laboratory to be in the order of 10°C, while the reduction in absolute water content along the unheated infusion line ranged from 10–20 mg/l. Thus, though the humidifier was capable of delivering saturated air at body temperature, the technical issues of maintaining sterility meant the actual water content hovered around 25 mg/l which is equivalent to saturated air at 27°C. Under standard ambient conditions (that is, without the humidifying the airline) the mean water content egressing from the eyes was 20.84 mg/l (SD 1.182) while the mean water content of the air egressing from the eye with humidified air was 22.84 mg/l (SD 0.604). The difference in the mean water content under these two circumstances is statistically significant (p>0.001). The introduction of the humidifier did not alter the flow rate of the air infusion as each unit was sealed and the tubing was of the same length and calibre as the ambient air line infusion. The following partial pressures of water vapour ea1 (ambient conditions in the operating room), and ea2 (output from the humidifier) were obtained in this study. The partial pressure of water vapour at body temperature (es) when the air is saturated is: es = 6.280 kPa (47.10387 mm Hg) (37°C, 100% relative humidity, 44 mg/l) ea1 = 1.145 kPa (8.588 mm Hg) (mean ambient conditions in operating room: 20°C, 46% relative humidity, 8 mg/l) (equivalent to 18% relative humidity at 37°C) ea2 = 5.725 kPa (42.94103 mm Hg) (maximum output of humidifier: 40 mg/l, 35°C) (equivalent to 91% relative humidity at 37°C) Substituting the appropriate values (in kPa) into Dalton’s law, we obtain the following rates of evaporation: The rate of evaporation E1 (when delivering ambient operating room air): E1 = f(u)*5.135 The rate of evaporation E2 (when delivering humidified air under ideal conditions): E2 = f(u)*0.555 Under ideal circumstances, the active humidifier therefore shows a reduction of 89.2% in the rate of evaporation when compared to ambient operating room air. DISCUSSION The complications of fluid-air exchange in vitreoretinal surgery are poorly understood. Some adverse effects such as field defects are more commonly described in macular hole surgery yet similar intraocular manipulations occur during other retinal procedures. The reported frequency of field defect also varies considerably.7,8 Welch has maintained the main cause of postoperative field defects seen in patients undergoing macular hole surgery is the result of dehydration of the retina.3 Kokame and others have highlighted the importance of infusion pressure as a determinant of the intraocular pressure and reporting on the drying effects of high flow systems.9,10 Furthermore Hirata et al demonstrated field defects occur more frequently in eyes with higher infusion pressures and confirmed Welch’s finding that field defects depended on the position of the infusion cannula.3,11 These authors concluded the field defect seen in their patients was likely to be caused by direct mechanical damage (by infusion pressure) to the inner retina. Similarly, Hasumura et al maintained direct mechanical trauma to the retina during air exchange was responsible for the adverse and localised effect on the retina seen in a series of experiments performed on rabbit eyes.2 More recently Hirata has demonstrated with a modified infusion cannula the pathological changes documented under similar experimental conditions could minimised with altered flow dynamics.12 We believe that altering infusion pressure and flow dynamics of infusion cannulae exerts a favourable effect on evaporation/dehydration by altering the wind function component of Dalton’s law. Consequently, we believe that dehydration therefore is the ultimate mechanism by which visual field defect occurs, but that dehydration can be influenced by either infusion pressure/flow dynamics or by humidifying the infused air. There is conflicting evidence on the merits of humidifying air in vitreoretinal surgery. Ohji et al13 found field defects could be eliminated by humidifying air but Hirata et al did not.11 Both these groups used a water bath to humidify the infused air. We have previously demonstrated that none of these experiments have effectively determined the underlying cause of the visual field defects as they have not distinguished between the interrelated factors that might determine dehydration fluxes within the eye.4 Furthermore, our previous study indicated that cold evaporation is a relatively ineffective method of humidifying air and the flaws inherent in using relative humidity in interpreting water content. We have demonstrated that the prototype MR820 humidifier used in our experiments can effectively humidify air to saturated body temperature levels. However, we have also documented in our experimental set up there are still heat losses as the humidified air passes from the humidifier to the eye through the unheated 20 gauge infusion line. This problem may be overcome by extending the heat coil to within millimetres from the eye, a technical issue which we are currently addressing. We believe this remains an important question and may help to provide an answer to the observed adverse effects on the eye. A novel approach to the issue of determining the optimal level of heat and humidity in respiratory medicine was to consider the energy balance under certain experimental conditions.6 These authors measured the temperature and humidity of inspired and expired air in intubated patients under variable conditions and found inspired air at body temperature and saturated was thermodynamically neutral. Air infusions for vitrectomy are an analogous situation and it is logical that infusing saturated body temperature air would also be thermodynamically neutral. Whether or not it is necessary to strive for this ideal in vitreoretinal surgery remains to be seen, as the threshold at which dehydration damage occurs is likely to be much lower than this. The concept of having a thermodynamic neutral value helps explain why the water content of the air egressing from the eyes is higher when the air is humidified. This study does not yet conclusively answer the question of causation in visual field defects or the role of dehydration. However it does confirm that dehydration of the intraocular surfaces does occur and is not insignificant. Furthermore we have demonstrated that effective humidification of infused airlines can be obtained (that is, saturated at body temperature) with our prototype humidifier. CONCLUSION A significant increase in water vapour loss occurs during fluid-air exchange if the infused air is not humidified. This may result in dehydration injury to the intraocular surfaces and contribute to psychophysical abnormalities seen following vitreoretinal surgery. The MR820 humidifier is able to deliver highly humidified air to an eye and would theoretically eliminate dehydration injury to the retina during fluid-air exchange. These findings allow further studies that can evaluate the importance of humidity and infusion pressure as independent risk factors during vitreoretinal surgery. Such an independent analysis will better determine the roles of dehydration and mechanical (infusion pressure) forces in visual fields defects during macular hole surgery. REFERENCES Thompson J , Glaser B, Sjaarda R, et al. Progression of nuclear sclerosis and long-term visual results of vitrectomy with transforming growth factor beta-2 for macular holes. Am J Ophthalmol 1995;119:48–54. Hasumura T , Yonemura N, Hirata A, et al. Retinal damage by air infusion during vitrectomy in rabbit eyes. Invest Ophthalmol Vis Sci 2000;41:4300–4. Welch J . Dehydration injury as a possible cause of visual field defect after pars plana vitrectomy for macular hole. Am J Ophthalmol 1997;124:698–9. Vote B , Newland A, Polkinghorne P. Humidity devices in vitreoretinal surgery. Retina 2002;22:616–21. Dalton J . On the absorption of gases by water and other liquids. Mem Liter Phil Soc Manchester 1805;1:271–87. Ryan S , Rankin N, Meyer E, et al. Energy balance in the intubated human airway is an indicator of optimal gas conditioning. Crit Care Med 2002;30:355–61. Pendergast S, McCuen B, 2nd. Visual field loss after macular hole surgery. Ophthalmology 1996;103:1069–77. Ezra E , Arden GB, Riordan-Eva P, et al. Visual field loss following vitrectomy for stage 2 and 3 macular holes. Br J Ophthalmol 1996;80:519–25. Kokame G . Visual field defects after vitrectomy with fluid-air exchange. Br J Ophthalmol 2001;85:121. Ishigooka H , Mawatari Y, Ogawa K. Prophylactic trials for prevention of visual field defect after vitrectomy for macular hole. Invest Ophthalmol Vis Sci 2000;41:1799B45. Hirata A , Yonemura N, Hasumura T, et al. Effect of infusion air pressure on visual field defects after macular hole surgery. Am J Ophthalmol 2000;130:611–16. Hirata A , Yonemura N, Hasumura T, et al. New infusion cannula for prevention of retinal damage by infusion air during vitrectomy. Retina 2003;23:682–5. Ohji M , Nao I, Saito Y, et al. Prevention of visual field defect after macular hole surgery by passing air used for fluid-air exchange through water. Am J Ophthalmol 1999;127:62–6....查看详细 (16668字节)
☉ 11333108:Screening for Retinopathy in the Pediatric Patient With Type 1 Diabetes Mellitus
ABSTRACT Diabetic retinopathy (DR) is the leading cause of blindness in young adults in the United States. Early identification and treatment of DR can decrease the risk of vision loss in affected patients. This clinical report reviews the risk factors for the development of DR and screening guidance for pediatric patients with type 1 diabetes mellitus. Key Words: type 1 diabetes mellitus diabetic retinopathy ophthalmic screening Abbreviations: DR, diabetic retinopathy DCCT, Diabetes Control and Complications Trial BACKGROUND Type 1 diabetes mellitus is one of the most common metabolic disorders in children, with a prevalence of approximately 2 per 1000 school-aged children in the United States. The prevalence of type 1 diabetes mellitus increases with age, and the overall incidence of the disease may be increasing. Although the incidence of type 2 diabetes in children is increasing, there are no data or guidelines regarding ophthalmic screening in children with this disorder. Diabetic retinopathy (DR) is one of the most important complications of type 1 diabetes mellitus, representing the leading cause of blindness in young adults. There are 3 main components of a strategy to minimize the risk of visual loss attributable to DR: (1) provide the most effective treatment of the underlying metabolic disorder and its comorbidities; (2) develop optimal treatment modalities for patients with ocular disease; and (3) identify risk factors for the development of ocular disease and implement effective screening programs to identify at-risk patients. The first 2 have been evaluated in well-conducted, large, prospective trials. Optimizing Metabolic Control The efficacy of providing intensive treatment of the underlying metabolic disorder was evaluated by the Diabetes Control and Complications Trial (DCCT),1 which clearly demonstrated the benefits of improving glycemic control and decreasing hemoglobin A1c concentrations in decreasing the complication rate. In this study, patients who received intensive treatment with either an insulin pump or 3 or more daily insulin injections, frequent phone calls and clinic visits, and self-management education substantially decreased their risk of both onset and progression of retinopathy, compared with patients treated with conventional therapy. The risk of retinopathy was decreased by 53% in children 13 to 17 years of age and with no retinopathy at study entry, and the risk of retinopathy progression was decreased by 70% in those who had retinopathy at the beginning of the study.2 One of the concerns regarding the institution of intensive metabolic control had been the potential for the acceleration of DR on the basis of a report by Daneman et al3 of 4 patients with poorly controlled diabetes mellitus and short stature who developed macular edema and severe proliferative DR shortly after initiation of appropriate insulin therapy. This complication was evaluated in patients enrolled in the DCCT, and early worsening over the first 6 to 12 months was found to be more prevalent in patients with intensive treatment (13.1%) compared with patients with conventional treatment (7.6%).4 However, the long-term outcomes in the patients with early worsening were the same or better than those treated with conventional therapy. The Kroc Collaborative Study Group5 also found that early worsening of DR was not sustained and was not associated with a worse long-term outcome. Additionally, the benefits of intensive therapy continued to be evident 7 years after the end of the DCCT, as demonstrated in the Epidemiology of Diabetes Interventions and Complications study.6–8 Thus, in most cases the potential for early worsening should not restrict institution of intensive glycemic control. Optimizing Treatment of Retinopathy The development of optimal treatment modalities for ocular disease has also been evaluated in several studies, one of the most important of which is the Early Treatment of Diabetic Retinopathy Study.9 This large study evaluated the benefit of early treatment for 2 ocular complications of type 1 diabetes mellitus, diabetic macular edema, and proliferative DR. Studies clearly demonstrated that patients with high-risk characteristics of these disorders experienced a marked improvement in outcome after laser therapy.9,10 The risk of moderate vision loss (eg, a doubling of the visual angle or 20/20 vision reduced to 20/40) from diabetic macular edema was decreased by approximately 50% with appropriate focal laser photocoagulation for clinically significant macular edema (from approximately 25% without treatment to approximately 12% with treatment). The risk of severe vision loss (best corrected vision of 5/200 or worse) from proliferative DR was decreased to <2% with appropriate scatter (panretinal) laser photocoagulation. Identification of Risk Factors for Ocular Disease DR typically follows a predictable progression.11 Early nonproliferative DR is characterized by changes in retinal blood flow and other microvascular changes, which may lead to ischemia, small retinal hemorrhages, and leakage of exudative fluid within the retina. More severe nonproliferative DR is characterized by intraretinal microvascular abnormalities, more extensive hemorrhages and microaneurysms, and changes in venous caliber and tortuosity, reflecting progressive capillary closure and retinal ischemia. Proliferative DR is marked by fibrovascular proliferations on either the optic disk (new vessels on the disk) or new vessels elsewhere on the retina. Proliferative DR may cause vision loss by vitreous hemorrhage or contraction of fibrovascular tissue with subsequent retinal detachment. Laser surgery is promptly indicated when an eye approaches or reaches high-risk proliferative DR. High-risk proliferative DR is clearly defined and characterized by one or more of the following lesions: (1) new vessels on the optic disk approximately one fourth to one third disk area or more in size; (2) new vessels on the optic disk less than one fourth the disk area in size when fresh vitreous hemorrhage or preretinal hemorrhage is present; or (3) new vessels elsewhere on the retina greater than or equal to one half the disk area in size when fresh vitreous hemorrhage or preretinal hemorrhage is present. The goal of a regular eye examination is to identify and treat patients before the development of vision-threatening complications. Diabetic macular edema can be present with any level of nonproliferative or proliferative DR. The role of ophthalmologic screening programs for DR will be the focus of this report. FACTORS THAT AFFECT ONSET OF DR Several epidemiologic studies have evaluated risk factors for development of DR. Some of these factors are amenable to treatment, resulting in a decreased risk of DR, such as optimizing metabolic control as reported in the DCCT, discontinuing smoking, avoiding obesity, and monitoring blood pressure. Other factors such as patient age, duration of disease, and the effects of puberty and pregnancy are not modifiable. The impact of the individual risk factors may be difficult to isolate, because they are not independent of one another (ie, the longer the duration of the disease, the older the patient will be). Duration of Disease The duration of diabetes is unequivocally one of the most important risk factors for the development of DR. Essentially all studies demonstrate that the risk of DR increases with time in individuals with diabetes. In a study of 996 patients who had been diagnosed with type 1 diabetes mellitus when they were younger than 30 years, Klein et al12 found that the prevalence of DR increased from 17% for patients with diabetes for less than 5 years to 98% for patients with diabetes for 15 or more years. The prevalence of proliferative DR increased from 1% in patients with diabetes for less than 10 years to 67% in patients with diabetes for 35 or more years. A few studies have reported mild DR in children with duration of disease as short as 1 to 2 years,13,14 but in most studies the duration is 3 or more years, with typical durations of 8 to 10 years before development of DR.15,16 Age The effect of age on the development of DR is linked to the duration of the disease (patients with longer durations are typically older). What is clear is that young children (younger than 10 years) with type 1 diabetes mellitus are at minimal risk of the development of significant ocular complications. The presence of any DR before 10 years of age has been reported rarely,13,14 and these cases have been mild. In a series of 996 patients with type 1 diabetes mellitus who had been diagnosed before 30 years old, Klein et al12 found that mild DR was identified in only 1 patient in the first decade of life, and moderate DR was identified in 1 patient between 10 and 14 years of age. Neither of these patients required treatment. In a follow-up study of 634 patients by Klein et al,17 no patient who was younger than 10 years at the time of diagnosis of type 1 diabetes mellitus developed proliferative DR within 10 years of diagnosis. In a comprehensive review of the literature, no report of proliferative DR could be found in a patient in the first decade of life. Puberty The effect of puberty on the development of DR has been difficult to clearly elucidate. Although the duration of diabetes before puberty affects the onset of DR,14,18 there is good evidence that the hormonal changes associated with puberty exert an effect that is independent of age and duration of disease. Rogers et al,19 in a study of 76 patients, found a significantly higher prevalence of DR in late pubertal subjects compared with prepubertal subjects despite similar duration of disease and similar glycosylated hemoglobin concentrations. In a similar study, Murphy et al20 found that the relative risk of having DR in a pubescent group of children compared with a prepubescent group was 4.8. Pregnancy Pregnancy represents another well-established risk factor for DR. Several studies have demonstrated progression of DR during pregnancy.21–24 Factors that exacerbate the acceleration of DR during pregnancy include poor metabolic control, hypertension, and a baseline degree of retinopathy. The large studies of pregnancy and DR do not include pediatric patients, and we are unaware of any study that specifically addresses the effects of pregnancy in adolescent patients with type 1 diabetes mellitus. GUIDELINES FOR OPHTHALMIC SCREENING FOR DR Screening guidelines for DR have been published previously by the American Academy of Pediatrics,25 the American Academy of Ophthalmology,26 and the American Diabetes Association.27 The recommendations regarding pediatric patients with type 1 diabetes mellitus are similar. The American Academy of Ophthalmology recommends annual screening beginning 5 years after the onset of diabetes.26 The guidelines from the American Diabetes Association include annual screening beginning 3 to 5 years after diagnosis of diabetes once the patient is 10 years or older.27 The American Academy of Pediatrics recommends an initial examination 3 to 5 years after diagnosis if older than 9 years, with annual follow-ups thereafter.25 The recommendations reflect the fact that the incidence of DR in young children is negligibly small, and therefore children younger than 9 years do not require screening for DR. The incidence of retinopathy in young adolescents is also very low, particularly for proliferative DR. Although the risk of DR typically does not increase significantly until 8 to 10 years after diagnosis, the recommendation for annual screening beginning 3 to 5 years after diagnosis (in children who are older than 9 years) is reasonable, given that DR has been reported occasionally within this time. Because children with type 1 diabetes mellitus are at a greatly increased risk of visual loss over the course of their lives, special attention should be given to identifying other causes of visual loss in these patients. Screening for potentially treatable visual disorders such as amblyopia is recommended for all children28 and should be performed with particular care in children with type 1 diabetes mellitus. Patient and parent education regarding the benefits of optimal metabolic control is also beneficial early in the course of the disease. IMPLEMENTATION The development of appropriate screening strategies for detecting DR in patients with type 1 diabetes mellitus is important, but guidelines are of little use if they are not implemented. Unfortunately, studies that evaluate this aspect of care have been discouraging. In a study by Witkin and Klein29 that included 902 young patients with type 1 diabetes mellitus, 26% had never had an ophthalmologic examination, including 11% of patients at high risk of visual loss. In an Australian study that was performed before and one year after distribution of ophthalmic screening guidelines, McCarty et al30 found that the guidelines had been distributed successfully, but there was no significant change in management practice. The usefulness of digital photography in detecting retinopathy has been demonstrated.31 This technology holds great promise but is unlikely to become widely used until it can be performed rapidly, simply, and at a reasonable cost. Studies that evaluate methods to improve implementation of guidelines could potentially provide great benefit to patients with type 1 diabetes mellitus. Section on Ophthalmology, 2003–2004 Steven J. Lichtenstein, MD, Chairperson Edward G. Buckley, MD George S. Ellis, Jr, MD Jane D. Kivlin, MD Gregg T. Lueder, MD James B. Ruben, MD Past Section Executive Committee Members Gary T. Denslow, MD, MPH, Immediate Past Chairperson Inger Hansen, MD Liaisons Kyle A. Arnoldi, CO American Association of Certified Orthoptists Thomas K. Koch, MD National Conference and Exhibition Planning Group Michael R. Redmond, MD American Academy of Ophthalmology Michael X. Repka, MD American Association for Pediatric Ophthalmology and Strabismus Staff S. Niccole Alexander, MPP Section on Endocrinology, 2003–2004 Janet Silverstein, MD, Chairperson Surendra Kumar Varma, MD, Chairperson-elect Stuart J. Brink, MD Kenneth C. Copeland, MD Francine R. Kaufman, MD Paul B. Kaplowitz, MD Robert P. Schwartz, MD, Immediate Past Chairperson Staff Laura Laskosz, MPH FOOTNOTES Lead authors REFERENCES The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329 :977 –986 The Diabetes Control and Complications Trial Research Group. Effect of intensive diabetes treatment on the development and progression of long-term complications in adolescents with insulin-dependent diabetes mellitus. J Pediatr. 1994;125 :177 –188 Daneman D, Drash AL, Lobes LA, Becker DJ, Baker LM, Travis LB. Progressive retinopathy with improved control in diabetic dwarfism (Mauriac's syndrome). Diabetes Care. 1981;4 :360 –365 Early worsening of diabetic retinopathy in the Diabetes Control and Complications Trial [published correction appears in Arch Ophthalmol. 1998;116:1469]. Arch Ophthalmol. 1998;116 :874 –886 The Kroc Collaborative Study Group. Diabetic retinopathy after two years of intensified insulin treatment. Follow-up of the Kroc Collaborative Study. JAMA. 1988;260 :37 –41 White NH, Cleary PA, Dahms W, Goldstein D, Malone J, Tamborlane WV. Beneficial effects of intensive therapy of diabetes during adolescence: outcomes after the conclusion of the Diabetes Control and Complications Trial (DCCT). J Pediatr. 2001;139 :804 –812 Writing Team for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy: the Epidemiology of Diabetes Interventions and Complications (EDIC) study. JAMA. 2003;290 :2159 –2167 The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. N Engl J Med. 2000;342 :381 –389 Early Treatment of Diabetic Retinopathy Study Research Group. Photocoagulation therapy for diabetic eye disease. JAMA. 1985;254 :3086 Photocoagulation treatment of proliferative diabetic retinopathy: the second report of diabetic retinopathy study findings. Ophthalmology. 1978;85 :82 –106 Wilkinson CP, Ferris FL III, Klein RE, et al. Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales. Ophthalmology. 2003;110 :1677 –1682 Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. The Wisconsin epidemiologic study of diabetic retinopathy. II. Prevalence and risk of diabetic retinopathy when age at diagnosis is less than 30 years. Arch Ophthalmol. 1984;102 :520 –526 Donaghue KC, Fairchild JM, Chan A, et al. Diabetes microvascular complications in prepubertal children. J Pediatr Endocrinol Metab. 1997;10 :579 –585 Holl RW, Lang GE, Grabert M, Heinze E, Lang GK, Debatin KM. Diabetic retinopathy in pediatric patients with type-1 diabetes: effect of diabetes duration, prepubertal and pubertal onset of diabetes, and metabolic control. J Pediatr. 1998;132 :790 –794 Verougstraete C, Toussaint D, De Schepper J, Haentjens M, Dorchy H. First microangiographic abnormalities in childhood diabetes—types of lesions. Graefes Arch Clin Exp Ophthalmol. 1991;229 :24 –32 Malone JI, Grizzard S, Espinoza LR, Achenbach KE, Van Cader TC. Risk factors for diabetic retinopathy in youth. Pediatrics. 1984;73 :756 –761 Klein R, Klein BE, Moss SE, Cruickshanks KJ. The Wisconsin Epidemiologic Study of Diabetic Retinopathy: XVII. The 14-year incidence and progression of diabetic retinopathy and associated risk factors in type 1 diabetes. Ophthalmology. 1998;105 :1801 –1815 Donaghue KC, Fung AT, Hing S, et al. The effect of prepubertal diabetes duration on diabetes. Microvascular complications in early and late adolescence. Diabetes Care. 1997;20 :77 –80 Rogers DG, White NH, Shalwitz RA, Palmberg P, Smith ME, Santiago JV. The effect of puberty on the development of early diabetic microvascular disease in insulin-dependent diabetes. Diabetes Res Clin Pract. 1987;3 :39 –44 Murphy RP, Nanda M, Plotnick L, Enger C, Vitale S, Patz A. The relationship of puberty to diabetic retinopathy. Arch Ophthalmol. 1990;108 :215 –218 Moloney JB, Drury MI. The effect of pregnancy on the natural course of diabetic retinopathy. Am J Ophthalmol. 1982;93 :745 –756 Klein BE, Moss SE, Klein R. Effect of pregnancy on progression of diabetic retinopathy. Diabetes Care. 1990;13 :34 –40 Effect of pregnancy on microvascular complications in the diabetes control and complications trial. The Diabetes Control and Complications Trial Research Group. Diabetes Care. 2000;23 :1084 –1091 Chew EY, Mills JL, Metzger BE, et al. Metabolic control and progression of retinopathy. The Diabetes in Early Pregnancy Study. National Institute of Child Health and Human Development Diabetes in Early Pregnancy Study. Diabetes Care. 1995;18 :631 –637 American Academy of Pediatrics, Section on Endocrinology and Section on Ophthalmology. Screening for retinopathy in the pediatric patient with type 1 diabetes mellitus. Pediatrics. 1998;101 :313 –314 American Diabetes Association. Diabetic retinopathy. Diabetes Care. 2002;25(suppl 1) :S90 –S93 American Academy of Pediatrics, Committee on Practice and Ambulatory Medicine, Section on Ophthalmology, American Association of Certified Orthoptists, American Association for Pediatric Ophthalmology and Strabismus, American Academy of Ophthalmology. Eye examination and vision screening in infants, children, and young adults. Pediatrics. 2003;111 :902 –907 Witkin SR, Klein R. Ophthalmologic care for persons with diabetes. JAMA. 1984;251 :2534 –2537 McCarty CA, Taylor KI, McKay R, Keeffe JE; Working Group on Evaluation of NHMRC Diabetic Retinopathy Guidelines. Diabetic retinopathy: effects of national guidelines on the referral, examination and treatment practices of ophthalmologists and optometrists. Clin Experiment Ophthalmol. 2001;29 :52 –58 Lin DY, Blumenkranz MS, Brothers RJ, Grosvenor DM. The sensitivity and specificity of single-field nonmydriatic monochromatic digital fundus photography with remote image interpretation for diabetic retinopathy screening: a comparison with ophthalmoscopy and standardized mydriatic color photography. Am J Ophthalmol. 2002;134 :204 –213...查看详细 (21160字节)

☉ 11333109:Model Contractual Language for Medical Necessity for Children
ABSTRACT The term "medical necessity" is used by Medicare and Medicaid and in insurance contracts to refer to medical services that are generally recognized as appropriate for the diagnosis, prevention, or treatment of disease and injury. There is no consensus on how to define and apply the term and the accompanying rules and regulations, and as a result there has been substantial variation in medical-necessity definitions and interpretations. With this policy statement, the American Academy of Pediatrics hopes to encourage insurers to adopt more consistent medical-necessity definitions that take into account the needs of children. Key Words: medical necessity medically necessary managed care contract INTRODUCTION The definition of "medical necessity" in this statement articulates model language that takes into account the unique needs of infants, children, adolescents, and young adults through 21 years of age. To the extent possible, this definition draws on model language developed by Stanford University.1 For contractual purposes, an intervention will be covered if it is an otherwise covered category of service, not specifically excluded, and medically necessary. DEFINITION Health insurers should define medical necessity as health interventions for children that take into account all of the following criteria. Scope of Health Problems Medically necessary health interventions are intended to promote normal growth and development and prevent, diagnose, detect, treat, ameliorate, or palliate the effects of a physical, mental, behavioral, genetic, or congenital condition, injury, or disability. They should: assist in achieving, maintaining, or restoring health and functional capabilities without discrimination to the nature of a congenital/developmental anomaly; be appropriate for the age and developmental status of the child; take into account the setting that is appropriate to the specific needs of the child and family; and reflect current bioethical standards. Evidence of Effectiveness Medically necessary interventions must be reasonably expected to produce the intended results for children and to have expected benefits that outweigh potential harmful effects. For new interventions, for which clinical trials have not been conducted, effectiveness should be determined on the basis of clinical judgment after assessing the professional standards of care for children or consensus pediatric expert medical opinion. For existing interventions, effectiveness for children should be determined first on the basis of scientific evidence. If insufficient scientific evidence for children is available, professional standards of care for children must be considered. If professional standards of care for children do not exist or are outdated or contradictory, decisions about existing interventions must be made on the basis of consensus pediatric expert opinion. Giving priority to scientific evidence does not mean that coverage of existing interventions should be denied in the absence of conclusive scientific evidence. Value Medically necessary interventions must consider value for children on the basis of effectiveness. Cost-effective does not necessarily mean lowest price. Process for Determining Medical Necessity The American Academy of Pediatrics recommends that health plans describe the processes by which physicians and other health care professionals provide justification for the medical necessity of health interventions that they prescribe or order. Descriptions of these processes should include: how to provide clinical evidence supporting coverage of interventions that meet the needs of the individual child; how to incorporate appropriate pediatric medical or surgical subspecialty or expert opinion or testimony supporting coverage of interventions; how to assist families or physicians who wish to appeal medical-necessity denials; and how and when coverage decisions will be made. Committee on Child Health Financing, 2004–2005 Thomas K. McInerny, MD, Chairperson Charles J. Barone, II, MD Anthony D. Johnson, MD Richard Lander, MD Richard Y. Mitsunaga, MD Mark S. Reuben, MD Corrine A. Walentik, MD Steven E. Wegner, MD, JD Mark J. Werner, MD, CPE Consultant Margaret McManus, MHS Ad Hoc Medical Necessity Working Group E. Stephen Edwards, MD, Chairperson Louis Z. Cooper, MD Jan Berger, MD Ted Kastner, MD Alan E. Kohrt, MD Margaret McManus, MHS Merle McPherson, MD, MPH Richard Mitsunaga, MD Cal Sia, MD Thomas K. McInerny, MD Staff Jean Davis, MPP FOOTNOTES Scientific evidence consists primarily of randomized, controlled clinical trials that either directly or indirectly demonstrate the effect of the intervention on health outcomes. If randomized, controlled clinical trials are not available, observational studies that demonstrate a causal relationship between the intervention and health outcomes can be used. Partially controlled observational studies and uncontrolled clinical series may be suggestive but do not by themselves demonstrate a causal relationship unless the magnitude of the effect observed exceeds anything that could be explained by either natural history of the medical condition or potential experimental biases. REFERENCE Integrated Health Care Association. Model Contractual Language for Medical Necessity. Palo Alto, CA: Center for Health Policy, Stanford University;2002 . Available at: www.iha.org/mnppmld.htm. Accessed January 12, 2005...查看详细 (5712字节)
☉ 11333110:Age related change of optokinetic nystagmus in healthy subjects: a study from infancy to senescence
1 Department of Ophthalmology, Kantonsspital, St Gallen, Switzerland 2 Department of Ophthalmology, University of Leicester, Leicester, UK ABSTRACT Background: Optokinetic nystagmus (OKN) gain is asymmetrical between temporal to nasal (TN) and nasal to temporal (NT) stimulation in infancy and decreases at older ages. The age at which OKN gain becomes symmetrical and decreases is debated. The aim was to investigate OKN over the whole lifespan in a large sample of healthy subjects. Methods: In a prospective, cross sectional study OKN was tested monocularly using TN and NT small field stimulation. Stimulation velocity was 15°/s and 30°/s for children aged under 1 year (n = 97), and 15°/s, 30°/s, 45°/s, and 60°/s for older subjects (1–9 years, n = 66; 10–89 years, n = 86). Gain was measured using infrared oculography. Results: Significant OKN gain asymmetry in favour of TN versus NT stimulation was found during the first 5 months of life (p4 weeks), low birth weight, ophthalmological, neurological or otological diseases, and abnormal binocular functions. Five subjects over 60 years were pseudophakic. Methods Generation of OKN OKN stimulation, eye movement recordings, and analysis were performed with vision monitor equipment (Metrovision, Perenchies, France). Visual stimuli were generated on a monitor measuring 51 cm diagonally placed 40 cm away from the patients (frame rate 120 Hz). The screen’s visual field was 54° horizontally and 41° vertically. OKN was elicited with alternate black (luminance <1 cd/m2) and white (luminance 70 cd/m2) vertical stripes of 2° visual angle (equivalent to a visual acuity of 20/2400). Stripes were presented monocularly to the right eye at constant velocities of 15°/s, 30°/s, 45°/s, or 60°/s either in TN or NT direction in random order, for 40 seconds with 2 minutes intervals between trials.22–24 Infants under 1 year were only investigated at velocities of 15°/s and 30°/s after attempts with higher velocities led to poor recordings. Subjects old enough to cooperate were instructed to look at the centre of the visual field to produce stare nystagmus without following the stripes. Eye movement recordings Eye movements were recorded by measuring the position of the corneal reflex with respect to the centre of the pupil with a near infrared illumination of the eye (880 nm). Sampling rate was 60 Hz with a resolution of 10 minutes of arc. Young children were placed in an infant car seat, older children and adults sat on a chair with their head stabilised on a chin headrest. Eye moment recordings were independent of head movements. Analysis and statistics Analysis of eye movements included the detection of OKN slow and fast phases and calculation of mean velocity of slow phases. The slope of the best fit regression line plotted across the sample points of the slow phases was used to estimate the velocity. Precision was no greater than 5%. The noise of the velocity measurement was approximately 0.3°/s RMS (company specifications). In young children, measurements were obtained from at least five consecutive slow phases. In cooperative subjects, the mean velocity of consecutive slow phases was measured 5 seconds after stimulus onset during a period of 10 seconds. The early OKN is dominant in humans and has a stable velocity after approximately 0.5 seconds.25 Accordingly, the OKN slow phases had reached a stable velocity over the time period analysed in our experiment. OKN gain analysis was carried out without knowledge of subjects’ age. ANOVA was performed to compare gains of different groups of age, and was corrected for multiple comparisons using Student-Newman-Keuls tests. To determine the number of subjects with asymmetrical OKN gain the mean TN gain and standard deviation for each age group was calculated. If the NT gain fell outside the plus or minus two standard deviations (95% confidence interval) it was considered asymmetrical. The percentage of subjects falling outside of these limits was determined for each month for the first year of life. RESULTS Examples of original recordings of OKN at five different ages are presented in figure 1. At 2 months of age the response for stimulation TN was clearly better than for stimulation NT. At older ages the TN/NT OKN responses were symmetrical. Figure 1 Original recordings of OKN for the right eye with stimulation at velocity of 30°/s from temporal to nasal (TN) (left) and from nasal to temporal (NT) (right) at 2 months (mean TN gain 0.66, mean NT gain 0.31), 1 year (mean TN gain 0.78, mean NT gain 0.73), 10 years (mean TN gain 0.82, mean NT gain 0.8), 20 years (mean TN gain 0.93, mean NT gain 0.92), and 80 years (mean TN gain 0.62, mean NT gain 0.58) of age. First year of age A significant asymmetry in favour of the stimulus TN versus NT was found during the first 5 months of life at velocities of 15°/s and 30°/s (p<0.05) (fig 2A). During the first year of life, OKN gain at velocity of 15°/s and 30°/s for stimulus TN was relatively stable with a range from 0.71 to 0.85, and 0.55 to 0.64, respectively. However, OKN gain for stimulus NT progressively increased with a range from 0.38 to 0.78 and 0.25 to 0.57 for 15°/s and 30°/s stimulation, leading to OKN symmetry after the fifth month of age. Symmetrical OKN developed earlier with slower stimulation (table 1). Symmetrical TN/NT OKN was obtained in all subjects at 10 months of age at 15°/s, and at 11 months at 30°/s. Figure 2 Mean values and standard errors of OKN gains of subjects under 1 year of age (15°/s and 30°/s) (A), between 1 and 9 years of age (B), and between 10 and 89 years of age (C) at stimulation velocities of 15°/s, 30°/s, 45°/s, and 60°/s. Number of examined subjects for each age group are indicated in italics on the X axis. Table 1 Number and percentage of subjects with symmetrical OKN for stimulation from temporal to nasal (TN) and from nasal to temporal (NT) at velocities of 15°/s and 30°/s during the first year of life During the first year of life, the OKN gain for stimuli TN and NT was significantly higher at velocity of 15°/s than at velocity of 30°/s (p<0.05). First decade The results of the changes in OKN gain for TN and NT stimuli at velocities of 15°/s, 30°/s, 45°/s, and 60°/s in 66 children aged between 1 and 9 are plotted in figure 2B. No TN/NT asymmetry was present. The mean gain appeared to increase with age between 1 year and 3 years for 15°/s (at 1 year: 0.84 for TN and 0.82 for NT; at 3 years: 0.94 for TN and 0.95 for NT), 30°/s (at 1 year: 0.74 for TN and 0. 72 for NT; at 3 years: 0.84 for TN and 0.83 for NT), and 45°/s (at 1 year: 0.57 for TN and 0.55 for NT; at 3 years: 0.68 for TN and 0.65 for NT). Above 3 years, the mean gain remained stable for these stimulus velocities. At 60°/s the mean gain appeared to remain unchanged during the first decade (at 1 year: 0.45 for TN and 0. 46 for NT; at 3 years: 0.44 for TN and 0.45 for NT). We tested whether a significant difference occurred in mean gains between 1–2 year olds and 3–9 year olds and found a significant difference for TN and NT stimulation at 15°/s (p<0.05) but not at other velocities. In the age group of 1–9 years, the OKN gain for stimuli TN and NT significantly diminished for each increase in stimulus velocity (p<0.05). 10–89 years Figure 2C shows OKN gains for TN and NT stimuli at the four velocities in the 86 subjects aged between 10 and 89 years. There was no TN/NT asymmetry. The OKN gain appeared to drop above the age of 50 years at all stimulus velocities. To test this we compared OKN gains for TN and NT stimulation of subjects 10–49 years old (n = 41) with subjects 50–89 years old (n = 45). A significant diminution in OKN gain was found in subjects between 50 and 89 years of age (n = 45) for all velocities (p<0.05). The decrease in gain between 10–49 years and 50–89 years was 7.5% and 6.5% for TN and NT stimuli at 15°/s; 15.4% and 15.4% for TN and NT stimuli at 30°/s; 17.1% and 16.5% for TN and NT stimuli at 45°/s; and 17.4% and 15.3% for TN and NT stimuli at 60°/s. All ages combined Figure 3 shows the change of TN and NT OKN gain for the velocities of 15°/s and 30°/s for all ages. They indicate that complete TN/NT symmetry is reached at approximately 1 year of age. OKN gain continues to increase during second and third years stabilising above 3 years of age and remaining stable until approximately 50 years of age significantly declining after this point (p<0.05). OKN gain for stimuli TN and NT was significantly lower in the infants under 1 year compared to older subjects (p<0.05). Figure 3 Mean values and standard errors of OKN gains of subjects over the whole age range with stimulation from temporal to nasal (TN) and from nasal to temporal (NT) at velocities of 15°/s (A) and 30°/s (B). DISCUSSION OKN symmetry Our results showed that OKN responses reached symmetry for TN and NT stimulation at the age of 6 months. However, OKN responses were only symmetrical in 100% of subjects at 10–11 months of age, becoming earlier symmetrical with slower stimulus velocity. The development of OKN symmetry resulted from the increase of NT gains, whereas TN gains remained stable during the first year of life. Different times of appearance of TN/NT symmetry in infants have been described in the literature. Studies based on observation of eye movements found symmetrical OKN at 3 months,4,5 5–6 months,6 12 months,7 or 24 months.8 Studies based on electro-oculography found a symmetrical OKN at 3 months,9 5–6 months,10or later than 7 months.11 In these studies, different stimulus velocities—for example, as low as 12°/s and up to 92°/s,4,6,7,8,9,10,11 were used, partly explaining the variation in the results. In agreement with our results, most studies found that higher velocity stimuli led to later achievement of symmetry. The development of OKN symmetry might also vary with the size of the stimulation field or size and contrast of stripes. For children under 1 year, our method allowed accurate analysis of OKN records at 15°/s and 30°/s, whereas 45°/s and 60°/s gave poor results. This may be explained by the use of small field stimulation in contrast with most other studies. Development of the fovea in infancy26 is unlikely to have a major role in OKN asymmetries since occlusion of the fovea or age related macula degeneration do not cause asymmetrical OKN.22,27 Conversely, dominant eyes of adult amblyopic subjects with a presumably normal fovea28 often show asymmetrical OKN. Development of symmetrical OKN in infants reflects probably maturation of projections from the retina through the visual cortex to the pretectum.13,29 The direct pathway from the retina to the contralateral nucleus of the optic tract (NOT) and the dorsal terminal nucleus (DTN) is present at birth, and can mediate TN OKN response in the cat.30 The indirect pathway from the retina through the ipsilateral visual cortex to the ipsilateral NOT-DTN is necessary to mediate NT OKN response, and develops later in life leading to the initial OKN asymmetry.31 If normal visual development is disrupted by unequal visual input from both eyes (that is, strabismus) OKN asymmetry can persist.32,33 Age related change of OKN gain We have shown that before 12 months of age, TN and NT responses were not adult-like. This is in agreement with Lewis13 who found that 6 month olds showed significantly less OKN than adults in either direction. We also found that for slower velocities (15°/s) OKN gain continues to significantly increase during the second and third years, while only a non-significant OKN gain increase was observed for faster velocities. This difference in significance is probably because of the lower variation of OKN gain at 15°/s (note lower standard errors on figures 2B and C) than at 30°/s. Increase in OKN gain during the first decade may partly be due to cortical maturation,34 and possibly caused by improving attention to stimulation. There is agreement in the literature that ageing decreases OKN gain; however, the age at which OKN gain starts to diminish is controversial. We showed a small but significant OKN gain; reduction for TN and NT stimuli at all tested velocities after 50 years of age. In the literature, most studies compare a population of young and older subjects without reporting the continuous change of the OKN response with ageing.2,15–19 Ura et al16 found a decrease in OKN gain between normal subjects comparing mean ages of 80–30 years. Baloh et al15 reported lower slow phase velocity saturation in normal subjects over 75 years of age compared to younger subjects. Simons and Büttner17 found that OKN maximum velocity decreased considerably with age in control groups after 40 years of age. They also found that maximal smooth pursuit gain and optokinetic after nystagmus (OKAN) was reduced in older age groups. They concluded that both the early component of OKN (related to smooth pursuit) and delayed component (the velocity storage component related to OKAN) were affected in older age. One of the largest series examining the OKN found, in agreement with our results, a decrease of OKN after 50 years of age.20 However, Ura et al16 did not find significant OKN gain differences in elderly subjects with or without vertigo. A possible reason was that only small groups of subjects were investigated and that the normal elderly control group was on average almost a decade older than patients. In our study the standard errors were similar for each age group, and therefore, we cannot confirm the wider variation of OKN response in the elderly.14 In agreement with Magnusson and Pyykk?35 we found no OKN asymmetry with ageing. As well as OKN gain, other oculomotor functions such as upgaze, saccadic latency, antisaccadic tasks, smooth pursuit, and vestibulo-ocular responses are reduced with ageing.12 While brainstem oculomotor structures are remarkably unaffected by ageing, neuroanatomical changes have been reported for vestibular nuclei, the cerebellum, and cortex in senescence.12 A decrease in cerebellar or cortical neuronal numbers and/or synapses could, therefore, explain reduced OKN gain with ageing. Changes in oculomotor functions could be used to investigate the effect of ageing on structures above the brainstem level. In summary, to our knowledge, we have performed the first extensive study of OKN evolution in healthy subjects between 18 days and 89 years of age. We found symmetrical OKN responses in infants at 6 months of age. However, only at 11 months of age did 100% of the subjects have symmetrical OKN using higher stimulus velocity. We have shown for the first time that OKN gain increases until the age of 3 years, remains unchanged until 50 years of age, and decreases later in life. REFERENCES Westheimer G , McKee S. Visual acuity in the presence of retinal-image motion. J Opt Soc Am 1979;65:847–50. Yee R , Baloh R, Honrubia V. Pathophysiology of optokinetic nystagmus. In: Honrubia V, Brazier M, eds. Nystagmus and vertigo. London: Academic Press, 1982:251–75. Teller D , Succop A, Mar C. Infant eye movement asymmetries: stationary counterphase gratings elicit temporal-to-nasal optokinetic nystagmus in two-month-old infants under monocular test conditions. Vis Res 1993;33:1859–64. Atkinson J , Bradick O. Development of optokinetik nystagmus in infants: an indicator of cortical binocularity? In: Fisher D, Monty R, Senders J, eds. Eye movements: cognition and visual perception. Hilldale, NJ: Laurence Erlbaum Associates, 1981:53–64. van Hof-van Duin J , Mohn G. Vision in the preterm infant. In: Prechtl H, ed. Continuity of neural functions from prenatal to postnatal life. Philadelphia: Lippincott, 1984:93–114. Roy M , Lachapelle P, Lepore F. Maturation of the optokinetic nystagmus as a function of the speed of stimulation in fullterm and preterm infants. Clin Vis Sci 1989;4:357–66. Lewis T , Maurer D, Holmes R. The development of OKN acuity for nasalward versus temporalward motion. Invest Ophthalmol Vis Sci 1991;32:961. Lewis T , Maurer D, Chung J, et al. The development of symmetrical OKN in infants: quantification based on OKN acuity for nasalward versus temporalward motion. Vis Res 2000;40:445–53. Mohn G . The development of binocular and monocular optokinetic nystagmus in infants. Invest Ophthalmol Vis Sci 1989;40:49. Naegele J , Held R. The post-natal development of monocular optokinetic nystagmus in infants. Vis Res 1982;22:341–6. Harris C , Jacobs M, Taylor D. The development of bi-ocular and monocular optokinetic gain from 1 to 7 months. Invest Ophthalmol Visual Sci 1994;35:1829. Katsanis J , Iacono W, Harris M. Development of ocular functioning in preadolescence, adolescence, and adulthood. Psychophysiology 1998;35:64–72. Lewis T , Maurer D, Smith R. The development of symmetrical optokinetic nystagmus during infancy. Clin Vis Sci 1992;7:211–18. Hajioff D , Barr-Hamilton R, Colledge N, et al. Re-evaluation of normative electronystagmographic data in healthy aging. Clin Otolaryngol 2000;25:249–52. Baloh R , Jacobson K, Socotch T. The effect of aging on visual-vestibulo-ocular responses. Exp Brain Res 1993;95:509–16. Ura M , Pfaltz C, Allum J. The effect of age on the visuo- and vestibulo-ocular reflexes of elderly patients with vertigo. Acta Otolaryngol 1991;481:399–402. Simons B , Büttner U. The influence of age on optokinetic nystagmus. Eur Arch Psychiatr Neurol Sci 1985;234:369–73. Kato I , Ishikawa M, Nakamura T. Quantitative assessment of influence of aging on optokinetic nystagmus. Acta Otolaryngol 1994;511:99–103. Matheson A , Darlington C, Smith P. Age-related changes in human optokinetic function. Neuroreport 1998;9:2175–7. Chiba Y , Furuya N. Aging and reference values of the parameters in optokinetic nystagmus. Nippon Jibiinkoka Gabbai Kaiho 1989;92:1416–23. Mayer D , Beiser A, Warner A, et al. Monocular acuity norms for the Teller Acuity Cards between ages one month and four years. Invest Ophthalmol Vis Sci 1995;36:671–85. Valmaggia C , Charlier J, Gottlob I. Optokinetic nystagmus in patients with central scotomas in age-related macular degeneration. Br J Ophthalmol 2001;85:169–72. Valmaggia C , Gottlob I. Optokinetic nystagmus elicited by filling-in in adults with central scotomas. Invest Ophthalmol Vis Sci 2002;43:1804–8. Valmaggia C , Proudlock F, Gottlob I. Optokinetic nystagmus in strabismus: are asymmetries related to binocularity? Invest Ophthalmol Vis Sci 2003;44:5142–50. Garbutt S , Harris C. A review of optokinetic nystagmus (OKN) in infants and children. Br Orthopt J 1999;56:1–10. Yuodelis C , Hendrickson A. A qualitative analysis of the human fovea during development. Vis Res 1986;26:847–55. Abadi R , Pantazidou M, Monocular optokinetic nystagmus in humans with age-related macular maculopathy. Br J Ophthalmol 1997;81:123–9. Schor C . Subcortical binocular suppression affects the development of latent and optokinetic nystagmus. Am J Optom Physiol Opt 1983;60:481–502. Hoffmann K . Visual inputs relevant for the optokinetic nystagmus in mammals. Prog Brain Res 1986;64:75–84. Hoffmann K . Cortical versus subcortical contribution to the optokinetic reflex in the cat. In: Zee D, Keller E, eds. Functional basis of ocular motility disorders. New York: Pergamon Press, 1982:303–11. Simson J , Giolli R, Blanks R. The pretectal nuclear complex and the accessory optic system. In: Buttner-Ennever J, ed. Neuroanatomy of the oculomotor system. New York: Elsevier, 1988:335–64. Maurer D , Lewis T, Brent H. Peripheral vision and optokinetic nystagmus in children with unilateral congenital cataract. Behav Brain Res 1983;10:151–61. Westall C , Schor C. Asymmetries of optokinetic nystagmus in amblyopia: the effect of selected retinal stimulation. Vis Res 1985;25:1431–8. Niessen F , Montezer N. The development of visual function. Arch Pediatr 2002;9:1189–94. Magnusson M , Pyykk? I. Velocity and asymmetry of optokinetic nystagmus in evaluation of vestibular lesions. Acta Otolaryngol 1986;102:65–74....查看详细 (23590字节)
☉ 11333111:Pediatric Care Recommendations for Freestanding Urgent Care Facilities
ABSTRACT Freestanding urgent care centers are not emergency departments or medical homes, yet they are sometimes used as a source of pediatric care. The purpose of this policy statement is to provide updated and expanded recommendations for ensuring appropriate stabilization in pediatric emergency situations and timely and appropriate transfer to a hospital for definitive care when necessary. Key Words: urgent care equipment standards emergency preparedness pediatric preparedness Freestanding urgent care facilities remain a fixture in the provision of health services for children in some communities. Although the American Academy of Pediatrics does not encourage the routine use of urgent care facilities because it may undermine the provision of coordinated, comprehensive, family-centered care consistent with the medical home concept,1 the use of these facilities as part of urgent and emergent care systems is not uncommon. The term "urgent care" may imply to the public that a facility is capable of managing critical or life-threatening emergencies. This was the case for the youngest victim of the sniper in the Washington, DC, area on October 7, 2002. After being shot in the abdomen, despite the advice of the 911 operator to stay and wait for help, this 13-year-old child was driven to a local freestanding urgent care center.2 He survived because this freestanding urgent care center was properly equipped and staffed to handle this child's initial stabilization and transfer to a level I pediatric trauma center. Freestanding urgent care centers are not emergency departments. However, they must have the capability to identify patients with emergency conditions, stabilize them, and coordinate timely access to definitive care. These facilities must have appropriate pediatric equipment and experienced staff trained to provide critical support for ill and injured children until transferred for definitive care. It is necessary for freestanding urgent care facilities to have prearranged access to comprehensive pediatric emergency services through transfer and transport agreements. Available modes of transport should be identified in advance and be appropriate for the acuity of illness of the child. If freestanding urgent care facilities are to be used as a resource for pediatric urgent care, they should first solicit help from the pediatric professional community to define expectations and levels of plans for pediatric consultation. Pediatricians who are prepared to assist in the stabilization and management of critically ill and injured children should be accessible. Pediatricians should be certain that freestanding urgent care centers are prepared to stabilize and transfer critically ill and injured children before they are recommended to their patients and families for after-hours use. RECOMMENDATIONS Freestanding Urgent Care Facility Emergency Preparedness Administrators at freestanding urgent care facilities should ensure that their staff is capable of providing resuscitation, stabilization, timely triage, and appropriate transfer of all pediatric patients. Although the minimum standards for drugs, equipment, and supplies are listed in Tables 1 and 2, freestanding urgent care facilities with emergency medical systems response times of >10 minutes and transport times of >20 minutes to an emergency department need to have all suggested equipment, resuscitation drugs, and supplies as detailed in "Care of Children in the Emergency Department: Guidelines for Preparedness," issued jointly by the American Academy of Pediatrics and American College of Emergency Physicians.3 Freestanding urgent care facilities that provide care for children must be staffed by physicians, nurses, and ancillary health care professionals with the certification, experience, and skills necessary for pediatric basic and advanced life support during all hours of operation. Triage, transfer, and transport agreements should be prearranged with definitive care facilities that are capable of providing the appropriate level of care based on the acuity of illness or injury of the child.4 Mechanisms for notifying the primary care physician or another on-call health care professional about the treatment given to ensure appropriate follow-up with the child's medical home should be in place and should be compliant with the regulations of the Health Insurance Portability and Accountability Act (HIPAA) (Pub L No. 101-191 [1996]). If a primary care physician is not identified, efforts should be made to refer the patient to a pediatrician able to promote a medical home environment. Administrators at freestanding urgent care facilities must ensure that there is an organized and structured quality-improvement program to monitor and improve care for ill or injured children. Freestanding urgent care facilities should have in place and should monitor compliance with policies, procedures, and protocols for emergency care of children consistent with those listed in "Care of Children in the Emergency Department: Guidelines for Preparedness."3 Freestanding urgent care facilities should have a policy for disaster preparedness and participate in their community disaster plan.5 Pediatrician's Role in Freestanding Urgent Care Facilities Pediatricians should refer patients for after-hours care only to freestanding urgent care facilities that have the capability to identify patients with emergency conditions, stabilize them, and arrange transfer for definitive care. When referring a patient, the pediatrician should provide to the freestanding urgent care facility necessary clinical information and be available to provide consultation. If freestanding urgent care centers are staffed and equipped properly and have appropriate triage, transfer, and transport guidelines, the safety of children using these services for emergencies can be protected.6 Committee on Pediatric Emergency Medicine, 2004–2005 Stephen E. Krug, MD, Chairperson Thomas Bojko, MD Margaret A. Dolan, MD Karen S. Frush, MD Patricia J. O'Malley, MD Robert E. Sapien, MD Kathy N. Shaw, MD, MCSE Joan E. Shook, MD, MBA Paul E. Sirbaugh, DO Loren G. Yamamoto, MD, MPH Past Committee Members Jane Knapp, MD, Past Chairperson Ronald A. Furnival, MD Daniel J. Isaacman, MD Liaisons Jane Ball, RN, DrPH EMSC National Resource Center Kathleen Brown, MD National Association of EMS Physicians Dan Kavanaugh, MSW Maternal and Child Health Bureau Sharon E. Mace, MD American College of Emergency Physicians David W. Tuggle, MD American College of Surgeons Staff Susan Tellez FOOTNOTES Lead author REFERENCES American Academy of Pediatrics, Medical Home Initiatives for Children With Special Health Care Needs Project Advisory Committee. The medical home. Pediatrics. 2002;110 :184 –186 Jones T. Speed and skill saved boy: first "golden" hour made the difference, doctors say. Washington Post. October 17, 2002; A01 American Academy of Pediatrics, American Academy of Pediatrics, Committee on Pediatric Emergency Medicine and American College of Emergency Physicians, and Pediatric Committee. Care of children in the emergency department: guidelines for preparedness. Pediatrics. 2001;107 :777 –781 American Academy of Pediatrics, Committee on Pediatric Emergency Medicine, and American College of Critical Care Medicine/Society of Critical Care Medicine, Pediatric Section/Task Force on Regionalization of Pediatric Critical Care. Consensus report for regionalization of services for critically ill or injured children. Pediatrics. 2000;105 :152 –155 American Academy of Pediatrics, Committee on Pediatric Emergency Medicine. The pediatrician's role in disaster preparedness. Pediatrics. 1997;99 :130 –133 Zimmerman DR, Applebaum D. Quality of pediatric care at a freestanding emergency facility. Pediatr Emerg Care. 1992;8 :265 –267...查看详细 (8123字节)
☉ 11333112:Acute orbital effects of retrobulbar injection on optic nerve head topography
Akdeniz University, School of Medicine, Department of Ophthalmology, Antalya-Turkey ABSTRACT Aim: To assess the effects of acute orbital volume changes after retrobulbar injection on optic nerve head topography. Methods: The study population consisted of 95 patients with type 2 diabetes mellitus with clinically significant macular oedema who required focal pattern laser photocoagulation therapy in one eye. Before each laser treatment, 49 patients required a retrobulbar injection (approximately 7 ml of a mix of lidocaine 2% with epinephrine and bupivacaine 0.75% in equal volumes) to provide ocular akinesia. Both eyes of all patients underwent optic nerve head topographic analysis once before laser treatment (within 30 minutes), and repeated within 1 hour, 1 day, 1 week, 2 weeks, and 4 weeks after treatment, respectively. Topographic analyses were performed using a confocal scanning laser ophthalmoscope, HRT-II. The disc area, topography standard deviation, and a total of 12 topographic parameters were calculated by HRT-II. Results: The mean age of the patients was 37.9 (SD 3.2) years. The mean disc area of the subjects was 2.12 (0.44) mm2. Fellow eyes which were not treated with laser, and those treated eyes which did not receive retrobulbar injection before therapy were found not to reveal significant changes in disc topography in any of the examinations (all p values >0.05). In the topographic examinations in the first hour, first day, and first week, laser treated eyes which underwent retrobulbar injection demonstrated significant increase in the disc area, rim area, rim volume, rim area/disc area, and cup shape measure parameters while optic cup parameters significantly decreased (all p values 0.05). By the fourth week, all of the optic nerve head topographic variables were not significantly different from the pre-injection values (all p values >0.05). Colour stereoscopic photographs did not reveal any differences in optic disc appearance. Conclusion: Acute orbital volume change following retrobulbar injection may cause significant topographic evidence of optic disc oedema lasting approximately 1 week. Significant changes in optic rim and cup area may last for 2 weeks after injection, with all topographic changes returning to baseline by 1 month after injection. The present findings could be a model to reflect the pathological processes that occur in cases of acute orbital volume changes such as retrobulbar haemorrhage. Abbreviations: CSMO, clinically significant macular oedema; HRT, Heidelberg retinal tomography Keywords: retrobulbar injection; focal laser photocoagulation; optic nerve head topography; confocal scanning laser ophthalmoscope Changes in the optic nerve head topography occurring with chronic intraocular pressure increase have been extensively studied.1,2 Optic nerve head topography obtained with confocal scanning laser ophthalmoscopes was used to detect glaucomatous changes many years before functional visual field changes.3,4 However, studies evaluating the changes in the optic nerve head topography caused by acute intraorbital pressure increase have been lacking. Bleeding such as retrobulbar haemorrhage into the intraorbital space may cause acute visual loss by compressing the optic nerve and its vascular supply.5 The emergent need for intervention (for example, lateral tarsorrhaphy and administration of intraocular pressure lowering agents) as well as the retrospective nature of most case series limits the ability to determine accurately the morphological effect of retrobulbar fluid on optic disc structure. In the current study, we attempted to evaluate how acute orbital volume increase following retrobulbar injection affected optic nerve head topography during a 4 week period. MATERIAL AND METHODS Both eyes from a series of 95 of 263 consecutive patients with clinically significant macular oedema (CSMO) who required focal laser photocoagulation therapy in one eye were enrolled in the study. Informed consent was obtained from each participant. The institutional review board approved the study. Patients were excluded for any of the following criteria: (1) best corrected visual acuity less than 20/60, (2) any corneal or lens opacities, (3) history of ocular hypertension or glaucoma, a family history of glaucoma, (4) intraocular pressure readings greater than 22 mm Hg, (5) optic disc areas outside the range of 2–2.25 mm2, (6) any evidence of strabismus, or failure to maintain central fixation in any of examinations, (7) a history of any ocular trauma, surgery, laser therapy, or retinal disease other than diabetic maculopathy with or without mild non-proliferative retinopathy, (8) more than 1 dioptre of cylindrical and 5 dioptres of spherical refractive error, (9) those with dyschromatopsia, (10) age more than 50 years, (11) proptosis, and (12) anioscoria. All patients were treated with focal argon green laser photocoagulaton, in a single session, according to ETDRS guidelines (including ETDRS indications for follow up treatment).6 Laser treated eyes (n = 95) of all patients had CSMO as defined by the ETDRS,6 with no or mild7 non-proliferative background diabetic retinopathy findings. Fellow non-treated eyes (n = 95) of all patients had no or mild7 non-proliferative background diabetic retinopathy findings with mild macular oedema which was not clinically significant.6 Fluorescein fundus angiography was performed in all patients using 5 ml of 10% fluorescein injected intravenously. All laser treated eyes had an exudative type of maculopathy and good capillary perfusion. All patients had type 2 diabetes with relatively short disease duration (range 3–8 years duration). All but 11 patients (six in injection, and five in non-injection group), had good metabolic control with blood glucose levels within normal limits. Cooperation of the patients in the injection group was not ideal to apply focal laser photocoagulation without the addition of the retrobulbar anaesthesia. Before anaesthesia and laser treatment, we evaluated the best corrected visual acuity using Snellen charts, determined refractive error, performed biomicroscopic examination, measured intraocular pressure by Goldmann applanation tonometry twice, and examined the optic disc and fundus with a 78 D lens. Keratometry was performed for all subjects. Standard achromatic visual field testing was performed (Humphrey Instruments Inc, Model 750, San Leandro, CA, USA) using full threshold strategy and the central 30-2 program. All subjects underwent perimetric examinations at least twice. Colour vision testing was performed using the Ishihara colour plates. Hertel exophthalmometric measurements were performed in cases that were suspected of having proptosis. Colour optic nerve head photographs were taken at each topographic examination with a Topcon Imagenet-2000 fundus camera. The pupils were dilated for laser treatment with phenylephrine HCl 2.5% and cyclopentolate HCl 1% drops, applied three times during a 30 minute period. All patients had a pupil diameter greater than 8 mm. Both eyes of all of the patients, whether laser treated or not, had all topographic exams performed under maximum pupillary dilatation. Both eyes of all patients underwent optic nerve head topographic examinations within 30 minutes of laser treatment. All fellow non-treated eyes received neither laser treatment nor retrobulbar injection. They underwent the same optic nerve head topographic examinations. Each patient, within 60 minutes of finishing his/her focal argon blue-green photocoagulation therapy, had the topographic examinations repeated by the same experienced observer (YA). Focal pattern laser procedures were performed with 38–61 argon blue-green 100 μm laser spots, with a power of 100 mW each. All focal argon green photocoagulation treatments were performed by one experienced ophthalmic laser surgeon (YA). Before the focal laser treatments, 49 patients required a retrobulbar anaesthesia block (using a 1:1 mixture of 0.75% bupivacaine and 2% lidocaine with hyaluronidase 0–7.5 IU/ml in equal volumes to a total of 7 ml). Within 5 minutes of the block, extraocular movements of these eyes were satisfactorily restricted in all fields of gaze. None of the subjects had oedema or ecchymosis of the eyelids. The optic nerve head analysis of all eyes was performed using a scanning laser ophthalmoscope, HRT II (Heidelberg retinal tomography II, software version 1.5, Heidelberg Engineering, Heidelberg, Germany). All images were acquired using 15° field of view. The region of interest in the mean topographic images was defined by a contour line, drawn by the same operator (YA) by determining 6–8 separate points to approximate the best margin of the optic disc (inner edge of Elschnig’s scleral ring).8 Magnification error was corrected using keratometry values for each individual. The topography standard deviation, disc area (mm2), and a total of 12 stereometric parameters are calculated with HRT II. The parameters were cup area (mm2), rim area (mm2), cup volume (mm3), rim volume (mm3), cup/disc area ratio, linear cup/disc ratio, mean cup depth (mm), maximum cup depth (mm), cup shape measure, height variation contour (mm), mean retinal nerve fibre layer thickness (mm), and retinal nerve fibre layer cross sectional area (mm2). Statistical analysis of the study was performed using Student’s t test, repeated measures of analysis of variance and descriptive statistics. Statistical significance was set as p0.05). Their mean refractive errors were –0.63 (1.01) D (range –4.25 D to +2.75 D) and 0.52 (0.93) D (range –4.00 D to +3.00 D), respectively (p>0.05). Their mean durations of diabetes were 4.9 (1.7) years and 5.3 (1.6) years (p>0.05). Their mean disc areas were 2.13 (0.45) mm2 and 2.11 (0.42) mm2, respectively (p>0.05). A total of one, two, four, seven, and 12 laser treated patients with retrobulbar anaesthesia, and a total of three, four, seven, nine, and 11 laser treated patients without retrobulbar anaesthesia were lost to follow up in the first hour study, first day, the first week, the second week, and the fourth week examinations, respectively. All eyes which were treated with laser without retrobulbar anaesthesia, and all fellow eyes which received neither laser nor retrobulbar anaesthesia, were found not to reveal any significant changes in any of the optic nerve head topographic examination during the 4 week study period (all p values >0.05). Those eyes that underwent laser treatment after retrobulbar anaesthesia (n:49) demonstrated significant increase in the disc area, rim area, rim volume, rim area/disc area and cup shape measure parameters, while they demonstrated significant decrease in linear cup to disc ratio, cup area/disc area, cup area and cup volume parameters in the first hour, first day and the first week topographic examinations, (all p values 0.05) (table 2). However, there were statistically significant differences in rim area, cup area, and cup shape measurements from baseline (table 2). By the fourth week, all of the optic nerve head topographic variables were not significantly different from the pre-injection values (table 2). Table 1 Changes in optic nerve head topography of laser treated eyes 1 hour, 1 day, and 1 week after retrobulbar anaesthetic injection Table 2 Changes in optic nerve head topography of laser treated eyes 2 weeks and 4 weeks after retrobulbar anaesthetic injection None of the patients received additional retinal laser therapy during the study period. By the end of the fourth week, six (in injection group) and seven (in non-injection group) patients demonstrated some degree of improvement in macular oedema ophthalmoscopically with significant increases in visual acuity. There were no visually detectable changes in clinically significant macular oedema in the rest of the patients, and no significant change in visual acuity. No patient developed any laser related complication or optic neuropathy after focal laser treatment. Representative colour optic nerve head photographs of multiple examination points for all patients were evaluated by two experienced examiners (masked to the cases). No evidence of optic nerve head oedema or blurring of the disc margins was noted in any of them. The eyes that underwent laser treatment with retrobulbar anaesthesia demonstrated a significant change in intraocular pressure, with a mean increase of 6.7 mm Hg, 1 hour after retrobulbar injection (p0.05). The rest of the eyes in the study did not show any significant changes in intraocular pressure in any of the examination points (all p values, >0.05). DISCUSSION The visual loss after retrobulbar haemorrhage has been attributed to the acute compression of the optic nerve by the haemorrhage, or optic neuropathy caused by the direct effect of blood degrading products on the optic nerve.9 Here, we studied the effects of acute orbital volume increase by retrobulbar anaesthetic injection on optic nerve head topography during a 4 week period. We enrolled diabetic patients who did or did not undergo retrobulbar anaesthetic injection for anaesthesia during focal pattern retinal photocoagulation. The current study was designed to simulate a model of optic nerve head effects following mild acute intraorbital volume increase. We found that acute volume change in the orbit caused by a retrobulbar injection of as much as 7 ml anaesthetic can potentially lead to a small, clinically not detected and reversible disc oedema. Significant changes in optic rim and cup area may last for 2 weeks after injection, with all topographic changes returning to baseline by 1 month after injection. Regional orbital anaesthesia has been associated with acute haemodynamic changes, including reduction in blood flow velocity, increased resistive index in the central retinal artery,10 and decreased ocular perfusion.11 Loken et al reported that electroretinogram is significantly reduced and delayed in patients during regional anaesthesia of the orbit.12 During the first 2 weeks after injection, laser treated eyes which received retrobulbar injection demonstrated significant increase in the rim area, rim area/disc area, and rim volume parameters while they showed significant decrease in optic cup parameters. Changes in rim and optic cup parameters may result from the temporary optic disc oedema. However, significant changes in these parameters lasted for one additional week after the optic disc area normalised. Beside the optic cup and rim parameters, none of the other optic nerve head topographic parameters (other than cup shape measure) was significantly affected by the retrobulbar injection. Topouzis et al, in their HRT study on 25 glaucomatous patients undergoing trabeculectomy, showed that changes in the optic disc that may be present 2 weeks after a trabeculectomy do not appear to persist up to 4 months later, other than cup shape measure, which was still different from preoperative values at 4 months but not at 8 months.13 Durukan et al, in their study on normal population using HRT II, found that cup shape measure was the only topographic parameter which is not associated with disc area, age, sex, laterality, refractive error, and any other topographic parameter.8 Meyer et al claimed that the presence of 10.5 ml of fluid in the retrobulbar and peribulbar space did not significantly affect the IOP of the anaesthetised eye.10 In the current study, each laser treated patient who required retrobulbar block for ocular akinesia, received a volume of 7 ml retrobulbar anaesthetic injection including lidocaine HCl 2% with adrenaline (epinephrine) and bupivacaine 0.75% in equal volumes. Immediately after retrobulbar injection, we found that the intraocular pressure increased significantly with a mean change of 6.7 mm Hg. Jay et al reported a mean increase in intraocular pressure of 4.4 mm Hg soon after completion of retrobulbar injection.14 Palay and Stulting found an average rise in intraocular pressure of 6.2 mm Hg after retrobulbar injection of 4 ml of anaesthetic.15 None of our patients had an intraocular pressure measuring more than 25 mm Hg immediately after the injection. Following retrobulbar haematoma, visual loss can be detected even in cases with intact retinal circulation.16 In these cases, visual loss can be explained from optic nerve ischaemia. Occlusion of the short posterior ciliary artery may result in optic nerve infarction.16 However, ophthalmoscopic examination performed immediately after our injections failed to reveal any retinal or vascular complication in any of the cases. Therefore, we speculate that any difference in optic nerve head topography most likely resulted from the effects of the anaesthetic agent on intraorbital volume. We applied focal laser application to the microaneurysms temporal to the fovea. Previous studies reported the effect of focal laser on retinal thickness and visual field. But these are relatively minor, and occur late.17–19 Shahidi et al, using optical coherence tomography, showed that retinal thickness decreased in 50% and remained unchanged in 36% of thickened locations 4 months after treatment, and new areas of thickening developed in 3% of the locations.17 Sims et al suggested that focal photocoagulation treatment produced small absolute scotomas in the treated regions of the visual field based on the statistically significant increase in the mean deviation compared to the untreated region of the field.19 However, threshold changes were small, less than 4 dB, and whole fields appeared essentially unchanged.19 In the current study, we found that laser treated eyes, which did not receive retrobulbar injection, and fellow eyes, which did not receive either laser or retrobulbar anaesthesia, did not demonstrate any significant changes in optic nerve head topography. Therefore, we speculate that changes seen in optic nerve head topography in the current study most probably resulted from the volume effect of retrobulbar anaesthesia rather than focal laser photocoagulation treatment. Owing to the limited capacity for expansion, increased volume because of haemorrhage results in increased pressure and compression of contained structures.5 The optic nerve may be compressed directly, or the vascular supply to the nerve may be compromised.5 We injected 7 ml of retrobulbar anaesthetic solution in 49 patients who required retrobulbar block.. Total volume of the orbital contents varied between 23.6 ml to 27.1 ml.20,21 The mean volume of the globe was found to be 7 ml for females and 7.5 ml for males.22 The present study demonstrates that an increase in orbital volume of 7 ml may potentially cause subclinical optic disc oedema. This finding may give some insight as to what happens after a mild retrobulbar haemorrhage following trauma. In summary, optic nerve head topographic changes seen in eyes which underwent focal laser photocoagulation treatment after receiving retrobulbar block seems to result from the retrobulbar block rather than laser treatment itself. Acute collection of even less fluid confined in the retrobulbar space may cause significant optic disc oedema together with significant changes in optic rim and cup parameters of the optic nerve head. These should be taken into consideration in the clinical evaluation, treatment, and follow up of patients who underwent orbital trauma with retrobulbar haemorrhage. ACKNOWLEDGEMENTS This study was supported by Akdeniz University Scientific Research Projects Unit. REFERENCES Wollstein G , Garway-Heath DF, Hitchings RA. Identification of early glaucoma cases with the scanning laser ophthalmoscope. Ophthalmology 1998;105:1557–63. Iester M , Mikelberg FS. Optic nerve head morphologic characteristics in high-tension and normal-tension glaucoma. Arch Ophthalmol 1999;117:1010–13. Caprioli J . Clinical evaluation of the optic nerve in glaucoma. Trans Am Ophthalmol Soc 1994;92:589–641. Quigley HA, Katz J, Derick RJ, et al. An evaluation of optic disc and nerve fiber layer examinations in monitoring progression of early glaucoma damage. Ophthalmology 1992;99:19–28. Vassallo S , Hartstein M, Howard D, et al. Traumatic retrobulbar hemorrhage: emergent decompression by lateral canthotomy and cantholysis. J Emerg Med 2002;22:251–6. Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Arch Ophthalmol 1985;103:1796–806. Lobo CL, Bernardes RC, de Abreu JR, et al. One-year follow-up of blood-retinal barrier and retinal thickness alterations in patients with type 2 diabetes mellitus and mild nonproliferative retinopathy. Arch Ophthalmol 2001;119:1469–74. Durukan AH, Yucel I, Akar Y, et al. The assessment of the optic nerve head topographic parameters with a confocal scanning laser ophthalmoscope. Clin Experiment Ophthalmol 2004;32:143–9. Mahaffey PJ, Wallace AF. Blindness following cosmetic blepharoplasty—a review. Br J Plast Surg 1986;39:213–21. Meyer D , Hamilton RC, Loken RG, et al. Effect of combined peribulbar and retrobulbar injection of large volumes of anesthetic agents on the intraocular pressure. Can J Ophthalmol 1992;27:230–2. Hessemer V , Wieth K, Heinrich A, et al. Changes in uveal and retinal hemodynamics caused by retrobulbar anesthesia using various injection volumes. Fortschr Ophthalmol 1989;86:760–6. Loken RG, Coupland SG, Deschenes MC. The electroretinogram during orbital compression following intraorbital regional block for cataract surgery. Can J Anaesth 1994;41:802–6. Topouzis F , Peng F, Kotas-Neumann R, et al. Longitudinal changes in optic disc topography of adult patients after trabeculectomy. Ophthalmology 1999;106:1147–51. Jay WM, Carter H, Williams B, et al. Effect of applying the Honan intraocular pressure reducer before cataract surgery. Am J Ophthalmol 1985;100:523–7. Palay DA, Stulting RD. The effect of external ocular compression on intraocular pressure following retrobulbar anesthesia. Ophthalmic Surg 1990;21:503–7. Pelit A , Haciyakupoglu G, Zorludemir S, et al. Preventative effect of deferoxamine on degenerative changes in the optic nerve in experimental retrobulbar haematoma. Clin Experiment Ophthalmol 2003;31:66–72. Shahidi M , Ogura Y, Blair NP, et al. Retinal thickness change after focal laser treatment of diabetic macular oedema. Br J Ophthalmol 1994;78:827–30. Rivellese M , George A, Sulkes D, et al. Optical coherence tomography after laser photocoagulation for clinically significant macular edema. Ophthalmic Surg Lasers 2000;31:192–7. Sims LM, Stoessel K, Thompson JT, et al. Assessment of visual field changes before and after focal photocoagulation for clinically significant diabetic macular edema. Ophthalmologica 1990;200:133–41. Adenis JP, Robert PY, Boncoeur-Martel MP. Abnormalities of orbital volume. Eur J Ophthalmol 2002;12:345–50. Forbes G , Gehring DG, Gorman CA, et al. Volume measurements of normal orbital structures by computed tomographic analysis. Am J NeuroRadiol 1985;6:419–24. Hintschich CR, Bonneveld FW, Bunce C, et al. Volumetry of bony and soft tissue compartments in the enucleated human orbit. Br J Ophthalmol. 2001;852:205–8....查看详细 (24168字节)

☉ 11333113:Living a Normal Life With the Nondominant Hemisphere: Magnetic Resonance Imaging Findings and Clinical Outcome for a Patient With Left-Hemis
Section of Neuroradiology, Department of Neurosurgery Department of Neuropediatrics, University Hospital of Schleswig-Holstein, Kiel, Germany Institute of Radiology, University Hospital of Schleswig-Holstein, Luebeck, Germany Institute of Physiology, Christian Albrechts University, Kiel, Germany ABSTRACT In hemihydranencephaly, the human brain lacks 1 complete hemisphere. An occlusion of the carotid artery, affecting all supplied territories, is thought to be the underlying mechanism. This extremely rare disorder, of which only 7 cases have been reported to date, is thought to occur before the last trimester of gestation (20th to 27th week), after neural migration but before synaptogenesis. We report on a 36-year-old man born at term, with no complications, from nonconsanguineous healthy parents. Cranial computed tomography had been performed because of left-sided headaches. Because of the imaging findings, the patient presented at our institution for additional MRI and clinical testing (including the Motor Activity Log, Wolf motor function test, 2-point discrimination test, Purdue pegboard test, gross motor function test, Physician Rating Scale, and Aachener aphasia test, including patterns for spontaneous speech, repetition, naming, comprehension, written language, and the token test). The patient's disabilities were related to deficits in fine motor control and reduced precision. Therefore, the patient was unable to perform the Purdue pegboard test with his affected hand. According to the Aachener aphasia test, no aphasia could be demonstrated for this strongly left-handed patient. Strong mirror movements were found. Cortical reorganization is possible if damage occurs in very early childhood. Motor function and speech were controlled by the remaining, nonaffected hemisphere, with a remarkable outcome. Because the damage is thought to occur before synaptogenesis, existing or prepared cortical areas and pathways have the potential to execute the lacking functions of the destroyed hemisphere. Key Words: adult outcomes brain development brain imaging cerebral infarction functional assessment children Hemihydranencephaly is an extremely rare disorder in which the human brain lacks 1 complete hemisphere. Occlusion of the ipsilateral carotid artery occurring before the last trimester of gestation (20th to 27th week of gestation) is thought to be the underlying mechanism for this brain damage, which affects all of the supplied territories.1,2 It is still not known why this disorder affects only 1 hemisphere. The circle of Willis does not seem to be able to compensate for the demands in the developing brain. In the adult brain, occlusion of a brain-supplying vessel results in a territorial infarction; postischemic defects and gliotic changes can be observed on MRI scans. Here, the circle of Willis and sufficient leptomeningeal collateral vessels can compensate for vessel occlusion, so that only partial territorial infarction occurs. In principle, these mechanisms should also work in the prenatal and perinatal periods. Therefore, fetal predisposing conditions, leading to additional vascular aplasia with vessel occlusion, are suspected for patients with hemihydranencephaly. The brain damage is assumed to occur after neural migration and before synaptogenesis.3 Only 7 cases have been reported to date. With perinatal brain damage, there is always an attempt to predict clinical outcomes according to computed tomographic and/or MRI findings.4–11 However, even for patients with large parenchymal defects, clinical outcomes may be excellent.2,12 CASE REPORT We present the case of a 36-year-old man born at term, with no complications, from nonconsanguineous healthy parents, as the second son among 3 otherwise healthy children. The parents noticed some clumsiness in early childhood. Right-sided hemiparesis and an equinus deformity at the ankle were diagnosed, with surgical treatment at the age of 18 years. During childhood, the patient received physical therapy. Additional sensorimotor and language development during childhood was not restricted. At the age of 28 years, the patient experienced his only general seizure. The rest of his medical history was unremarkable. Our patient was and is not receiving any medication. Intellect and language were unimpaired; the patient could complete school and is now working in a security department. He reported some disabilities concerning fine motor control of his affected right hand in tasks of daily living but had no other complaints. At the time of our investigation, a computed tomographic study had been performed at a different institution, where the patient had presented with left-sided headaches and nuchal pain. Because of his symptoms and the imaging findings, the patient presented at our institution. We performed MRI and magnetic resonance angiography with a 1.5-T scanner (Magnetom Vision; Siemens, Erlangen, Germany). MRI scans demonstrated a nearly complete absence of the left hemisphere, which was replaced by cerebrospinal fluid. Only a small residual hippocampus, a small rim of the occipital cortex, and a small cerebral peduncle attributable to Wallerian degeneration could be identified on the left side (Fig 1). However, the cerebellum, which is usually supplied by the posterior vascular territory, was completely normal. Time-of-flight angiography demonstrated the absence of the left internal carotid artery. Because conventional grading of hemiparesis (as proposed by the Medical Research Council in 196413) was thought to be too inaccurate to describe the extent of motor disability, we performed additional motor and language tests. Self-assessment was performed with the Motor Activity Log.14 The patient reported that he is able to drive a car with a standard transmission. Although natural prehension movements are almost unimpaired, the patient is unable to open a door with a key, button or unbutton clothing, switch between television programs with a remote control, turn the pages of a newspaper, use a spoon or fork while eating, put on socks, or brush his hair with the disabled hand. For the upper extremity, the Wolf motor function test,15 2-point discrimination test, and Purdue pegboard test16,17 were used to examine gross and fine motor function. In the Wolf motor function test, the patient scored 64 of 85 possible points (75%), because of reduced speed and/or precision in almost all of the performed tasks and because of impaired fine motor control in 3 tasks. Functionality and quality of movement did not differ in terms of the score. The threshold for 2-point discrimination in pinprick testing was 10 mm for the examined dermatomes (C5–C7) on the affected side. In the Purdue pegboard test, the patient was unable to perform any required task with the affected hand. Strong mirror movements were found when the patient was moving both hands.18 For the lower extremity, we performed the gross motor function test, part E.19 Because of incomplete performance and the inability to jump with the affected leg alone, the patient scored 93 of 100 possible points on the gross motor function test. With the Physician Rating Scale,20 only 10 of a total of 14 points were scored, because of impairment in the patient's ankle. For language testing, the Aachener aphasia test,21 a standardized, German, reference test for spontaneous speech, repetition, naming, comprehension, and written language, was administered, including the token test. The results confirmed our impression that speech was not affected, according to the criteria for aphasia of the Aachener aphasia test. The token test was completed correctly. The patient is strongly left-handed (92%, according to the handedness test described by Milner et al22). DISCUSSION Hemihydranencephaly is a rare disorder. To our knowledge, only 7 other cases have been reported in the literature.2,23–29 Hemiparesis on the contralateral side was observed in 5 of those cases,2,25–29 mild mental retardation in 4,2,25,26,28,29 severe retardation in 1,27 and seizures in 1.27 In two publications,23,24 the clinical outcome was not reported for 1 patient, who died at the age of 4 years, as a result of bronchopneumonia.23 The immature brain may compensate for neuronal injury through cortical reorganization that is superior to such capacities in the adult brain.12,30–33 Our patient is remarkable for several reasons. First, according to previous reports, severe hemiparesis would have been expected, considering the subtotal hemispheric damage.4,5,7,34,35 Second, the left hemisphere is thought to be the dominant side, harboring speech areas; however, speech is not impaired. Third, living with only 1 hemisphere could lead to severe intellectual impairment; however, our patient has completed school and is integrated fully in social life. Fourth, according to the current literature, this is the oldest patient alive and healthy, living an almost normal life. According to the results of the clinical tests, especially the Wolf motor function test, disabilities were related to deficits in fine motor control, as predicted with the Motor Activity Log, and reduced speed and/or reduced precision of the performed tasks and inability to perform 3 of the tasks. Quality of motion was not significantly worse with respect to functionality if the patient was able to execute a movement. Fine motor control requires unaffected 2-point discrimination; therefore, the patient was unable to perform the tasks of the Purdue pegboard test with his affected right hand. Mirror movements are thought to be caused by loss of transcallosal inhibition.36,37 Among patients with cerebral palsy, studies with transcranial magnetic brain stimulation revealed that branching corticospinal fibers projecting both ipsilaterally and contralaterally were associated with strong mirror movements.31,38,39 In congenital hemiparesis, motor function can be controlled by the nonaffected hemisphere through ipsilateral pathways.12,30–33 In their transcranial magnetic brain stimulation study, Carr et al31 demonstrated projections innervating both left and right motoneuron pools of homologous muscles simultaneously, with distally pronounced mirror movements. Our findings are in accordance with those of others, demonstrating that cortical reorganization is possible if the damage occurs in very early childhood.30,40 However, Ogden40 reported that severe deficits of complex extrapersonal orientation ability, spatial memory, and higher cognitive visuospatial skills might occur as a result of right-hemispheric speech dominance. He concluded that a shift of language representation to the right side might cause "crowding of function" in the remaining hemisphere, which might lead to deficits in spatial memory and orientation. Our patient demonstrates that normal development of verbal skills after left-hemispheric brain damage does not necessarily compromise memory or spatial orientation. We cannot predict with certainty from the morphometric features whether a child will develop impaired motor and/or higher cognitive functions. Some patients with only minor lesions are hampered severely, and it is still unclear what determines clinical outcomes. Activation of already existing pathways, development of new connections, or axonal migration or sprouting may be responsible for patients being able to achieve almost normal skills. Because the lesion is thought to occur before synaptogenesis,3 it seems most likely that already existing or prepared pathways that have the potential to execute the lacking functions of the destroyed hemisphere are used in this disease. Although there must be a genetic predisposition to define the precentral gyrus as the motor cortex, cortical areas may exist in the immature brain that can adopt similar or contralateral functions and enable cortical plasticity, with protocols executed through the uncrossed corticospinal fibers. FOOTNOTES Accepted Oct 14, 2004. No conflict of interest declared. REFERENCES Myers RE. Cerebral ischemia in the developing primate fetus. Biomed Biochim Acta. 1989;48 :S137 –S142 van Doornik MC, Hennekam RC. Hemi-hydranencephaly with favourable outcome. Dev Med Child Neurol. 1992;34 :454 –458 Eyre JA, Miller S, Clowry GJ, Conway EA, Watts C. Functional corticospinal projections are established prenatally in the human foetus, permitting involvement in the development of spinal motor centres. Brain. 2000;123 :51 –64 Wiklund LM, Uvebrant P, Flodmark O. Computed tomography as an adjunct in etiological analysis of hemiplegic cerebral palsy, II: children born at term. Neuropediatrics. 1991;22 :121 –128 Wiklund LM, Uvebrant P. Hemiplegic cerebral palsy: correlation between CT morphology and clinical findings. Dev Med Child Neurol. 1991;33 :512 –523 Molteni B, Oleari G, Fedrizzi E, Bracchi M. Relation between CT patterns, clinical findings and etiological factors in children born at term, affected by congenital hemiparesis. Neuropediatrics. 1987;18 :75 –80 Kotlarek F, Rodewig R, Brull D, Zeumer H. Computed tomographic findings in congenital hemiparesis in childhood and their relation to etiology and prognosis. Neuropediatrics. 1981;12 :101 –109 Steinlin M, Good M, Martin E, Banziger O, Largo RH, Boltshauser E. Congenital hemiplegia: morphology of cerebral lesions and pathogenetic aspects from MRI. Neuropediatrics. 1993;24 :224 –229 Uvebrant P. Hemiplegic cerebral palsy: aetiology and outcome. Acta Paediatr Scand Suppl. 1988;345 :1 –100 Cioni G, Sales B, Paolicelli PB, Petacchi E, Scusa MF, Canapicchi R. MRI and clinical characteristics of children with hemiplegic cerebral palsy. Neuropediatrics. 1999;30 :249 –255 Niemann G, Wakat JP, Krageloh-Mann I, Grodd W, Michaelis R. Congenital hemiparesis and periventricular leukomalacia: pathogenetic aspects on magnetic resonance imaging. Dev Med Child Neurol. 1994;36 :943 –950 Kuhtz-Buschbeck JP, Dreesmann M, Golge M, Stephani U. Prenatal infarction of the left middle cerebral artery: a case report of excellent functional outcome. NeuroRehabilitation. 2000;15 :167 –173 Monrad-Krohn GHRS. The Clinical Examination of the Nervous System. 12th ed. New York, NY: Harper and Row; 1964 Taub E, Miller NE, Novack TA, et al. Technique to improve chronic motor deficit after stroke. Arch Phys Med Rehabil. 1993;74 :347 –354 Wolf SL, LeCraw DE, Barton LA, Jann BB. Forced use of hemiplegic upper extremities to reverse the effect of learned nonuse among chronic stroke and head-injured patients. Exp Neurol. 1989;104 :125 –132 Tiffin J, Asher EJ. The Purdue pegboard: norms and studies of reliability and validity. J Appl Psychol. 1948;32 :234 –247 Reddon JR, Gill DM, Gauk SE, Maerz MD. Purdue pegboard: test-retest estimates. Percept Mot Skills. 1988;66 :503 –506 Woods BT, Teuber HL. Mirror movements after childhood hemiparesis. Neurology. 1978;28 :1152 –1157 Russell DJ, Rosenbaum PL, Cadman DT, Gowland C, Hardy S, Jarvis S. The gross motor function measure: a means to evaluate the effects of physical therapy. Dev Med Child Neurol. 1989;31 :341 –352 Koman LA, Mooney JF III, Smith B, Goodman A, Mulvaney T. Management of cerebral palsy with botulinum-A toxin: preliminary investigation. J Pediatr Orthop. 1993;13 :489 –495 Huber W, Poeck K, Weniger D, Willmes K. Aachener Aphasietest: AAT. Goettingen, Germany: Hogrefe; 1983 Milner B, Branch C, Rassmussen T. Observations on cerebral dominance. In: De Rueck AVS, O'Conner M, eds. Ciba Foundation Symposium on Disorders of Language. London, United Kingdom: Churchill; 1964 Muir CS. Hydranencephaly and allied disorders: a study of cerebral defect in Chinese children. Arch Dis Child. 1959;34 :231 –246 Warkany I. Congenital Malformations: Notes and Comments. Chicago, IL: Year Book Medical; 1971 Moser RP, Seljeskog EL. Unilateral hydranencephaly: case report. Neurosurgery. 1981;9 :703 –705 Suzuki M, Seki H, Yoshimoto T. Unilateral hydrocephalus combined with occlusion of the ipsilateral internal carotid artery. Surg Neurol. 1985;24 :27 –30 Ohtsuka H. A rare patient with a false median cleft lip associated with multiple congenital anomalies. Ann Plast Surg. 1986;17 :155 –160 Porro G, Wittebol-Post D, de Graaf M, Van Nieuwenhuizen O, Schenk-Rootlieb AJ, Treffers WF. Development of visual function in hemihydranencephaly. Dev Med Child Neurol. 1998;40 :563 –567 Greco F, Finocchiaro M, Pavone P, Trifiletti RR, Parano E. Hemihydranencephaly: case report and literature review. J Child Neurol. 2001;16 :218 –221 Cao Y, Vikingstad EM, Huttenlocher PR, Towle VL, Levin DN. Functional magnetic resonance studies of the reorganization of the human hand sensorimotor area after unilateral brain injury in the perinatal period. Proc Natl Acad Sci USA. 1994;91 :9612 –9616 Carr LJ, Harrison LM, Evans AL, Stephens JA. Patterns of central motor reorganization in hemiplegic cerebral palsy. Brain. 1993;116 :1223 –1247 Lewine JD, Astur RS, Davis LE, Knight JE, Maclin EL, Orrison WW Jr. Cortical organization in adulthood is modified by neonatal infarct: a case study. Radiology. 1994;190 :93 –96 Nirkko AC, Rosler KM, Ozdoba C, Heid O, Schroth G, Hess CW. Human cortical plasticity: functional recovery with mirror movements. Neurology. 1997;48 :1090 –1093 Eliasson AC, Gordon AM, Forssberg H. Basic co-ordination of manipulative forces of children with cerebral palsy. Dev Med Child Neurol. 1991;33 :661 –670 Forssberg H, Eliasson AC, Redon-Zouitenn C, Mercuri E, Dubowitz L. Impaired grip-lift synergy in children with unilateral brain lesions. Brain. 1999;122 :1157 –1168 Nass R. Mirror movement asymmetries in congenital hemiparesis: the inhibition hypothesis revisited. Neurology. 1985;35 :1059 –1062 Heinen F, Kirschner J, Fietzek U, Glocker FX, Mall V, Korinthenberg R. Absence of transcallosal inhibition in adolescents with diplegic cerebral palsy. Muscle Nerve. 1999;22 :255 –257 Carr LJ. Development and reorganization of descending motor pathways in children with hemiplegic cerebral palsy. Acta Paediatr Suppl. 1996;416 :53 –57 Farmer SF, Harrison LM, Ingram DA, Stephens JA. Plasticity of central motor pathways in children with hemiplegic cerebral palsy. Neurology. 1991;41 :1505 –1510 Ogden JA. Visuospatial and other "right-hemispheric" functions after long recovery periods in left-hemispherectomized subjects. Neuropsychologia. 1989;27 :765 –776...查看详细 (18730字节)
☉ 11333114:Effect of niacin on the choroidal circulation of patients with age related macular degeneration
Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA, USA ABSTRACT Aim: To investigate the effects of niacin on choroidal blood flow in age related macular degeneration (AMD). Methods: 12 AMD patients with bilateral drusen and visual acuity of 20/40 or better in the study eye received a single oral dose of niacin (six subjects received 500 mg and six received 250 mg) or matching placebo on two separate occasions. Laser Doppler flowmetry was used to assess relative choroidal blood velocity (ChBVel), volume (ChBVol), and flow (ChBFlow) in the foveola of the study eye at baseline, 30, and 90 minutes after dosing. Results: In comparison with placebo, a statistically significant 24% increase in ChBVol was observed 30 minutes after niacin administration (ANOVA, p = 0.01). In comparison with placebo, a significant decrease in ChBVel of 23% was observed in the 500 mg group (p = 0.04) and no significant change in ChBVel was seen in the 250 mg group at 30 minutes. No significant changes in ChBFlow were detected at 30 or 90 minutes. Also, there were no statistically significant changes in ChBVol or ChBVel at 90 minutes. Conclusion: In comparison with placebo, a significant 24% increase in ChBVol was observed 30 minutes after niacin administration. Owing to simultaneous decrease in ChBVel, however, no significant change in ChBFlow was detected. Abbreviations: AMD, age related macular degeneration; CS, contrast sensitivity; CV, coefficient of variability; LDL, low density lipoproteins; VA, visual acuity; VLDL, very low density lipoprotein Keywords: choroidal blood flow; laser Doppler flowmetry; age related macular degeneration; niacin Immediate release niacin (crystalline nicotinic acid) is a widely used lipid lowering agent which was first introduced in 19541 and was the first monotherapy shown to significantly reduce cardiovascular all-cause mortality.2,3 Niacin inhibits the production of very low density lipoprotein (VLDL) particles by the liver and consequently reduces the levels of circulating VLDL available for conversion to low density lipoproteins (LDL).4 The oral administration of a standard therapeutic dose of 500 mg of immediate release niacin induces intense flushing reactions in humans.5 The cutaneous capillary vasodilatation observed after niacin administration is the result of a massive release of prostaglandin PGD2 from niacin responsive skin cells.5,6 Potentially, this vasodilatory quality of niacin could be of use in the treatment of age related macular degeneration (AMD) and other ocular diseases characterised by a decreased choroidal perfusion. Several recent reports have suggested that choroidal blood flow is reduced in AMD.7,8,9,10,11,12,13,14,15 Results obtained in our laboratory have shown a significant 37% decrease in choroidal blood flow in subjects with the non-exudative form of macular degeneration.16 The purpose of this study was to perform a preliminary assessment of the effects of niacin on the choroidal circulation of patients with AMD. Evidence of an effect of niacin on the choroidal circulation could open the way for further studies looking at the efficacy of niacin in the treatment of AMD. METHODS This was a double blinded, randomised, placebo controlled, crossover study, which was carried out in a group of 12 white patients (nine women and three men) ranging in age from 62 to 84 years (mean 72 (SD 7) years). All patients had AMD features similar to those of AMD category 3 or worse of the AREDS study. In each patient, the eye with better visual acuity was considered as the study eye. All study eyes had large drusen and no evidence of choroidal neovascularisation (CNV). Retinal pigment epithelium hypertrophic changes were present in seven eyes and two eyes had a small area of extrafoveal geographic atrophy. Two patients had exudative AMD with disciform scar in the fellow eye. External, slit lamp, and funduscopic examination were unremarkable, except for the presence of mild nuclear sclerosis changes in nine study eyes and intraocular lens implants in two eyes. All subjects had visual acuity of 20/40 or better in the study eye and normal intraocular pressure (IOP) of 21 mm Hg or less. Four patients had a history of systemic hypertension and two of them were on antihypertensive medications. All study subjects took the same medications throughout the length of the study. Seven of the 12 patients enrolled in the study were taking aspirin on a regular basis and they were asked to discontinue this drug the night before the study visit. This was done because aspirin is known to block prostaglandin mediated, nicotinic acid induced flushing17 and we wanted to prevent blunting of the vasodilatory response. The study and data accumulation were carried out with approval from University of Pennsylvania institutional review board. Detailed explanations of the study procedures were provided to all study participants. All subjects signed an appropriate institutional review board approved consent form. Since the study was completed before 14 April 2003, a HIPPA consent form was not required. The tenets of the Declaration of Helsinki were followed. A single dose of immediate release niacin or matching placebo was administered orally on two separate occasions, at least 3 days apart. All subjects were initially randomised to receive either 500 mg of immediate release niacin or matching placebo. Two of the first six patients experienced intense drug related reactions with pronounced cutaneous flushing, strong nausea, dizziness, and loss of balance. Because of these strong side effects we decreased the dose of niacin and the next six subjects were randomised to receive either 250 mg of immediate release niacin or placebo. Placebo pills were designed to be identical to the niacin ones, but they did not contain the active component. To reduce the measurement bias, both the investigators and the patients were blinded to the treatment. All circulatory measurements were performed in one eye of each patient (study eye). Measurements were obtained in the right eye in eight patients and in the left in four patients. Before administration of the drug, visual acuity (VA) was measured using ETDRS charts at 3.2 metres and contrast sensitivity (CS) testing was performed at 1 metre using Pelli-Robson contrast sensitivity charts. Pupils were dilated with 1% Mydriacyl (Alcon, Ft Worth, TX, USA) and 10% Neo-Synephrine (Sanofil-Synthelabo, NY, USA) and VA and CS testing were repeated after dilatation. Laser Doppler flowmetry (Oculix, Inc, Berwyn, PA, USA) was used to assess the foveolar choroidal circulation. This non-invasive technique provides measurements of relative choroidal blood velocity (ChBVel), volume (ChBVol), and flow (ChBFlow) in the centre of the foveola. We have chosen this location because in the centre of the foveola there is no retinal circulation to interfere with our choroidal blood flow determinations. A diode laser beam (670 nm) with a 20 mW intensity and diameter of 200 μm was delivered to the eye through a fundus camera (model TRC; Topcon, Tokyo, Japan). Subjects were asked to fixate on the probing laser beam. Proper fixation was monitored by observation through the fundus camera. The light scattered back was electronically analysed. A detailed description of the technique has been previously reported.18–21 Three measurements of choroidal circulation of approximately 30 seconds were obtained while patients were seated in the darkened room. Following ocular circulatory measurements, heart rate (HR) and brachial artery systemic blood pressure were assessed by automated sphygmomanometry (Accutorr 1A, Datascope, Paramus, NJ, USA). IOP was measured by Tonopen in both eyes. To assess the reproducibility of our blood flow data, we calculated for each of the 12 subjects a coefficient of variability (CV) derived from three subsequent measurements in time (baseline, 30 minutes, and 90 minutes) on the day of placebo administration. CV was calculated using the following formula: CV = (standard deviation/mean)x100. The mean brachial artery pressure (BPm) was calculated from the systolic blood pressure (BPs) and diastolic blood pressure (BPd) according to the following formula: BPm = BPd + (BPs – BPd). Perfusion pressure (PP) for the study eye was estimated according to the following formula: PP = BPm – IOP. All measurements were repeated 30 and 90 minutes after drug administration. The same protocol was performed on the second study visit, and the alternative drug was tested. None of the study participants was under fasting conditions. An individual masked to treatment information performed analysis of the blood flow measurements using a NEXT computer. VA and CS data obtained at 30 and 90 minutes were compared to those obtained at the baseline after pupillary dilatation. Statistical analysis of the data was performed using analysis of variance (ANOVA) for repeated measures comparing the effects of niacin with those of placebo. Simple regression analysis was also performed. Statview software (Cary, NC, USA) was used for this purpose. Findings with p0.05 were considered to be statistically significant. All circulatory measurements are shown in arbitrary units (AU). RESULTS When all 12 subjects were analysed together, mean ChBVol at baseline, 30 minutes, and 90 minutes was 0.21 (SD 0.05) AU, 0.21 (0.05) AU, and 0.21 (0.06) AU following placebo, and 0.19 (0.06) AU, 0.23 (0.06) AU, and 0.19 (0.06) AU following administration of niacin, respectively (fig 1). In comparison with placebo, a statistically significant 24% increase in mean ChBVol was observed 30 minutes after niacin administration (ANOVA; p = 0.01). Figure 1 Average choroidal blood volume (ChBVol) in arbitrary units (AU) at baseline, 30 minutes, and 90 minutes after treatment with placebo and niacin for the 12 subjects (500 and 250 mg dose of niacin) analysed together. In comparison with placebo, a significant effect on ChBVol was detected following niacin administration (ANOVA; p = 0.01). Error bars correspond to ±1 SE. Most of the circulatory effect of niacin on ChBVol was dose related and derived from the six subjects who received the 500 mg dose. Further analysis carried out in this group of six patients, showed a 39% increase in mean ChBVol at 30 minutes after niacin administration (ANOVA, p = 0.03, fig 2) in contrast with a 10% increase in mean ChBVol in the group of six subjects who received 250 mg of niacin (ANOVA, p = 0.36). Figure 3 shows the individual values for percentage change in ChBVol for the subjects who received 250 mg and 500 mg of niacin. There were no statistically significant changes in mean ChBVol at 90 minutes. Figure 2 Percentage change in choroidal blood volume (ChBVol) at 30 minutes after treatment with placebo and niacin for the six subjects who received 500 mg dose of niacin. In comparison with placebo, a significant effect on ChBVol was detected following niacin administration (ANOVA; p = 0.03). Error bars correspond to ±1 SE. Figure 3 For each subject, a comparison of the percentage change in choroidal blood volume (ChBVol) 30 minutes following placebo and niacin 250 and 500 mg. In comparison with placebo, there was no statistically significant change in mean ChBVel after niacin administration at 30 minutes or 90 minutes for the group of 12 patients (ANOVA; p = 0.17; fig 4). Mean ChBVel at baseline, 30 minutes, and 90 minutes were 0.43 (0.09) AU, 0.42 (0.08) AU, and 0.41 (0.08) AU following administration of placebo, and 0.43 (0.07) AU, 0.38 (0.1) AU, and 0.42 (0.1) AU after niacin, respectively. When the analysis of ChBVel was conducted separately for the six subjects who received 500 mg of niacin, however, we found a significant 23% decrease in mean ChBVel at 30 minutes (ANOVA; p = 0.04; fig 5). No significant effect on mean ChBVel was observed in the niacin 250 mg group. Figure 6 shows the individual values for percentage change in ChBVel for the subjects who received 250 mg and 500 mg of niacin. There were no statistically significant changes in mean ChBVel at 90 minutes. Figure 4 Average choroidal blood velocity (ChBVel) in arbitrary units (AU) at baseline, 30 minutes, and 90 minutes after treatment with placebo and niacin for the 12 subjects (500 and 250 mg dose of niacin) analysed together. In comparison with placebo, no significant effect on ChBVel was detected following niacin treatment (ANOVA; p = 0.17). Error bars correspond to ±1 SE. Figure 5 Percentage change in choroidal blood velocity (ChBVel) at 30 minutes after treatment with placebo and niacin for the six subjects who received 500 mg dose of niacin. In comparison with placebo, a significant effect on ChBVel was detected following niacin administration (ANOVA; p = 0.04). Error bars correspond to ±1 SE. Figure 6 For each subject, a comparison of the percentage change in choroidal blood velocity (ChBVel) 30 minutes following placebo and niacin 250 and 500 mg. In comparison with placebo, no statistically significant change in mean ChBFlow was detected after niacin at any of the time points (ANOVA; p = 0.64; fig 7). Mean ChBFlow at baseline, 30 minutes, and 90 minutes was 8.1 (2.2) AU, 8.0 (2.5) AU, and 7.8 (2.5) AU following administration of placebo and 7.5 (2.4) AU, 7.9 (2.7) AU, and 7.2 (2.9) AU after niacin, respectively. No changes in ChBFlow were detected in the group of six subjects, who received 500 mg of niacin (ANOVA; p = 0.93; fig 8). Figure 7 Average choroidal blood flow (ChBFlow) in arbitrary units (AU) at baseline, 30 minutes, and 90 minutes after treatment with placebo and niacin for the 12 subjects (500 and 250 mg dose of niacin) analysed together. In comparison with placebo, no significant effect on ChBFlow was detected following niacin administration (ANOVA; p = 0.64). Error bars correspond to ±1 SE. Figure 8 Percentage change in choroidal blood flow (ChBFlow) at 30 minutes after treatment with placebo and niacin for the six subjects that received 500 mg dose of niacin. In comparison with placebo, no significant effect on ChBFlow was detected following niacin administration (ANOVA; p = 0.93). Error bars correspond to ±1 SE. Because we found no significant change in ChBFlow it is important to provide information on the magnitude of the changes that we would be able to detect with our methodology. We have estimated that we have 96% power to detect 20% changes in ChBFlow at type I error of 0.05. The coefficients of variability for ChBVel, ChBVol and ChBFlow were 6% (4%), 10% (7%) 10% (6%) respectively. There were no statistically significant changes in mean contrast sensitivity or mean visual acuity at any of the time points (table 1). In comparison with placebo, there was a 9% decrease in BPm at 30 minutes after niacin administration (t test, p = 0.02), a 7% increase in heart rate at 30 minutes (p = 0.01), and a decrease of 9% at 90 minutes (p = 0.05). A significant decrease in IOP of 23% was also seen at 30 minutes after niacin administration (p = 0.01). Table 1 Mean number of letters correctly identified during contrast sensitivity and visual acuity testing There was no significant correlation between the percentage changes in BPm, PP, or IOP and the percentage changes in ChBVel, ChBVol and ChBFlow after administration of placebo or niacin. We observed a direct correlation of borderline significance between age and the % change in ChBVol at 30 minutes after administration of niacin (R = +0.565, p = 0.055; fig 9); in other words, after niacin administration older individuals tended to show larger increases in ChBVol than younger ones. No such significant correlation was seen after placebo treatment. Figure 9 Percentage change in choroidal blood volume (ChBVol) 30 minutes after niacin treatment versus age (R = +0.565; p = 0.055; % change in ChBVol = 160 + 2.6 age). From the 12 subjects who participated in the study six experienced side effects related to niacin treatment. Two people experienced intense flushing with nausea, dizziness, and loss of balance. These two subjects were not taking aspirin before the study. The other four subjects experienced mild hyperaemia of face and neck. Two of them were taking aspirin before the study and two of them were not. There was no association between flushing reactions and changes in circulatory parameters. DISCUSSION The peak plasma concentration of niacin occurs about 30 minutes after oral administration.22 Our results suggest at this time there is a statistically significant increase in ChBVol of 24% when all 12 subjects are analysed together. Concurrently, however, there is also a decrease in ChBVel that is statistically significant in the group of six subjects that received the 500 mg dose. Because the increase in ChBVol is accompanied by a simultaneous decrease in ChBVel there is no significant change in ChBFlow. Possibly, this could be due to an autoregulatory attempt to maintain a constant choroidal blood flow. Interestingly, 30 minutes after niacin we observed a direct correlation of borderline significance (p = 0.055) between age and the percentage change in ChBVol. In other words, older individuals tended to show larger increases in ChBVol, suggesting that perhaps older individuals may have less robust autoregulatory responses (fig 9). This increase in ChBVol seen in our study is similar to the results of Chandra and Friedman,23 who used the krypton desaturation technique in anaesthetised cats and found decreased choroidal vascular resistance after niacin administration. Our results show that a larger increase in ChBVol is present in the six patients who received the higher dose of 500 mg (39% increase, p = 0.03) than in the group with a lower dose of 250 mg (10% increase, p = 0.36). This suggests that the lower concentration of systemically administered niacin may not be sufficient to saturate the receptor sites in the choroidal vasculature to cause a large increase in ChBVol. This finding is in agreement with the results of Chandra and Friedman,23 who did not detect choroidal circulatory changes with systemic doses but observed decrease in vascular resistance following direct niacin administration through the posterior ciliary artery. This last route of administration most probably achieved a higher concentration in the choroid. An increase in the ChBVol parameter measured by the LDF technique most probably represents an increase in the number of red blood cells present within the tissue measured by the laser Doppler flowmetry technique. Such an increase may be caused by vasodilatation, capillary recruitment, or increase in the haematocrit. We have previously reported that ChBFlow is reduced by 37% in patients with age related macular degeneration (AMD) in comparison with age matched normal controls. This phenomenon is mainly due to a 33% reduction in ChBVol. Studies showing obliteration of choriocapillaries in the macular area,24 narrowing of the lumen and loss of the cellularity of choriocapillaries,25 and thinning of the choroid, especially the choriocapillaris layer9 provide evidence of AMD related morphological changes that could explain a decrease in choroidal blood volume and flow observed in AMD. Because of this decrease in ChBFlow in AMD it is possible that therapies that increase the circulation of the choroid may be of benefit in the treatment of AMD. Further studies are needed to investigate whether niacin may have a potential role in the treatment of AMD. Our current study suggests increases in ChBVol in AMD patients after treatment with niacin. Whether this may be of benefit to patients with AMD is beyond the scope of this article. Theoretically, however, it is possible that an increase in ChBVol may facilitate the diffusion of gases and substances across the RPE-Bruch’s membrane. This may improve removal of the waste products and metabolic debris from the outer retina, a process that is probably impaired in AMD leading to the accumulation of drusen material. The circulatory changes observed after niacin ingestion may have a role in the development of reversible nicotinic acid maculopathy, which has been observed in patients taking high doses of niacin as a lipid lowering agent. Gass26 was the first one to report three cases of nicotinic acid maculopathy. Similar cases were reported by Millay27 and Callanan28 in patients who took 1–6 g of niacin daily and recovered upon discontinuation of niacin. A recent study by Spirn29 showed the presence of cystoid spaces mainly in the outer plexiform layer. Although the mechanism responsible for this type of reversible maculopathy is not well known, impairment of the blood-retinal barrier does not seem to play a large part, since there is no evidence of increased leakage on fluorescein angiography.27 Possibly, changes in the choroidal circulation such as the increased ChBVol and decreased ChBVel, observed in our study with the higher doses of nicotinic acid may facilitate extravasation of fluid from the blood vessels leading to a disturbed metabolism of the outer retina with intracellular fluid accumulation.27 Our results show a significant increase in heart rate at 30 minutes after niacin, similar to those reported by Gadegbeku et al30 and decrease in heart rate at 90 minutes. These effects represent a compensatory response to a decrease in peripheral vascular resistance and as a result decreased BPm, which we observed 30 minutes after treatment with niacin. They are aimed to maintain constant cardiac output. Our results do not show any effect of niacin on visual acuity or contrast sensitivity suggesting that the changes in ChBVol and ChBVel do not result in a large effect on visual function. In summary, our results suggest that therapeutic doses of niacin produce changes in choroidal circulation in AMD patients. Additional studies are needed in order to find out whether this type of therapy may be of benefit in patients with this condition. Commercial relationship: None. REFERENCES Knopp RH. Drug treatment of lipid disorders. N Engl J Med 1999;341:498–511. The Coronary Drug Project Research Group. Clofibrate and niacin in coronary heart disease. JAMA. 1975;231 :360–81. Canner PL, Berge KG, Wenger NK, et al. Fifteen-year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol 1986;8:1245–55. Clark AB, Holt JM. Identifying and managing patients with hyperlipidemia. Am J Managed Care 1997;3:1211–19. Morrow JD, Awad JA, Oates J, et al. Identification of skin as a major site of prostaglandin D2 release following oral administration of niacin in humans. J Invest Dermatol 1992;98:812–15. Marrow JD, Parsons WG, Roberts LJ. Release of markedly increased quantities of prostaglandin D2 in vivo in humans following the administration of nicotinic acid. Prostaglandins 1989;28:263–74. Pauleikhoff D , Chen JC, Chisholm IH, et al. Choroidal perfusion abnormality with age-related Bruch’s membrane change. Am J Ophthalmol 1990;109:211–17. Boker T , Fang T, Steinmetz R. Refractive error and choroidal perfusion characteristics in patients with choroidal neovascularization and age-related macular degeneration. Ger J Ophthalmol 1993;2:10–13. Sarks SH. Aging and degeneration in the macular region: a clinicopathological study. Br J Ophthalmol 1976;60:324–341. Sarks SH, Sarks J, Killingsworth C. Evolution of geographic atrophy of the retinal pigment epithelium. Eye 1988;2:552–8. Chen JE, Fitzke FW, Pauleikhoff D, et al. Functional loss in age-related Bruch’s membrane change with choroidal perfusion defect. Invest Ophthalmol Vis Sci 1992;33:334–40. Holz FG, Wolfensberger TJ, Piguet B, et al. Bilateral macular drusen in age related macular degeneration: prognosis and risk factors. Ophthalmology 1994;101:1522–8. Prunte C , Niesel P. Quantification of choroidal blood-flow parameters using indocyanine green video-fluorescence angiography and statistical picture analysis. Graefes Arch Ophthalmol 1988;226:55–8. Friedman E , Ivry M, Ebert E, et al. Increased scleral rigidity and age-related macular degeneration. Ophthalmology 1989;196:104–8. Friedman E , Krupsky S, Lane AM, et al. Ocular blood flow velocity in age-related macular degeneration. Ophthalmology 1995;102:640–646. Grunwald JE, Hariprasad SM, DuPont J, et al. Foveolar choroidal blood flow in age-related macular degeneration. Invest Ophthalmol Vis Sci 1998;39:385–90. Wilkin JK, Wilkin O, Kapp R, et al. Aspirin blocks nicotinic acid–induced flushing. Clin Pharmacol Ther 1982;3:478–82. Riva CE, Cranstoun SD, Grunwald JE, et al. Choroidal blood flow in the foveal region of the human ocular fundus. Invest Ophthalmol Vis Sci 1994;35:4273–81. Riva CE, Harino S, Petrig BL, et al. Laser-Doppler flowmetry in the optic nerve. Exp Eye Res 1992;55:499–506. Petrig BL, Riva CE. Optic nerve head laser Doppler flowmetry: principles and computer analysis. In: Kaiser JH, Flammer J, Hendrickson P, eds. Ocular blood flow. Basel: Karger, 1996:120–7. Riva CE, Mendel M, Petrig BL. Flicker-induced optic nerve blood flow change. In: Kaiser HJ, Flammer J, Hendrickson P, eds. Ocular blood flow. Basel: Karger, 1996:128–37. Craig CR, Stitzel RE. Modern pharmacology. Boston/Toronto: Little, Brown and Company, 1986:1–338. Chandra SR, Friedman E. Choroidal blood flow. IV. Effect of vasodilating agents. Arch Ophthalmol 1979;97:1331–2. Duke-Elder S . System of ophthalmology. St Louis: CV Mosby, 1966, 9;609–13. Korenzweig AB. Changes in the choriocapillaries associated with senile macular degeneration. Ann Ophthalmol 1977;9:753–64. Gass JD. Nicotinic acid maculopathy. Am J Ophthalmol 1973;76:500–510. Millay RH, Klein ML, Illingworth DR. niacin maculopathy. Ophthalmology 1988;95:930–936. Callanan D , Blodi BA, Martin DF. Macular edema associated with nicotinic acid (niacin). JAMA 1998;279:1702. Spirn MJ, Warren FA, Guyer DR, et al. Optical coherence tomography findings in nicotinic acid maculopathy. Am J Ophthalmol 2003;135:913–44. Gadegbeku CA, Dhandayuthapani A, Shrayyef MZ, et al. Hemodynamic effects of nicotinic acid infusion in normotensive and hypertensive subjects. Am J Hypertens 2003;16:67–71....查看详细 (26639字节)
☉ 11333115:Acute Arsenic Poisoning in Two Siblings
Regional Center for Poison Control and Prevention Serving Massachusetts and Rhode Island Divisions of Emergency Medicine Critical Care Medicine Nephrology, Children's Hospital, Boston, Massachusetts Harvard Medical School, Boston, Massachusetts Department of Emergency Medicine, University of Massachusetts, Worcester, Massachusetts Department of Emergency Medicine, Mount Auburn Hospital, Cambridge, Massachusetts ABSTRACT We report a case series of acute arsenic poisoning of 2 siblings, a 4-month-old male infant and his 2-year-old sister. Each child ingested solubilized inorganic arsenic from an outdated pesticide that was misidentified as spring water. The 4-month-old child ingested a dose of arsenic that was lethal despite extraordinary attempts at arsenic removal, including chelation therapy, extracorporeal membrane oxygenation, exchange transfusion, and hemodialysis. The 2-year-old fared well with conventional therapy. Key Words: arsenic poisoning toxicokinetics pharmacokinetics British anti-lewisite dimercaprol succimer DMSA DMPS chelation therapy extracorporeal membrane oxygenation ECMO exchange transfusion hemodialysis heavy metal poisoning survival pediatric lethal dose Abbreviations: DMSA, 2,3-dimercaptosuccinic acid DMPS, 2,3-dimercapto-1-propanesulfonate BAL, British anti-lewisite ECMO, extracorporeal membrane oxygenation Arsenic is a heavy metal that is odorless, colorless, and tasteless in solubilized form. It is ubiquitous throughout our environment at low background levels and is used most commonly in mining operations (for smelting), in the agricultural field (as an herbicide and pesticide, although not for food crops in the United States), and in the electronics industry (for semiconductors and lasers). Inorganic arsenic is a highly toxic transition metal; poisoning from this metal has been treated primarily with supportive care and antidote administration. Children in the United States are unlikely to ingest significant amounts from concentrated sources, and clinically significant dermal absorption of arsenic from "pressure-treated" wood (lumber treated with chromated copper arsenate), which has been used to build numerous playgrounds and decks, has not been demonstrated.1,2 However, accidental poisonings still occur, and there is the potential for therapeutic dosing errors with arsenic trioxide (Trisenox [Cell Therapeutics, Seattle, WA]), which is used to treat patients with acute promyelocytic leukemia. Arsenic also still plays a role in acts of suicidal and homicidal intent. Unfortunately, no existing therapies have been effective in massive overdoses. We describe a child who was treated successfully with conventional therapy for arsenic poisoning, as well as the use of several adjunctive therapies for an infant with life-threatening acute arsenic poisoning. These novel approaches may be useful for other patients with sublethal ingestions for whom conventional treatments are ineffective or inadequate. CASE REPORTS Ingestion A 4-month-old male patient and his 2-year-old sister attended a cookout with their parents. The host provided the parents with a clear, unmarked, plastic container that contained a liquid and purportedly stored spring water (Fig 1). A drinking cup was filled for the toddler, and Enfamil with Iron (Mead Johnson Nutritional Division, Evansville, IN) was reconstituted with the liquid and given to the infant. The 4-month-old patient (patient 1) ingested between 2 and 3 fl oz of the material. The 2-year-old patient (patient 2) drank a small amount and spat it out, telling her parents that it "tasted bad." Within 10 minutes, both children began vomiting. The parents brought their children to a local emergency department in their private vehicle. En route, patient 1 developed bloody emesis. On arrival at the community hospital emergency department, both children were still vomiting but had normal vital signs. Notably, the emergency department staff observed that the reconstituted infant formula was purple in color. While the father retrieved the bottle of "spring water" from the cookout, supportive measures were started at the hospital, including intravenous fluid therapy for both children. Approximately 3 hours after ingestion, both children had ceased vomiting and their father returned with the bottle that contained the liquid. A nurse found a product label that described an outdated herbicide that was 40% arsenic by volume (23.1% by weight) (Fig 2). The children were transferred to a tertiary care pediatric hospital. Course of Patient 1 During transfer, patient 1 became comatose. On arrival, he was orotracheally intubated and central venous access was obtained. The patient was tachycardic and hypotensive despite intravenous administration of 30 mL/kg normal saline solution. A continuous infusion of dopamine was initiated, and the patient was admitted to the ICU. Standard chelation therapy with British anti-lewisite (BAL) through intramuscular injection of 5 mg/kg every 4 hours was provided. Within 6 hours after ingestion, the pupils of patient 1 became fixed and dilated; he had no spontaneous movement despite withholding of sedation after intubation. Blood gas analysis showed severe metabolic acidosis despite treatment with sodium bicarbonate, and the patient had evidence of disseminated intravascular coagulation (Table 1). Continuous resuscitation with intravenous crystalloid and colloid therapy and vasoactive infusions failed to prevent cardiovascular collapse. The patient developed ventricular fibrillation and multiple ventricular nonperfusing tachyarrhythmias, devolving into torsades de pointes (Fig 3), and was treated with lidocaine hydrochloride, magnesium sulfate, bretylium tosylate, and defibrillation. Twelve hours after ingestion, the patient underwent extracorporeal membrane oxygenation (ECMO) on an emergency basis. For a brief period after cannulation, some pupillary reactivity returned and the patient exhibited some spontaneous and nonposturing movement. He was anuric from the time of ingestion until 2 hours after initiation of ECMO, when he produced 107 mL of urine in 2.5 hours and then became anuric again. The patient had an ongoing capillary leak and became markedly edematous. He continued to receive intramuscular injections of BAL (5 mg/kg) every 4 hours for chelation. Extracorporeal elimination of arsenic through 2 runs of hemodialysis and a single-volume exchange transfusion was attempted. Because of the failure of the preceding therapies, patient 1 received the experimental chelator 2,3-dimercapto-1-propanesulfonate (DMPS). This therapy also failed to produce clinical improvement. The patient sustained ventricular tachyarrhythmias refractory to pharmacologic and electrical conversion. Supportive measures were discontinued 36 hours after ingestion. Although the patient weighed 8 kg at admission, his weight at autopsy was 23 kg. A spot urinary arsenic concentration had been obtained during the patient's brief period of urine production, 14 hours after ingestion and after 2 doses of BAL; the urinary arsenic concentration was 9000 μg/L. During the patient's first hemodialysis session, dialysis was performed with 102 L of dialysate. Dialysate toward the end of this session had an arsenic concentration of 20 μg/L, indicating a minimal arsenic removal of 2.04 mg. At autopsy, the patient's serum arsenic concentration was 730 μg/L. Course of Patient 2 Patient 2 was admitted to the ICU for hemodynamic monitoring. She had sinus tachycardia, with heart rates ranging from 130 to 180 beats per minute in the initial 12 hours after ingestion. She demonstrated no hypotension or arrhythmias. She received intravenous fluids at twice the maintenance rate and standard chelation therapy with BAL (5 mg/kg) through intramuscular injection every 4 hours. While in the ICU, her QTc prolonged to as long as 527 milliseconds at 22 hours after ingestion, decreasing to 4 Weeks) Patients exposed to frequent small amounts of arsenic are subject to less severe but more insidious manifestations of toxicity. These findings have been monitored and reported numerous times since the installation of thousands of tube wells throughout Bangladesh in the 1970s. These wells became contaminated with arsenic due to its high content within the earth’s crust in this area. Multiple articles chronicle the higher rates of hyperkeratoses, hyperpigmentation, and lung and skin cancers that are seen throughout the region. Peripheral neuropathies may persist from large single acute ingestions or may develop from chronic small exposures to the metal. Management of Acute Arsenic Poisoning Aggressive Fluid Resuscitation and Cardiovascular Support Fluid resuscitation remains the mainstay of initial management of arsenic poisoning.19 Because arsenic and its chelators are excreted principally in the urine, maintaining renal perfusion is critical. Clinicians often fail to appreciate the volume of intravenously administered fluid required for adequate resuscitation. Acutely poisoned patients develop enormous fluid deficits through gastrointestinal losses alone (vomiting and diarrhea), which can lead to hypovolemic shock. Intravascular volume depletion is aggravated by increased capillary permeability and a systemic inflammatory response syndrome-like response.14,20 The degree of capillary leak and resultant tissue edema is dramatic. As noted, patient 1 weighed 8 kg at admission; at autopsy, his weight was 23 kg. Chelation Chelating agents scavenge arsenic and bind it into a stable metal-chelate complex. Although chelators are not thought to reverse the enzymatic inhibition produced by arsenic, early chelation before confirmation of arsenic ingestion has produced increased rates of survival in small case series of acutely poisoned individuals.21–24 Unfortunately, only a limited number of chelating agents are available, and they are limited by bioavailability, binding ratios, weight-based dosing, mode of administration, and adverse effect profiles. Dimercaprol (BAL in oil [Taylor Pharmaceuticals, San Clemente, CA]) remains the standard chelator for acute arsenical poisoning in the United States. It is estimated to bind 30 mg of arsenic for every 50 mg of BAL given.25 Because it is administered as an intramuscular injection, BAL may have unpredictable bioavailability among patients with severe shock and uncertain peripheral perfusion. As the only arsenical chelator able to cross the blood-brain barrier, BAL may offer some protection against toxicity in the central nervous system; however, concern exists that BAL could enhance arsenic redistribution to the brain and worsen central nervous system effects.26,27 BAL has significant adverse effects. The chelator causes fever and hypertension and can exacerbate fluid losses attributable to nausea and vomiting. Sterile abscesses may form at injection sites. BAL is also contraindicated for patients with glucose-6-phosphate dehydrogenase deficiency, because it may cause hemolysis, and it should not be given in cases of suspected iron toxicity, because the BAL-iron complex is itself toxic.28 Finally, BAL is lipid soluble and is constituted in peanut oil to prevent oxidation. It is therefore contraindicated for patients with peanut allergy, and it is constrained to administration only as an intramuscular injection, which impairs its distribution and effectiveness in shock states. Succimer (DMSA, Chemet) is a water-soluble analog of BAL that can be administered orally. Pediatricians may be most familiar with its use as a chelator for childhood lead poisoning. Approximately 20% of an oral dose of succimer is absorbed from the gastrointestinal tract, with nearly all absorbed DMSA being available to chelate metal in a 1:1 ratio.29 DMSA had effectiveness comparable to that of BAL in decreasing arsenic concentrations in mouse livers, kidneys, brains, and spleens.30 No standardized protocol for DMSA administration in arsenic poisoning exists; current dosing guidelines are extrapolated from methods for lead chelation. Described adverse effects of DMSA include transient increases in transaminase levels, nausea and vomiting, rash, thrombocytosis, paresthesias, and pruritus. DMPS (Unithiol) is a water-soluble analog of BAL that can be administered orally, intravenously, or intramuscularly. Developed in the former Soviet Union in the 1950s, DMPS is not approved by the Food and Drug Administration but has been used successfully in Europe for arsenic chelation.23,31,32 In the United States, DMPS was used for the mass arsenic poisonings in New Sweden, Maine, in April 2003, when the regional stocks of BAL had been exhausted. At that time, it was found to enhance excretion and to increase urinary arsenic concentrations, even after several days of BAL therapy.33 Increased urinary elimination of arsenic from DMPS may be attributable to chelation of metabolized (methylated) arsenic species. Biomethylation of As3+ may activate or enhance arsenic toxicity.34 DMPS forms a complex with the first methylated species of the biomethylation sequence, monomethylarsonic acid, reducing availability for subsequent biomethylation and additional toxicity.35 Up to triple the urinary monomethylarsonic acid concentration was seen within 2 hours after oral administration of DMPS to patients suffering from chronic arsenic intoxication.32 This increase in arsenic metabolite elimination may support the effectiveness of immediate administration of DMPS in acute arsenic poisoning in the future. d-Penicillamine is no longer recommended for use in arsenic intoxication. It showed little efficacy in an animal model.36 Extracorporeal Elimination Numerous methods have been directed toward the mechanical removal or extracorporeal elimination of arsenic, including N-acetylcysteine, endoscopy, gastric irrigation with alkaline irrigant, alternative parenteral chelators, and hemodialysis.37,38 Because of arsenic's short distribution half-life of only 1 hour, extracorporeal elimination methods are ineffective for removal of the metal once it is distributed to the tissues, and the metal-chelate complex may be of too great a mass for hemodialysis or hemofiltration.39,40 Children, however, may be better candidates for extracorporeal elimination methods, because they retain less arsenic in soft tissues than do adults,41 which possibly permits some reequilibration of arsenic into the vascular system. This finding correlates with a report of pediatric spontaneous excretion twice as fast as in adults.42 These distinctions may make extracorporeal elimination techniques more effective in the pediatric population. The estimated arsenic burden of 3430 mg for patient 1 could not have been eliminated through conventional chelation methods. Administration of BAL and DMSA according to standard dosing guidelines would have chelated at most 192 mg, <6% of the patient's estimated arsenic burden, in a 24-hour period. The gravity of the condition of patient 1 dictated that adjunctive therapies be applied. Therefore, he received additional extracorporeal detoxifying treatments. Patient 1 underwent venoarterial ECMO beginning 12 hours after ingestion, in response to refractory shock and cardiac rhythm disturbances. Because of the urgency of the situation, a saline-primed circuit with a volume of 500 mL was used. The patient's hematocrit level decreased from 28% to 17% after cannulation and then increased to 38% with the use of packed red blood cell replacement and ultrafiltration. With an estimated blood volume of 642 mL for patient 1, these changes represented diluting and then replacing nearly one half of the patient's total blood volume. Once ECMO was begun, patient 1 had a return of pupillary activity and spontaneous movement, even before hemodialysis and an exchange transfusion were initiated. In addition, ECMO produced sufficient hemodynamic support to restore renal perfusion and urine output. These events suggest that ECMO may serve as a partial exchange transfusion that decreases tissue arsenic concentrations transiently and may produce an improvement in organ function. Because arsenic redistributes rapidly to tissues including erythrocytes, exchange transfusion may be beneficial in decreasing the body burden of arsenic in major intoxication. A single-volume exchange transfusion was performed for patient 1 at 28 hours after ingestion, with the goal of mobilizing arsenic from the tissues before administration of the experimental chelating agent DMPS. Hemodialysis has been reserved traditionally for the elimination of arsenic from patients in renal failure.21,23,43,44 Patient 1 developed renal insufficiency and underwent his first hemodialysis session with 102 L of dialysate at 18 hours after ingestion, for the purpose of removing arsenic and arsenic-BAL complexes. His dialysate arsenic concentration was 20 μg/L toward the end of the dialysis session, which indicates a minimal arsenic removal of 2.04 mg (compared with his spot urinary level of 9 mg/L). This amount of arsenic elimination is consistent with reports of adults cases, in which 4-hour hemodialysis sessions removed 2.9 to 4.68 mg of arsenic.43–45 Arsenic's large volume of distribution (3.3–4 L/kg)46,47 and the small amount of arsenic removed through hemodialysis suggest that arsenic is redistributed to tissues too rapidly, with too small a serum concentration gradient, for effective removal through hemodialysis. It is notable that although BAL does not impede arsenic removal through dialysis, the DMPS-arsenic complex may not be as readily dialyzable.48 Hemodialysis may be useful only to treat the electrolyte and fluid imbalances of renal failure and is unlikely to be helpful for removal of arsenic or arsenic-chelator complexes. Elimination of the DMPS-arsenic complex may be enhanced with convective mass transport through continuous venovenous hemodiafiltration.48 In addition, continuous venovenous hemodiafiltration provides continuous exposure of the circulating blood volume to the dialysate and may be better tolerated by patients with hemodynamic instability. For patient 1, continuous venovenous hemodiafiltration was considered concurrent with DMPS administration, but life support measures were discontinued before its implementation. On the basis of this patient's experience with hemodialysis, we suggest consideration of continuous venovenous hemodiafiltration for arsenic-poisoned patients given DMPS. Plasmapheresis was also considered but was not used because the arsenic-chelator complex would be too large to be removed with this method. CONCLUSIONS Inorganic arsenic is a highly toxic metal that produces life-threatening conditions by inhibiting energy production and depleting energy stores. Because of the severity and rapidity with which poisoned patients develop arsenic toxicity, clinicians should administer fluid resuscitation and chelation agents presumptively, without formal laboratory confirmation. However, clinicians may be confronted by patients so severely intoxicated that they will die regardless of aggressive conventional therapies. Adjunctive approaches such as administration of DMPS, exchange transfusion, ECMO, and continuous venovenous hemodiafiltration may offer clinical benefit in situations where standard methods will fail. ACKNOWLEDGMENTS Dr Ed Boyer is also supported by the National Institutes of Health (grant DA-14929). We thank Shannon Manzi, PharmD, and Michael W. Shannon, MD, MPH, for tremendous help and suggestions in reviewing the manuscript. We thank Doug, Sonja, and Morgan, and we remember Benjamin. FOOTNOTES Accepted Nov 8, 2004. No conflict of interest declared. REFERENCES Wester RC, Hui X, Barbadillo S, et al. In vivo percutaneous absorption of arsenic from water and CCA-treated wood residue. Toxicol Sci.2004; 79 :287 –295 Hemond HF, Solo-Gabriele HM. Children's exposure to arsenic from CCA-treated wooden decks and playground structures. Risk Anal.2004; 24 :51 –64 Stephanopoulos DE, Willman DA, Shevlin D, Pinter L, Gummin DD. Treatment and toxicokinetics of acute pediatric arsenic ingestion: danger of arsenic insecticides in children. Pediatr Crit Care Med.2002; 3 :74 –80 Shen ZX, Chen GQ, Ni JH, et al. Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL), II: clinical efficacy and pharmacokinetics in relapsed patients. Blood.1997; 89 :3354 –3360 Mealey J Jr, Brownell GL, Sweet WH. Radioarsenic in plasma, urine, normal tissues, and intracranial neoplasms: distribution and turnover after intravenous injection in man. AMA Arch Neurol Psychiatry.1959; 81 :310 –320 Delnomdedieu M, Styblo M, Thomas DJ. 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Survival following massive arsenic ingestion. Am J Emerg Med.1988; 6 :602 –606 Watson WA, Veltri JC, Metcalf TJ. Acute arsenic exposure treated with oral d-penicillamine. Vet Hum Toxicol.1981; 23 :164 –166 Kruszewska S, Wiese M, Kolacinski Z, Mielczarska J. The use of haemodialysis and 2,3-propanesulphonate (DMPS) to manage acute oral poisoning by lethal dose of arsenic trioxide. Int J Occup Med Environ Health.1996; 9 :111 –115 Shum S, Whitehead J, Vaughn L, Hale T. Chelation of organoarsenate with dimercaptosuccinic acid. Vet Hum Toxicol.1995; 37 :239 –242 Saady JJ, Blanke RV, Poklis A. Estimation of the body burden of arsenic in a child fatally poisoned by arsenite weedkiller. J Anal Toxicol.1989; 13 :310 –312 Muckter H, Liebl B, Reichl FX, Hunder G, Walther U, Fichtl B. Are we ready to replace dimercaprol (BAL) as an arsenic antidote Hum Exp Toxicol.1997; 16 :460 –465 Snider TH, Wientjes MG, Joiner RL, Fisher GL. 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Ann Emerg Med.1987; 16 :702 –704 Smith SB, Wombolt DG, Venkatesan R. Results of hemodialysis and hemoperfusion in the treatment of acute arsenic ingestion. Clin Exp Dial Apheresis.1981; 5 :399 –404 Westervelt P, Pollock JL, Oldfather KM, et al. Adaptive immunity cooperates with liposomal all-trans-retinoic acid (ATRA) to facilitate long-term molecular remissions in mice with acute promyelocytic leukemia. Proc Natl Acad Sci USA.2002; 99 :9468 –9473 Lam MS, Ignoffo RJ. Arsenic trioxide for the treatment of acute promyelocytic leukemia. Cancer Pract.2001; 9 :155 –157 Pai P, Thomas S, Hoenich N, Roberts R, House I, Brown A. Treatment of a case of severe mercuric salt overdose with DMPS (dimercapo-1-propane sulphonate) and continuous haemofiltration. Nephrol Dial Transplant.2000; 15 :1889 –1890...查看详细 (35228字节)
☉ 11333116:Not Your Routine Foreign Body: Endobronchial Tuberculosis in an Infant
Department of Pediatrics Division of Pediatric Otolaryngology, Lucile Packard Children's Hospital at Stanford University, Palo Alto, California ABSTRACT Foreign-body aspiration is a common cause of respiratory distress among children. Here we describe an 8-month-old, previously 34-week premature, male patient who presented with a 1-day history of fever and increased work of breathing. Of note, 3 weeks before presentation, the patient had been treated with orally administered amoxicillin for presumed pneumonia and exhibited good clinical response. No chest radiograph was obtained at that time. A current chest radiograph revealed hyperexpansion of the left lung, with a mediastinal shift. Although the patient was referred because of possible foreign-body aspiration, no clear history of an aspiration event was obtained, and computed tomographic scans of the chest were recommended. These showed extensive hilar and mediastinal lymphadenopathy, resulting in obstruction of the left bronchus. Bronchoscopy revealed a cheesy granulomatous mass in the left mainstem bronchus, which was ball-valving into the upper bronchus. Removal resulted in improvement of the patient's respiratory status. Pathology, bronchial lavage, and gastric aspirate specimens all revealed acid-fast bacilli, consistent with Mycobacterium tuberculosis infection. This unusual presentation of tuberculosis may become more common in the United States as the incidence of immigrants carrying tuberculosis increases. Key Words: pediatric foreign body tuberculosis respiratory distress bronchoscopy Abbreviations: CT, computed tomographic Mycobacterium tuberculosis is considered by many to be the great imitator. It is especially difficult to diagnose among children, with the distinction between exposure and disease being difficult to make.1 The rates of tuberculosis have been declining nationwide since a peak in 1992, but some states observed elevation of their rates during 2003. This, coupled with a continued high incidence of tuberculosis in certain at-risk populations such as immigrants and minorities, means that pediatricians must be even more vigilant in tuberculin testing and have a higher index of suspicion in cases in which a child does not present with a classic cavitary lesion.2 This case report details an unusual and interesting case in which tuberculosis presented with findings suggesting foreign-body aspiration. CASE REPORT An 8-month-old, formerly 34-week premature, male infant presented for treatment of fever to 38.5°C, cough, and increased work of breathing. Three weeks before admission, the patient was diagnosed as having pneumonia and was treated with amoxicillin, with good clinical response. No chest radiograph was obtained at that time. One day before transfer, the patient was admitted to an outside hospital because of similar symptoms. He was transferred to our institution after a chest radiograph revealed hyperexpansion of the left lung, with a mediastinal shift to the right (Fig 1). Although the patient was referred because of possible foreign-body aspiration, no clear history of an aspiration event was obtained. The patient was born at 34 weeks' gestational age in the Philippines. The mother had a 10-day history of severe coughing, which led ultimately to premature rupture of membranes and delivery. The patient's birth weight was 1.75 kg. He was never intubated during his 2-week hospitalization in the nursery in the Philippines. Immunizations, including BCG vaccine, were up to date. The family immigrated to the United States 3 months before patient presentation. Family members denied any illness. The family history was significant for a 12-year-old cousin with asthma. On physical examination, the patient was afebrile, with a respiratory rate of 35 breaths per minute and a heart rate of 140 beats per minute. Oxygen saturation measured 100% with room air. The examination results were significant for abdominal breathing with mild subcostal and supraclavicular retractions, decreased breath sounds on the left side, and heart sounds displaced to the right, with a displaced point of maximal impulse. There was no tracheal deviation. The rest of the physical examination results were normal. Because of the absence of a clear aspiration event, computed tomographic (CT) scans of the chest were obtained; they showed extensive hilar and mediastinal lymphadenopathy, resulting in obstruction of the left bronchus (Fig 2). A Mantoux skin test was performed for the infant. Bronchoscopy revealed a cheesy granulomatous mass in the left mainstem bronchus, which was ball-valving into the upper bronchus (Fig 3). Removal resulted in improvement of the patient's respiratory status. Pathology, bronchial lavage, and gastric aspirate specimens were smear positive and culture positive for acid-fast bacilli, consistent with M tuberculosis infection. In addition, the Mantoux skin test developed >10 mm of induration. The patient began standard 4-drug therapy with isoniazid, rifampin, ethambutol, and pyrazinamide and was discharged from the hospital with directly observed therapy. The isolate was sensitive to all antituberculosis drugs, and the patient completed 6 months of treatment. He has not had any additional problems with wheezing, retractions, cough, or difficulty breathing and is growing well. DISCUSSION Endobronchial tuberculosis can be found for up to 57% of children with pediatric pulmonary tuberculosis.3 Symptoms are often nonspecific and may include fever, cough, wheezing, prolonged expiratory component, or diminished breath sounds. These lesions are often not evident on simple chest radiographs.4 Because of the decreased incidence of tuberculosis in the United States, it is usually not one of the first things considered when children present with these symptoms. In the pediatric otolaryngology literature, however, endobronchial tuberculosis presenting as suspected foreign-body aspiration has been described.5–7 With bronchoscopy, these patients are described typically as having a polypoid spongy mass, white fibrinous exudate, or granulation tissue in the bronchus. The right upper and right main bronchi are involved most frequently.8 Chest CT scans are often more useful than chest radiographs for the evaluation of endobronchial tuberculosis. There is a risk of development of bronchial stricture with endobronchial tuberculosis, which can result in some degree of permanently increased airway resistance, with dyspnea on exertion. Lee and Chung4 reported that the length of bronchial involvement in endobronchial tuberculosis varied between 10 and 55 mm on chest CT scans for 26 patients. Bronchial stricture was noted in 25 of those cases, and the CT scans were found to be extremely helpful for measuring both the length and severity of the stricture. Other authors found a somewhat lower incidence (58% of 22 patients) of stricture, although these cases were diagnosed with bronchoscopy rather than CT studies.9 Ip et al10 reevaluated 12 of 20 patients after a mean of 27 months of chemotherapy and found 11 of them to have bronchial stricture. The authors did not think steroid therapy was helpful. A prospective, randomized study of 34 patients confirmed no significant differences in healing rate, stenosis, or pulmonary function with the addition of corticosteroids.11 Rikimaru,12,13 however, observed that the progression of bronchial stenosis could be prevented among patients treated with aerosolized steroids. Although it is controversial, many experts would recommend treating pediatric patients with steroids. Steroid treatment might benefit these patients with minimal risk.14 CONCLUSIONS Despite its relatively low incidence in the United States, pulmonary tuberculosis may present as endobronchial lesions that mimic the findings found in foreign-body aspiration. A high index of suspicion is necessary to diagnose and to treat these cases correctly. Useful adjunctive diagnostic evaluations include chest CT scans, tuberculin skin tests, and acid-fast bacilli stains and cultures of bronchoscopy specimens or gastric aspirates. Serial bronchoscopic or CT evaluations may be helpful after treatment, to assess the degree of bronchial stenosis that is seen commonly despite adequate therapy. This case highlights one of the many different ways that tuberculosis can present among young infants. Although our patient's clinical appearance and chest radiographs were consistent with foreign-body aspiration, he was a little younger than typical aspirators. Physicians must have a heightened awareness regarding tuberculosis, especially in high-risk populations. FOOTNOTES Accepted Nov 16, 2004. No conflict of interest declared. REFERENCES Van Hest R, De Vries G, Morbano G, Pijnenburg M, Hartwig N, Baars H. Cavitating tuberculosis in an infant: case report and literature review. Pediatr Infect Dis J.2004; 23 :667 –670 Division of Tuberculosis Elimination, National Center for HIV, STD, and TB Prevention, Centers for Disease Control and Prevention. Trends in tuberculosis: United States, 1998–2003. MMWR Morb Mortal Wkly Rep.2004; 53 :209 –214 de Blic J, Azevedo I, Burren CP, Le Bourgeois M, Lallemand D, Scheinmann P. The value of flexible bronchoscopy in childhood pulmonary tuberculosis. Chest.1991; 100 :688 –692 Lee JH, Chung HS. Bronchoscopic, radiologic and pulmonary function evaluation of endobronchial tuberculosis. Respirology.2002; 5 :411 –417 Park AH, Fowler SS, Challapalli M. Suspected foreign body aspiration in a child with endobronchial tuberculosis. Int J Pediatr Otorhinolaryngol.2000; 53 :67 –71 Caglayan S, Coteli I, Acar U, Erkin S. Endobronchial tuberculosis simulating foreign body aspiration. Chest.1989; 95 :1164 Wood GS, Gonzalez C, Done S, Albus RA. Endobronchial tuberculosis in children: a case report and review. Int J Pediatr Otorhinolaryngol.1990; 20 :241 –245 Lee JH, Park SS, Lee DH, Shin DH, Yang SC, Yoo BM. Endobronchial tuberculosis: clinical and bronchoscopic features in 121 cases. Chest.1992; 102 :990 –994 Hoheisel G, Chan BK, Chan CH, Chan KS, Teschler H, Costabel U. Endobronchial tuberculosis: diagnostic features and therapeutic outcome. Respir Med.1994; 88 :593 –597 Ip MS, So SY, Lam WK, Mok CK. Endobronchial tuberculosis revisited. Chest.1986; 89 :727 –730 Park IW, Choi BW, Hue SH. Prospective study of corticosteroid as an adjunct in the treatment of endobronchial tuberculosis in adults. Respirology.1997; 2 :275 –281 Rikimaru T. Therapeutic management of endobronchial tuberculosis. Expert Opin Pharmacother.2004; 5 :1463 –1470 Rikimaru T. Endobronchial tuberculosis. Expert Rev Anti Infect Ther.2004; 2 :245 –251 Iseman, M. Clinician Guide to Tuberculosis. Baltimore, MD: Lippincott, Williams & Wilkins; 2000:140...查看详细 (10958字节)

☉ 11333117:Screening and Interventions for Overweight in Children and Adolescents: Recommendation Statement
US Preventive Services Task Force, Rockville, Maryland ABSTRACT The U.S. Preventive Services Task Force (USPSTF) is an independent panel of non-federal experts in prevention and primary care that systematically reviews the evidence of effectiveness and develops recommendations for clinical preventive services. This recommendation addresses the evidence for the accuracy of screening children and adolescents using BMI, the effectiveness of behavioral and pharmacologic interventions in improving health outcomes in these children, and the potential harms of routine screening and intervention. Using USPSTF methodology, an analytic framework with key questions was developed to guide the systematic review, which serves as the basis for this recommendation. The number of children and adolescents who are overweight has more than doubled in the last 25 years. Childhood and adolescent overweight is associated with increased health risks. The USPSTF found insufficient evidence for the effectiveness of behavioral counseling or other preventive interventions with overweight children and adolescents that can be conducted in primary care settings. Currently, available studies are limited by factors such as small sample sizes, poor generalizability, and variable follow-up. Based upon this critical gap in the evidence for effectiveness, the USPSTF concludes that the evidence is insufficient to recommend for or against routine screening for overweight in children and adolescents as a means to prevent adverse health outcomes ("I" recommendation). There are several gaps in the research evidence on screening and interventions for overweight children and adolescents in the primary care setting. Research is needed to provide well-defined and effective approaches to medical and psychological screening in children, as well as effective clinical approaches for the prevention and treatment of overweight in children that can be implemented by primary care clinicians. Key Words: children overweight obesity screening USPSTF Abbreviations: USPSTF, US Preventive Services Task Force RCT, randomized, controlled trial This statement summarizes the US Preventive Services Task Force (USPSTF) recommendations on screening and interventions for overweight in children and adolescents and the supporting scientific evidence and updates the 1996 recommendations contained in the Guide to Clinical Preventive Services, Second Edition.1 Explanations of the ratings and of the strength of overall evidence are given in Appendices A and B, respectively. The complete information on which this statement is based, including evidence tables and references, is included in the summary of evidence2 and evidence synthesis3 on this topic, available on the USPSTF Web site (www.preventiveservices.ahrq.gov). The recommendation is also posted on the Web site of the National Guideline Clearinghouse (www.guideline.gov). SUMMARY OF RECOMMENDATION The USPSTF concludes that the evidence is insufficient to recommend for or against routine screening for overweight in children and adolescents as a means to prevent adverse health outcomes. I recommendation. Approximately 15% of children and adolescents aged 6 to 19 years are overweight and are at risk for diabetes, elevated blood lipids, and increased blood pressure and their sequelae, as well as slipped capital femoral epiphysis, steatohepatitis, sleep apnea, and psychosocial problems. The USPSTF found fair evidence that BMI is a reasonable measure for identifying children and adolescents who are overweight or are at risk for becoming overweight. There is fair evidence that overweight adolescents and children aged 8 years and older are at increased risk for becoming obese adults. The USPSTF found insufficient evidence for the effectiveness of behavioral counseling or other preventive interventions with overweight children and adolescents that can be conducted in primary care settings or to which primary care clinicians can make referrals. There is insufficient evidence to ascertain the magnitude of the potential harms of screening or prevention and treatment interventions. The USPSTF, therefore, was unable to determine the balance between potential benefits and harms for the routine screening of children and adolescents for overweight. CLINICAL CONSIDERATIONS It is important to measure and monitor growth over time in all children as an indicator of health and development. The number of children and adolescents who are overweight has more than doubled since the early 1970s, with the prevalence of overweight (BMI 95th percentile for age and gender) for children aged 6 to 19 years now at 15%. The conclusion that there is insufficient evidence to recommend for or against screening for overweight in children and adolescents reflects the paucity of good-quality evidence on the effectiveness of interventions for this problem in the clinical setting. There is little evidence for effective, family-based or individual approaches for the treatment of overweight in children and adolescents in primary care settings. The Centers for Disease Control and Prevention's Guide to Community Preventive Services has identified effective population-based interventions that have been shown to increase physical activity, which may help to reduce childhood overweight.4 BMI (calculated as weight in kilograms divided by height in meters squared) percentile for age and gender is the preferred measure for detecting overweight in children and adolescents because of its feasibility, reliability, and tracking with adult obesity measures.5 BMI values are Centers for Disease Control and Prevention population-based references for comparison of growth distribution with those of a larger population. Being at risk for overweight is defined as a BMI between the 85th and 94th percentile for age and gender, and overweight is defined as a BMI at or above the 95th percentile for age and gender.6,7 Disadvantages of using BMI include the inability to distinguish increased fat mass from increased fat-free mass and reference populations derived largely from non-Hispanic whites, potentially limiting its applicability to nonwhite populations. Indirect measures of body fat, such as skinfold thickness, bioelectrical impedance analysis, and waist-to-hip circumference, have potential for clinical practice, treatment, research, and longitudinal tracking, although there are limitations in measurement validity, reliability, and comparability between measures. Childhood overweight is associated with a higher prevalence of intermediate metabolic consequences and risk factors for adverse health outcomes, such as insulin resistance, elevated blood lipids, increased blood pressure, and impaired glucose tolerance. Severe childhood overweight is associated with immediate morbidity from conditions such as slipped capital femoral epiphysis, steatohepatitis, and sleep apnea. Medical conditions that are new to this age group, such as type 2 diabetes, represent "adult" morbidities that are now seen more frequently among overweight adolescents. For most overweight children, however, medical complications do not become clinically apparent for decades. DISCUSSION Overweight refers to increased body weight in relation to height when compared with an acceptable weight standard8 and can be related to health risks and problems in children and adolescents. National data that track BMI show an increasing proportion of overweight children and adolescents, as well as an increasing degree of overweight.9 In 1999–2000, the prevalence of overweight (BMI 95th percentile for age and gender) for children aged 2 to 19 years ranged from 9.9% to 15.5%. Prevalence increases with age and is higher in racial-ethnic minorities than in non-Hispanic whites. For example, Mexican American children are significantly more overweight (23.7%) than non-Hispanic white children (11.8%) beginning at age 6.10 Representative national data are unavailable to estimate reliably the prevalence of overweight in Asian children and adolescents. Severe childhood overweight is associated with relatively rare immediate morbidity from conditions such as pseudotumor cerebri, slipped capital femoral epiphysis, steatohepatitis, cholelithiasis, and sleep apnea.11,12 Perhaps the most significant morbidities for overweight children and adolescents are psychosocial.13 Overweight is also associated with a higher prevalence of intermediate metabolic consequences, such as insulin resistance, elevated blood lipids, increased blood pressure, and impaired glucose tolerance. These conditions, which are often asymptomatic, increase the long-term risk for developing diabetes and heart disease in adulthood and are associated with persistent obesity into adulthood. However, the recent emergence of medical conditions that are "new" to overweight children, such as type 2 diabetes, represents the increasing prevalence of more serious, shorter term morbidity.12,14 The USPSTF examined the evidence to determine the benefits and harms of screening and earlier treatment of overweight in children and adolescents in clinical settings for reducing both childhood and adult morbidity and mortality. The USPSTF found no direct evidence that screening for overweight in children and adolescents improves age-appropriate behavioral or physiologic measures or health outcomes. BMI is the most commonly used index of overweight and obesity in childhood and adolescence. Single BMI measures track reasonably well from childhood and adolescence (aged 6–18 years) into young adulthood (aged 20–37 years) as evidenced by longitudinal studies showing low to moderate (r = 0.3–0.4) or moderate to high (r = 0.5–0.9) correlations between childhood BMI and adult BMI measures. Increased tracking (r 0.5) is seen in older children (after age 12–13 years and particularly after sexual maturity), in younger children (aged 6–12 years) and older children who are more overweight (usually above the 95th or 98th percentile), and in younger children with 1 or more obese parents. Gender differences in tracking are not consistent across ages or within age categories, and limited data are available to compare white and black children.15–21 Several fair- to good-quality longitudinal studies have examined the risks associated with childhood overweight and various adult health outcomes, including mortality, morbidity, socioeconomic status, and cardiovascular risk factors.18,22–27 These data are useful in demonstrating health outcomes that may occur when childhood overweight persists into adulthood. However, few of these studies controlled for adult BMI, thereby limiting the independent predictive value of childhood weight measures. One good-quality, longitudinal study that controlled for adult BMI eliminated the association of childhood BMI with adult cardiovascular risk factors.28 Insufficient evidence is available on the effectiveness of interventions for overweight children and adolescents that can be conducted in primary care settings or to which primary care clinicians can make referrals. Most research has investigated intensive group and individual family-based behavioral counseling interventions conducted by specialists in multidisciplinary obesity clinics involving small, selected groups of children aged 8 to 12 years with variable completeness of follow-up. Twelve to 24 months after intensive treatment, these studies have shown 7% to 26% decreases in the mean percentage of overweight, which may be maintained or improved after 5 to 10 years in a subset of patients.29,30 One fair-quality, randomized, controlled trial (RCT) compared a reduced-glycemic-load diet with a conventional reduced-fat diet in adolescents in an intensive 6-month educational and behavioral weight-control program. At 12 months, mean BMI decreased in the reduced-glycemic-load diet group (–1.2 ± 0.7 kg/m2) and increased in the reduced-fat diet group (0.6 ± 0.5 kg/m2; P < .02).31 A fair- to poor-quality RCT examined 3 physical activity interventions that consisted of behavioral modification and general nutrition education components. Lifestyle education only was compared with lifestyle education plus moderate or high-intensity physical activity. No differences were seen between the groups in their percentage of body fat or visceral adipose tissue.32 In a good-quality RCT with predominantly white adolescents, investigators compared an intervention group that received a single, computer-based, individually tailored counseling session followed by 9 to 12 follow-up telephone calls with a control group that received a single, nontailored counseling session in a primary care setting. At 7 months' follow-up, those in the intervention group reported no more physical activity (kcal/kg per day), no less sedentary behavior (minutes per day), and no decrease in kilocalories or percentage of calories from fat than the control group. Changes in mean BMI z scores were not different between groups (P < .09).33 A fair-quality RCT compared weight loss differences of children aged 8 to 12 years in an intervention group that received a comprehensive, family-based behavior change program plus an increased physical activity and decreased sedentary behavior component, with a control group receiving a comprehensive, family-based behavior change program plus an increased physical activity component. At the 12-month follow-up, BMI decreased significantly more in boys in the intervention group (–1.76 ± 1.86 kg/m2) than in boys in the control group or girls in either the intervention or the control group (P < .05). Girls in the intervention group showed a slight BMI increase from baseline, whereas girls in the control group showed a modest decrease in BMI (–0.27 ± 1.37 kg/m2).29 A good-quality RCT compared BMI loss differences of adolescents in an intervention group that was treated with sibutramine with a control group that was treated with a placebo; both groups were in a comprehensive behavioral treatment program. Outcomes, limited to a 12-month follow-up, showed a significantly greater mean BMI loss (4.6 kg; 95% confidence interval: 2.0–7.4) among the adolescents in the intervention group than among those in the control group. Open-label medication that continued for 6 months resulted in weight maintenance in the intervention group and in weight loss in the control group, such that both groups had similar reductions (6.4–8.6%) from initial BMI at 12 months. A large number of patients in the control group had their sibutramine dosage reduced or discontinued because of adverse events.34 No acceptable quality evidence is available for children or adolescents to be able to evaluate the effectiveness of surgical approaches to reducing overweight. There is insufficient evidence on the harms of screening. Potential harms include labeling, induced self-managed dieting with negative sequelae, poor self-concept, poor health habits, disordered eating, or negative impact from parental concerns. These theoretical harms are inferred from studies of limited design. There also is insufficient evidence on the harms of interventions. Among 4 recent behavioral intervention trials, adverse effects were reported in 1 trial.33 Among those who completed an intervention (37 of 44) in a good-quality RCT in a primary care setting, no problematic eating was detected in the adolescent participants after treatment. During the placebo-controlled phase of the sibutramine trial, 19 (44%) of 43 patients in the group that received sibutramine had their dosage reduced or discontinued because of elevated blood pressure, pulse rate, or both. No other adverse events were reported.34 The direct health costs of childhood overweight can only be estimated, particularly because the major impact is likely to be felt in the next generation of adults.11 One recent study estimated that hospital costs for overweight-related disorders in children and adolescents have more than tripled in the past 2 decades on the basis of the doubling of children who have been hospitalized for overweight-related asthma, diabetes, sleep apnea, and gall bladder disease and on lengthened hospital stays for overweight children.35 Future Research There are several gaps in the research evidence on screening and interventions for overweight children and adolescents in the primary care setting. Research that is needed to improve the definition of overweight in children includes refinement of BMI measurement for use in children, longitudinal studies from childhood to adulthood that control for risk factors and sociodemographics, and continued investigation of growth trajectories and susceptible periods for the development of overweight and their role as predictors of adult overweight and obesity. Research is needed to provide well-defined and effective approaches to medical and psychological screening in children. Research is also needed on effective clinical approaches for the prevention and treatment of overweight in children that can be implemented by primary care clinicians, as well as on whether screening and intensive management of cardiovascular disease, diabetes, or other disease risk factors in overweight adolescents is beneficial. Research is needed to examine changes in morbidity among children and adolescents who lose weight and maintain their weight loss and those who regain weight in adulthood. Last, research is needed to help us understand whether preventing current or future excess costs associated with overweight is cost-effective, given different scenarios for treatment reimbursement and intervention effectiveness.36 Recommendations of Other Groups The American Academy of Pediatrics and the Expert Committee from the Maternal and Child Health Bureau, Health Resources and Services Administration,37,38 recommend using BMI to follow the weight status of children and adolescents. Both groups recommend identifying familial risk factors and possible health complications associated with childhood overweight (eg, hypertension, dyslipidemias, insulin resistance). In 2004, the Institute of Medicine developed a prevention-focused action plan, "Preventing Childhood Obesity: Health in the Balance," which calls for "immediate action" and provides recommendations that are "based on the best available evidence—as opposed to waiting for the best possible evidence." The Institute of Medicine action plan also recommends that health professionals routinely track BMI in children and adolescents, in addition to other community-based recommendations.39 APPENDIX A: USPSTF RECOMMENDATIONS AND RATINGS The USPSTF grades its recommendations according to 1 of 5 classifications (A, B, C, D, I), reflecting the strength of evidence and magnitude of net benefit (benefits minus harms): The USPSTF strongly recommends that clinicians provide [the service] to eligible patients. The USPSTF found good evidence that [the service] improves important health outcomes and concludes that benefits substantially outweigh harms. The USPSTF recommends that clinicians provide [the service] to eligible patients. The USPSTF found at least fair evidence that [the service] improves important health outcomes and concludes that benefits outweigh harms. The USPSTF makes no recommendation for or against routine provision of [the service]. The USPSTF found at least fair evidence that [the service] can improve health outcomes but concludes that the balance of benefits and harms is too close to justify a general recommendation. The USPSTF recommends against routinely providing [the service] to asymptomatic patients. The USPSTF found at least fair evidence that [the service] is ineffective or that harms outweigh benefits. The USPSTF concludes that the evidence is insufficient to recommend for or against routinely providing [the service]. Evidence that [the service] is effective is lacking, of poor quality, or conflicting, and the balance of benefits and harms cannot be determined. APPENDIX B: USPSTF STRENGTH OF OVERALL EVIDENCE The USPSTF grades the quality of the overall evidence for a service on a 3-point scale (good, fair, poor): Good: Evidence includes consistent results from well-designed, well-conducted studies in representative populations that directly assess effects on health outcomes. Fair: Evidence is sufficient to determine effects on health outcomes, but the strength of the evidence is limited by the number, quality, or consistency of the individual studies; generalizability to routine practice; or indirect nature of the evidence on health outcomes. Poor: Evidence is insufficient to assess the effects on health outcomes because of limited number or power of studies, important flaws in their design or conduct, gaps in the chain of evidence, or lack of information on important health outcomes. ACKNOWLEDGMENTS This is AHRQ Publication No. AHRQ 05-0574-A and is being published here first. MEMBERS OF THE USPSTF Members of the US Preventive Services Task Force are Ned Calonge, MD, MPH, Chair, USPSTF (Acting Chief Medical Officer and State Epidemiologist, Colorado Department of Public Health and Environment, Denver, CO); Janet D. Allan, PhD, RN, CS, Vice-Chair, USPSTF (Dean, School of Nursing, University of Maryland, Baltimore, Baltimore, MD); Alfred O. Berg, MD, MPH (Professor and Chair, Department of Family Medicine, University of Washington, Seattle, WA); Paul S. Frame, MD (Family Physician, Tri-County Family Medicine, Cohocton, NY, and Clinical Professor of Family Medicine, University of Rochester, Rochester, NY); Joxel Garcia, MD, MBA (Deputy Director, Pan American Health Organization, Washington, DC); Russell Harris, MD, MPH (Professor of Medicine, Sheps Center for Health Services Research, University of North Carolina School of Medicine, Chapel Hill, NC); Mark S. Johnson, MD, MPH (Professor and Chair, Department of Family Medicine, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, NJ); Jonathan D. Klein, MD, MPH (Associate Professor, Department of Pediatrics, University of Rochester School of Medicine, Rochester, NY); Carol Loveland-Cherry, PhD, RN (Executive Associate Dean, School of Nursing, University of Michigan, Ann Arbor, MI); Virginia A. Moyer, MD, MPH (Professor, Department of Pediatrics, University of Texas Health Science Center, Houston, TX); C. Tracy Orleans, PhD (Senior Scientist, The Robert Wood Johnson Foundation, Princeton, NJ); Albert L. Siu, MD, MSPH (Professor and Chairman, Brookdale Department of Geriatrics and Adult Development, Mount Sinai Medical Center, New York, NY); Steven M. Teutsch, MD, MPH (Executive Director, Outcomes Research and Management, Merck & Company, Inc, West Point, PA); Carolyn Westhoff, MD (Professor of Obstetrics and Gynecology and Professor of Public Health, Columbia University, New York, NY); and Steven H. Woolf, MD, MPH (Professor, Department of Family Practice and Department of Preventive and Community Medicine and Director of Research, Department of Family Practice, Virginia Commonwealth University, Fairfax, VA). For a list of current Task Force members, go to www.ahrq.gov/clinic/uspstfab.htm. FOOTNOTES Accepted Apr 19, 2005. Recommendations made by the US Preventive Services Task Force are independent of the US government. They should not be construed as an official position of the Agency for Healthcare Research and Quality or the US Department of Health and Human Services. No conflict of interest declared. REFERENCES US Preventive Services Task Force. Guide to Clinical Preventive Services. 2nd ed. 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Relationship of childhood obesity to coronary heart disease risk factors in adulthood: the Bogalusa Heart Study. Pediatrics.2001; 108 :712 –718 Epstein LH, Roemmich JN, Raynor HA. Behavioral therapy in the treatment of pediatric obesity. Pediatr Clin North Am.2001; 48 :981 –993 Epstein LH, Valoski A, Wing RR, McCurley J. Ten-year outcomes of behavioral family-based treatment for childhood obesity. Health Psychol.1994; 13 :373 –383 Ebbeling CB, Leidig MM, Sinclair KB, Hangen JP, Ludwig DS. A reduced-glycemic load diet in the treatment of adolescent obesity. Arch Pediatr Adolesc Med.2003; 157 :773 –779 Gutin B, Barbeau P, Owens S, et al. Effects of exercise intensity on cardiovascular fitness, total body composition, and visceral adiposity of obese adolescents. Am J Clin Nutr.2002; 75 :818 –826 Saelens BE, Sallis JF, Wilfley DE, Patrick K, Cella JA, Buchta R. Behavioral weight control for overweight adolescents initiated in primary care. 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☉ 11333118:The Food and Drug Administration’s Deliberations on Antidepressant Use in Pediatric Patients
Children’s Hospital, Child and Adolescent Services Research Center, San Diego, California Departments of Epidemiology and Biostatistics and Pediatrics, University of California, San Francisco, California Department off Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee MGH Center for Child and Adolescent Health Policy, Harvard Medical School, Boston, Massachusetts ABSTRACT On February 2, 2004, the Food and Drug Administration organized a joint meeting of the Neuro-Psychopharmacologic Advisory Committee and Pediatric Subcommittee of the Anti-Infective Drugs Advisory Committee to examine the occurrence of suicidality in clinical trials that investigate the use of the newer antidepressant drugs in pediatric patients. Committee members reconvened on September 13–14, 2004, and concluded that there was a causal link between the newer antidepressants and pediatric suicidality. This article provides a summary of the Food and Drug Administration deliberations for the pediatric clinician. We also provide research, regulation, education, and practice implications for care for children and adolescents who may be eligible for treatment with these medications. Key Words: depression pediatrics children adolescents antidepressants suicide regulation mental health FDA Abbreviations: FDA, Food and Drug Administration MDD, major depressive disorder DD, dysthymic disorder BPD, bipolar disorder CBT, cognitive behavioral therapy SSRI, selective serotonin reuptake inhibitor FDAMA, Food and Drug Administration Modernization Act BPCA, Best Pharmaceuticals for Children Act MHRA, Medicines and Healthcare Products Regulatory Agency TADS, Treatment for Adolescents With Depression Study On February 2, 2004, the Food and Drug Administration (FDA) organized a joint meeting of the Neuro-Psychopharmacologic Advisory Committee and Pediatric Subcommittee of the Anti-Infective Drugs Advisory Committee and expertise consultants to evaluate the safety of selected antidepressants in children and adolescents. Specifically, these 2 committees were charged with examining the occurrence of suicidality (suicidal thinking, behavior, or attempts) in clinical trials that investigate the use of the newer antidepressant drugs in pediatric patients with major depressive disorder (MDD) and other psychiatric disorders. At the February meeting, committee members concurred with the FDA’s decision to reanalyze data available from current pediatric trials, which had been conducted by or in conjunction with pharmaceutical companies. On September 13–14, 2004, the Neuro-Psychopharmacologic Advisory Committee and the newly formed Pediatric Advisory Committee and consultants met again to review these data and advise the FDA on the use of these medications in pediatric patients. The committee’s conclusion: there was a causal link between the newer antidepressants and pediatric suicidality. On October 15, 2004, the FDA ordered pharmaceutical companies to add to antidepressant advertisements, package inserts, and information sheets developed for patients and clinicians a "black-box" warning (a statement in prominent, bold-faced type and framed by a black border) regarding pediatric use. By issuing this warning, the federal drug regulators imposed one of their toughest requirements, short of banning a medication. The intense controversy surrounding these antidepressants and the concurrent public media coverage have spawned widespread discussion regarding the use of antidepressants in pediatric patients. The question of whether there is a causal link between the newer antidepressants and suicidality has major consequences. Suicidality is associated with several of the mental health disorders for which these medications are used, and treatments to protect against this outcome are desperately needed. However, it is equally important not to indiscriminately give youths medications that may increase risk for suicidality. This article provides a summary of the FDA deliberations for the pediatric clinician. We begin by reviewing the scope of problems that children and adolescents with depression and other psychiatric disorders face. We then review the role of the FDA in evaluating these medications in the past decade and summarize the information presented to members of the committees. We delineate the decisions reached by the FDA committees during their deliberations. Last, we provide research, regulation, education and practice implications for quality care for children and adolescents who may be eligible for treatment with these medications. SCOPE OF THE PROBLEM Mental Health Needs of Children and Adolescents Recent estimates of the rates of mental health disorders in pediatric populations are staggering, suggesting that at least 1 in 10 children and adolescents has mental illness severe enough to cause some level of impairment.1–5 Taken in the aggregate, mental health disorders are the most common pediatric disorders that negatively affect quality of life across the domains of home, school, and peer functioning. Many youths with these disorders go on to display an inability to function fully as adults, costing society in terms of both human and fiscal resources.6 Of particular concern are the mood disorders, including MDD, dysthymic disorder (DD) and bipolar disorder (BPD). These disorders can be identified in youths of all ages but become increasingly prevalent in adolescence, with cumulative rates of 16% to 22% by late adolescence.3,5 Although MDD, DD, and BPD can result in serious morbidity, including interpersonal difficulties, poor social and school performance, family problems, and substance abuse, these disorders also carry with them the very real possibility of suicidal ideation, attempts, and completion. Suicidality is common in youths; data from the Centers for Disease Control and Prevention’s National Youth Risk Behavior Survey for the year 2003 indicated that 16.9% of students in grades 9 to 12 had seriously considered suicide and 2.9% had made an injurious suicide attempt during the 12 months preceding the survey.7 Data from the year 2001 indicate that although rates of suicide completion decreased in the 1990s, suicide was documented as the third leading cause of death among young people aged 10 to 24 years and accounted for 6.8% of total deaths in youths aged 10 to 14 years and 11.9% of youths aged 15 to 24.8 The high prevalence rates of the mood disorders and the serious consequences of suicidality have prompted research regarding possible treatments, including both psychotherapeutic and psychopharmacologic regimens. In the past decade, studies have provided a growing evidence base for psychotherapeutic treatments for these disorders, especially cognitive behavioral therapy (CBT).9 Psychopharmacologic treatments have also been commonly used in the treatment of mood disorders in youths for a variety of reasons, including child, family, or provider choice; lack of responsiveness to psychotherapeutic techniques; possible synergism of combined psychotherapeutic medication treatment strategies; and limited access to psychotherapeutic services (as a result of provider, insurance, or geographic constraints). The use of antidepressants in pediatric patients, particularly the selective serotonin reuptake inhibitors (SSRIs), has rapidly increased in the past decade. Because of their limited anticholinergic side effects and cardiovascular toxicity, SSRIs offered several therapeutic advantages over earlier antidepressants.10 In the 1990s, the SSRIs were used increasingly as first-line treatment for affective disorders in pediatric patients.11–15 Published research estimated that the rate of antidepressant use in youths aged 18 years and younger was 1.0 per 100 people by 1996.16 More recent analyses, conducted by the FDA Division of Surveillance, Research & Communication Support on data collected through the IMS Health, National Prescription Audit Plus and National Disease and Therapeutic Index programs, found that an estimated 10.8 million prescriptions were dispensed in 2002 for youths aged 1 to 17 years. The primary pediatric diagnoses associated with the use of the SSRIs and newer antidepressants were anxiety disorders in children aged 1 to 11 years and mood disorders in adolescents aged 12 to 17 years. More than 60% of the prescriptions for children aged 1 to 11 years and adolescents aged 12 to 17 years were prescribed by psychiatrists, with 17% of prescriptions written by pediatricians.17 Status of Drug Testing for Safety and Efficacy in Pediatric Patients Much of the use of these newer antidepressants occurred "off-label," without adequate testing regarding their safety and efficacy in pediatric populations. Off-label usage of many medications in pediatric populations had always been common and necessary, as most drugs had not been studied adequately in children. In the 1990s, the extent of off-label usage for medications such as the SSRIs in pediatric patients became increasingly important. Research in many clinical areas suggested very real differences in the absorption, distribution, metabolism, excretion, efficacy, and safety of some medications in children and adolescents compared with adults.18 Most salient to this paper were a series of published findings from multiple studies that provided no evidence of efficacy of the typical tricyclic antidepressants in the pediatric population, despite evidence to the contrary in adults.19–26 The absence of specific pediatric labeling information potentially exposes pediatric patients to both safety- and efficacy-related risks. First, if pediatric pharmacokinetic studies are not available and dosing regimens are extrapolated from adult data, then pediatric patients might experience potential adverse reactions that would not be expected, either as a result of physiologic differences between children and adults or as a result of improper dosing. Second, pediatric patients might receive ineffective treatment through underdosing or through treatment with a less effective medication in the face of insufficient pediatric information about a more effective drug.27 These concerns led to the passage of several seminal policy initiatives in the 1990s regarding medications in pediatric populations. On December 13, 1994, the FDA published its Pediatric Labeling and Extrapolation Regulation (59 FR 64240), with the aim to foster the study of drug pharmacokinetics, efficacy, and safety in youths.28 The FDA proposed an additional guideline on August 15, 1997, which required new drugs to have labeling regarding how the medication could be used safely in pediatric patients. Two months later, on November 21, 1997, Congress enacted Section 505a of the Food and Drug Administration Modernization Act (FDAMA),29 further addressing the needs for improved information about drug use in youths. This legislation included a provision that authorized market exclusivity incentives to manufacturers who voluntarily conducted and submitted to the FDA safety and efficacy studies in pediatric patients in concert with FDA guidance documents. The drugs that required such studies would be decided by the FDA in consultation with pediatric organizations; the SSRIs and other new antidepressants were included in the list of medications that needed additional studies.30 After passage of FDAMA, the FDA received 8 pharmaceutical reports investigating the effects of antidepressants on pediatric patients. Over the next several years, additional regulations regarding the FDA review process for pediatric medications were put into place. In 1998, the FDA published the "Pediatric Rule," which required that all new applications with new active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of administration include an assessment of efficacy in all relevant pediatric subpopulations, unless the sponsoring organization had obtained a waiver or deferral of pediatric studies.27 In 2002, Congress passed the Best Pharmaceuticals for Children Act (BPCA),31 which renewed the exclusivity clause, provided a process for off-patent drug development, required public posting of results, and mandated reporting of all adverse events for 1 year after exclusivity was granted.28 This was quickly followed in 2003 by the Pediatric Research Equity Act,32 requiring the study of drugs and biologics for pediatric populations and creating a new Pediatric Advisory Committee to advise the FDA. Why a Focus on the Newer Antidepressants As part of the regulatory process, the FDA reviewed studies that were provided by pharmaceutical companies to identify any adverse effects identified during the medication trials. The FDA reviewer for the paroxetine study in 2003 noted that events suggestive of possible suicidality were categorized under the term "emotional lability" rather than under a phrase more directly suggestive of suicidality, possibly obscuring any results regarding potentially serious adverse events. This raised concern that additional adverse events might have been misclassified. After an internal review, the FDA requested that GlaxoSmithKline, the manufacturer of paroxetine, separate out all terms suggestive of suicidal ideation, attempts, or completion. The possibility that these medications could trigger suicidality was not unheard of; similar concerns had been raised in adults during the early 1990s.33–37 In 1991, the FDA had assembled an expert panel to probe reports that suggested a causal link between SSRIs and suicidality in adults. The advisory group concluded that there was insufficient evidence for causality.38 Questions regarding both the efficacy and the safety of antidepressants in adults, however, have continued to be raised.39–46 In addition, 2 studies in the literature reported increased psychiatric adverse effects in children and adolescents who used SSRIs.47,48 One GlaxoSmithKline-sponsored study did report more psychiatric adverse events with paroxetine compared with placebo,49 but the article failed to report that the increase was statistically significant and claimed that because the clinical investigators did not consider these events to be related to paroxetine, causality could not be determined. In response to the FDA request, GlaxoSmithKline conducted a reanalysis of their data. The revised analyses documented an increased risk for suicidality in pediatric patients who take paroxetine compared with placebo, which was greater than what would be expected by chance alone. This report was submitted in May 2003 to the Medicines and Healthcare Products Regulatory Agency (MHRA; the British equivalent to the FDA) in the United Kingdom and to the FDA. On June 10, 2003, the MHRA ruled that the use of paroxetine by general practitioners was contraindicated for children under the age of 18. This contraindication, however, did not prohibit psychiatrists from using these medications if they believed that they were indicated. Nine days later, the FDA issued a public health advisory, suggesting that paroxetine should not be used in children and adolescents for the treatment of MDD until the results of additional analyses became available. The FDA also asked pharmaceutical manufacturers of 8 other newer antidepressants to review data from their research trials for the occurrence of suicidality in pediatric patients. These medications included 4 other SSRIs (fluoxetine, sertraline, fluvoxamine, and citalopram) as well as several of the atypical antidepressants (bupropion, venlafaxine, nefazodone, and mirtazapine; Table 1). Several events followed this request. First, Wyeth, the producers of venlafaxine, addressed the FDA’s mandate by voluntarily changing their labels to discourage use of venlafaxine in pediatric patients and publishing a Dear Health Care Professional letter in August 22, 2003. Both the label alteration and the letter reflected increased reports of hostility and suicidality in pediatric patients who participated in the venlafaxine arm during clinical trials, particularly those trials of medication in youths who had a diagnosis of MDD. Second, the data that were available for each of the 8 antidepressants (other than paroxetine) were reviewed by FDA staff; their studies suggested an increase in the risk for suicidality. Although the increase in suicidality in many individual trials was not statistically significant, most studies had trends in that direction and none had confidence intervals that excluded a significant increase in suicidality. This association prompted the FDA to release an updated public health advisory on October 27, 2003, stating that preliminary data showed an excess of reports of suicidality in the SSRIs and the related antidepressants but that there was a need for additional data analyses before anything definitive could be concluded. Last, as the FDA received and reviewed the pharmaceutical companies’ reports on pediatric suicidality and the newer antidepressants, it became clear that there was a lack of methodologic uniformity across the drug manufacturers’ responses. Different analyses were performed by each company with respect to ascertaining all events of potential suicidality in the drug treatment group as well as in control subjects. For example, 1 company acknowledged that they had excluded cases that were not considered "treatment emergent." Another company selected cases on the basis of knowledge of treatment assignment. Review of excluded cases by another drug sponsor demonstrated substantial differences in risks for suicidality between the FDA analysis and the analysis submitted by the sponsor.50 INFORMATION AVAILABLE TO THE ADVISORY COMMITTEE Because of the nonstandardized use of definitions of suicidality across the studies, the FDA contracted with experts at Columbia University to develop a standard classification scheme for reclassifying all adverse events suggestive of suicidality across available studies. In addition, the Neuro-Psychopharmacologic Advisory Committee and the Pediatric Subcommittee of the Anti-Infectives Committee were jointly convened to review the data and provide recommendations to the FDA. Also invited were expert consultants in pediatric and psychiatric care processes, psychopharmacology, and epidemiology and biostatics. These 2 advisory committees and consultants first met in February 2004 to review preliminary information regarding the antidepressants and to approve the FDA’s analytic plan. In September 2004, the newly formed Pediatric Advisory Committee to the FDA and the Neuro-Psychopharmacologic Advisory Committee reconvened. Materials that were reviewed by the committees at this meeting addressed both safety and, to a lesser extent, efficacy of the newer antidepressants. These materials came primarily from 3 sources: (1) narrative testimonies from >100 families, health care providers, and representatives from consumer groups; (2) the FDA reanalyses of the data from the pharmaceutical trials recoded by Columbia University researchers; and (3) an additional National Institute of Mental Health–funded randomized clinical trial on the use of fluoxetine in pediatric patients. Narrative Testimonies During both the February and the September meetings, committee members heard from family members, community organizations, and health care professionals regarding the use of newer antidepressants in pediatric patients. The committee did not view these narratives as evidence about a causal link between the newer antidepressants and suicidality because case reports of this nature are subject to both sample and information biases. However, the members did see the narratives as important to their deliberations in 3 ways. First, the narratives reminded committee members of the importance of weighing potential harm to families regardless of the decisions made regarding a causal link between the newer antidepressants and suicidality. Second, some of the narratives also described hostile acts of violence to others by youths who took these medications and emphasized the importance of studies to examine these additional adverse effects of antidepressants.33,48 Third, families described the use of these medications for indications such as nail biting, insomnia, and migraine headaches as well as lack of follow-up by prescribing physicians, suggesting that non–evidence-based, casual use of these medications might be occurring and that this perspective needed to be shared with professional medical organizations. Data Classified by Columbia University and Reanalyzed by the FDA Data from the Columbia Project was also presented to the Advisory Committees. The FDA had pooled data from 24 studies to provide to the Columbia investigators to examine the association between suicidality and the newer antidepressants. These studies included published and unpublished studies conducted by pharmaceutical sponsors for a variety of mental health indications as well as data from the Treatment for Adolescents with Depression Study (TADS), a randomized, clinical trial that compared fluoxetine, CBT, and combination therapy with placebo.51 The FDA contracted with suicide experts at Columbia University to review all narratives of reports of adverse events from these trials and recode the narratives with respect to suicidality. Of the 24 studies, only 109 events were classified as pertinent to the FDA’s question regarding suicidality. It is important to note that there were no cases of completed suicide in the 24 studies. The FDA then conducted a reliability study on the Columbia classification and used the recoded narratives in a pooled analysis of the data. Because many of the studies that were reviewed by the FDA Advisory Committees were conducted under the FDAMA provisions described above, before implementation of the BPCA and Pediatric Research Equity Act legislation, it is important to review how this legislation may have affected the data that were available to both the Columbia and the FDA investigators. FDAMA required that, if requested by the FDA, manufacturers provide documentation of at least 1 clinical investigation in pediatric age groups in which the drug’s use was anticipated, although some group other than the manufacturer could perform the study. In addition, studies needed to be conducted and filed with the FDA before expiration of an existing exclusivity period to gain an additional 6 months of exclusivity. However, the FDA did not require the manufacturer to provide definitive information on pediatric efficacy (ie, the results could be inconclusive). In addition, exclusivity not only would apply to the product being studied in the pediatric population but also would be expanded to cover all formulations, dosage forms, and indications that contained the same active moiety.52 Companies could have substantial financial benefit from the exclusivity extension if the drug had a large adult market. The studies that were provided to the FDA regarding the use of antidepressants in pediatric patients thus had several limitations. First, because many of these drugs were already in use in adults, pharmaceutical companies were allowed to estimate study sample size and pediatric dosages on the basis of studies that were conducted in adults. Pediatric pharmacokinetic studies were not required. Second, the absence of requirement that the studies demonstrate efficacy may have provided less incentive to ensure careful management of the studies. These criteria also may have influenced study design; studies often were short in duration (none was longer than 16 weeks), with small sample sizes. Committee members were informed by the FDA that sponsors may have had more incentive to complete studies quickly for new drugs or off-label drugs rather than to maintain the quality of the study at the level required by the FDA. Fourth, because the studies were not specifically designed to assess suicidality, most were not powered adequately. The studies also lacked detailed, methodical instrumentation to capture these results. Most of the studies did not use specific instruments to identify adverse events such as suicidality; rather, adverse events were collected using open-ended probes. A recent study by Greenhill et al.53 showed that the open-ended method is more likely to result in underreported adverse events. Finally, investigators for the different studies used a variety of exclusionary criteria, diagnostic mechanisms, data collection methods, and coding strategies, making it difficult to compare across the studies. For example, only 4 of the 24 studies did an extensive diagnostic screen at the beginning of the trial to delineate participants’ diagnosis and the presence of any coexisting conditions. Studies varied as to whether they evaluated a youth for BPD before inclusion. Only 11 of the 24 studies excluded children when there was a family history of BPD. Studies varied in their inclusion of youths with a history of suicidality; 5 of the studies permitted youths who were identified as being at risk for suicide (at baseline), and 16 studies did not exclude youths despite a history of suicidal attempts. Fifteen of the studies examined the use of the newer antidepressants in MDD; the others studied their use in obsessive compulsive disorder (4), anxiety disorders (3), and attention-deficit/hyperactivity disorder (1).54 These limitations make the results of the pooled analyses even more compelling. When all 24 studies were pooled, the rate of possible or definitive suicidality among youths who were assigned to receive antidepressants was 2.19 times greater compared with youths who were assigned to the placebo groups (95% confidence interval: 1.50–3.19).55 An excess of suicidality in 1 group at least this large would occur by chance only 1 time in 20000 (P = .00005). Importantly, most of the limitations of the data (small sample size, inadequate power, wide variations in sample inclusion, and possible misclassification of outcomes) would make it more, not less, difficult to detect differences between groups in randomized, double-blind trials, causing falsely low estimates for the relative risk of suicidality and falsely high P values.56 Members of the 2 committees also realized the importance of weighing the benefit-to-harm ratio of these medications for use in pediatric patients. Limited information regarding efficacy was summarized for committee members on the efficacy trials, specifically, that FDA analyses indicated that only 3 of the 15 trials of the newer antidepressants in youths with depression found a statistically significant benefit of drug over placebo.55 However, specific analyses were not shared with committee members, and committee members were not able to determine efficacy adequately from the brief amount of information provided. Two published meta-analyses that delineated the limitations and potential biases of the available studies were also presented. These meta-analyses suggested that the efficacy of the antidepressants in children and youths was likely to be overestimated, because published trials had more favorable results than unpublished trials.57,58 Alternatively, the committees were cautioned that the time limitations under FDAMA might have subjected the trials to a type II error, ie, missing a finding when one was present. One other aspect regarding the FDA analyses bears consideration. There were no completed acts of suicide in the 24 studies; the causal link demonstrated in the FDA analyses therefore focused entirely on suicidal ideation and behavior. Analyses were conducted to examine these 2 outcomes as a single construct. Data From the TADS Study The committees last examined data from the recent TADS study alluded to above. The TADS study recruited a volunteer sample of 439 patients who were between the ages of 12 and 17 years and had a diagnosis of MDD. Patients were randomized to 4 treatment arms: (1) fluoxetine alone, (2) CBT alone, (3) CBT with fluoxetine, and (4) placebo. Youths in all 4 arms of the study, including placebo, improved significantly on the primary outcome, the Children’s Depression Rating Scale–Revised, although fluoxetine with CBT was the only treatment arm that showed statistical significance compared with placebo. On some of the other outcome measures, planned pairwise contrasts indicated that the combination treatment and fluoxetine alone were superior to placebo, whereas CBT was not. Thus, although there was evidence for the efficacy of treatment with fluoxetine alone or in combination with CBT in the TADS study, the high placebo response rate indicates why families and clinicians believe that these medications are effective, even if 85% of the benefits observed also would have occurred with placebo. Suicidal ideation was present in 29% of the TADS sample at baseline, despite the exclusion of youths who were at high risk for suicidality. Ultimately, suicidality improved significantly in all 4 treatment arms. Suicide attempts were rare (1.6%), and there were no completed suicides. The only statistically significant adverse finding was an odds ratio of 2.19 (1.03–4.62) for harm-related adverse events in youths who were taking fluoxetine compared with youths who were not taking fluoxetine. Data from the TADS study also suggested a possible protective effect of CBT against suicidality when used in combination with fluoxetine. CONCLUSIONS OF THE FDA ADVISORY COMMITTEES AND CONSULTANTS Members reached the following 4 conclusions. First, the reclassification of adverse events conducted under the direction of Columbia University as described to the committee members seemed to have been conducted appropriately with sufficient scientific rigor to decrease biases inherent in previous classification schemas and to draw conclusions, despite serious limitations of the available data. Second, analyses that were conducted using the reclassified data demonstrated that there was an increased risk for suicidality causally related to use of the SSRIs and related antidepressants. Third, although the data in aggregate supported the finding of increased suicidality, the studies were too underpowered to draw any conclusions regarding safety for specific antidepressant agents or for specific disorders. The committees also considered whether to include "older" antidepressants, although the committees had not specifically reviewed data on these drugs. Monoamine oxidase inhibitors and tricyclics had even less evidence for efficacy than the SSRIs and the newer atypical antidepressants and high risks (especially the possibility of suicide from overdoses). The committees decided to recommend to the FDA that all antidepressants, both current and future products, have language added to their label regarding the risk for suicidality. Finally, the committee addressed the issue of whether the FDA should strengthen the existing warning on the label of antidepressants or pursue a more aggressive course by applying a black-box warning for antidepressants. Black-box warnings are used to signal an extremely serious risk and have implications for the public marketing of drugs with this type of warning. Committee members were in agreement that warnings on antidepressants needed to have sufficiently strong wording to provide adequate protection to the public. Many committee members and public speakers expressed concerns that the black-box warning might decrease access to treatment for some youths, if the warning made nonpsychiatrists reluctant to prescribe the drugs. Members cited the current limited number of child and adolescent psychiatrists and the small numbers projected for the next decade.59 In addition, many members commented on the difficulties encountered in gaining access to psychotherapeutic mental health services for some pediatric subpopulations, including inner-city underserved, underinsured youths and youths who reside in rural communities. The final vote was in favor of the black-box warning. Committee members also urged the FDA to develop an antidepressant MedGuide, patient educational material to be included with medications that are distributed by pharmacists when an antidepressant prescription is filled for an adult or a pediatric patient. Members recognized that this strategy would provide families and caregivers access to education about antidepressants but would not guarantee that the patient, family, and clinician would discuss the risk/benefit ratio of these medications before initiation of medication treatment. It should be noted that the committees did not address the specific wording of the black-box warning. The committees did not recommend that antidepressants be contraindicated for pediatric patients, as had been decided by the MHRA in the United Kingdom. Although a "contraindication" in the United Kingdom would confine use to patients who are cared for by subspecialists, a contraindication in the United States signifies that these medications could not be used in pediatric patients. Committee members were unwilling to ban medications that in the future may demonstrate efficacy in some patients, given adequately designed research studies, and did not want to preclude treatment for those patients. RECOMMENDATIONS During the deliberations of the committees, many issues regarding the diagnosis and treatment of children and adolescents with MDD and other mood disorders were raised. Although both committee members and public speakers individually urged that a number of strategies be taken to address these issues, no formal recommendations were made by the committees. However, as members of and consultants to the committees, we propose that a number of follow-up actions be considered by the appropriate federal agencies, professional organizations, and health plans. These steps fall into 2 categories: (1) research and regulations and (2) clinical education and practice. Research and Regulations The debate over the newer antidepressants highlights considerable flaws in the current system of medication testing and approval. The SSRI controversy was quickly followed in the fall of 2004 by other signs and symptoms of a system of regulation and research needing change, including (1) reports of selective dissemination of data regarding adverse drug reactions with other medications such as rofecoxib (Vioxx)60 and cerivastatin (removed from the market in 2001),61,62 (2) federal hearings by the Committee on Energy and Commerce regarding the FDA’s role in protecting the public health and publication and disclosure issues, and (3) the ongoing lawsuit filed by the New York Attorney General against GlaxoSmithKline claiming suppression of adverse events information regarding Paxil. Journal editors have also called for changes in the current system; several journals now require that researchers publicly register all trials if they plan to pursue publication at a later date. The FDA has asked the Institute of Medicine to conduct a report on the current system of drug safety assurance and provide the FDA with recommendations for change. In addition, the FDA recently announced a plan to restructure their current drug testing, approval, and monitoring system.63 We advocate a number of changes in the current system and available research: Guarantee the FDA sufficient independence, authority, and freedom from political and economic influence to demand high-quality drug trials. These studies should pass a peer-review process that ensures use of diagnostic assessments, standardized measures, and appropriate data collection and coding. Develop a mechanism for postmarketing surveillance, whether as part of the FDA or through a separate agency that does not rely on physicians and pharmaceutical companies to report voluntarily problems with new drugs after the mandated period required of the pharmaceutical companies. New drugs may introduce new risks that are relatively rare and may be not apparent until the medication has been in wide use after marketing. Push for disclosure to the public of all safety and efficacy results found in drug trials, including those that do not support the hypothesis being tested or that are contrary to the intended outcome. Provide disclosure of results, in a standardized and interpretable format, on publicly available clinical trial registries such as the new US government web site www.clinicaltrials.gov and in other informational sources that are available to the public and the medical professions. Additional study is needed regarding suicidality when these medications are used for other indications, such as anxiety. Data from existing pharmacologic studies presented to the FDA as well as available large data sets, such as the data from the Research Unit on Pediatric Psychopharmacology Anxiety Study Group’s randomized, clinical trial regarding the efficacy of the SSRIs in childhood anxiety, could potentially be examined to answer this question more specifically.64 Encourage long-term studies in larger samples that are more reflective of the target population to examine better both the efficacy and the safety of the newer antidepressants. These studies should be conducted across mental health conditions for which the newer antidepressants are used, including the mood, anxiety, and obsessive-compulsive disorders. They should examine both hostility and suicidality as outcomes and consider the role of pharmacogenetic variation. Because of the rarity of these types of adverse events, studies will probably not be undertaken by individual pharmaceutical companies and will require substantial fiscal and scientific support from the National Institutes of Health. There is legal precedent for this action; the 2002 BPCA ruling does authorize several institute funding mechanisms as vehicles for funding studies of drugs if the manufacturers of those drugs decline to conduct the requested safety and efficacy studies. Clinical Education and Practice One of the major concerns of the committees was the need for access to effective and safe care for children and adolescents with mental health disorders, provided by thoughtful, well-trained clinicians. Although the FDA regulates pharmaceutical products, its role should not include the regulation of the practice of medicine. Nonetheless, the black-box warning developed by the FDA includes specific language detailing that physicians who prescribe these medications should closely monitor patients with observation that "would generally include at least weekly face-to-face contact during the first 4 weeks of treatment" with specific visit intervals specified after those 4 weeks.65 Professional organizations, including the American Academy of Pediatrics (AAP) and the American Academy of Child and Adolescent Psychiatry, have rapidly mobilized internal working groups to respond to the FDA’s proposed black-box warning. Both organizations are concerned about the potential access issues for patients and their families, reimbursement under many health plans, and the medicolegal implications of specified numbers and types of visits. In addition, both organizations are developing provider and family fact sheets regarding these medications and recommended practice guidelines. The American Academy of Child and Adolescent Psychiatry is already fast-tracking revision of their 1998 guidelines on the use of antidepressants in children and adolescence.66 Similarly, evidence-based guidelines for the diagnosis and treatment of MDD, DD, obsessive compulsive disorder, and the anxiety disorders need to be updated. We see the AAP, the American Academy of Family Physicians, and the National Association of Pediatric Nurse Practitioners as critical primary care partners in the development of these guidelines. The scope of pediatric mental health disorders is predicted to continue to grow; recent evidence compiled by the World Health Organization indicates that, by the year 2020, these disorders will increase proportionately by >50%, internationally, to become 1 of the 5 most common causes of morbidity, mortality, and disability in children.6 Clearly, out of necessity, the management of these disorders will continue to fall to primary care clinicians. Professional organizations will have to balance the need to ensure the provision of high-quality care with the limited availability of psychiatric providers in certain communities and the potential medicolegal complications of overly rigid practice pattern standards. We recommend that these organizations partner with medical education groups and health plans to Design practical tools and educational programs to assist the primary care clinician in the diagnosis, referral, and treatment of these disorders and in the evaluation of risk factors for suicidal ideation and attempts and ensure that the content of these programs address practical aspects of care, including risk/benefit ratios of psychotropic medication treatment, indications for pharmacologic treatment, the use of psychotherapy both as solo and as adjuvant therapy, the content of informed consent and discussions regarding risks and benefits, mechanisms for monitoring pediatric patients for both benefits and side effects from treatment, and the importance of and mechanisms for reporting adverse events. Concurrently, conduct studies to determine the role of primary care clinicians in the identification and treatment of youths with mood disorders. There is currently a paucity of research regarding the ability of primary care clinicians to identify correctly youths with these types of disorders and then partner with other professionals in their treatment. Similarly, studies regarding feasible and effective follow-up and monitoring schedules need to be conducted in primary care settings. Last, 3 events in winter 2004–2005 that have implications for ongoing medical education included (1) announcements of previously unreported adverse effects with other psychotropic medications including atomoxetine (Strattera) and mixed amphetamine salts (Adderall), (2) the recent publication of several contrasting large-scale studies that examined the association between suicide attempts and the SSRIs in adults,40,41,67 and (3) another recently published observational study that found no association between suicide attempts and the SSRIs in pediatric patients.68 These events highlight that medical knowledge regarding medications is not static. We need to remind the medical community, health plan administrators, and the public that treatment recommendations and practice standards must continue to be reexamined and updated to incorporate new knowledge as it becomes available. CONCLUSIONS The FDA Commission hearings on the use of antidepressants in youths raised a number of important issues regarding the safety and the efficacy of the SSRIs and related antidepressant medications. Furthermore, the investigation brought attention to the needed areas of improvement in our current system for drug approval and postmarketing surveillance in pediatric as well as adult populations. It will require strong advocacy, greater oversight, and cross-organizational partnerships between clinicians, professional organizations, federal agencies, health plans, and consumers to ensure the provision of safe and efficacious treatments for children and adolescents with mental health needs. ACKNOWLEDGMENTS We thank the families, clinicians, and professionals who provided testimony and advice regarding this important issue. We also thank all members of the advisory committees for thoughtful contributions during the proceedings. Last, we sincerely thank Tricia Ty and Cynthia C. Fuller for research and editorial assistance with this article. FOOTNOTES Accepted Mar 30, 2005. The authors of this article all were voting members of or expert consultants to 1 or both joint meetings of the Neuro-Psychopharmacologic Advisory Committee, the Pediatric Subcommittee of the Anti-Infective Drugs Advisory Committee, and the Pediatric Advisory Committee to the FDA on the use of antidepressants in children and adolescents. The comments reflect the perspectives of the authors and should not be interpreted as reflecting the position of the FDA, the FDA Advisory Committees, or the American Academy of Pediatrics. No conflict of interest declared. 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Washington, DC: Department of Health and Human Services;2000 Methods of suicide among persons aged 10–19 years—United States, 1992–2001. MMWR Surveill Summ.2004; 53 :471 –474 Anderson RN, Smith BL. Deaths: leading causes for 2001. Natl Vital Stat Rep.2003; 52 :1 –88 Burns BJ, Hoagwood KE. Preface: evidence-based practice, part 1: research update. Child Adolesc Psychiatr Clin N Am.2004; 13 :xi –xiii Leonard HL, March J, Rickler KC, et al. Pharmacology of the selective serotonin reuptake inhibitors in children and adolescents. J Am Acad Child Adolesc Psychiatry.1997; 36 :725 –736 Zito JM, Safer DJ, DosReis S, et al. Psychotropic practice patterns for youth: a 10-year perspective. Arch Pediatr Adolesc Med.2003; 157 :17 –25 Zito JM, Safer DJ, DosReis S, et al. Rising prevalence of antidepressants among US youths. Pediatrics.2002; 109 :721 –727 Chan RT, Rey JM, Hazell PL. Clinical practice guidelines for depression in young people: are the treatment recommendations outdated Med J Aust.2002; 177 :448 –451 Safer DJ, Zito JM, DosReis S. Concomitant psychotropic medication for youths. Am J Psychiatry.2003; 160 :438 –449 Olfson M, Marcus SC, Weissman MM, et al. National trends in the use of psychotropic medications by children. J Am Acad Child Adolesc Psychiatry.2002; 41 :514 –521 Yaffe SJ, Aranda JV. Introduction and historical perspectives. In: Yaffe SJ, Aranda JV, eds. Pediatric Pharmacology: Therapeutic Principles in Practice. 2nd ed. Philadelphia, PA: WB Saunders Company; 1992:3–9 Hazell P, O’Connell D, Heathcote D, et al. Efficacy of tricyclic drugs in treating child and adolescent depression: a meta-analysis. BMJ.1995; 310 :897 –901 Gilman JT. Therapeutic drug monitoring in the neonate and paediatric age group. Problems and clinical pharmacokinetic implications. Clin Pharmacokinet.1990; 19 :1 –10 Brown RD, Campoli-Richards DM. 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☉ 11333119:Hormonal Effects in Infants Conceived by Assisted Reproductive Technology
Department of Endocrinology and Nutrition, Hospital Clinico San Carlos, C/Martin Lagos s/n Madrid, Spain Department of Pediatrics, Division of Pediatric Endocrinology, New York University School of Medicine, New York, New York ABSTRACT OBJECTIVE.: The purpose of this report is to describe 7 infants conceived by assisted reproductive technology (ART) who presented with breast development and/or pubic hair. The clinical presentation in these infants raises awareness that an altered intrauterine hormonal milieu may impact the fetal and infant stages of children conceived by ART. METHODS.: Between May 2001 and April 2004, 7 children between the ages of 5 and 21 months conceived by ART were referred by their pediatricians to the Division of Pediatric Endocrinology at the New York University School of Medicine for evaluation of possible precocious puberty. Patients were evaluated for the possibility of centrally mediated precocious puberty and pseudoprecocious puberty, with a possible ovarian or adrenal origin. RESULTS.: Endocrine evaluation in all patients indicated sex-steroid and hormone levels in the prepubertal range; pelvic sonography confirmed prepubertal ovaries with unstimulated uteri. Clinical follow-up of our patients thus far has not revealed progression of breast development, pubarche, or elevation in sex steroids. CONCLUSIONS.: It is well established that the developing endocrine system in the fetus and maturation of endocrine-control systems are influenced by hormone concentrations in the fetus. Whether ART alters the intrauterine hormonal milieu for the growing fetus conceived by ART is as yet unknown and is an area of ongoing investigation. Patients conceived through ART, including our patients who presented with hormonal manifestations, will need to be monitored throughout childhood and into adolescence and adulthood to determine if any perturbation exists on the timing of puberty and later fertility. Key Words: prenatal care prenatal exposure puberty early-onset puberty in vitro fertilization Abbreviations: ART, assisted reproductive technology IVF, in vitro fertilization FSH, follicle-stimulating hormone LH, luteinizing hormone DHEA, dehydroepiandrosterone DHEA-S, dehydroepiandrosterone sulfate r-FSH, recombinant follicle-stimulating hormone r-hCG, recombinant human chorionic gonadotrophin H-P-G, hypothalamic-pituitary-gonadal With the development of new techniques in assisted reproductive technology (ART), progress has been made in the ability of infertile couples to conceive a child. Data from the American Society of Reproductive Medicine's national in vitro fertilization (IVF) registry indicate that in the year 1999, a total of 88 077 cycles of assisted reproductive treatment led to 21904 deliveries, with the birth of 30967 neonates.1 This represents a success rate (deliveries per transfer) of 30.5%, an increase from 17% in 1992. This increase is related to the higher rate of successful implantations as well as an increase in the number of multiple gestations. At present, ART is responsible for 1% to 2% of births in the United States.1 Numerous studies have explored the type and incidence of ART-related side effects in offspring. Included among the most common adverse effects are low birth weight (2500 g) among term (risk ratio: 2.6; 95% confidence interval: 2.4–2.8) and preterm (risk ratio: 1.3; 95% confidence interval: 1.2–1.4) singleton infants conceived by ART.2 This increased risk persists after adjustment for maternal age and parity, gestational age at delivery, multifetal reduction procedures, and cause of infertility. Although several studies do not report an increased risk of congenital malformations in children conceived through ART,3,4 others have shown that the prevalence of 1 major birth defects by the age of 1 year is twice as high in infants conceived by ART.5 In a Beckwith-Wiedemann registry of 65 children with this syndrome, 3 infants (5%) had been conceived by IVF, indicating a higher-than-expected rate (0.8%).6 Initial studies did not demonstrate an increase in cancer risk among children conceived by ART.7,8 More recently, several reports (including a study from the Netherlands9) conclude that the relative risk of retinoblastoma is significantly higher. There are a range of possible factors associated with ART treatment that may contribute to potential adverse outcomes. These factors include the relatively advanced age of infertile couples seeking ART, the underlying causes of their infertility, the medications used to induce ovulation or to maintain the pregnancy in its early stages, and the ART procedures themselves. The purpose of this report is to describe 7 infants born by ART who presented with breast development and/or pubic hair. The data available to the authors for this report were obtained through direct patient care and retrospective chart review. METHODS Analyses All patients underwent baseline hormone analysis. Patients who demonstrated both breast development and pubic hair were evaluated for the possibility of sexual precocity. In these patients, tests to determine the levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, and dehydroepiandrosterone sulfate (DHEA-S) and ovarian sonography were performed (patients 1–4). Patients presenting primarily with pubic hair (patients 5–7) were evaluated as well for causes of hyperandrogenism (eg, congenital adrenal hyperplasia). DHEA-S, serum testosterone, and 17-hydroxyprogesterone were performed in these patients (Table 1). In addition, a left-hand- and wrist-for-skeletal-age test was performed for each patient. Laboratory analysis was performed at Quest Diagnostics (Teterboro, NJ) for patients 1, 3, and 5. Cortisol, estradiol, DHEA-S, and testosterone were measured by chemiluminescence; tests for 17-hydroxyprogesterone, 4-androstenedione, and estrone levels were performed by radioimmunoassay. LH and FSH measures were performed by microenzyme immunoassay. For patients 2, 4, 6, and 7, laboratory analysis of androgen levels was performed in-house. Radioimmunoassays for testosterone, 17-hydroxyprogesterone, and DHEA-S levels were performed in our laboratory using a well-described methodology.10 Radioimmunoassays for testosterone and 17-hydroxyprogesterone were performed after purification by Celite chromatography. The intra- and interassay coefficients were 6% and 11%, respectively, for testosterone and 11% and 15%, respectively, for 17-hydroxyprogesterone. DHEA-S, however, was immunoassayed without purification. Adrenocorticotrophic hormone-stimulation testing of patient 7 was performed by using cosyntropin 0.25 mg (Amphastar Pharmaceuticals, Inc, Rancho Cucamonga, CA) administered intravenously at 0 minutes. Serum sampling was performed at 60 minutes for serum testosterone and 17-hydroxyprogesterone. Assessment of skeletal age was performed by well-established methods.11 Pelvic and adrenal sonography were performed at the Division of Pediatric Radiology at the New York University School of Medicine for all patients except patient 1, who underwent the procedure at Lenox Hill Hospital (New York, NY). With the exception of 2 patients (patients 2 and 4), who have been evaluated recently, all patients have been seen in follow-up consultation for a period of 3 months to as long as 20 months. Patient Population Between May 2001 and April 2004, 7 children between the ages of 5 and 21 months who were conceived by ART were referred by their pediatricians to the Division of Pediatric Endocrinology at the New York University School of Medicine for evaluation of breast development and/or pubic hair. Six patients were female, and 1 was male. The characteristics of the sample, including the clinical findings, are presented in Table 2. All of the mothers had been treated with recombinant FSH (r-FSH) followed by recombinant human chorionic gonadotropin (r-hCG) and progesterone by established ART protocols.12–15 With the exception of families 4 and 5, verbal reporting by the families indicated that maternal anovulation or an inability to conceive spontaneously prompted medical therapy with ART. The family of patient 5 underwent ART and treatment of paternal oligospermia. In addition to standard maternal hormonal therapy (for IVF), the father of patient 5 was treated with Teslac, clomiphene, and indomethacin. Patient 4 was conceived by IVF using a sperm donor. Family history for all patients was negative for congenital adrenal hyperplasia, polycystic ovary syndrome, or precocious puberty. All of the mothers denied using medication for systemic or endocrine disorders during the pregnancy. Patients 1 and 2 were born at 7 months of gestation and had birth weights of 3.5 and 1.81 kg, respectively. Patients 3, 4, 6, and 7 were born at term and had birth weights that were appropriate for gestational age. The genetic backgrounds of the families were diverse, with no predominance within the patient population. Patient 5 was the 8-month product of a set of fraternal twins that was originally a quadruple pregnancy. According to the mother, the male twin was growing normally, with no evidence of pubarche. On physical examination, all subjects were healthy appearing infants. Patients 1 through 4 presented with bilateral, well-developed breast tissue and pubic hair (Tanner stages II–III). Patients 5 and 6, both female, presented with Tanner III pubic hair and minimal breast tissue. There was no clitoral enlargement or posterior labial fusion in the female patients. Patient 7, a male infant, presented with terminal pubic hair along the scrotum but no gonadal or genital enlargement. Review of the linear growth trajectories indicated that all term infants were growing consistently along their centile channels. Patients 1, 2, and 5, who had been born prematurely, were demonstrating catch-up growth consistent with growth patterns of prematurity. RESULTS Results are presented in Table 1. Levels of LH, FSH, estradiol, DHEA-S, testosterone, 4-androstenedione, 17-hydroxyprogesterone, and estrone were in the prepubertal range in all patients. Pelvic sonography indicated the appearance of prepubertal ovaries (ovarian volumes measuring <1.2 cm3) and a nonstimulated uterus in all females. The skeletal ages were within ±2 SD for chronologic age in all patients (Table 1). During the follow-up visits, there was no evidence of pubertal progression or linear growth acceleration in any of the patients. DISCUSSION We present data on 7 patients conceived by ART, ages 5 to 21 months, referred for endocrine evaluation of possible precocious puberty and who presented with breast development and/or pubic hair. Patients who demonstrated both breast development and pubic hair were evaluated for the possibility of sexual precocity. Patients presenting primarily with pubic hair were evaluated as well for causes of hyperandrogenism (eg, congenital adrenal hyperplasia). Endocrine evaluation in all patients indicated hormonal levels in the prepubertal range; pelvic sonography confirmed prepubertal ovaries with unstimulated uteri. Clinical follow-up of our patients did not reveal progression of the breast development or an increase in pubarche. Linear growth velocity continued along prior centile channels. Our patients were unusual in their clinical presentation. In those infants conceived by ART who were referred for evaluation of breast development, the size and maturation of breast glandular tissue exceeded that generally seen in our patient population with isolated thelarche, a benign but not well-explained condition seen in normal infants that may result from a delay in the transition from the active fetal hypothalamic-pituitary-gonadal (H-P-G) axis to the quiescent prepubertal H-P-G axis. The degree of breast tissue seen in our ART patients, either isolated or in association with pubic hair, raised the possibility of precocious puberty, either centrally mediated or of ovarian or adrenal origin. By clinical history, it was apparent that the 1 common link among this group of patients was that they had all been conceived by ART. All mothers had received r-FSH, r-hCG, and progesterone as defined by standard ART protocols.12–16 Review of the literature regarding the pharmacokinetics and pharmacodynamics of r-FSH and r-hCG suggests that theses compounds alone cannot be the cause of the clinical findings. Additionally, the timing of administration of both medications for ovulation induction renders it unlikely that there may be a direct effect of theses drugs on the fetal H-P-G axis.16 We reviewed the literature on the possible relation between ART procedures and the appearance of estrogen and/or androgen effect on offspring. Recent data indicate that maternal serum and amniotic fluid levels of hCG are elevated in pregnancies conceived after ART.17,18 In addition, ART twin pregnancies have higher levels of hCG than are seen in spontaneous twin pregnancies. The increase in hCG is seen even in pregnancies after spontaneous frozen-embryo transfer. Thus, the increase in hCG seems not to be related to superovulation hormonal therapy.17,18 Although we cannot exclude other factors, we suspect that the elevation of maternal hCG seen in ART may play an etiologic role. It is known that placental hCG induces maternal and fetal adrenal steroidogenesis of DHEA.18,19 DHEA-S is then converted to 4-androstenedione in the placenta. DHEA-S and 4-androstenedione are the major precursors for placental estrogen production.18,19 Elevated levels of DHEA and 4-androstenedione are metabolized to estrogens and androgens that may impact the developing fetus.20–22 We speculate that elevated levels of estrogen and androgens in utero may directly mediate the development of breast tissue and pubic hair and may further alter the maturation of the H-P-G axis in the developing fetus. Although the etiology of the elevation in hCG in ART pregnancies is uncertain, it is known that maternal hCG levels are higher in twin pregnancies than in singleton pregnancies. Therefore, it is conceivable that, in our patient population, multiple embryo implantations early in gestation could have been a factor in increasing maternal hCG levels and altering the maternal-fetal hormonal milieu. We should note, however, that 1 study did not find any elevation consistent with the number of implantation and posterior multifetal reduction.23 Additionally, the impact of artificial fertilization or the embryo culture and the effect of progesterone on the fetus are also unknown. The impact on the developing fetus of an altered hormonal milieu is unclear. It is known that fetal life is an early and important stage in the development of the H-P-G axis that culminates in adult life with the achievement of full sexual maturation and fertility. In both humans and primates, the fetal hypothalamic gonadotrophin-releasing hormone pulse generator is operant in the fetus by the end of the first trimester. Studies suggest that hormonal imprinting or programming occurs in fetal life during a critical period of maturation24 and may modulate gene expression and nuclear and/or plasma membrane receptors.25 Evidence exists to indicate that prenatal androgens program the timing of neuroendocrine puberty in sheep; the higher the dose of prenatal testosterone, the earlier the initiation of the pubertal LH rise.26 It has been shown that estrogen administration to pregnant rats during the last third of gestation produces cryptorchid male offspring and may suppress spermatogenesis permanently in adult males. Additionally, perinatal estrogen administration to the developing female rodent produced long-term effects including persistent vaginal cornification, hyperplastic vaginal lesions, and cervicovaginal cancer; synthetic nonsteroidal estrogens (diethylstilbestrol) had similar effects.25,27 Whatever the mechanisms, the developing endocrine system in the fetus and maturation of endocrine-control systems are influenced by the hormone concentrations in the fetus. Patients conceived through ART, including our patients who presented with hormonal manifestations, will need to be monitored throughout childhood and into adolescence and adulthood to determine what impact, if any, exists on the timing of puberty and, later, fertility. We recognize the limitations of our study. Our data represent a compilation of our experience in ART-conceived infants referred for evaluation of clinical signs of precocious puberty. Although we postulate that elevation in maternal hCG may play a critical role in the development of a hormonal effect in these infants, serial maternal hCG levels are not available for our study. Additionally, the number of ART-conceived infants presenting with clinical signs of puberty is extremely small when compared to the hundreds of infants conceived by ART within our referral area. Well-controlled, prospective studies to include fetal ovarian sonography, hormonal levels in amniotic fluid (when available), and careful ongoing evaluation of the ART-conceived infant will provide additional insight into the mechanism of this entity in infants conceived by ART. ACKNOWLEDGMENTS We acknowledge the contributions of Dr V.K. Prasad, associate director of our pediatric endocrine laboratory, for the in-house steroid-hormone assays. FOOTNOTES Accepted Feb 28, 2005. No conflict of interest declared. 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The risk of major birth defects after intracytoplasmic sperm injection and in vitro fertilization. N Engl J Med.2002; 346 :725 –730 Gicquel C, Gaston V, Mandelbaum J, Siffroi JP, Flahault A, Le Bouc Y. In vitro fertilization may increase the risk of Beckwith-Wiedemann syndrome related to the abnormal imprinting of the KCN1OT gene. Am J Hum Genet.2003; 72 :1338 –1341 Klip H, Burger CW, de Kraker J, van Leeuwen FE; OMEGA-project group. Risk of cancer in the offspring of women who underwent ovarian stimulation for IVF. Hum Reprod.2001; 16 :2451 –2458 Bruinsma F, Venn A, Lancaster P, Speirs A, Healy D. Incidence of cancer in children born after in-vitro fertilization. Hum Reprod.2000; 15 :604 –607 Moll AC, Imhof SM, Cruysberg JR, Schouten-van Meeteren AY, Boers M, van Leeuwen FE. Incidence of retinoblastoma in children born after in-vitro fertilisation. Lancet.2003; 361 :309 –310 Manlimos F, Abraham GE. Chromatographic purification of tritiated steroids prior to use in radioimmunoassay. Anal Lett.1975; 8 :403 –410 Greulich WW, Pyle SI. Radiographic Atlas of Skeletal Development of the Hand and Wrist. Stanford, CA: Stanford University Press; 1959 Rowell P, Braude P. Assisted conception. I—General principles. BMJ.2003; 327 :799 –801 Rowell P, Braude P. Assisted conception. II—in vitro fertilisation and intracytoplasmic sperm injection. BMJ.2003; 327 :852 –855 Daya S, Gunby J, Hughes EG, Collins JA, Sagle MA. Follicle-stimulating hormone versus human menopausal gonadotropin for in vitro fertilization cycles: a meta-analysis. Fertil Steril.1995; 64 :347 –354 Filicori M, Cognigni GE, Pocognoli P, Ciampaglia W. Choice of ovarian stimulation regimens in assisted reproduction: finding the thread in the gonadotropin maze. Fertil Steril.2003; 80 :1114 –1116 le Cotonnec JY, Loumaye E, Porchet HC, Beltrami V, Munafo A. Pharmacokinetic and pharmacodynamic interactions between recombinant human luteinizing hormone and recombinant human follicle-stimulating hormone. Fertil Steril.1998; 69 :201 –209 Perheentupa A, Ruokonen A, Tuomivaara L, Ryynanen M, Martikainen H. Maternal serum beta-HCG and alpha-fetoprotein concentrations in singleton pregnancies following assisted reproduction. Hum Reprod.2002; 17 :794 –797 Hui PW, Lam YH, Tang MH, Ng EH, Yeung WS, Ho PC. Amniotic fluid human chorionic gonadotrophin and alpha-fetoprotein levels in pregnancies conceived after assisted reproduction. Prenat Diagn.2003; 23 :484 –487 Braunstein G. Endocrine changes in pregnancy. In: Larsen PR, Kronenberg HM, Melmed S, Polonsky K, eds. Williams Textbook of Endocrinology. 10th ed.Philadelphia, PA: WB Saunders;2003 :800 –803 Miller WL. Steroid hormone biosynthesis and actions in the materno-feto-placental unit. Clin Perinatol.1998; 25 :799 –817 Vaskivuo TE, Aittomki K, Anttonen M, et al. Effects of follicle-stimulating hormone (FSH) and human chorionic gonadotropin in individuals with an inactivating mutation of the FSH receptor. Fertil Steril.2002; 78 :108 –113 Barnes RB, Rosenfield RL, Namnoum A, Layman LC. Effect of follicle-stimulating hormone on ovarian androgen production in a woman with isolated follicle-stimulating hormone deficiency. N Engl J Med.2000; 343 :1197 –1198 Rotmensch S, Celentano C, Shalev J, et al. Midtrimester maternal serum screening after multifetal pregnancy reduction in pregnancies conceived by in vitro fertilization. J Assist Reprod Genet.1999; 16 :8 –12 Grumbach MM. The neuroendocrinology of human puberty revisited. Horm Res.2002; 57 :2 –14 Csaba G. Receptor ontogeny and hormonal imprinting. Experientia.1986; 42 :750 –759 Kosut SS, Wood RI, Herbosa-Encarnacion C, Foster DL. Prenatal androgens time neuroendocrine puberty in the sheep: effect of testosterone dose. Endocrinology.1997; 138 :1072 –1077 Bern HA, Talamentes FJ Jr. Neonatal mouse models and their relation to disease in the human female. In: Herbst AL, Bern HA, eds. Developmental Effects of Diethylstilbestrol (DES) in Pregnancy. New York, NY: Thieme-Stratton; 1981: 129–147...查看详细 (22749字节)
☉ 11333120:Five year follow up of biocolonisable microporous fluorocarbon haptic(BIOKOP) keratoprosthesis implantation in patients with high risk of c
1 Department of Ophthalmology, Miguel Hernández University, Alicante, Spain 2 Instituto Oftalmologico de Alicante, Department of Research and Development, Alicante, Spain 3 Instituto Oftalmologico de Alicante, Spain 4 Instituto de Oftalmobiologia Aplicada (IOBA), Valladolid University, Spain ABSTRACT Aim: To study the anatomical and visual performance following implantation of a model of artificial cornea and to evaluate the postoperative long term complications. Methods: 11 eyes of 11 patients with bilateral corneal blindness considered as potentially having high risk of failure of penetrating corneal keratoplasty were implanted with biocolonisable Kpro keratoprosthesis (BIOKOP I, FCI, Rantigny, France) in the period between January 1996 and May 1998. Only one eye was implanted in all patients and followed up for a period of 60 months. The visual outcome, anatomical and functional stability, complications, and the general performance of the keratoprosthesis were evaluated. Results: The keratoprosthesis (BIOKOP I) only 36.3% remained in position to date. In the patients’ last visit five eyes (45.4%) were blind and one (9.0%) showed a slight improvement in the best corrected visual acuity (BCVA) in comparison to preoperative tests. Six eyes (54.5%) showed improved BCVA before having postoperative complications. Four eyes underwent replacement of a BIOKOP I Kpro with a BIOKOP II as a result of extrusion. The keratoprostheses remained anatomically in situ for a mean of 25.5 months and their functional performance period was limited to a mean of 22 months. Conclusion: Corneal keratoprosthesis (BIOKOP I, II) does not provide a stable anatomical relation with the surrounding ocular structures. Its ability to restore vision is limited to a short postoperative period in eyes implanted with severe ocular surface disease. Abbreviations: BCVA, best corrected visual acuity; BIOKOP, biocolonisable microporous fluorocarbon haptic; CF, count fingers; CP, colour perception; ECCE, extracapsular cataract extraction; Kpro, keratoprosthesis; LP, light perception; LPP, light projection; PKP, penetrating keratoplasty Keywords: corneal graft failure; penetrating keratoplasty; keratoprosthesis Major causes of blindness in developing countries include infectious corneal diseases such trachoma and xerophthalmia, whereas in industrialised countries it is mainly caused by herpetic disease, acid or alkaline burns, rheumatoid arthritis, pemphigoid, and Stevens- Johnson syndrome.1 Many patients who have visual impairment as a result of corneal opacity can be successfully treated by corneal transplant. A number of these patients are considered as having a high risk of failure of corneal graft procedures because of potential risk of rejection or severe ocular surface disorders despite the advances in immunosuppression on ocular reconstruction.2–4 Moreover, in certain countries, donor corneas are unavailable, as a result of custom or religious practice. In such cases, keratoprosthesis (Kpro) provides the only alternative to avoid corneal graft failure in an attempt to achieve visual rehabilitation. Kpro has the goal of replacing the central cornea with a clear optical cylinder of adequate refractive power in the visual axis.4,5,6,7,8,9,10,11,12,13 However, postoperative complications are still frequent and severe enough to limit its use. Recent advances in Kpro aim at preventing and managing complications after implantation to improve prognosis and general outcomes.11,14–18 Emerging biocompatible materials are opening the way for visual rehabilitation in cases of severe and intractable corneal blindness. The concept of biocompatibility has been recently implemented with the development of new biomaterials that have the potential of being populated by cells from the surrounding tissues, in this case, the cornea. Such materials, which are called "biocolonisable," might further improve the integration of the Kpro and are a new way to increase the biocompatibility of new designs of Kpro. In this study we present the long term outcome of patients, considered as having a high risk of corneal graft failure as a result of severe ocular surface disease, when implanted with one of these new models of the biocolonisable Kpro (BIOKOP I, (FCI, Rantigny, France).15,16 MATERIALS AND METHODS In this prospective, non-randomised, observational case series 11 eyes (11 patients, six females and five males) were included. The patients were followed for up to 5 years. Ethics board committee approval was obtained for the study. Adequate informed consent was obtained from each patient following the tenets of Helsinki Declaration (Washington, 2002). Prosthesis BIOKOP I prosthesis is composed of a biointegrable synthetic hydrogel "core and skirt" with a central transparent optic surrounded by a white porous skirt that allows biointegration to ensure fixation and prevents epithelial downgrowth. The optical and physical characteristics were published in a previous report.15 There are two models, 43 dioptres (D) for phakic eyes and 58 D for aphakic eyes (fig 1). Figure 1 BIOKOP I before implantation. In cases where severe peripheral melting and potential extrusion occurred, the BIOKOP I was explanted and replaced with the BIOKOP II (FCI, Rantigny, France). The BIOKOP II has the same haptics design as the previous prosthesis, but the optic is manufactured in silicone and has a diameter of 6 mm. Patients Indication for surgery included bilateral corneal blindness not treatable by penetrating or lamellar keratoplasty because of chronic unfavourable ocular surface or lid disease or previous repetitive history of corneal graft failure. The mean age of the patients was 62.9 (range 18–85 years). All patients were diagnosed as having bilateral blindness caused by severe ocular surface disease preventing the success of corneal grafting. The preoperative best corrected visual acuity (BCVA) ranged between ability to count fingers (CF) and light perception (LP) (see table 1). Table 1 Pre-existing conditions of trial patients and surgery associated with the Kpro implantation All the patients had good light projection (LPP) and good (CP). B-scan ultrasound was performed routinely in the preoperative evaluation and in the follow up to study the intraocular structures. Patients with no light perception or having structural vitreous or retinal abnormalities with the B-scan were excluded from the study. Other exclusion criteria included antecedents with clinical evidence of glaucoma, the inability to self administer medication, or inability to fulfil the postoperative follow up visits. The surgical procedure was performed by the same surgeon (JLA) using the standard method previously described by Legeais and Renard.16 The haptic was inserted into lamellar pocket delaminated in the stroma and the optic was positioned through a hole trephined in the central cornea. In five of the eyes, extracapsular cataract extraction (ECCE) was accompanied by the implantation of a posterior chamber intraocular lens (IOL) (AcrySof, Alcon, Fort Worth, TX, USA) and we used the aphakic Kpro model. The procedure was associated with an anterior vitrectomy in five of the cases. A buccal mucous membrane was placed in front of the Kpro following implantation and a temporary tarsorrhaphy was performed and opened after 2 weeks (fig 2). At the end of the procedure dexamethasone and gentamicin were injected subconjunctivally and tobramycin ointment was applied. Mucous membrane opening was performed to expose the optic at the end of the second postoperative month using radiofrequency probe (Ellman International Inc, USA). During the follow up the patients used one drop of tobramycin (Tobrex, Alcon Cusi, Barcelona, Spain) twice a day and artificial tears (Liquifilm, Alcon-Cusi, Barcelona, Spain) at least four times daily. The patients were followed up weekly for the first 2 months, then every 15 days until the fourth month, then every 3 months thereafter. At each visit, the visual performance, the stability of the prosthesis and the mucous membrane, leak from Kpro, and the condition of the ocular surface, were evaluated. Figure 2 An implanted BIOKOP I opening the mucous membrane. RESULTS The preoperative ocular diagnosis of the patients, their clinical condition leading to corneal blindness, and the surgical procedures are presented in table 1. The follow up after Kpro implantation was 60 months. Preoperative BCVA was LP in 81.8% (nine) of the eyes, CF in 9.1% (one) of eyes, and HM in another 9.1% (one) of eyes. Other existing preoperative ocular conditions included ocular pemphigoid in five (45.5%) eyes, corneal alkali burn two (18.2%) eyes, trachoma in one (9.1%) eye, ocular leprosy in one (9.1%) eye, and keratomalacia in one (9.1%) eye. One eye (9.1%) developed total corneal opacity following local radiotherapy followed by graft failure. Associated general conditions included diabetes in four (36.4%) patients, rheumatoid arthritis in one (9.1%), and retinitis pigmentosa in one (9.1%). Four eyes (36.4%) had single previous unsuccessful penetrating keratoplasty (PKP), and one patient underwent repeated PKP. The visual outcomes at the different postoperative visits, the evolution of the BCVA, and the complications developed during the follow up visits are given in table 2. Table 2 Ophthalmic complications and visual outcome Complications At the end of surgery, the Kpro were anatomically well attached in all eyes and no significant intraoperative complications were detected. Postoperatively and throughout the follow up, 72.7% of the patients showed partial dislocation of the Kpro or melting. 36.4% of the first implanted Kpro were retained to date with a mean duration of anatomical retention of the Kpro being 25.5 months as shown in figures 3 and 4. Endophthalmitis developed in four patients (36.4%) and the isolated pathogens included Gram positive cocci (Streptococcuspneumoniae) in two eyes, Staphylococcus epidermidis in one eye, and Staphylococcusaureus in one eye (fig 5). All these eyes were previously in good condition before endophthalmitis and showed no evidence of leakage in any case. Figure 3 Exposure of Kpro skirt in an extruded implant. Figure 4 Kaplan-Meyer curve of keratoprosthesis extrusion. Figure 5 Severe endophthalmitis caused by Staphylococcus in patient 4 at 12 months. Corneal melting was the most frequent complication and occurred in eight cases (table 3). Corneal melting led to the exteriorisation of the Kpro skirt and was treated in all cases by partial mucous membrane grafting, which only solved the problem permanently in one case, multiple mucous regrafts being necessary in the rest. Table 3 Kpro retention and its complications Retroprosthetic membrane Immediately after removing the mucous graft and opening the median tarsorrhaphy at 2 months, a retroprosthetic membrane was observed in three of the cases. During the follow up period, it was further developed in another seven cases, giving a total incidence of retroprosthetic membrane development of 90.1%. Such membranes were surgically removed in all cases but recurred in 45.5% of the eyes despite the use of systemic corticosteroids (fig 6). Figure 6 A dense vascularised retroprosthetic membrane observed 3 months after the surgical procedure. Retinal detachment (RD) was also a serious complication that affected the postoperative recovery. In table 3, we show the data concerning Kpro retention and the different complications observed during follow up. Retinal detachment developed in three (27.3%) eyes—one eye had a history of repeated multiple corneal grafts and postoperative endophthalmitis, another eye suffered an advanced stage of diabetic retinopathy following the surgery, and one eye had a history of corneal graft and developed recurrent postoperative retroprosthetic membranes resistant to all treatments. At the time of writing, the postoperative BCVA was LP in five (45.5%), hand movement (HM) in one (9.1%), and no light perception in five (45.5%). Five patients (45.5%) maintained their preoperative BCVA, one eye had a better postoperative BCVA compared to the preoperative value, and the rest of the eyes (five, 45.5%) reported no PL (see table 2). DISCUSSION Autologous tooth, bone graft, and cartilage have been used with relative success for Kpro haptics fixation, despite the complexity of the procedures required and the development of complications such as extrusion or glaucoma.19 A combination of PMMA prosthesis and a clear corneal graft in association with anticollagenase were used to prevent tissue ulceration around the PMMA collar.3 Choyce used perforated PMMA discs20 while Cardona used non-stick coatings of the haptic (non-porous Teflon).13 Despite many attempts, adequate cellular colonisation failed because of lack of appropriate porosity.21–23 The Polack Kpro provided considerable visual results with limited ability to remain in place for a long follow up period (20% with BCVA of 0.2 or better at 1 year, but 100% were extruded or removed within the first 2 years).15,22 The Proplast was studied because of its gas and fluid permeability but remained too rigid for the corneal tissue.24 Some studies have approached the development of microporous biocompatible polymers to decrease the mechanical tissue damage, especially the interconnection pore size to improve the biointegration of the implant.9,15,16,23 Designs such as the Seoul-type,9 AlphaCor,25 and the BIOKOP15,16 have followed this principle. Legeais and Renard developed the BIOKOP implant based on the theory of improved biointegration. The implant had biocolonisable micropores of 80 μm that improved the results of biointegration and safety in a follow up period of up to 28 months.15,16 In their series, two (18.9%) eyes developed peri-prosthesis leak from the Kpro skirt, and required additional mucous membrane grafting. In our study, phthisis bulbi was detected in two eyes (18.2%) as a complication of postoperative RD and endophthalmitis, endophthalmitis occurred in five (45.5%) eyes, and Kpro extrusion occurred in four (36.4%) eyes. In four (36.4%) eyes, the Kpro was replaced by BIOKOP II keratoprosthesis to prevent further melting of the ocular tissue. In those eyes, peripheral inflammatory reaction and melting, endophthalmitis, and extrusion followed the surgery, and further treatment was discarded. Among the difficulties arising during this study were the problems of symblepharon, severe cicatrising conjunctival and adnexal disease, and recurrent inflammatory corneal conditions with a densely opaque, vascularised cornea. We compared the preoperative BCVA of the patients included in this study with those in the study of Legeais et al,15 who implanted the same Kpro. The relatively better results obtained in their study could be explained by the better preoperative conditions of their patients, more specifically the severity of ocular surface disease of the patients reported in both series. Comparing the visual outcome and the complications with those in the study by Legeais et al, in this study 6/11 patients (27.3%) showed improvement in BCVA before having further complications such as endophthalmitis, extrusion or deterioration of vision to preoperative values and only one eye maintained its postoperative BCVA (9.1%). Legeais et al had 70.8% of patients who maintained or improved their preoperative BCVA up to 28 months and only 4.1% of their cases developed endophthalmitis.15 Nouri et al reported endophthalmitis in 12% of the eyes implanted in their animal model study,26 while other authors reported no cases of endophthalmitis,18 but in a series of patients with much better preoperative conditions. The role of postoperative corticosteroids in Kpro surgery is not clear. It seems that systemic corticosteroids might induce ulceration at the junction between the fluorocarbon and PMMA skirt with extrusion of the Kpro; therefore, in order to prevent the possibility of infection the use of systemic corticosteroids should be kept to a minimum.26 Retroprosthetic membrane developed in 90.1% of the eyes and recurred in 45.5% of the eyes despite the use of systemic corticosteroids which seems to have no role in the prevention of the risk of developing intraocular inflammation and membrane formation. The aetiology remains unknown and might include inflammation, wound exposure, and bleeding during surgery which could be related to the preoperative ocular surface situation.27 The membranes were very thick, vascularised, and required a vitrectomy probe cut for their removal in all the eyes except one (YAG laser). Legeais et al reported intraocular membranes developing in 20.8% of their patients15 and membranes did not develop in other series using a different Kpro.18 Lund hypothesised that the aphakic eyes without vitrectomy were predisposed to retroprosthetic membrane so cataract extraction combined with vitrectomy could prevent further membrane formation and occlusion of the optic of the prosthesis.28 The results of this report do not support this hypothesis. All the eyes underwent cataract extraction, and a group of these patients underwent a combined procedure of cataract removal and anterior vitrectomy (45.5%). Studying the incidence of postoperative membranes (90.9%), this complication therefore contradicts Lund’s theory28; the only significant difference is that retroprosthetic membrane recurred less frequently when the combined procedure was performed, but unfortunately it was not avoided. According to our results the biocompatible inert microporous polymers did not eliminate all the complications associated with this surgery. The patients included in our study are considered a poor prognostic category because of higher risk of significant complications, not only affecting final visual acuity but also reducing the chance of successful long term device retention caused by factors such as severe cicatrising conjunctival disease or recurrent inflammatory corneal conditions.3,10,26,29 In summary, the BIOKOP Kpro evaluated in this clinical study was unsuccessful in restoring visual acuity and was followed by high proportion of significant complications. Long term follow up of eyes implanted with this type of Kpro showed a high percentage of complications resulting in explantation or extrusion. This study shows that for adequate estimation of the potential of new models of Kpro, long term follow up is necessary to prove the anatomical stability and visual improvement. REFERENCES Whitcher JP. Neonatal ophthalmia: have we advanced in the last 20 years? Int Ophthalmol Clin 1990;30:39–41. Yaghouti F , Nouri M, Abad JC, et al. Keratoprosthesis: preoperative prognostic categories. Cornea 2001;20:19–23. Dholman CH, Doane MG. Some factors influencing outcome after keratoprosthesis surgery. Cornea 1994;13:214–18. Hull CC, Liu CS, Sciscio A, et al. Optical cylinder designs to increase the field of vision in the osteo-odonto-keratoprosthesis. Graefes Arch Clin Exp Opthalmol 2000;238:1002–8. Hiks CR, Lou X, Platten S, et al. Keratoprosthesis results in animals: an update. Aust N Z J Ophthalmol 1997; 1 :S50–2. Chirila TV. An overview of the development of artificial corneas with porous skirts and the use of phema for such an application. Biomaterials 2001;22:3311–17. Linnola RJ, Happonen RP, Vedel E, et al. Titanium and bioactive glass-ceramic coated titanium as materials for keratoprosthesis. Exp Eye Res 1996;63:474–8. Zhao H , Xie D, Zou H. Current researches in keratoprosthesis. Sheng Wu yi Xue Gong Cheng Xue Za Zhi 2002;19:112–16. Kim MK, Lee JL, Wee WR, et al. Seoul-type keratoprosthesis: preliminary results of the first 7 human cases. Arch Ophthalmol 2002;120:761–6. Khan B , Dudenhoefer EJ, Dohlman CH. Keratoprosthesis: an update. Curr Opin Ophthalmol 2001;12:282–7. Krug A , Kompa S, Schrage NF. The Aachen-keratoprosthesis—a flexible kpro that permits intraocular pressure measurements. Int J Artif Organs 2002;25:238–42. Trinkaus-Randall V , Capecchi J, Newton A, et al. Development of a biopolymeric keratoprosthetic mater evaluation in vitro and in vivo. Invest Ophthalmol Vis Sci 1988;29:393–400. Cardona H . Keratoprosthesis-acrylic optical cilinder with supporting intralamellar plate. Am J Ophthalmol 1962;54:284–94. Ray S , Khan BF, Dohlman CH, et al. Management of vitreoretinal complications in eyes with permanent keratoprosthesis. Arch Ophthalmol 2002;120:559–66. Legeais JM, Renard G, Parel JM, et al. Expanded fluorocarbon polymer for keratoprosthesis: cellular ingrowth and transparency. Exp Eye Res 1994;58:41–51. Legeais JM, Renard G, Parel JM, et al. Keratoprosthesis with biocolonizable microporous fluorocarbon haptic. Preliminary results in a 24-patient study. Arch Ophthalmol 1995;113:757–63. Hille K . Keratoprostheses. Clinical aspects. Ophthalmologe 2002;99:523–31. Crawford GJ, Hicks CR, Lou X, et al. The Chirila keratoprosthesis: phase I human clinical trial. Ophthalmology 2002;109:883–9. Marchi V , Ricci R, Pecorella I, et al. Osteo-odontokeratoprosthesis: description of surgical technique with results in 85 patients. Cornea 1994;13:125–30. Choyce DP. Results of keratoprosthesis in Britain. Am J Ophthalmol 1987;103:331–2. Heimke G , Polack FM. Ceramic keratoprosthesis: biomechenics of extrusion in throught the lid implantation. Cornea 1983;2:187–201. Crawford GJ, Constable IJ, Chirila TV, et al. Tissue interaction with hydrogel sponges implanted in the rabbit cornea. Cornea 1993;12:348–57. Huang YF, Wang LQ, Wang FX. Clinical application of keratoprosthesis for corneal opacity unsuitable for keratoplasty. Zhonghua Yan Ke Za Zhi 2003;39:578–81. Barber JC, Feaster F, Priour D. The acceptance of vitreous carbon alloplastic material, Proplast, in rabbit eye. Invest Ophthalmol Vis Sci 1980;19:182–91. Hicks CR, Crawford GJ, Lou X, et al. Corneal replacement using a synthetic hydrogel cornea, AlphaCor: device, preliminary outcomes and complications. Eye 2003;17:385–92. Nouri M , Terada H, Alfonso EC, et al. Endophthalmitis after keratoprosthesis. Arch Ophthalmol 2001;119:484–9. Dudenhoefer EJ, Nouri M, Gipson IK, et al. Histopatology of explanted collar button keratoprostheses: a clinicopathologic correlation. Cornea 2003;22:425–8. Lund OE. Keratoprosthesis: 25 years of experience. Refract Corneal Surg 1993;9:186–7. Dohlman CH, Terada H. Keratoprosthesis in pemphigoid and Stevens-Johnson syndrome. Adv Exp Med Biol 1998;438:1021–5....查看详细 (22925字节)

☉ 11333121:The Pediatrician Workforce: Current Status and Future Prospects
ABSTRACT The effective and efficient delivery of children's health care depends on the pediatrician workforce. The number, composition, and distribution of pediatricians necessary to deliver this care have been the subject of long-standing policy and professional debate. This technical report reviews current characteristics and recent trends in the pediatric workforce and couples the workforce to a conceptual model of improvement in children's health and well-being. Important recent changes in the workforce include (1) the growth in the number of pediatricians in relation to the child population, (2) increased numbers of female pediatricians and their attainment of majority gender status in the specialty, (3) the persistence of a large number of international medical graduates entering training programs, (4) a lack of ethnic and racial diversity in pediatricians compared with children, and (5) the persistence of marked regional variation in pediatrician supply. Supply models projecting the pediatric workforce are reviewed and generally indicate that the number of pediatricians per child will increase by 50% over the next 20 years. The differing methods of assessing workforce requirements are presented and critiqued. The report finds that the pediatric workforce is undergoing fundamental changes that will have important effects on the professional lives of pediatricians and children's health care delivery. Key Words: child health workforce diversity family medicine female pediatricians geographic distribution health manpower internal medicine-pediatrics international medical graduates nonphysician clinicians physician workforce pediatrics pediatric medical subspecialists pediatric surgical specialists Abbreviations: AAP, American Academy of Pediatrics FOPE II, Future of Pediatric Education II ABP, American Board of Pediatrics AMA, American Medical Association GME, graduate medical education IMG, international medical graduate med-peds, internal medicine-pediatrics FTE, full-time equivalent HMO, health maintenance organization GMENAC, Graduate Medical Education National Advisory Committee GDP, gross domestic product INTRODUCTION Our common mission to attain the optimal physical, mental, and social health and well-being for all infants, children, adolescents, and young adults (mission statement of the American Academy of Pediatrics [AAP]) depends on the pediatrician workforce. The improvement of children's health occurs through the efforts of these professionals who draw on their training and experience to deliver within a medical home the best possible pediatric care and to serve as child advocates. How, then, can we ensure that the right number of qualified clinicians are located where needed to provide pediatric care that is effective and efficient Market forces alone are insufficient to meet these public and professional workforce goals given the inherent imperfections in the market for health care labor and health care services.1–6 With a continuing need to influence the number and characteristics of child health professionals, this technical report seeks to inform pediatricians and child health policy makers of the status of the child health workforce and the public policies that will influence its future. The last AAP policy statement on the pediatric workforce, prepared by the Committee on Pediatric Workforce and published in 1998,7 combined a status report of the workforce with policy recommendations. In this current effort, the technical report provides the background to recommendations included in the separate but companion policy statement "Pediatrician Workforce Statement."8 To accomplish this, the report draws mostly on published sources, many of them from the AAP or the Future of Pediatric Education II (FOPE II) Project, to identify salient trends, possible future challenges to the profession, and critical domains of underdeveloped information. When published sources of data were not available, unpublished data have been cited from the Center for the Evaluative Clinical Sciences at Dartmouth Medical School (data sources and methods are available on request). The focus of the report is on general and medical subspecialty board-certified (by the American Board of Pediatrics [ABP]) pediatricians and the 99 million patients younger than 21 years whom they serve. Surgical and non–ABP-boarded pediatricians also provide essential services to children, but a detailed discussion of their status is beyond the scope of this report. HEALTH WORKFORCE TRENDS A full understanding of recent trends and current challenges facing the pediatric health workforce requires an examination of 4 general workforce themes.9 First, the number of physicians in the United States continues to grow in both absolute and per-capita numbers.10,11 In 2001 (December 31), the number of total patient-care physicians (defined by the American Medical Association [AMA] Masterfile as >50% of professional time spent in clinical care) was 668939, reflecting a 28% absolute and 18% per-capita increase during the decade. The number of residency or graduate medical education (GME) positions, the best predictor of entry into practice, was virtually unchanged at 93674, with an 11% decrease in per-capita numbers. The per-capita decrease in the number of residency positions is slow enough that the physician workforce will continue its per-capita growth for another 20 years before decreasing. These figures do not include osteopathic physicians, who increased by 41% per capita during the decade and are a particularly important provider of primary care in many regions (Center for the Evaluative Clinical Sciences, unpublished data, 1998). The second notable trend was the continued growth in the number of female medical students.12 Although men continued to outnumber women in some specialties in both residency programs and practice,13 most specialties have experienced a shift in their gender mix. Overall, the per-capita number of female physicians increased 53% during the decade, reflecting an increase from 100024 to 173254.10,11 Third, the physician workforce still fails to reflect the growing racial and ethnic diversity of the nation despite efforts to broaden medical school opportunities for individuals of traditionally underrepresented minority groups (black, Hispanic, and American Indian/Alaska Native). From information primarily collected by medical schools and residencies, in 2001 the AMA Masterfile listed 20738 black (2.5%), 28626 Hispanic (3.4%), 73849 Asian, (8.8%) and 504 American Indian/Alaska Native (50% of professional time spent directly caring for patients) pediatric subspecialists and an additional 740 researchers, 331 teachers, and 260 administrators (Table 3). 11 Many of these pediatricians, of course, have more than one professional role. AMA data are also likely to undercount subspecialists, because physicians will retain their initial GME specialty in the database until updated by a response to a survey. The alternative to AMA data has its own weakness. The ABP reports granting 14699 subspecialty diplomas since 1961,116 but the current practice status of these pediatricians is not known. Pediatric subspecialists are a heterogeneous group of pediatricians that eludes generalizations with respect to their type of practice, workforce size, and future opportunities. Some subspecialists such as neonatologists provide services not offered by other specialties, and others such as pediatric allergists provide care for conditions that are within the scope of practice of general pediatricians, pulmonologists, or internist-allergists. New specialties continue to develop and establish their role in caring for children before formal fellowships and board certification are established. Hospitalists are the most recent example. Certain subspecialists may have decreased the patient load of general pediatricians (neonatologists and hospitalists, for example) as they assume care for infants and children that were formerly central to the practice of many general pediatricians. Most important are the differences in the sizes of the subspecialties. At one extreme are neonatologists and pediatric cardiologists, who number 2847 (post-GME clinically active) and 1310, respectively, using AMA data, and at the other extreme are pediatric endocrinologists and rheumatologists, which, by the AMA system of enumeration, number less than 100 each in full-time clinical practice.11 The number of board-certified subspecialists is higher.117 The ABP has certified 828 infectious-disease subspecialists and 192 rheumatologist subspecialists,116 but these figures do not identify those returning to general pediatrics and those with research, teaching, or administration as their primary focus. The proportion of professional time devoted to academic work also varies across these specialties, adding another factor to be considered in workforce planning. The heterogeneity in pediatric subspecialists has 2 important implications. The first is that workforce statistics, forecasting models, and health services studies that report the general experience of pediatric subspecialists will be driven by the largest subspecialties. These generalizations may lead to policies that suit no particular group of children's health services needs. Pediatric subspecialists, as a whole, have already suffered this fate by being subject to the same policy brush as have adult subspecialists, an extremely large group of physicians who, unlike pediatricians, are largely nonacademically based and more highly remunerated. The second implication is that workforce analysts must recognize, from a measurement viewpoint, that many pediatric subspecialists qualify in epidemiologic terms as "rare events." Enumeration, workforce models, and measures of local availability have relatively low precision and, for the smallest subspecialties, great uncertainty. The geographic variation in subspecialists can lead to additional confusion about the overall adequacy of supply. Pediatric subspecialists are more likely to be based academically than as general pediatricians or adult subspecialists,118,119 although this differs by specialty. Most pediatric subspecialists, nevertheless, spend most of their professional time in patient care. Pediatric departments have difficulty recruiting subspecialists, at the same time that subspecialists interested in nonacademic practices have trouble finding positions, and those in practice may experience significant competition.117,120 Failure to differentiate the academic and community labor markets for pediatric subspecialists perpetuates shortages of academic subspecialists who have unique roles in education and research. These shortages may be exacerbated in the future if there is a decrease in the number of IMGs and a greater number of female pediatricians, trends that are likely to lead to fewer pediatricians seeking subspecialty education.121 Notwithstanding these possible future influences, the recent trend is toward a greater interest in subspecialty education by third-year residents.70 It is the pediatrician-scientist supply that remains at highest risk, facing particularly long training periods and shrinking clinical revenues while competing with PhD-trained investigators for research funding. For these reasons, subspecialty workforce policy and planning need to occur by specialty, with an eye to finding commonality when it is present and rejecting it when it is not. Although the recommendations of the recent FOPE II report are not universally accepted,36 FOPE II has produced an important literature about pediatric medical subspecialists and surgical specialists through the review of primary literature and surveys of pediatricians.117–120,122–126 FORECASTING THE CHILD HEALTH WORKFORCE SUPPLY The 2 fundamental questions in any consideration of the child health workforce are: How many will we have in the future, and will that number be enough or too many As the previous discussion suggests, future child health workforce supply and requirements are related to many factors, each with their own uncertainties (Fig 1). Methods of projecting the number of pediatricians are on safest ground. Using simple actuarial models with assumptions about training (box 3), retirement (box 10), and death rates (box 9 [the last 2 are sometimes combined as a separation rate]), the models have finite solutions. The robustness of forecasting models using these 3 rates can be tested with simple sensitivity analysis. Training rates depend on the number of pediatric GME positions (Fig 1, boxes 3 and 5). Changes in the size of US medical schools (Fig 1, box 1) alter the makeup of the workforce but not the number of pediatricians. Positions unfilled by US medical school graduates48,127 are filled by physicians trained in other countries (Fig 1, box 2). Since 1997, the number of categorical pediatric residency positions offered in the match has increased by 11% and the number filled has increased by 6%.48 ABP data indicate a 5% increase in the number of categorical first-year positions from 1997 to 2002.116 Changes in GME funding could quickly alter the size of this pipeline, although none are on the immediate horizon. We can expect that death rates will continue their downward drift for physicians, but these rates are already low in the preretirement years and a further decrease will not appreciably alter supply-projection models. There are many opinions about trends in retirement rates,128 but there is no dominant a priori direction that can be asserted. Much has been made of physician frustration with managed care, greater administrative tasks, and increasingly litigious families. Without a doubt, these are less attractive sides of the medical profession. On the other hand, health care professionals are retiring later, not earlier, as they follow a general labor trend to a longer work life. Pediatricians and their employers are also faced with the same dramatic short-term challenges of decreasing financial markets that devalue pension funds and 401(k) accounts alike. This inevitably will lead to postponed retirement, at least in the short run. By the time this report is published, it is hoped that the country's economic health along with the rate of return of financial investments will have improved. Still, no credible economist predicts a return to the "irrational exuberance" of the 1990 equity markets, as attractive as that might be for retirement expectations. In a model forecasting the number of clinically active pediatricians, 2 additional gender-related variables are of increasing importance: personal leave (Fig 1, box 8) and part-time employment (Fig 1, box 15), typically for child care responsibilities. The former affects the number of clinically active pediatricians employed at any given time, and the latter modifies the full-time equivalence of those physicians. The dominant influence on these event rates will be the number of women entering pediatric residencies. Current rates are known and can be added to actuarial models with assumptions about future changes in these rates. Forecasting becomes increasingly complex as we incorporate additional parameters into the model. Many of the desired variables are difficult to measure, requiring the substitution of proxies. Other measures lack a theoretic or definitional consensus within the health policy and medical community. Even with perfect measurement, simply adding more variables to the model introduces additional uncertainty to the results. One domain that bedevils child health workforce-supply forecasting is workforce productivity, how it is defined and measured.12,129–132 For the moment, we will restrict productivity to its common measures that are more aptly named medical services productivity (Fig 1, box 14). Examples include visits or hours of clinical activity per week per physician full-time equivalent (FTE). These measures are not equivalent. As previously discussed, the hours worked per week are not strongly related to pediatrician gender. Full-time female and male pediatricians work similar clinical hours.39 Data are not available about gender differences in patient visits per week. Organizational factors are increasingly important in medical productivity as pediatricians continue to shift from solo and partnership practice to employee-based work arrangements. Employee pediatricians work an average of 6.4 fewer hours per week compared with those practicing solo or in partnerships.133 Financial incentives related to patient insurance types or the compensation plans by physician employers can also affect the number of medical services delivered per physician FTE.134,135 For all of these factors, the consistent trend is for pediatricians to work fewer hours and provide fewer visits per week. In 1989, pediatricians (those working at least 20 hours per week in patient care) worked an average of 53 hours per week in patient-care activities; by 1999, they worked 50 hours. During the same period, the average number of office visits decreased from 102 visits per week to 95 (Table 4). 136,137 The numbers indicate a decrease in the medical services productivity of pediatricians but do not account for possible but still unmeasured changes in patient complexity. It is also not known if these trends stem from fewer patients, lifestyle choices of pediatricians, or both. How will medical services productivity change in the future Answers offered to this question are highly speculative. Medical services productivity ignores the very purpose of the profession. The difficulty becomes obvious when one is reminded that the unit of production (in an economic sense) in health care is improvement in health outcomes (Fig 1). Therefore, a strict measure of productivity would be the labor input required per unit of greater health outcomes. In this instance, "health outcomes" is defined broadly to include the maintenance of health, the care and cure of illness, and the restoration of a sense of well-being in children and families through education and counseling. Although operationalizing the theory of health outcomes productivity with actual measurements is difficult, it should at least be understood that the number of hours worked or patients seen per week is not always related to the health status, reduction of risk, or sense of well-being of a physician's patient population. By using default assumptions, the model forecasts a 36% increase (from 38457 to 52169) in general pediatricians in 10 years and a 64% increase (62952) in 20 years. Using middle-census estimates, the number of general pediatricians per 100000 children will increase 31% in 10 years and 50% in 20 years. Adjusting the number of future pediatricians for age and gender productivity will require 4% more pediatricians in 20 years, in large part to compensate for part-time status. This assumes that the current gender mix of residents continues into the future. Sensitivity testing included retirement rates, ranging from a 20% decrease to a doubling of current rates within all age and gender strata, decreased productivity of at least 30% for pediatricians older than 50 years, GME downsizing to 110% of US medical graduates, increase in pediatric residency positions by 1% per year, and substituting low- or high-census child-population estimates. At 20 years, these resulted in differences from the default model pediatrician-to-child ratio of less than 16%. This model demonstrates that the growth in the pediatrician-to-child ratio is robust to varied alternative-forecasting scenarios. PEDIATRICIAN-WORKFORCE REQUIREMENTS Workforce analyses usually run aground when forecasting the physician requirements of populations. The most important parameter is simply the size of the population or its age definition, in this instance the number of children (Fig 1, box 13); from this, future FTEs per child (or per capita) are calculated. Population projections may seem straightforward, but there are uncertainties in both the number and composition of the future population, leading to contentious and seemingly arcane arguments among forecasters.138,139,142 Requirements for general pediatricians are also related to substitution within the broader child health workforce (Fig 1, box 11). As discussed in this report, the number of child health professionals includes a complex mix of physicians and nonphysician clinicians with differing training and education, skills, and knowledge that provide, at times, similar services. Two examples come to mind. Within pediatrics, subspecialists such as neonatologists and hospitalists provide care that once was part of nearly every pediatrician's daily professional life. For whatever factors that may increase the need for pediatric services in the future, rearrangement of clinical work within pediatrics decreases the need for general pediatricians. Similarly, the growth in numbers of nonphysician clinicians may spare the efforts of pediatricians within a practice while decreasing the need for pediatricians in aggregate. More difficult to measure, and usually ignored, are the rich and complex factors that relate the number of health services delivered per child to children's health and well-being, termed health outcome productivity (Fig 1, box 17). A short list of factors includes the technical excellence and appropriateness of the service and the division of labor across the many possible clinicians (Fig 1, box 11) or even across the nonmedical workforce—parents, teachers, coaches, clergy, and therapists (Fig 1, box 16). Relative health needs are also of central importance (Fig 1, box 17). All else held equal, we would also expect a greater production of health (ie, improvement in health status or well-being) when care is delivered to a less healthy child. The organizational and community milieu can also modify the efforts of the child health workforce (Fig 1, box 14). When these factors are considered together, it becomes apparent that successful health outcomes might occur with a widely differing number of pediatricians. Workforce forecasters have accounted for these factors through 5 different models.130,139,143,144 Each model requires particular theoretic assumptions and data, and none of these methods should be viewed as mutually exclusive of the others. The acceptance of a particular framework partly depends on the definition of "requirement" and the policy goal of the forecasting process. Another way of looking at the task of assessing requirements is that it is not a science in the traditional sense but is intertwined with the values expressed in the assumptions. Is the goal to optimize health or the perception of access to physicians or to maximize employment opportunities for physicians Is reducing disparities in the access and use of medical services one goal What level of public funding in education and payment of health services is assumed, and what is the rationale for public funding at all if it is thought that markets will drive the health care system to desirable outcomes Although the values inherent in different requirement models may not be explicitly stated, the careful reader will find them implicit in the models' assumptions. Employment Opportunities for Pediatricians The most basic approach to assess the requirements for pediatricians is to determine their employment opportunities and competition for patients. Both measures are indicative of the pediatrician's short-term prospects, although no forecasting models have been constructed that formally incorporate these economic signals. Studies from the mid- to late 1990s show that although there were wide employment opportunities for general pediatricians, there was also significant competition for jobs and patients. In 1996, 17% of residents finishing training had difficulty finding a position, 15% received only 1 job offer, 9% accepted positions that were not their first choice, 17% accepted a position in a location that was not their first choice, and 18% accepted a job with a salary that was less than expected. Although discouraging at first glance, pediatricians had less difficulty finding a position than did physicians in 25 of the 32 specialties examined. The specialty with the most favorable employment prospects was family medicine; job prospects in general internal medicine were slightly less favorable than in general pediatrics. The specialties with the poorest job prospects were pathology, adult pulmonary disease/critical care medicine, and adult infectious disease.145 Another study found that between 1990 and 1995, the number of employment ads for pediatricians decreased, and ads for pediatric subspecialists remained nearly constant. At the same time, the number of ads for family physicians grew close to 25%.146 Perhaps the most pessimistic view of general pediatrics was reported to the Council on Graduate Medical Education by the Center for Workforce Studies in Albany, NY.147 In exit surveys of residents completing training in New York State and Texas, 6 measures were used to assess relative demand by specialty; general pediatrics was second to last of the 28 specialties studied. The most recent information comes from Cull et al,70 who used survey data from third-year pediatric residents. Over a 5-year period ending in 2002, the proportion of residents with a general pediatrics goal without a position increased from 5% to 15%, and the proportion reporting that their position was their first choice decreased from 86% to 80%. Our information about the competition experienced by practicing pediatricians is limited to subspecialists. Competition is highest for pediatric allergy/immunology, cardiology, pulmonary medicine, and critical care medicine; lower levels of competition were perceived by infectious disease, genetics, and adolescent medicine pediatricians. The strongest predictors of competition were working in solo, group, or medical school practices in contrast to staff- or group-model health maintenance organizations (HMOs) or community hospitals. Pediatricians working in the Midwest or southern regions also experienced the strongest competition. Less competition was felt by IMGs, those working in rural areas, and female physicians.120 Salary information also indicates a weak demand for pediatricians compared with other primary care specialties. In one nationally representative survey conducted between 1996 and 1998, general pediatricians reported an average income of $126000 compared with $144000 for general internists; pediatric subspecialists reported an average salary of $156000, whereas the average salary of internal medicine subspecialists was $192000.148 When adjusted for inflation, the salary of pediatricians changed little between 1989 and 1999 (Table 4).136,137 Starting salaries for graduating residents entering general pediatric practices decreased (in 2002 dollars) from $103161 in 1997 to $99123 in 2002.70 Data from the National Resident Matching Program indicated that pediatric residency positions are among the most highly sought by medical students. At its peak in 1998, 98.9% of pediatric positions offered through the match were filled, with 82.2% filled by US medical graduates; these match rates exceeded internal medicine and family medicine. By 2002, the overall pediatric match rate had fallen to 90.5%, with 70.7% filled by US medical graduates, and then increased slightly in 2003 to 93.8%, with 71.3% filled by US medical graduates. Other primary care specialties experienced similar decreases, particularly with respect to the proportion of US medical graduates matching: 55.2% for internal medicine and 42.0% for family medicine in 2003. For all first-year positions in 2003, 89.9% were match-filled, 63.9% by US medical graduates.48,127,149,150 Despite these marketplace signals, it is worth noting that once in practice, general pediatricians have higher satisfaction with their job, career, and specialty than do general internists. Satisfaction, job stress, and burnout for pediatric subspecialists were less favorable and similar to general and subspecialty internal medicine physicians. These findings show a lack of correlation with salary levels and attitudes about practice and also identify stress experienced by pediatric subspecialists.148 Needs-Based Models One formal model for forecasting future physician requirements was that developed by the Graduate Medical Education National Advisory Committee (GMENAC).151 GMENAC estimated physician requirements in the late 1970s through a complicated process of defining the need for efficient medical services to optimize health. For each specialty, clinicians and epidemiologists estimated the future disease burden, the necessary treatments, and the workforce required to provide those services. The GMENAC report predicted a physician surplus for both generalists and specialists, pediatricians included. From the standpoint of physician employment, this obviously did not occur, and in the absence of unemployed physicians, GMENAC predictions have generally been rejected.9,152 What went wrong with GMENAC First, the data requirements of the models were unrealistic. Needs-based planning assumes that the disease burdens of populations are measurable and that it is known which medical interventions can most effectively and efficiently improve health today and in the future.153 In actuality, the measurement of health status in populations is imperfect, and knowledge of medical care effectiveness is incomplete and likely to remain so as technologic developments outpace effectiveness studies.154,155 Second, there was an assumption by the readers of GMENAC that as physician supply approached levels needed for populations to be healthy, demand would attenuate. In this instance, surplus would be evidenced in unemployment or, at the very least, pressure on physician salaries. Populations with higher health status, however, do not consume necessarily less health care, as might be expected, but continue to demand (in an economic sense) services to address an ever-elusive definition of "health." With most health care costs borne by third parties and the general sense that more medical care always leads to better health, physicians continue to be fully employed even as health status improves. This would be of little public policy interest except that societal resources for medical care reimbursement are not without limits, and many populations remain with unmet health care needs, even as the healthy seek more care. The lesson learned from GMENAC is that in the complex market for medical care and physician labor, population needs are poorly related to demand for physicians. Demand-Based Models Demand-based forecasting uses current medical services utilization as an indication of medical need and projects future utilization to determine the required number of physicians under different conditions of productivity. In its most elegant form, utilization is measured for many different combinations of population characteristics such as age, gender, and race and for different medical care settings and financing. These include the mixture of fee-for-service or managed care penetration and patient insurance status. Once these are measured in the present, then populations for each of these characteristics are projected into the future, and the number of required pediatricians can be calculated. Demand-based models are the most common type of forecasting.138,139,156 Medical service utilization data are available for many populations and types of service delivery. The model assumes that current delivery patterns are rational and desirable and that similar populations in the future will require utilization rates close to those delivered today. The acceptance of current utilization patterns as normative measures also assumes that the current market for health care services maximizes the well-being of children. The 2 merits of demand forecasting are the availability of data and the simple assumption that the medical marketplace reasonably delivers health care consistent with societal values and expectations. Among the many criticisms that can be leveled, the most obvious is that the supply of physicians, as seen with general pediatricians and neonatologists, is not located where child health needs are greater20,114 and that medical utilization similarly varies widely across regions without detectable population differences. Current demand for health care cannot be used as a normative standard when the location of resources is idiosyncratic. The health services literature is replete with studies that show the irrationality of health care delivery.18,157–160 Critics of demand-based planning ask: Why would we want to perpetuate these delivery patterns into the future Trend Analysis Recently, a new method of projecting physician requirements was proposed: trend analysis.144,152 The method uses a macroeconomic conceptual framework that asserts that growth in physician requirements is tightly linked with increases in the gross domestic product (GDP). In addition to long-term trends in GDP, 8 "macro" trends are emphasized in the model, some that can be reasonably measured and others that are highly speculative. The model attempts to separate trends that are "the natural evolution of the current fiscal and organizational characteristics of the health care system and the societal fabric in which it exists" (attrition, productivity, substitution, geographic distribution, technology, demographics, health systems, and economic dependency) from trends that are "value judgments" (technology controls, specialist controls, volume controls, and cost controls).161 The developers of this model have used it to advance the idea of an "impending" physician shortage. Although the method forecasts physicians in aggregate, they have interpreted trends as indicating a future shortage in specialists and an "abundance of generalists."162,163 Trend analysis has been criticized for its view that the macroeconomic association of GDP and the workforce is causal, inevitable, and a self-evident expression of societal wants. Many other criticisms have also been vigorously advanced.164–170 When this model is applied to the pediatrician workforce, a contradiction emerges. Just as Cooper et al162 have observed a correlation between the growth of GDP per capita and total physicians per capita, Freed et al171 have presented a similar correlation with pediatricians per 100000 children. Projecting this trend into the future, Freed et al171 find, instead of Cooper et al's "abundance of generalists," that "the current net inflow of pediatricians will not be sufficient to meet future demand as expressed by the trend line." These conclusions need to be considered in the context of the estimate of Shipman et al141 that the per-child number of pediatricians will grow more than 5 times faster than the per-capita number of internists or family physicians. One interpretation is that there is an impending shortage of primary care as well as specialist physicians. Another interpretation is that macroeconomic correlations are an overly simple estimator of workforce requirements. A potential weakness with these models is that the number of physicians per capita has increased over time and will correlate highly with any other upward trend. Bivariate time-series analyses are subject to the same limitations as any other observational study, with the added problems of a small number of observations (n = number of time periods) and difficulty in identifying and measuring time-dependent confounders. When the models are technically correct,172 health care planners still must decide whether previous patterns of physician growth should be used as the primary guide of the child health workforce in the future. Benchmarking Benchmarking is a final method of determining workforce requirements. Benchmarking exploits natural experiments in workforce levels by using physician-to-population ratios found in regions of the United States or within health care systems as indications of real life and attainable physician levels.19,139,143,173,174 Benchmarking seeks to find regions in which workforce deployment is efficient and effective in delivering health care. A slightly different approach is to use the staffing levels in efficient capitated health systems that deliver high-quality care as measured by medical care processes, family satisfaction, and health outcomes. Benchmarking rejects the notion that the current national physician labor or health services markets have any particular normative value in terms of optimizing health outcomes and offers a variety of available reference points to help guide physicians' employment decisions. In the short term, benchmarks can caution a health plan about adding additional specialists to an area with a high per-capita number or point to areas with a low supply that may be an opportunity for expanded services. As the marginal effects of physician supply on patient satisfaction and outcomes are better understood, benchmarks may provide a means of improving systems of care for populations enrolled in health plans or residing within regions. To the degree we fall short of the need or desire to develop effective delivery systems with constrained resources, benchmarking will fail to predict physician employment opportunities. Requirements for Pediatricians In Table 5 we present published projections of pediatrician supply and requirements. It is evident from this list that relatively little work has been done in this area. The supply of general pediatricians forecasted by Shipman et al141 for 2010 is similar to the earlier predictions of Kletke et al.175 The current supply (53 general pediatricians per 100000 children younger than 18 years) exceeds the requirement suggested by GMENAC in 1980 (49 per 100000) and by Abt Associates in 1991176 (41 per 100000). The only other estimates of requirements that are available are from the AAP Pediatric Research in Office Settings Network (71 per 100000) and various group and HMO practices (49–89 per 100000). These figures assume that children receive care only within pediatrician-dominated practices with staffing levels observed in practices serving largely employer-insured populations.107,177 Even with these assumptions, Shipman et al141 and Kletke et al175 forecast a supply in 2010 (72 per 100000) that exceeds staffing levels observed in most of these groups. As discussed elsewhere in this report, a level of supply judged sufficient for the United States as a whole still leaves pockets of underservice or possible pediatrician excess. In addition, the effects of the growing supply of pediatricians on employment opportunities will depend on both the financing and organization of health care. General pediatrician unemployment would most likely occur if pediatric care were delivered entirely under the organizational systems that carefully manage panel size, the mix of physicians and nonphysician clinicians, and utilization, such as staff- or group-model HMOs. To the extent that pediatric care is less explicitly planned and financed, there are likely to be substantial regional differences in future opportunities for pediatricians. Which Supply of Pediatricians Is "Right" This report does not recommend a particular supply of pediatricians but instead challenges the reader to consider the values worth promoting through workforce policy. Much of the disagreement about physician requirements is seen as a consequence of uncertainty in the data and analytic methods when, in fact, these debates are driven by fundamental, and often unstated, conflicts in values. The differences in values are embedded in both the means and ends of the pediatrician workforce. With respect to the "means," there are significant disagreements among pediatricians, health care planners, and families about the appropriate and effective mix of market-based and publicly funded programs in the education and deployment of the workforce. Should public funding of medical education (eg, GME Medicare and Health Resources and Services Administration monies) be accompanied by an obligation to care for underserved populations Who should decide on the size of the pediatrician pipeline Should it continue to be residency programs or a quasi-public entity How much of medical education should be funded publicly if markets are considered the best arbiter of workforce supply As far as the "ends" of workforce policy, should the workforce be equitably available to children If not, how much disparity is acceptable, and who should pay the associated uneven costs How much should workforce policy be influenced by the interest in tempering pediatric competition and thereby ensuring practice opportunities and stable incomes If this is ignored, will we able to attract the best and the brightest of rising medical talent to pediatrics These are only a few of the questions that need to be considered in developing workforce policy, including the target supply. The answers are linked to the values held as individuals and jointly as a profession. If producing better health and well-being of children remains the goal of pediatricians and associated workforce policy, there are still areas in which sound policy is hindered by inadequate data. The 2 related and unanswered questions in pediatrician-workforce research are: How much of an improvement in child health outcomes is derived from a given increase in the number of pediatricians, and would an equal investment in an alternative input provide a greater benefit Past investments in pediatricians have brought good value in children's health outcomes improvement. At the same time, there is a need to evaluate the effectiveness of additional growth in pediatrician supply. Committee on Pediatric Workforce, 2005–2006 Michael R. Anderson, MD, Chairperson Aaron L. Friedman, MD David C. Goodman, MD, MS Beth A. Pletcher, MD Scott A. Shipman, MD, MPH Richard P. Shugerman, MD Rachel Wallace Tellez, MD, MS Past Committee Members Carmelita V. Britton, MD, Past Chairperson Carol D. Berkowitz, MD Gerald S. Gilchrist, MD Kristan M. Outwater, MD Richard J. Pan, MD, MPH Debra R. Sowell, MD Liaison Gail A. McGuinness, MD American Board of Pediatrics Staff Ethan Alexander Jewett, MA REFERENCES Ginzberg E. The Medical Triangle: Physicians, Politicians, and the Public. Cambridge, MA: Harvard University Press; 1990 Fuchs VR. The basic forces influencing the costs of medical care. In: Fuchs VR, ed. Essays in the Economics of Health and Medical Care. New York, NY: National Bureau of Economic Research; 1972: 39–50 Reinhardt UE. Health manpower planning in a market context: the case of physician manpower. In: Bailey NTJ, Thompson M, eds. Systems Aspects of Health Planning. Baden, Austria: North-Holland Publishing; 1974: 131–164 Pauly MV. Is medical care different Old questions, new answers. J Health Polit Policy Law. 1988;13 :227 –237 Rice T. 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☉ 11333122:Bullous "Cellulitis" With Eosinophilia: Case Report and Review of Wells' Syndrome in Childhood
Dermatology Pediatrics, University of California, San Francisco, California Department of Dermatology, Stanford University School of Medicine, Stanford, California Children's Hospital and Research Center, Oakland, California ABSTRACT A 1-year-old girl presented with acute onset of edematous erythematous plaques associated with bullae on her extremities and accompanied by peripheral eosinophilia. She was afebrile, and the skin lesions were pruritic but not tender. The patient was treated with intravenously administered antibiotics for presumed cellulitis, without improvement. However, the lesions responded rapidly to systemic steroid therapy. On the basis of lesional morphologic features, peripheral eosinophilia, and cutaneous histopathologic features, a diagnosis of Wells' syndrome was made. Wells' syndrome is extremely rare in childhood, with 27 pediatric cases reported in the literature. Because it is seen so infrequently, there are no specific guidelines for evaluation and management of Wells' syndrome among children. The diagnosis should be considered for children with presumed cellulitis and eosinophilia who fail to respond to antibiotics. Evaluation should include a directed history, physical examination, complete blood count, and stool testing for ova and parasites, to identify potential triggers. Treatment is with systemic steroid therapy unless disease is limited, in which case medium/high-potency topical steroids may be indicated. If systemic features are prominent or disease is chronic (lasting >6 months), then a referral to hematology/oncology should be considered. Key Words: cellulitis eosinophilia eosinophilic cellulitis Wells' syndrome Abbreviations: CSS, Churg-Strauss syndrome HES, hypereosinophilic syndrome IL, interleukin Wells' syndrome, or eosinophilic cellulitis, is a rare, recurrent, inflammatory dermatosis of unknown pathogenesis. In 1971, Wells1 described 4 patients with an acute pruritic dermatitis clinically resembling bacterial cellulitis but with histopathologic findings characterized by dermal eosinophilia, phagocytic histiocytes, and the presence of flame figures. He initially called this syndrome recurrent granulomatous dermatitis with eosinophilia but later simplified the name to eosinophilic cellulitis.2 Wells' syndrome is seen more commonly among adults but has been observed among children. Some hypothesize that this syndrome may represent a hypersensitivity response to a circulating antigen.2 Associated precipitants include insect bites, medication reactions, recent immunization, myeloproliferative disorders, malignancies, and infections. We describe a case of a young child with no identifiable triggering factors, and we review the evidence for evaluation and management of these pediatric cases. CASE REPORT A previously healthy, 1-year-old girl presented with acute onset of edematous erythematous plaques, with associated bullae, on her lower extremities and left arm (Fig 1). These lesions were pruritic but not painful, and the patient was afebrile. Her parents denied a history of insect bites, ingestion of medications, trauma, or other intercurrent illness. The patient's most recent immunizations had been received 3 months earlier. The patient did not have a history of asthma, and there was no family history of asthma or atopic disease. The patient was admitted with presumed bacterial cellulitis and was treated with intravenously administered oxacillin, without improvement. Her laboratory studies were significant for an elevated white blood cell count of 30 x 109 cells per L, with peripheral eosinophilia of 48%. After the patient failed to respond to systemically administered antibiotics, examination of vesicle fluid was performed and revealed numerous eosinophils. Subsequently, the diagnosis of probable Wells' syndrome was made. Oral steroid therapy was started at 2 mg/kg, and the patient's cutaneous symptoms improved within 24 hours, leaving residual erythema and hyperpigmentation (Fig 2). Five days after the initiation of oral steroid therapy, a skin biopsy was performed from a persistently indurated area. Histopathologic assessment showed an interstitial infiltrate of histiocytes and waning flame figures, represented by collections of eosinophilic granules surrounded by a palisade of histiocytes (Fig 3). Oral steroid treatment was tapered over 3 weeks, and a topical triamcinolone preparation was applied to residual lesions twice daily until the lesions resolved. At 1 year, the patient has not experienced recurrent disease. DISCUSSION Wells' syndrome is extremely rare in childhood, with only 27 pediatric cases reported (Table 1). It is characterized by a combination of distinct clinical and histopathologic findings. Classically, patients present with pruritic erythematous plaques, sometimes with associated bullae, that evolve rapidly over 2 to 3 days. These resolve spontaneously over 2 to 8 weeks, leaving residual skin atrophy and hyperpigmentation, resembling morphea.2 There is usually no improvement with antimicrobial therapy; instead, a rapid response to oral corticosteroid treatment is observed, as in our case. It is not uncommon for patients to have recurrent disease, with exacerbations and remissions occurring over several years. The histopathologic findings are quite specific and are characterized by flame figures, which are composed of eosinophil major basic protein deposited on collagen bundles.3 With resolution, there is a granulomatous phase of histiocytes palisading around the flame figures. Vasculitis is absent, and direct immunofluorescence findings are negative.4,5 Associated laboratory findings include an elevated white blood cell count and peripheral eosinophilia, which is found in up to 50% of cases during the active phase of disease.5,6 The erythrocyte sedimentation rate is elevated for some patients, and there are several reports of associated elevated IgE levels.7–14 Fever, lymphadenopathy, arthralgias, and other systemic symptoms (such as pulmonary involvement) have been described for Wells' syndrome, and these findings may be indicative of a more severe or progressive course.7 The differential diagnosis of Wells' syndrome includes bacterial cellulitis, Churg-Strauss syndrome (CSS), eosinophilic fasciitis, and hypereosinophilic syndrome (HES) (Table 2). The skin lesions of Wells' syndrome are distinguished from those of bacterial cellulitis by the absence of tenderness and the presence of pruritus, which is often the primary symptom of Wells' syndrome. Lack of warmth, failure to respond to antibiotic therapy, and characteristic histologic findings are the other features that differentiate Wells' syndrome from bacterial cellulitis. CSS should be considered for patients with persistent peripheral eosinophilia and skin lesions. Although more commonly seen among adults, CSS can present in childhood.15–17 This syndrome is characterized by asthma, peripheral eosinophilia, and vasculitis and is associated with autoantibodies to perinuclear antineutrophil cytoplasmic antibody, as well as cutaneous and systemic granulomas. Palpable purpura, tender subcutaneous nodules, and cutaneous infarctions are more often the associated skin findings in CSS, whereas patients present with bullae and vesicular lesions in Wells' syndrome. In both conditions, flame figures can be identified histopathologically, as can peripheral blood and tissue eosinophilia. However, the presence of vasculitis with extensive fibrinoid necrosis of collagen is more suggestive of CSS.2,9 Eosinophilic fasciitis is another condition that can resemble Wells' syndrome. Also seen more frequently among adults but reported in children,18,19 it presents with acute onset of skin inflammation and resolves with hyperpigmentation and scleroderma-like skin changes. Unlike Wells' syndrome, eosinophilic fasciitis is characterized by arthritis as a prominent symptom, and it follows a more chronic course, with individual lesions requiring months or years to resolve.12 It is distinguishable from Wells' syndrome by the depth of inflammation, with eosinophilic invasion into deeper fascial tissues. Finally, idiopathic HES also should be considered when the diagnosis of Wells' syndrome is being entertained. This condition is extremely rare in the pediatric age group but has been reported in childhood.20 HES is a lymphoproliferative disorder characterized by overproduction of eosinophils with a predilection to damage specific organs, especially the cardiovascular system. It is defined by sustained eosinophilia (>1.5 x 109 cells per L, lasting for >6 months), with evidence of multiple-organ system involvement, in the absence of parasitic disease, allergic diatheses, or other conditions known to cause eosinophilia. The heart, lungs, central and peripheral nervous systems, kidneys, and gastrointestinal tract can be affected, and the cutaneous findings are similar to those of Wells' syndrome, including erythematous pruritic papules and nodules, urticaria, and angioedema.9,21–23 Histopathologically, the skin lesions of HES are nonspecific, and the flame figures and granulomatous infiltrate seen in Wells' syndrome are absent.21 The pathogenesis of Wells' syndrome is not well defined. One hypothesis is that it represents a hypersensitivity mechanism triggered by factors such as infections, drugs, or internal disease. However, in approximately one half of reported cases among children, there is no identifiable precipitating factor.24 Reported precipitants have included bites or stings from ticks, bees, and spiders8,9,12,25–28 and infections with mumps, molluscum contagiosum, varicella, and herpes simplex virus.1,24,29,30 There are also several reports of Wells' syndrome associated with bacterial, parasitic, and fungal infections.2,9,14,31–33 Numerous medications have been implicated as triggers for Wells' syndrome.1–3,5,9,34–38 Also, several cases of Wells' syndrome occurred after vaccinations,39,40 and it was proposed that the preservative thimerosol was the causative agent in those cases.39 Several cases of Wells' syndrome among adults have been associated with hematologic disorders,9,41 lymphoproliferative malignancies,1,34,42 and carcinoma.34,43–45 Zachary et al45 reported a case of Wells' syndrome in a 17-year-old girl with nasopharyngeal carcinoma, which is the only pediatric case of Wells' syndrome associated with malignancy reported in the literature. One of the key events in disease expression of Wells' syndrome appears to be aberrant and inadequate eosinophil skin homing. Increased interleukin (IL)-5 levels have been observed in Wells' syndrome, and IL-5 not only mobilizes eosinophils from the bone marrow but also promotes homing of eosinophils by altering expression of adhesion molecules. In addition, increased levels of IL-5 appear to induce expression of CD25, the chain of the IL-2 receptor, which enhances eosinophil degranulation and subsequent tissue destruction.46–48 Treatment for Wells' syndrome is sometimes unnecessary, because cases often resolve spontaneously. If an infection or other treatable precipitating factor can be identified, then there is often improvement with treatment of the underlying condition.14,30,33,44 However, when no treatable underlying factor can be identified, systemic corticosteroid therapy is used frequently for both adults and children. Most cases resolve after a single course of systemic corticosteroid therapy; when recurrences occur, however, alternative treatments should be considered, to avoid the side effects of chronic systemic steroid therapy.36 Topical steroid treatment has also been reported as successful therapy, both alone2,29,39 and in combination with systemic steroid therapy.5 Specifically, topical steroid therapy alone resolved skin lesions for 2 children, which suggests that topical steroid therapy may be a safe alternative to systemic corticosteroid therapy in the pediatric age group.29,39 Other therapies reported to be successful include various antimicrobial agents,2,5,6,9,10,13,49 colchicine,13 antimalarial drugs, cyclosporine,50 azathioprine,5 interferon-,51 psoralen with ultraviolet A,52 and antihistamines.10,43,53 The small numbers of cases and the fact that most reports are anecdotal make it difficult to draw conclusions regarding whether these therapies are truly effective or these cases resolved spontaneously. However, we think that first-line treatment for children should be systemic corticosteroid therapy, with the addition of topical steroid treatment depending on the extent of disease. A dose of orally administered prednisolone or prednisone of 2 mg/kg per day for 5 to 7 days, with a taper over 2 to 3 weeks, is appropriate. Topical steroid treatment may be used in combination. In cases in which there is limited body surface area involved (15–30%) and an absence of systemic symptoms, it may be prudent to consider medium-potency topical steroid therapy alone, with close follow-up monitoring. This would also be appropriate for recurrent cases of Wells' syndrome identified early, when disease may be limited. Evaluation should be directed at ruling out other conditions that mimic Wells' syndrome, as well as evaluating possible triggering factors. We recommend a complete history and review of systems, with specific attention to recent medications, vaccinations, insect bites, infections, or illnesses and associated medical problems such as asthma. A thorough physical examination should be performed, with attention to the liver, spleen, and lymph nodes. Stool samples should be sent for ova and parasite testing, and a complete blood count with differential evaluation should be performed. If there is uncertainty regarding the diagnosis, then a skin biopsy should be performed to distinguish between Wells' syndrome and other conditions that mimic it. We do not recommend a complete hematologic evaluation in all cases, because it is rare to see cases of either HES or Wells' syndrome triggered by hematologic or oncologic disorders in childhood. However, if a child presents with either systemic features, such as fevers, arthralgias, or other organ system involvement, or a chronic course, defined as >6 months of peripheral eosinophilia or recurrences of clinical disease, then a referral to hematology/oncology should be considered. FOOTNOTES Accepted Dec 29, 2004. No conflict of interest declared. REFERENCES Wells GC. Recurrent granulomatous dermatitis with eosinophilia. Trans St Johns Hosp Dermatol Soc.1971; 57 :46 –56 Wells GC, Smith NP. Eosinophilic cellulitis. Br J Dermatol.1979; 100 :101 –109 Peters MS, Schroeter AL, Gleich GJ. Immunofluorescence identification of eosinophil granule major basic protein in the flame figures of Wells' syndrome. Br J Dermatol.1983; 109 :141 –148 Bonvalet D, Caron C, Levet R, et al. Wells' syndrome or eosinophilic cellulitis: apropos of 2 cases: review of the literature [in French]. Ann Dermatol Venereol.1983; 110 :899 –907 Moossavi M, Mehregan DR. Wells' syndrome: a clinical and histopathologic review of seven cases. Int J Dermatol.2003; 42 :62 –67 Fisher GB, Greer KE, Cooper PH. Eosinophilic cellulitis (Wells' syndrome). Int J Dermatol.1985; 24 :101 –107 Kamani N, Lipsitz PJ. Eosinophilic cellulitis in a family. Pediatr Dermatol.1987; 4 :220 –224 Anderson CR, Jenkins D, Tron V, Prendiville JS. Wells' syndrome in childhood: case report and review of the literature. J Am Acad Dermatol.1995; 33 :857 –864 Aberer W, Konrad K, Wolff K. Wells' syndrome is a distinctive disease entity and not a histologic diagnosis. J Am Acad Dermatol.1988; 18 :105 –114 Stam-Westerveld EB, Daenen S, Van der Meer JB, et al. Eosinophilic cellulitis (Wells' syndrome): treatment with minocycline. Acta Derm Venereol.1998; 78 :157 Lindskov R, Illum N, Weismann K, et al. Eosinophilic cellulitis: five cases. Acta Derm Venereol.1988; 68 :325 –330 Saulsbury FT, Cooper PH, Bracikowski A, et al. Eosinophilic cellulitis in a child. J Pediatr.1983; 102 :266 –269 Paquet P, Laso-Dosal F, de la Brassinne M. Wells' syndrome: report of 2 cases. Dermatology.1992; 184 :139 –141 Tsuda S, Tanaka K, Miyasoto M, Nakama T, Sasai Y. Eosinophilic cellulitis (Wells' syndrome) associated with ascariasis. Acta Dermatol Venereol.1994; 74 :292 –294 Wang SJ, Yang YH, Lin YT, et al. Childhood Churg-Strauss syndrome: report of a case. J Microbiol Immunol Infect.2000; 33 :263 –266 Lin TL, Wang CR, Liu MF, et al. Multiple colonic ulcers caused by Churg-Strauss syndrome in a 15-year-old girl. Clin Rheumatol.2001; 20 :362 –364 Louthrenoo W, Norasetthada A, Khunamornpong S, et al. Childhood Churg-Strauss syndrome. J Rheumatol.1999; 26 :1387 –1393 Ching DW, Petrie JP. Childhood eosinophilic fasciitis presenting as inflammatory polyarthritis and associated with selective IgA deficiency. Ann Rheum Dis.1991; 50 :647 –648 Huppke P, Wilken B, Brockmann K, et al. Eosinophilic fasciitis leading to painless contractures. Eur J Pediatr.2002; 161 :528 –530 Schulman H, Hertzog L, Zirkin H, Hertzanu Y. Cerebral sinovenous thrombosis in the idiopathic hypereosinophilic syndrome in childhood. Pediatr Radiol.1999; 29 :595 –597 Kazmierowski JA, Chusid MJ, Parrillo JE, et al. Dermatologic manifestations of the hypereosinophilic syndrome. Arch Dermatol.1978; 114 :531 –535 Fujii K, Tanabe H, Kanno Y, et al. Eosinophilic cellulitis as a cutaneous manifestation of idiopathic hypereosinophilic syndrome. J Am Acad Dermatol.2003; 49 :1174 –1177 Tsuji Y, Kawashima T, Yokota K, et al. Wells' syndrome as a manifestation of hypereosinophilic syndrome. Br J Dermatol.2002; 147 :811 –812 Stavropoulos PG, Kostakis PG, Panagiotopoulos AK, et al. Molluscum contagiosum and cryosurgery: triggering factors for Wells' syndrome Acta Derm Venereol.2003; 83 :380 –381 Nielsen T, Schmidt H, Sogaard H. Eosinophilic cellulitis (Wells' syndrome) in a child. Arch Dermatol.1981; 117 :427 –429 Wood C, Miller AC, Jacobs A, et al. Eosinophilic infiltration with flame figures. Am J Dermatopathol.1986; 8 :186 –193 Clark P, Anderson PC. Eosinophilic cellulitis caused by arthropod bites. Int J Dermatol.1988; 27 :411 –412 Schorr WF, Tauscheck AL, Dickson KB, Melski JW. Eosinophilic cellulitis (Wells' syndrome): histologic and clinical features in arthropod bite reactions. J Am Acad Dermatol.1984; 11 :1043 –1049 Reichel M, Isseroff RR, Vogt PJ, Gendour-Edwards R. Wells' syndrome in children: varicella infection as a precipitating event. Br J Dermatol.1991; 124 :187 –190 Ludwig RJ, Grundmann-Kollmann M, Holtmeier W, et al. Herpes simplex virus type 2-associated eosinophilic cellulitis (Wells' syndrome). J Am Acad Dermatol.2003; 48 (suppl):S60 –S61 Prendiville JS, Jones RR, Bryceson A. Eosinophilic cellulitis as a manifestation of onchocerciasis. J R Soc Med.1985; 78 :21 –22 Van den Hoogenband HM. Eosinophilic cellulitis as a result of onchocerciasis. Clin Exp Dermatol.1983; 8 :405 –408 Hurni MA, Gerbig AW, Braathen LR, Hunzinker T. Toxocariasis and Wells' syndrome: a causal relationship Dermatology.1997; 195 :325 –328 Brehmer-Andersson E, Kaaman T, Skog E, Frithz A. The histopathogenesis of the flame figure in Wells' syndrome based on five cases. Acta Derm Venereol.1986; 66 :213 –219 Seckin D, Demirhan B. Drugs and Wells' syndrome: a possible causal relationship Int J Dermatol.2001; 40 :133 –152 Coldiron BM, Robinson JK. Low-dose alternate-day prednisone for persistent Wells' syndrome. Arch Dermatol.1989; 125 :1625 –1626 Spigel GT, Winkelmann RK. Wells' syndrome: recurrent granulomatous dermatitis with eosinophilia. Arch Dermatol.1979; 115 :611 –613 Ferrier MC, Janin-Mercier A, Souteyrand P, et al. Eosinophilic cellulitis (Wells' syndrome): ultrastructural study of a case with circulating immune complexes. Dermatologica.1988; 176 :299 –304 Koh KJ, Warren L, Moore L, et al. Wells' syndrome following thiomersal-containing vaccinations. Australas J Dermatol.2003; 44 :199 –202 Moreno M, Luelmo J, Monteagudo M, Bella R, Casanovas A. Wells' syndrome related to tetanus vaccine. Int J Dermatol.1997; 36 :524 –525 Horn MJ, Katz DA, Bewtra C, Fusaro RM, Koh JK. Eosinophilic cellulitis (Wells' syndrome). Arch Dermatol.1985; 121 :836 Varrotti C, Tosti A, Gobbi M, Martinelli G, Patrizi A. Eosinophilic cellulitis: a new case. Dermatologica.1982; 164 :404 –406 Farrar CW, Guerin DM, Wilson NJE. Eosinophilic cellulitis associated with squamous cell carcinoma of the bronchus. Br J Dermatol.2001; 145 :667 –690 Murray D, Eady RAJ. Migratory erythema and eosinophilic cellulitis associated with nasopharyngeal carcinoma. J R Soc Med.1981; 74 :845 –847 Zachary CB, Wong E, Wilson-Jones E. Eosinophilic cellulitis [in French]. Ann Dermatol Venereol.1984; 111 :777 –778 Espana A, Sanz ML, Sola J, et al. Wells' syndrome (eosinophilic cellulitis): correlation between clinical activity, eosinophil levels, eosinophil cation protein and interleukin-5. Br J Dermatol.1999; 140 :127 –130 French LE, Shapiro M, Junkins-Hopkins JM, et al. Eosinophilic fasciitis and eosinophilic cellulitis in a patient with abnormal circulating clonal T cells: increased production of interleukin 5 and inhibition by interferon . J Am Acad Dermatol.2003; 49 :1170 –1174 Mould AW, Matthaei KI, Young IG, Foster PS. Relationship between interleukin-5 and eotaxin in regulating blood and tissue eosinophilia in mice. J Clin Invest.1997; 99 :1064 –1071 Marks R. Eosinophilic cellulitis: a response to treatment with dapsone: case report. Aust J Dermatol.1980; 21 :10 –12 Herr H, Jai-Kyoung K. Eosinophilic cellulitis (Wells' syndrome) successfully treated with low-dose cyclosporine. J Korean Med Sci.2001; 16 :664 –668 Husak R, Goerdt S, Orfanos CE. Interferon treatment of a patient with eosinophilic cellulitis and HIV infection. N Engl J Med.1997; 337 :641 –642 Dirdil E, Honigsmann H, Tanew A. Wells' syndrome responsive to PUVA therapy. Br J Dermatol.1997; 137 :479 –481 Aroni K, Aivaliotis M, Liossi A, Davaris P. Eosinophilic cellulitis in a child successfully treated with cetirizine. Acta Derm Venereol.1999; 79 :332 Correia S, Garcia e Silva L. Childhood Wells syndrome [in Portuguese]. Med Cutan Ibero Lat Am.1988; 16 :221 –224 Garty BZ, Feinmesser M, David M, et al. Congenital Wells' syndrome. Pediatr Dermatol.1997; 14 :312 –315 Kuwahara RT, Randall MB, Eisner MG. Eosinophilic cellulitis in a newborn. Pediatr Dermatol.2001; 18 :89 –90 Davis MD, Brown AC, Blackston D, et al. Familial eosinophilic cellulitis, dysmorphic habitus, and mental retardation. J Am Acad Dermatol.1998; 38 :919 –928...查看详细 (23017字节)
☉ 11333124:US Department of Education Data on "Autism" Are Not Reliable for Tracking Autism Prevalence
the Department of Biology, Portland State University, Portland, Oregon ABSTRACT Many autism advocacy groups use the data collected by the US Department of Education (USDE) to show a rapidly increasing prevalence of autism. Closer examination of these data to follow each birth-year cohort reveals anomalies within the USDE data on autism. The USDE data show not only a rise in overall autism prevalence with time but also a significant and nearly linear rise in autism prevalence within a birth-year cohort as it ages, with significant numbers of new cases as late as 17 years of age. In addition, an unexpected reduction in the rise of autism prevalence occurs in most cohorts at 12 years of age, the age when most children would be entering middle school. These anomalies point to internal problems in the USDE data that make them unsuitable for tracking autism prevalence. Key Words: autism prevalence education Abbreviations: USDE, United States Department of Education IDEA, Individuals With Disabilities Education Act DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition OAR, Oregon Administrative Rules The prevalence of autism and whether that prevalence is rising are 2 of the many controversies surrounding this disorder. Much of the controversy is attributable to the difficulty of finding good data. A number of studies have examined the prevalence of autism and related disorders1–6 in a number of different populations and periods. However, all of these studies are constrained by time and funding to examining either a relatively small population or relatively few points in time. Many autism advocates have used data from the United States Department of Education (USDE) in their presentations to lawmakers7 and the public to show a dramatic and accelerating rise in the prevalence of autism in the United States. Because these data are being used to influence public policy, it is critically important to know if they can be used to reliably measure the prevalence of autism. This study examined the autism data collected by the USDE by following individual birth-year cohorts through time. It also examined the methods used to collect the USDE autism data and compared those with the methods used by medical practitioners to diagnose autism. METHODS Under the provisions of the Individuals With Disabilities Education Act (IDEA), the USDE Office of Special Education Programs collects data on children who qualify for special education assistance. This information is presented to Congress each year in an annual report that is available to the public. The number of children with a qualifying condition of autism has been collected and reported every year since 1992 (voluntary in 1992, mandatory 1993 to present). USDE data provided the number of children in each single-year age group with the IDEA-qualifying condition of autism. This information was found in the Office of Special Education and Rehabilitation Services’ 14th through 25th Annual Reports to Congress.8 These data are collected by the USDE from the education departments of each state (also from the District of Columbia, Puerto Rico, Guam, and other US possessions and territories), which in turn collect them from the individual school districts. The assessment criteria for autism (and the other IDEA-qualifying categories) are based on legislation passed by the individual state legislatures, as interpreted by the state education departments and local school districts. Only data from 1993 and later were used, as autism was not reported separately until 1992 and mandatory reporting did not begin until 1993. The study was also restricted to ages 6 through 17 years because children who are younger than 6 and older than 17 are generally not required to attend school and seem to be underrepresented in the USDE data. Population figures for each single-year age group were obtained from the US Census Bureau and were derived from the 1990 and 2000 decennial censuses. Populations of noncensus years were estimated by the US Census Bureau using their estimation algorithm. Information was extracted from the US Census Bureau’s online database using the DataFerret search and retrieval program (www.dataferrett.census.gov). Autism prevalence was calculated by dividing the number of children with autism of each age reported to the USDE by the total number of people in the United States of that age in that year. August census estimates were used for noncensus years. Birth-year cohorts were developed by assigning children of each age to the birth year that corresponded to the middle of that age group (eg, all 6-year-olds in 2000 were assigned to the 1994 birth-year cohort). 2 analysis was used to compare autism prevalence within a birth-year cohort from year to year as well as between birth-year cohorts at a specific age. The expected number of autistic children was calculated by taking the prevalence from the reference group and applying it to the population figure for the group being analyzed. RESULTS According to the USDE data, overall autism prevalence in children aged 6 to 17 years shows an exponential increase (y = 3.2e0.19x; r2 = 0.999) from 1993 to 2003 (Fig 1). When the data are segregated by birth year, every cohort born after 1980 shows a continuing rise in autism prevalence as the cohort ages (Fig 2). The rise in autism prevalence is surprisingly linear, with r2 values >0.95 in all cohorts from 1984 onward. The rate of rise in autism prevalence also increases in later born cohorts: every cohort in this study had a higher rate of rise in autism prevalence than all earlier born cohorts. The autism prevalence from year to year (Table 1) shows a statistically significant increase within birth-year cohorts as they age. This continues to 16 years of age in most cohorts, with half (5 of 10) of the cohorts also showing a significant increase in autism prevalence between ages 16 and 17 years. Later born cohorts have a higher initial prevalence of autism in addition to a faster rate of rise. A regular exception to the rising prevalence of autism is the interval between ages 11 and 12 years. Most birth-year cohorts showed either no significant change in autism prevalence (7 of 10) or a small decrease in prevalence (1 of 10) during this interval. Even in the cohorts that had a rise in autism prevalence between ages 11 and 12 years, the rise during this period was less than half the rate of rise for the preceding or (if available) the following age interval (Table 2). DISCUSSION The USDE data on autism seem to indicate that there has been an exponential rise in autism prevalence between 1993 and 2003. They also suggest that there are as many children who are newly categorized as autistic at 15 years of age as there are at 8 years of age. These data also seem to show a consistent break in the rise of autism prevalence between ages 11 and 12 years, with 1 cohort (1988) showing a statistically significant decrease in autism prevalence in this interval. Instead of showing a rise in autism prevalence at the age when most children move from elementary school to the more challenging and less structured environment of middle school, the USDE data show the opposite. All of these point to problems within the USDE data. Autism, as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV), is a developmental disorder that is usually first observed between birth and 3 years of age. Although it is often diagnosed later, the impairments must be present by age 3 years to make the diagnosis of autism.9 Four recent studies examined age of first diagnosis of autism and suggested that the majority of diagnoses are made before the age of 8 years. A study of records from British general practitioners found that the mean age at first diagnosis was 6.25 years (SD: 4.52 years).10 A study of 2 cohorts (born 1974–1983 and 1984–1993) in Iceland showed an even younger age at first diagnosis: 3.6 years and 4.0 years, respectively (ranges: 1.7–17 and 2.2–13.8 years, respectively).1 A study of Medicaid-eligible children in Philadelphia, Pennsylvania, had a mean age at first diagnosis of 7.4 years (SD: 3.1 years).11 One study of a single health district in Northern England looked specifically at the difference in timing of medical diagnosis and educational assessment (statement of special educational needs). They found that, for children in mainstream schools, the mean age at diagnosis was 6.5 years (range: 2–12 years) and the mean age of receiving a statement of special educational needs was 5.6 years, indicating that the educational assessment of autism generally preceded the medical diagnosis.12 The interval between ages 11 and 12 years is the time when most children make the transition from elementary school to middle school. Although it might be expected that moving from the structured academic and social environment of elementary school to the more self-directed environment of middle school would "unmask" milder cases of autism, the USDE data show just the opposite. Most (5 of 6) of the cohorts that have complete data for the period surrounding this transition show a greater rise in autism prevalence for the 2 years before middle school than in the 2 years after the transition to middle school. The USDE data suggest that the prevalence of autism is rising, but is this attributable to an actual increase in prevalence or to a broader definition of autism and greater public awareness A number of studies have suggested that the diagnosis of autism, even by medical practitioners, has experienced significant drift over time.1,4,5 A review by Wing and Potter13 provides an excellent overview of this problem. A recent study of autism incidence between 1976 and 1997 concluded that the timing of the increase in autism diagnoses suggests that it was attributable to increased awareness and changes in diagnostic criteria.14 Despite the specific diagnostic criteria provided by the DSM-IV, the diagnosis of autism is completely subjective. There are no objective findings, radiologic studies, or laboratory tests that are diagnostic for autism. Even the presence of disorders such as fragile X15,16 or tuberous sclerosis,17,18 which are often associated with autism, are not diagnostic of autism, because only a fraction of patients with these conditions have autism. Finally, at least 2 studies have suggested that autistic traits are not a discrete feature seen only in the presence of autism but rather are a continuum. As such, a certain degree of "autistic" behaviors can be expected in many "typical" individuals.19,20 This further complicates the diagnosis of autism, because there is no distinct "cutoff" point between typical and autistic. There are indications that the increasing awareness of autism in the medical and educational communities may have led to a gradual shift in diagnosis to include less disabled individuals who would not previously have been described as autistic13 or would have received a different diagnosis.5 Although the diagnosis of autism seems to have changed with time, the guidelines for educational assessment of autism also vary from state to state. With only 10 qualifying disabilities under IDEA,21 the assessment criteria used by the states are understandably broad. As, perhaps, an extreme example of this, compare a section of the diagnostic criteria for autism from the DSM-IV with the corresponding section of the assessment criteria used in the state of Oregon (from the Oregon Administrative Rules [OAR]): DSM-IV: "(1) qualitative impairment in social interaction, as manifested by at least two of the following: (a) marked impairment in the use of multiple nonverbal behaviors such as eye-to-eye gaze, facial expression, body postures, and gestures to regulate social interaction (b) failure to develop peer relationships appropriate to developmental level (c) a lack of spontaneous seeking to share enjoyment, interests, or achievements with other people (eg, by a lack of showing, bringing, or pointing out objects of interest) (d) lack of social or emotional reciprocity"10 OAR: "(ii) Impairments in social interaction"22 The criteria found in the OAR are obviously much broader and more general than those in the DSM-IV. The choice of Oregon for this comparison was not random: Oregon has consistently had the highest prevalence of autism in the USDE data of any state (2 to 3 times the national prevalence) since autism was first reported as a separate disability. As has been shown, the USDE data on autism are at odds with studies of autism prevalence, largely because the criteria used by the school districts (the source of the USDE data) to categorize children as autistic are neither rigorous nor consistent. They are inconsistent over time, as are the medical criteria, and are inconsistent from region to region. The USDE data are not reliable for tracking the prevalence of autism, and they in fact never were meant to fill this need. FOOTNOTES Accepted Jan 13, 2004. No conflict of interest declared. REFERENCES Magnusson P, Saemendsen E. Prevalence of autism in Iceland. J Autism Dev Disord.2001; 31 :153 –163 Chakrabarti S, Fombonne E. Pervasive developmental disorders in preschool children. JAMA.2001; 285 :3093 –3099 Bertrand J, Mars A, Boyle C, Bove F, Yeargin-Allsopp M, Decoufle P. Prevalence of Autism in a United States population: the Brick Township, New Jersey, investigation. Pediatrics.2001; 108 :1155 –1161 Baker H. A comparison study of autism spectrum disorder referrals 1997 and 1989. J Autism Dev Disord.2002; 32 :121 –125 Croen L, Grether J, Hoogstrate J, Selvin S. The changing prevalence of autism in California. J Autism Dev Disord.2002; 32 :207 –215 Yeargin-Allsopp M, Rice C, Karapurkar T, Doernberg N, Boyle C, Murphy C. Prevalence of autism in a US metropolitan area. JAMA.2003; 289 :49 –55 US Department of Education. Twenty-fifth Annual Report to Congress on the Implementation of the Individuals with Disabilities Education Act. Washington DC: US Government Printing Office; 2003 (data extracted from 14th through 25th annual reports) American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed, Text Revision. Washington, DC: American Psychiatric Association;2000 :70 –75 Mandell DS, Listerud J, Levy SE, Pinto-Martin JA. Race differences in the age at diagnosis among Medicaid-eligible children with autism. J Am Acad Child Adolesc Psychiatry.2002; 41 :1447 –1453 Keen D, Ward S. Autistic spectrum disorder: a child population profile. Autism.2004; 8 :39 –48 Wing L, Potter D. The epidemiology of autistic spectrum disorders: in the prevalence rising Ment Retard Dev Disabil Res Rev.2002; 8 :151 –161 Barbaresi WJ, Katusic SK, Colligan RC, Weaver AL, Jacobsen SJ. The incidence of autism in Olmsted County, Minnesota, 1976–1997. Arch Pediatr Adolesc Med.2005; 159 :37 –44 Philofsky A, Hepburn SL, Hayes A, Hagerman R, Rogers SJ. Linguistic and cognitive functioning and autism symptoms in young children with fragile X syndrome. Am J Ment Retard.2004; 109 :208 –218 Bregman JD, Leckman JF, Ort SI. Fragile X syndrome: genetic predisposition to psychopathology. J Autism Dev Disord.1988; 18 :343 –354 Bolton PF, Griffiths PD. Association of tuberous sclerosis of temporal lobes with autism and atypical autism. Lancet.1997; 349 :392 –395 Baker P, Piven J, Sato Y. Autism and tuberous sclerosis complex: prevalence and clinical features. J Autism Dev Disord.1998; 28 :279 –285 Constantino JN, Todd RD. Autistic traits in the general population: a twin study. Arch Gen Psychiatry.2003; 60 :524 –530 Constantino JN, Hudziak JJ, Todd RD. Deficits in reciprocal social behavior in male twins: evidence for a genetically independent domain of psychopathology. J Am Acad Child Adolsc Psychiatry.2003; 42 :458 –467 Education of Individuals With Disabilities, USC Title 20, Ch. 33, Sect 1401 (1997 ) Special Education, Oregon Administrative Rules, Sect. 581-015-0051 (1998 )...查看详细 (16381字节)
☉ 11333125:Water-Pipe(Narghile) Smoking: An Emerging Health Risk Behavior
the Department of Mother, Child and Adolescent Health, Israel Ministry of Health, Jerusalem, Israel ABSTRACT Narghile, or water-pipe smoking (WPS), has been practiced extensively for 400 years. It is common in the Arabian Peninsula, Turkey, India, Pakistan, and other countries. In recent years, there has been a revival of WPS, notably among youth. Most US health professionals are unfamiliar with the practice and health consequences of WPS. Therefore, this trend presents a new challenge for adolescent health care providers. The composition of the tobacco used in WPS is variable and not well standardized. Studies that have examined narghile smokers and the aerosol of narghile smoke have reported high concentrations of carbon monoxide, nicotine, "tar," and heavy metals. These concentrations were as high or higher than those among cigarette smokers. The few scientific data regarding the adverse health consequences of WPS point to dangers that are similar to those associated with cigarette smoking: malignancy, impaired pulmonary function, low birth weight, and others. Additional dangers not encountered with cigarette smoking are infectious diseases resulting from pipe sharing and the frequent addition of alcohol or psychoactive drugs to the tobacco. Public health strategies for controlling the emerging epidemic of WPS include carrying out epidemiologic and toxicologic research; implementation of laws to limit acquisition and use; and health education, targeting adolescents in particular. Key Words: adolescents cigarettes health risk behaviors narghile nicotine smoking tobacco water pipe Abbreviations: WPS, water-pipe smoking Narghile, or water-pipe smoking (WPS), has been practiced extensively for 400 years. In recent years, there has been a revival of WPS, notably among youth. This trend, reflecting globalization's impact on developed nations, presents a new challenge for adolescent health care providers. Narghile is known by a number of different names, including argileh, goza, hookah, hubblebubble, and shisha. Its origin is often traced to India, although there are theories that it was first used in South Africa, Persia, Ethiopia, or other countries.1,2 The narghile pipe is usually decorated with floral or other motifs and has served as an artistic medium for craftsmen in many countries. Its use declined considerably during the past century and had principally become the habit of elderly and retired men who spent their time in bazaar cafes, particularly in poor areas. There has been a resurgence of WPS in the past several years. This phenomenon has been attributed to the perception that WPS is less dangerous than cigarette smoking, its easy availability, its low cost, and a number of other factors. It is usually a social activity, engaged in by peer groups and families, and often practiced in special cafes.2,3 The expanding influence of Eastern and Arab cultures in the United States and Europe places WPS as a potentially important public health issue for adolescents in these countries. EPIDEMIOLOGY It has been claimed that >100 million people worldwide smoke water pipes daily.1,2 It is a common practice in the Arabian Peninsula, Turkey, India, Pakistan, Bangladesh, and some regions of China. In some areas, WPS is more prevalent than cigarette smoking. Among Arab women in many countries, there is less of a stigma associated with narghile than with cigarette smoking and therefore less of a gender differential.3–6 Most of the epidemiologic studies of water pipe use have been conducted among adults; only a few reports have been published about university students and only 1 of middle and high school students. In Lebanon, WPS rates of 14.6% among adults7 and 25% among pregnant women8 have been reported. A survey of Lebanese university students found that 32% smoked narghile, with higher rates among men, and no differences according to socioeconomic status.4 A recent cross-sectional survey of 587 university students in Syria found that 62.6% of the men and 29.8% of the women had ever smoked narghile, and 25.5% of the men and 4.9% of the women were current smokers. Of these, only 7% of the men and none of the women were daily smokers. The mean age of initiation was 19.2 and 21.7 years, respectively. Smoking usually took place in dormitories, cafes, or restaurants and was almost always practiced in groups.9 The recent trend of increased narghile use was illustrated in another Syrian study of 268 water-pipe smokers: most of them, regardless of age, had begun smoking in the 1990s.10 A survey of 4000 Kuwaiti government employees found that 57% of men and 69% of women had ever used a narghile.11 In Israel, where there is a natural merging of Jewish and Arab cultures, WPS has recently become a common and growing phenomenon among Jewish youth. A national survey of 6000 middle and high school students found that 37.7% had ever smoked narghile. The rates were higher among Jewish (39.5%) than among Arab (30.5%) students.12 Another survey of 388 Jewish middle and high school students found that 41% smoked narghile, and 22% smoked at least every weekend. The rate of WPS was 3 times greater than that of cigarette smoking and increased from 15% in the seventh grade to 58% in the ninth grade. Fifteen percent reported that their parents smoked narghile, and approximately one quarter of the smokers reported smoking with their parents.13 In France and other European nations, there has been an upsurge of narghile use in the past several years. In the United States, national data are not currently available, and questions regarding its use are not included in national surveys of health risk behaviors, such as the Centers for Disease Control and Prevention's Youth Risk Behavior Surveillance System.14 A recent review of WPS does not cite any published epidemiologic data from the United States.15 One report of 28 Arab American adolescents who participated in a focus group in Michigan on smoking found that all of them had used narghile,16 suggesting that this is a common practice among these youth. In addition, several dozen "hookah bars" have been opened in New York, Los Angeles, and other areas. Although most patrons are immigrants from Moslem countries, where WPS is common, Internet and lay press stories report that these bars are becoming increasingly popular among college students and young adults.17 With globalization and immigration from these countries, the continued growth of this practice should be anticipated. THE WATER PIPE AND ITS USE Tobacco The tobacco used in WPS typically weighs 10 to 20 g and has 3 main forms. "Mu'essel" or "maasel" (literally, "honeyed") contains 30% tobacco and 70% honey or molasses (treacle). "Tumbak" or "ajami" is a pure, dark paste of tobacco. "Jurak," mainly of Indian origin, is an intermediate form that often contains fruits or oils but that may also be treacled and unflavored. "Muessel" is usually flavored with apple, mango, banana, strawberry, orange, grape, mint, cappuccino, or other additives. It is generally sold in cardboard boxes or plastic jars decorated with fruit illustrations. Drugs or alcohol is often added to the tobacco.1 Apparatus There are different types of water pipes, varying in size, shape, and composition. A typical, modern water pipe (Fig 1) is composed of a head, metal body, glass bottle, and a flexible connecting tube with a mouthpiece. The head, in which the tobacco is placed, consists of a bowl positioned into the body and is usually covered with a conical cap to protect the flame from extinction. The body is fixed to the neck of the bottle, which is partially filled with water and placed on the ground. The tube is attached to an aperture in the side of the pipe. Tobacco combustion begins in the water-pipe head, where the moist tobacco is placed, with burning charcoals placed close to the tobacco. The smoke passes through the water in the body of the pipe, where it is diluted and cooled and where soluble compounds are dissolved. It then passes through the connecting tube and is inhaled by the smoker. Consecutive inhalations are required to inhale the smoke and to keep the tobacco burning. Smoking Practice WPS is usually practiced in groups, with "rites" associated with preparation of the instrument and with the smoking itself. The water pipe is the center of a social activity of conversation and passing time. The hose is passed from person to person, and the same mouthpiece is usually used by all of the participants. Most smoking sessions last 45 to 60 minutes but may also continue for several hours. COMPOSITION OF NARGHILE AND ITS SMOKE AEROSOL The composition of the tobacco used in WPS is variable and not well standardized. The nicotine content of water-pipe tobacco has been reported to be 2% to 4%, in comparison with 1% to 3% for cigarettes.18 Only a small number of studies have examined the composition of narghile smoke. A study of carbon monoxide in water-pipe and cigarette smoke found carbon monoxide concentrations of 0.34% to 1.40% for water-pipe smoke and 0.41% for cigarette smoke. The carbon monoxide concentration in water-pipe smoke was significantly greater for smaller water-pipe size and for commercial as opposed to domestic charcoal.19 Another study found elevated end-expiratory carbon monoxide levels in a group of 18 healthy Jordanian water-pipe smokers.20 In a separate report, the carboxyhemoglobin concentration was measured in 1832 healthy Saudi Arabian male volunteers after smoking for 10 to 40 minutes. The mean carboxyhemoglobin concentrations were higher among water-pipe smokers (10.1%) than among cigarette smokers (6.5%) or nonsmokers (1.6%), and a linear relationship was found between smoking intensity and carboxyhemoglobin concentration.21 A study of nicotine and cotinine in water-pipe smokers found high values of these substances after smoking. After a single 45-minute smoking session, the mean plasma concentration of nicotine rose from 1.11 to 60.31 ng/mL, and cotinine rose from 0.79 to 51.95 ng/mL. Saliva nicotine concentration rose from 1.05 to 624.74 ng/mL, and cotinine rose from 0.79 to 283.49 ng/mL. The mean amounts of nicotine and cotinine excreted in a 24-hour urine sample after smoking were 73.59 μg and 249 μg, respectively.22 According to another report, urinary cotinine concentrations were similar for water-pipe smokers (median of 2 pipes per day) and for cigarette smokers (median of 30 cigarettes per day).23 An analysis of mainstream smoke aerosol found that narghile smoke contains significant amounts of nicotine, "tar," and heavy metals. Using a standard smoking protocol of 100 puffs of 3 seconds' duration in a single smoking session, 2.25 mg of nicotine and 242 mg of nicotine-free dry particulate matter were obtained. In addition, high levels of arsenic, chromium, and lead were found, in comparison with smoke from a single cigarette. Increasing the puff frequency increased the nicotine-free dry particulate matter, whereas removing water from the bowl increased the amount of nicotine.24 These studies provide limited data to suggest that water-pipe smoke is at least as toxic as cigarette smoke. Water-pipe smokers may absorb higher concentrations of these substances because of higher concentrations in the smoke itself or because of the mode of smoking, including frequency of puffing, depth of inhalation, and length of smoking session. Water-pipe smokers may smoke for several hours at a time and may breathe in more deeply because of the less irritating nature of the moisturized smoke. Carbon monoxide concentration, specifically, may also be elevated because of the charcoal used to burn the narghile tobacco. Contrary to popular opinion, the water in the pipe probably filters out only a small portion of the noxious substances. More research is needed to compare the toxic effects of the 2 types of smoking, taking into account the presmoking carbon monoxide levels, frequency and intensity of inhalation, and other factors. HEALTH EFFECTS Despite its widespread use, few studies to date have documented the adverse health consequences of WPS. This lack of data results from that WPS is mostly a non-Western habit, the high prevalence of smoking is a relatively recent phenomenon, lack of standardization of narghile content, and the difficulty in studying the isolated effects of narghile because most of the smokers are also current or past cigarette smokers. Existing studies suggest pathologic consequences for the most part similar to those induced by cigarettes and additional risks of infection related to smoking practice. These studies have examined either clinical or biological effects (Table 1). Malignancy A survey of 25 men with bronchogenic carcinoma in India found that 22 were narghile smokers.25 A case-control study of 214 Chinese tin miners found a twofold risk for lung cancer among those who had ever used water pipes compared with nonsmokers and a dose-response relation with increasing pipe-year usage.26 WPS was associated with esophageal and gastric carcinoma in a preliminary survey from Yemen.27 A case-control study of bladder cancer patients in Egypt showed no difference in rates between water-pipe smokers and nonsmokers.28 Two cases of squamous cell carcinoma and 1 of keratoacanthoma of the lower lip have been reported among Egyptian narghile smokers.29 These reports suggest that WPS has a carcinogenic role in a number of body systems. Pulmonary (Nonmalignant) WPS has been associated with noncarcinogenic morbidity and pathophysiologic effects in the respiratory system. In a study of 595 smokers in Saudi Arabia, the mean vital capacity, forced expiratory volume in 1 second, and the forced vital capacity were lower among water-pipe smokers than among nonsmokers, and these values declined with age. Water-pipe smokers were at greater risk than cigarette smokers for decreased pulmonary function.30 A decrease in the peak expiratory flow rate was found among water-pipe smokers in 1 study of 203 Turkish men,31 whereas no association was found between pulmonary function and WPS in another group of 54 Turkish men.32 A third study of 397 Turkish men reported a detrimental effect on pulmonary function, specifically on the peak expiratory flow rate, although the decrease was smaller than with cigarette smoking.18 Infectious Diseases In addition to its intrinsic pathogenic ability, WPS has the potential for spreading infectious diseases, given that smokers often share the same mouthpiece and pipe. The spread of infectious diseases could also result from the uncontrolled, manual preparation of narghile, in contrast to tobacco marketed by the cigarette industry. In a group of Egyptian patients with Helicobacter pylori, water-pipe smokers who smoked in groups had increased rates of infection when compared with nonsmokers, similar to the rates among moderate to mild cigarette smokers.33 Pulmonary aspergillosis has been reported in a leukemia patient as a result of smoking contaminated tobacco and marijuana in a water pipe.34 Sharing a marijuana water pipe has been associated with the transmission of tuberculosis.35 Other pathogens that could potentially be transmitted include hepatitis C, herpes simplex, Epstein-Barr virus, respiratory viruses, and HIV. Miscellaneous A case-control study of 100 Egyptian infertile women found that WPS of the husband was associated with infertility of the couple.36 Low birth weight was reported to be approximately twice as common among the newborns of Lebanese women who smoked narghile (approximately the same as for cigarette smokers) and nearly 3 times as common among those who began smoking narghile in the first trimester than among nonsmokers. Their infants also had lower Apgar scores and higher rates of respiratory distress.37 Elevations in heart rate and systolic, diastolic, and mean arterial blood pressure were found after smoking in a group of 18 healthy Jordanian water-pipe smokers.20 A case-control study of patients with recently diagnosed coronary heart disease found higher rates among those who had ever engaged in WPS.38 Egyptian patients who underwent oral surgery were more likely to develop postextraction dry socket when they were water-pipe or cigarette smokers.39 Biological Effects In a study of peripheral blood neutrophils, both cigarette and narghile smokers had higher production of superoxide anion and higher total leukocyte counts than nonsmokers, changes that may cause injury to lung tissue and have a role in the pathogenesis of chronic obstructive lung disease.40 A study of the somatic chromosomes of male water-pipe smokers found genotoxic effects, including increases in the mitotic index, chromosomal aberrations, sister chromatid exchanges, and satellite associations, in comparison with nonsmokers.41 Another study found that WPS resulted in impaired platelet function, including hemostatic changes and long-lasting oxidation injury.2 Dependence Given its nicotine content, narghile would be expected to have a great addictive potential. Indeed, tobacco dependence has recently been suggested in adult water-pipe smokers.42 However, WPS among youth is typically not on a daily basis,9,13 thus decreasing the potential for dependence at this age. ATTITUDES TOWARD WPS WPS is perceived by many adolescents, the general public, and even health professionals as being less dangerous than cigarette smoking. Table 2 summarizes some common myths and misconceptions: (1) the nicotine content is lower than that of cigarettes; (2) water filters out all the noxious chemicals, including carbon monoxide, nicotine and tar; (3) WPS is less irritating and thus less harmful to the throat and respiratory tract than cigarette smoking; (4) narghile tobacco contains fruit, making it a healthy choice. These myths are reinforced by the media. For example, Internet sites praise the behavior, offer information about WPS, and provide sources for buying WPS products. Only 1 study to date has reported on attitudes of adolescents regarding narghile use. Among the Israeli students in this survey, at least 50% believed that WPS is less harmful than cigarette smoking. Approximately half of the smokers did so without their parents' knowledge, but only 24% believed that their parents objected to their smoking, 38% reported that their parents even supported this behavior, and 53% reported that their parents preferred narghile to cigarette smoking. The reasons for smoking were "pleasurable experience" (77%), "adds to intimacy in a social gathering" (38%), "helps to deal with pressure" (11%), and "to be accepted by peers" (7%).13 Among the Syrian university students surveyed, reasons for periodic increases in WPS included weather and outdoor recreation (27% of men and 17% of women), stress relief (19% and 8%), meeting and socializing with friends (17% and 58%), and time availability and boredom (33% and 17%).9 Common positive perceptions of narghile use related to its smell and taste, whereas negative perceptions related to the smoke produced, pollution, and perceived adverse health effects. Half of the students believed WPS to be more harmful than cigarette smoking.6 WPS AS A HEALTH RISK BEHAVIOR WPS may be viewed as a "traditional" health risk behavior that is undergoing a revival. In addition to its intrinsic health risks, WPS carries dangers in that adolescent smokers often mix the tobacco with marijuana or hashish, and many replace the water in the pipe with alcoholic beverages. In the Israeli sample, 6% of the respondents reported adding drugs or alcohol to the tobacco.13 The combination undoubtedly has additive, acute health hazards. Some experts believe that WPS is a gateway substance to cigarette smoking or to the use of other psychoactive substances. Most Arab American adolescents who participated in a focus group had used narghile as their initial experience with smoking.16 WPS, like cigarette smoking, may be seen as meeting certain developmental tasks of adolescence, such as attaining maturity and autonomy. Being a group activity, the initiation of narghile smoking is often a result of peer pressure and the desire to be accepted by others, thus providing the perceived benefits of belonging. WPS is also a relatively inexpensive activity, with a typical once-a-week smoker paying far less than a dollar per week. In Syria, daily cigarette smokers have reported spending 26% more than daily water-pipe smokers.9 Because most narghile smokers are not daily smokers, the cost is considerably lower, which may make it more appealing to adolescents. WPS also has characteristics that set it apart from other health risk behaviors. For example, tacit parental acceptance and the practice of parents' smoking with their teens place this behavior outside the realm of adolescent rebellion in many cases. The teen's perception that the practice is "less harmful" than smoking cigarettes even provides the feeling that the behavior is, at least in relative terms, a healthy choice. The frequently reported clustering of health risk behaviors may be less strong regarding narghile than for other practices. In the survey of Lebanese university students, cigarette smoking was associated with a range of other health risk behaviors, whereas WPS was associated only with drinking excessive amounts of alcohol.4 PUBLIC HEALTH IMPLICATIONS WPS, as a health risk behavior enjoying an impressive revival, deserves the attention of public health policy makers and academic researchers. There is a paucity of epidemiologic data regarding water pipe use in general and among adolescents in particular. Investigation into the prevalence of narghile use in Western countries should be conducted, with ongoing surveillance. Adolescent cigarette smoking is the leading preventable cause of future morbidity and mortality, and its health implications have been studied extensively. In contrast, little is known about the toxicology and long-term health effects of narghile. There is a need to study the content of narghile tobacco and its smoke aerosol in various countries, as well as the many potential health consequences that may result from its use. A number of public health control measures should be considered in locations where WPS is commonly practiced. Narghile content should be regulated and monitored. Other measures that have been used in tobacco control, such as labeling packages with warnings about health effects (usually not done currently for narghile), prohibiting sale to minors, and increasing the cost through taxation, might be implemented. Personal risk reduction measures might include using disposable, plastic nozzles to avoid mouth-to-mouth contamination. Health education is important to dispel myths about narghile's alleged safety. Primary care physicians who care for adolescents should be aware of the emerging phenomenon of WPS in Western countries and should know about its many potential health implications. They should be prepared to counsel their patients on the individual level and to advocate for control measures that will minimize the health hazards on the community level of this "new" health risk behavior. FOOTNOTES Accepted Dec 29, 2004. No conflict of interest declared. REFERENCES Wolfram RM, Chehne F, Oguogho A, Sinzinger H. Narghile (water pipe) smoking influences platelet function and (iso-)eicosanoids. Life Sci. 2003;74 :47 –53 Kandela P. Nargile smoking keeps Arabs in Wonderland. Lancet. 2000;356 :1175 Tamim H, Terro A, Kassem H, et al. Tobacco use by university students, Lebanon, 2001. Addiction. 2003;98 :933 –939 Maziak W, Rastam S, Eissenberg T, et al. Gender and smoking status-based analysis of views regarding waterpipe and cigarette smoking in Aleppo, Syria. Prev Med. 2004;38 :479 –484 Maziak W, Eissenberg T, Rastam S, et al. Beliefs and attitudes related to narghile (waterpipe) smoking among university students in Syria. Ann Epidemiol. 2004;14 :646 –654 Chaaya M, Awwad J, Campbell OM, Sibai A, Kaddour A. Demographic and psychosocial profile of smoking among pregnant women in Lebanon: public health implications. Matern Child Health J. 2003;7 :179 –186 Maziak W, Fouad FM, Asfar T, et al. Prevalence and characteristics of narghile smoking among university students in Syria. Int J Tuberc Lung Dis. 2004;8 :882 –889 Rastam S, Ward KD, Eissenberg T, Maziak W. Estimating the beginning of the waterpipe epidemic in Syria. BMC Public Health. 2004;4 :32 Memon A, Moody PM, Sugathan TN, et al. Epidemiology of smoking among Kuwaiti adults: prevalence, characteristics and attitudes. Bull WHO. 2000;78 :1306 –1315 Harel Y, Molcho M, Tillinger E. Youth in Israel: Health, Well-Being and Risk Behavior. Summary of Findings from the Third National Study (2002) and Trend Analysis (1994–2002) [in Hebrew]. Ramat Gan, Israel: Bar Ilan University; 2004 Varsano S, Ganz I, Eldor N, Garenkin M. Water-pipe tobacco smoking among school children in Israel: frequencies, habits, and attitudes [in Hebrew]. Harefuah. 2003;142 :736 –741 Maziak W, Ward KD, Afifi Soweid RA, Eissenberg T. Tobacco smoking using a waterpipe: a re-emerging strain in a global epidemic. Tob Control. 2004;13 :327 –333 Kulwicki A, Rice VH. Arab American adolescent perceptions and experiences with smoking. Public Health Nurs. 2003;20 :177 –183 Kiter G, Ucan ES, Ceylan E, Kilinc O. Water-pipe smoking and pulmonary functions. Respir Med. 2000;94 :891 –894 Sajid KM, Akhter M, Malik GQ. Carbon monoxide fractions in cigarette and hookah (hubble bubble) smoke. J Pak Med Assoc. 1993;43 :179 –182 Shafagoj YA, Mohammed FI. Levels of maximum end-expiratory carbon monoxide and certain cardiovascular parameters following hubble-bubble smoking. Saudi Med J. 2002;23 :953 –958 Zahran FM, Ardawi MSM, al-Fayez S. Carboxyhaemoglobin concentrations in smokers of sheesha and cigarettes in Saudi Arabia. BMJ. 1985;291 :1768 –1770 Shafagoj YA, Mohammed FI, Hadidi KA. Hubble-bubble (water pipe) smoking: levels of nicotine and cotinine in plasma, saliva and urine. Int J Clin Pharmacol Ther. 2002;40 :249 –255 Macaron C, Macaron Z, Maalouf MT, Macaron N, Moore A. Urinary cotinine in narguila or chicha tobacco smokers. J Med Liban. 1997;45 :19 –20 Shihadeh A. Investigation of mainstream smoke aerosol of the argileh water pipe. Food Chem Toxicol. 2003;41 :143 –152 Nafae A, Misra SP, Dhar SN, Shah SN. Bronchogenic carcinoma in Kashmir Valley. Indian J Chest Dis. 1973;15 :285 –295 Qiao Y-L, Taylor PR, Yao S-X, et al. Relation of radon exposure and tobacco use to lung cancer among tin miners in Yunnan Province, China. Am J Ind Med. 1989;16 :511 –521 Gunaid AA, Sumairi AA, Shidrawi RG, et al. Oesophageal and gastric carcinoma in the Republic of Yemen. Br J Cancer. 1995;71 :409 –410 Bedwani R, el-Khwsky F, Renganathan E, et al. Epidemiology of bladder cancer in Alexandria, Egypt: tobacco smoking. Int J Cancer. 1997;73 :64 –67 El-Hakim IE, Uthman MA. Squamous cell carcinoma and keratoacanthoma of the lower lip associated with "Goza" and "Shisha" smoking. Int J Dermatol. 1999;38 :108 –110 Al-Fayez SF, Salleh M, Ardawi M, Zahran FM. Effects of sheesha and cigarette smoking on pulmonary function of Saudi males and females. Trop Geogr Med. 1988;40 :115 –123 Bayindir U, Ucan ES, Sercin B, Ikiz F. The effect of water-pipe smoking on the peak flow rate . Eur Respir J. 1993;6 (suppl 17):608 Altinsik G, Ucan ES, Akpinar O. Effect of water pipe smoking on pulmonary functions . Eur Respir J. 1995;8 (suppl 19):233 Szyper-Kravitz M, Lang R, Manor Y, Lahav M. Early invasive pulmonary aspergillosis in a leukemia patient linked to Aspergillus contaminated marijuana smoking. Leuk Lymphoma. 2001;42 :1433 –1437 Munckhof WJ, Konstantinos A, Wamsley M, Mortlock M, Gilpin C. A cluster of tuberculosis associated with use of marijuana water pipe. Int J Tuberc Lung Dis. 2003;7 :860 –865 Inhorn MC, Buss KA. Ethnography, epidemiology and infertility in Egypt. Soc Sci Med. 1994;39 :671 –686 Nuwayhid IA, Yamout B, Azar G, Kambris MAK. Narghile (hubble-bubble) smoking, low birth weight, and other pregnancy outcomes. Am J Epidemiol. 1998;148 :375 –383 Jabbour S, El-Roueiheb Z, Sibai AM. Narghile (water-pipe) smoking and incident coronary heart disease: a case-control study . Ann Epidemiol. 2003;13 :570 Al-Belasy FA. The relationship of "shisha" (water pipe) smoking to postextraction dry socket. J Oral Maxillofac Surg. 2004;62 :10 –14 Sharma RN, Deva C, Behera D, Khanduja KL. Reactive oxygen species formation in peripheral blood neutrophils in different types of smokers. Indian J Med Res. 1997;106 :475 –480 Yadav JS, Thakur S. Genetic risk assessment in hookah smokers. Cytobios. 2000;101 :101 –113 Maziak W, Ward KD, Eissenberg T. Factors related to frequency of narghile (waterpipe) use: the first insights on tobacco dependence in narghile users. Drug Alcohol Depend. 2004;76 :101 –106...查看详细 (29420字节)
☉ 11333126:Heat Stress From Enclosed Vehicles: Moderate Ambient Temperatures Cause Significant Temperature Rise in Enclosed Vehicles
Division of Emergency Medicine, Stanford University, Palo Alto, California Department of Geoscience, San Francisco State University, San Francisco, California ABSTRACT Objective. Each year, children die from heat stroke after being left unattended in motor vehicles. In 2003, the total was 42, up from a national average of 29 for the past 5 years. Previous studies found that on days when ambient temperatures exceeded 86°F, the internal temperatures of the vehicle quickly reached 134 to 154°F. We were interested to know whether similarly high temperatures occurred on clear sunny days with more moderate temperatures. The objective of this study was to evaluate the degree of temperature rise and rate of rise in similar and lower ambient temperatures. In addition, we evaluated the effect of having windows "cracked" open. Methods. In this observational study, temperature rise was measured continuously over a 60-minute period in a dark sedan on 16 different clear sunny days with ambient temperatures ranging from 72 to 96°F. On 2 of these days, additional measurements were made with the windows opened 1.5 inches. Analysis of variance was used to compare how quickly the internal vehicle temperature rose and to compare temperature rise when windows were cracked open 1.5 inches. Results. Regardless of the outside ambient temperature, the rate of temperature rise inside the vehicle was not significantly different. The average mean increase was 3.2°F per 5-minute interval, with 80% of the temperature rise occurring during the first 30 minutes. The final temperature of the vehicle depended on the starting ambient temperature, but even at the coolest ambient temperature, internal temperatures reached 117°F. On average, there was an 40°F increase in internal temperature for ambient temperatures spanning 72 to 96°F. Cracking windows open did not decrease the rate of temperature rise in the vehicle (closed: 3.4°F per 5 minutes; opened: 3.1°F per 5 minutes or the final maximum internal temperature. Conclusions. Even at relatively cool ambient temperatures, the temperature rise in vehicles is significant on clear, sunny days and puts infants at risk for hyperthermia. Vehicles heat up rapidly, with the majority of the temperature rise occurring within the first 15 to 30 minutes. Leaving the windows opened slightly does not significantly slow the heating process or decrease the maximum temperature attained. Increased public awareness and parental education of heat rise in motor vehicles may reduce the incidence of hyperthermia death and improve child passenger safety. Key Words: child passenger safety injury prevention and control hyperthermia Abbreviations: CI, confidence interval Every year, children die from heat stroke after being left unattended in a vehicle. From 1998 to 2002, the average number was 29 children per year (Fig 1). In 2003, this number increased to 42 (Fig 2) and was 35 in 2004. In addition to death, it is estimated that annually hundreds of children experience varying degrees of heat illness from being left in cars.1 This danger exists despite public education efforts and lobbying for laws against leaving children unattended in vehicles. In a survey performed by Roberts and Roberts,2 approximately one quarter of interviewed women who had infants or toddlers admitted to leaving their children unattended in cars. Previous studies have examined the internal environment of motor vehicles. King et al3 found that in an ambient temperature of 36.8°C (98.2°F), 75% of the maximum temperature rise occurred within 5 minutes of closing the doors and maximized within 15 minutes to 51 to 67°C (124–153°F). Opening the windows 20 cm (8 inches) had minimal effect on the temperature rise and maximum temperature attained. Roberts and Roberts2 had similar findings. Most studies examined temperature rise on days with ambient temperatures >90°F, except for the study of Robert and Roberts, in which the ambient temperature was 83°F. These studies show that, not surprising, significant heat rise occurs on hot days. We hypothesized, however, that even on cooler days, the risk for heat illness is significant inside a vehicle. This study was designed to quantify the amount and the rate of heating inside vehicles over a broader range of ambient temperatures. We also sought to determine whether "cracked" windows made any difference on the heating of vehicles, because in a survey, fewer than one third of mothers would leave the windows half open because of theft concerns. METHODS Study Design This was an observational study in which we measured the interior vehicle temperature on 16 different cloud-free days between May 16 and August 8, 2002, in Fremont, California. Ambient temperatures ranged from 72 to 96°F. The vehicle was parked in full sun, oriented 45 degrees to the sun’s rays to minimize direct sunlight through the windshield. Internal vehicle temperature was measured continuously from time 0 to 1 hour. Temperature was recorded at time 0 and every 5 minutes for 1 hour. The vehicle was a dark-blue 2000 Honda Accord with medium-gray interior and without tinted windows. Recordings were made with closed windows on 16 different days. On 2 of these days, recordings were made first with the windows closed. Then the doors were opened to return the vehicle to ambient temperature, and a second hour of measurements was made with the windows cracked 1.5 inches. It was ensured that no significant change in ambient temperature occurred during these 2 hours. Data Collection Ambient temperature was recorded continuously with a Davis Instruments Vantage Pro Sensor Suite. Wireless temperature sensors were placed in the test vehicles in the rear passenger section 15 inches above the seat, in the shade and not in direct contact with any part of the car. The temperature sensors had a resolution of 1°F and accuracy of ±1°F. All recorded data were transmitted to the Vantage Pro base station. Statistical Analysis Data were recorded on an excel spreadsheet (Microsoft Corp, Seattle, WA) and imported into SPSS 11.0 (Chicago, IL) for statistical analysis. Analysis of variance evaluated for differences in the rate of temperature rise and final enclosed temperatures for the varying ambient temperatures. Analysis of variance was also used to compare the rate of temperature rise and maximum temperature attained with windows cracked open or closed. The recordings on the 2 separate days for these measures were averaged at each 5-minute interval, before analysis. RESULTS Rate of Temperature Rise Versus Ambient Temperature Regardless of the ambient temperature, the rate of internal vehicle temperature rise was similar (P = 1.0). Figure 3 shows how the slope of the temperature over time was virtually the same for the different ambient temperatures. Eighty percent of the temperature rise occurred during the first 30 minutes (P 40°C with central nervous system dysfunction resulting in delirium, convulsions, coma, and death.4 Young children and infants are more susceptible to heat illness than adults for several reasons. Physiologically, toddlers and infants, despite their increased body surface area to mass ratio, seem to have less effective thermoregulation in comparison with adults as proposed by Tsuzuki-Hayakawa and Tochihara.5 In their study, they demonstrated that children (aged between 9 months and 4.5 years) who were placed for 30 minutes in rooms that were 35°C (95°F) had a rectal temperature that increased more rapidly and was significantly higher than their mothers’. This was despite that children and infant perspire more by body mass in comparison with their mothers. This finding was speculated to occur because smaller masses warm more quickly and that young children have an immature thermoregulatory system. In addition to the potential physical and physiologic differences, adults have the ability to modify behavior on the basis of the environment. They can undergo cooling measures: take off excess clothing, obtain cold drinks, and seek cooler environments (eg, get out of a hot car). Although these results are significant numerically and perhaps would be sufficient to influence parental behavior and perhaps lawmakers, the question still remains as to what is an unsafe temperature for an infant and how long until the infant experiences adverse effects from a particular heat. Intuitively, it would seem unconscionable to subject a child to an 117°F environment, and that is probably why the literature is sparse in quantifying the effect of heat on infants and children. As mentioned earlier, Tsuzuki-Hayakawa and Tochihara5 found that infants and young children developed significantly higher core and surface body temperatures compared with their mothers despite increased perspiration. Studies by Levine and Ginandes6–8 proposed that a 12-month-old infant loses 1 to 2 mL/kg per hour through perspiration at an ambient temperature of 86°F. In studies of adults in extreme heat exposure, the maximum loss measured has been 10 to 20 mL/kg per hour.9 It is thought that similar fluid loss is possible in children and probably greater according to the work of Tsuzuki-Hayakawa. This would conservatively amount to a loss of 400 to 800 mL over a 4-hour period, or 4% to 8% dehydration of a 10-kg infant. Future study to evaluate heat stress in infants and children would be difficult to do for obvious ethical reasons, so although we may never know the rate of dehydration and body temperature rise for infants and children in enclosed vehicles, the risk is clear. Our results were consistent with previous research for similar temperature ranges except in 1 respect.2,3,10,11 King et al3 noted 75% of the maximum stabilized temperature within 5 minutes of closing the doors as opposed to our finding of 30 minutes required for attaining 80% of the maximum temperature. We believe that this difference occurred because their sensor was placed in direct sun, whereas our sensor was in the shade. This suggests that if a child were positioned in full sun, then the heat stress would be greater and more rapid in onset than stated here. In addition to heat illness, leaving children unattended in vehicles puts them at risk for other harm, such as thermal burns from buckles, abduction, and injury from the child’s putting the car in motion or operating power control features. The Morbidity and Mortality Weekly Report found that 78 children died from July 2000 to June 2001 from being left unattended in or around motor vehicles. In addition, there were 9160 nonfatal injuries reported. Of those who died, 35% were attributable to heat illness and 82% were between the ages of 0 and 3 years.12 Prevention of heat illness in children and potentially other injuries is straightforward. Do not leave them in the car. Parental attitudes and behavior may be related to erroneous beliefs regarding the internal heat rise of vehicles on milder and even cool sunny days as well as the effects of cracking the windows. Laws regarding kids in cars currently exist in 9 states and are proposed in an additional 9.13 Although the problem of nonexertional hyperthermia in children pales in comparison with that of the top 3 causes of unintentional death (motor vehicle accidents, drowning, and burns) heat illness is conceivably easier to prevent if their caregivers are aware of the danger. It is worth considering incorporating this message along with a discussion of the importance of car seats as part of child passenger safety education for caregivers. Legislation efforts may help to raise awareness, but as these events are mostly unintentional, additional public education efforts ultimately are necessary to decrease the incidence of this fatal yet preventable behavior. FOOTNOTES Accepted Feb 14, 2005. No conflict of interest declared. REFERENCES Roberts KB, Roberts EC. The automobile and heat stress. Pediatrics.1976; 58 :101 –104 King K, Negus K, Vance JC. Heat stress in motor vehicles: a problem in infancy. Pediatrics.1981; 68 :579 –582 Bouchama A, Knochel JP. Heat stroke. N Engl J Med.2002; 346 :1978 –1988 Tsuzuki-Hayakawa K, Tochihara Y. Thermoregulation during heat exposure of young children compared to their mothers. Eur J Appl Physiol.1995; 72 :12 –17 Levine SZ, Kelly M, Wilson JR. The insensible perspiration in infancy and childhood. 2. Proposed basal standards for infants. Am J Dis Child.1930; 39 :917 Levine SZ, Marples E. The insensible perspiration in infancy and in childhood: BASAL metabolism and basal insensible perspiration of the normal infant: a statistical study of reliability and of correlation. Am J Dis Child.1930; 40 :269 Ginandes GJ, Topper A. Insensible perspiration in children: statistical correlation of insensible perspiration and various body measurements: proposed basal standards for children. Am J Dis Child.1936; 52 :1335 Hardy JD. Physiology of temperature regulation. Physiol Rev.1961; 41 :521 Surpure JS. Heat-related illness and the automobile. Ann Emerg Med.1982; 11 :263 –266 Gibbs LI, Lawrence DW, Kohn MA. Heat exposure in an enclosed automobile. J La State Med Soc.1995; 147 :545 –546 Danks DM, Webb DW, Allen J. Heat illness in infants and young children. Br Med J.1962; 53 :287 –293...查看详细 (15651字节)
☉ 11333127:Improvement in Bone Mineral Density and Body Composition in Survivors of Childhood Acute Lymphoblastic Leukemia: A 1-Year Prospective Study
Pediatric Endocrinology Unit and Institut National de la Santé et de la Recherche Médicale U 457 Department of Radiology Department of Hematology Department of Biostatistics Department of Biochemistry, Hpital Robert Debré, Paris, France ABSTRACT Objectives. Abnormalities in bone mineral density (BMD), body composition, and bone metabolism have been reported in children who were treated for acute lymphoblastic leukemia (ALL) during and after completion of therapy. However, these studies are cross-sectional, and no longitudinal data are available in a large group of patients after completion of therapy. In the present study, 1-year longitudinal changes in BMD, body composition, and bone metabolism were evaluated in children with ALL during the first 3 years after completion of therapy without cranial irradiation. Methods. BMD of total body (TB; g/cm2), areal and apparent volumetric lumbar spine (L2–L4), lean body mass, and percentage of body fat were measured by dual-energy x-ray absorptiometry in 37 children (median age: 7.9 years; range: 4.7–20.6 years) who were treated for ALL at a median age of 3.3 years (range: 1.1–16.6 years), after a median time of 2.2 years after the completion of treatment, and after a 1-year follow-up period. Two control subjects (n = 74) who were matched for gender, age, and pubertal stage were also longitudinally investigated for body composition for 1 year. Usual serum biochemical markers of calcium metabolism and bone turnover were measured in patients during the study period. Results. A slight decrease in TB BMD was found after a median time of 2.2 years after the completion of therapy for ALL in childhood. Patients showed a significantly lower median TB BMD when evaluated 8 years after completion of treatment.16,18–22 Defects in the hypothalamic-pituitary axis leading to abnormalities in growth hormone and gonadotropin secretion are probable causes, leading to disturbed bone metabolism.36 The effect of chemotherapy alone on BMD is much less clear; normal12,14,24,25 or reduced BMD8,23 have been reported. After completion of treatment with chemotherapy alone, no decrease in either areal or volumetric BMD for LS and TB was found 9.6 years (mean) after completion of treatment in 23 patients aged 17 years,24 whereas a significant decrease in volumetric LS BMD was demonstrated 5 years (mean) after completion of treatment in 28 patients aged 10.7 years.23 As is the case in our study (although only for areal BMD), this was associated with male gender and current level of physical activity.23 Male gender as a risk factor for decreased BMD after completion of treatment was also shown in 2 other studies in which cranial irradiation was conducted.17,22 A gender difference of sensitivity to cytotoxic gonadal damage and/or to glucocorticoids was hypothesized to be a probable explanation.23 As is the case for normal children,37–39 physical activity level was also shown to be an important determinant of BMD and of body fat mass in these patients.23,40 Excessive overweight after childhood ALL has been reported frequently.26,27 It has been postulated that the increase in body fat mass was related to multifactorial causes such as cranial irradiation (thus partly resulting from growth hormone insufficiency), to glucocorticoids (as part of treatment protocols), to increased energy intake and to the reduced energy expenditure resulting from decreased physical activity.19,26,28,40–42 Only 2 studies have investigated long-term body composition 5 to 9.6 years (mean) after completion of treatment with chemotherapy alone. A significantly higher percentage of body fat mass was found after 5 years in only a subgroup of patients who received intravenous high-dose methotrexate.23,24 As is the case in our study, the difference in BMI was not significant. However, our study demonstrated a significantly higher percentage of body fat mass in patients 2.2 years after completion of therapy that was not found later during the follow-up period. Concern has also been expressed regarding the detrimental effects of methotrexate and glucocorticoid on bone5,13,43 as well as the harmful effects of the disease process itself. At diagnosis, children with ALL have reduced bone alkaline phosphatase, insulin-like growth factor 1 (IGF-1) and IGF binding protein 3 (IGFBP-3), all of which suggest low bone turnover resulting from the disease.4,5,7,44–46 Bone alkaline phosphatase remained low throughout the treatment with an increase of bone resorption markers, probably as a result of the effects of methotrexate and corticosteroid treatment. These effects occurred independent of circulating IGF-1 and IGFBP-3, which were restored to normal values during treatment.4,5,7,43,44,46 However, it has been seen in a small study on a limited number of patients that bone alkaline phosphatase increased to normal levels during the first month after cessation of therapy.44 In our study, all serum markers of bone turnover were normal after completion of treatment. Moreover, no factors such as age at diagnosis of ALL, higher methotrexate dosage, calcium intake, or physical activity were identified as contributing to impairment of body composition and/or bone metabolism. Except for TB BMD measurements, no relationship was found between body-composition parameters and follow-up time after completion of treatment. The number of patients who were investigated in our study was small; however, this was compensated for by the fact that the study population was very homogeneous regarding malignancy (only 2 patients in a high-risk group) and treatment schedule. In conclusion, a significant increase in TB BMD and a tendency to a lesser increase in percentage of body fat mass were seen during the study period in patients as compared with control subjects who were matched for chronological age, gender, and pubertal stage. Moreover, as seen after a 1-year follow-up period, body composition, biochemical markers of bone turnover, and physical activity all recovered to normal levels at 3.2 years (median) after the end of treatment. These findings were seen across ages and independent of gender and pubertal status, suggesting a positive effect of long-term completion therapy as well as increase in physical activity on BMD, body composition, and bone metabolism in patients who have been treated for ALL. ACKNOWLEDGMENTS We thank Isabelle Legendre and Didier Chevenne for help with statistical analysis and biochemical evaluation, respectively, and the nurses of the Clinical Investigation Center at the Robert Debre hospital for excellent technical assistance. FOOTNOTES Accepted Nov 22, 2004. No conflict of interest declared. REFERENCES Vilmer E, Suciu F, Ferster A, et al. Long term results of three randomized trials (58831, 58832, 58881) in childhood acute lymphoblastic leukemia: a CLCG-EORTC report. Leukaemia.2000; 14 :2257 –2266 Pui CH, Cheng C, Leung W Rai, et al. Extended follow-up of long term survivors of childhood acute lymphoblastic leukaemia. N Engl J Med.2003; 14 :640 –649 Halton JM, Atkinson SA, Fraher L, et al. Mineral homeostasis and bone mass at diagnosis in children with acute lymphoblastic leukemia. J Pediatr.1995; 126 :557 –564 Sorva R, Kivivuori SM, Tufpeinen M, et al. Very low rate of type l collagen synthesis and degradation in newly diagnosed children with acute lymphoblastic leukemia. Bone.1997; 20 :39 –43 Crofton PM, Ahmed SF, Wade JC, et al. Effects of intensive chemotherapy on bone and collagen turnover and the growth hormone axis in children with acute lymphoblastic leukemia. J Clin Endocrinol Metab.1998; 83 :3121 –3129 Atkinson SA, Halton JM, Bradley C, Wu B, Barr RD. Bone and mineral abnormalities in childhood acute lymphoblastic leukaemia: influence of disease, drugs and nutrition. Int J Cancer.1998; 11 :35 –39 Arikoski P, Komulainen J, Riikonen P, Voutilainen R, Knip M, Kroger H. Alterations in bone turnover and impaired development of bone mineral density in newly diagnosed children with cancer: a year prospective study. J Clin Endocrinol Metab.1999; 84 :3174 –3181 Arikoski P, Komulainen J, Riikonen P, et al. Impaired development of bone mineral density during chemotherapy: a prospective analysis of 46 children newly diagnosed with cancer. J Bone Miner Res.1999; 14 :2002 –2009 Boot AM, van den Heuvel-Eibrink MM, Hahlen K, Krenning EP, de Muinck Keizer-Schrama SM. Bone mineral density in children with acute lymphoblastic leukaemia. Eur J Cancer.1999; 35 :1693 –1697 Van der Sluis IM, van den Heuvel-Eibrink MM, Hahlen K, Krenning EP, de Muinck Keizer-Schrama SM. Altered bone mineral density and body composition, and increased fracture risk in childhood acute lymphoblastic leukaemia. J Pediatr.2002; 141 :204 –210 Halton JM, Atkinson SA, Fraher L, et al. Altered mineral metabolism and bone mass in children during treatment for acute lymphoblastic leukaemia. J Bone Miner Res.1996; 11 :1774 –1783 Henderson RC, Madsen CD, Davis C, Gold SH. Longitudinal evaluation of bone mineral density in children receiving chemotherapy. J Pediatr Hematol Oncol.1998; 20 :322 –326 Manolagas SC, Weinstein RS. New developments in the pathogenesis and treatment of steroid-induced osteoporosis. J Bone Miner Res.1999; 14 :1061 –1066 Gilsanz V, Carlson ME, Roe TF, Ortega JA. Osteoporosis after cranial irradiation for acute lymphoblastic leukaemia. J Pediatr.1990; 117 :238 –244 Henderson RC, Madsen CD, Davis C, Gold SH. Bone density in survivors of childhood malignancies. J Pediatr Hematol Oncol.1996; 18 :367 –371 Brennan BMD, Rahim A, Adams JA, Eden OB, Shalet SM. Reduced bone mineral density in young adults following cure of acute lymphoblastic leukaemia in childhood. Br J Cancer.1999; 79 :1859 –1863 Arikoski P, Komulainen J, Vouti1ainen R, et al. Reduced bone mineral density in long-term survivors of childhood acute lymphoblastic leukemia. J Pediatr Hematol Oncol.1998; 20 :234 –240 Hesseling PB, Hough SF, Nel ED, van Riet FA, Beneke T, Wessels G. Bone mineral density in long-term survivors of childhood cancer. Int J Cancer.1998; 11 :44 –47 Nysom K, Holm K, Michaelsen KF, Hertz H, Muller J, Molgaard C. Bone mass after treatment for acute lymphoblastic leukaemia in childhood. J Clin Oncol.1998; 16 :3752 –3760 Hoorweg-Nijman JJ, Kardos G, Roos JC, et al. Bone mineral density and markers of bone turnover in young adult survivors of childhood lymphoblastic leukaemia. Clin Endocrinol.1999; 50 :237 –244 Warner JT, Evans WD, Webb DKH. Relative osteopenia after treatment for acute lymphoblastic leukemia. Pediatr Res.1999; 45 :544 –551 Kaste SC, Jones-Wallace D, Rose SR, et al. Bone mineral decrements in survivors of childhood acute lymphoblastic leukemia: frequency of occurrence and risk factors for their development. Leukemia.2001; 15 :728 –734 Tillmann V, Darlington AS, Eiser C, Bishop NJ, Davies HA. Male sex and low physical activity are associated with reduced spine bone mineral density in survivors of childhood acute lymphoblastic leukemia. J Bone Miner Res.2002; 17 :1073 –1080 Van der Sluis IM, van den Heuvel-Eibrink MM, Hahlen K, Krenning EP, de Muinck Keizer-Schrama SM. Bone mineral density, body composition, and height in long-term survivors of acute lymphoblastic leukemia in childhood. Med Pediatr Oncol.2000; 35 :415 –420 Kadan-Lottick N, Marshall JA, Baron AE. Normal bone mineral density after treatment for childhood acute lymphoblastic leukaemia diagnosed between 1991 and 1998. J Pediatr.2002; 138 :898 –904 Nysom K, Holm K, Michaelsen KF, Hertz H, Muller J, Molgaard C. Degree of fatness after treatment for acute lymphoblastic leukaemia in childhood. J Clin Endocrinol Metab.1999; 84 :4591 –4596 Mayer EIE, Reuter M, Dopfer RE, Ranke MB. Energy expenditure, energy intake and prevalence of obesity after therapy for acute lymphoblastic leukemia during childhood. Horm Res.2000; 53 :193 –199 Van Dongen-Melman JEWM, Hokken-Koelega ACS, Hhlen K, De Groot A, Tromp CG, Egeler RM. Obesity after successful treatment of acute lymphoblastic leukemia in childhood. Pediatr Res.1995; 38 :86 –90 Sempé M, Pedron G, Roy-Pernot MP. Auxologie, Méthodes et Séquences. Paris, France: Théraplix;1979 Rolland-Cachera MF, Cole TJ, Sempé M, Tichet J, Rossignol C, Charraud A. Body mass index variations: centiles from birth to 87 years. Eur J Clin Nutr.1991; 45 :13 –21 Tanner JM. Growth at Adolescence. Oxford, United Kingdom: Blackwell;1978 :28 –39 Greulich WW, Pyle SI. Radiographic Atlas of Skeletal Development of the Hand and the Wrist. 2nd ed. Stanford, CA: Stanford University Press; 1959 Tricopoulou A, Vassilakou T. Recommended dietary intakes in the European Community member states: an overview. Eur J Clin Nutr.1990; 44 :51 –125 Carter DR, Bouxsein ML, Marcus R. New approaches for interpreting projected bone densitometry data. J Bone Miner Res.1992; 7 :137 –145 Leeuw JA, Koudstaal J, Wiersema-Buist J, Kamps WA, Timens W. Bone histomorphometry in children with newly diagnosed acute lymphoblastic leukemia. Pediatr Res.2003; 54 :814 –818 Arikoski P, Voutilainen R, Kroger H. Bone mineral density in long-term survivors of childhood cancer. J Pediatr Endocrinol Metab.2003; 16 :343 –353 Ruiz JC, Mandel C, Garabedian M. Influence of spontaneous calcium intake and physical exercise on the vertebral and femoral bone mineral density of children and adolescent. J Bone Miner Res.1995; 1 :675 –681 Cooper C, Cawley M, Bhalla A, et al. Childhood growth, physical activity, and peak bone mass in women. J Bone Miner Res.1995; 10 :940 –947 Rubin K, Schirduan V, Gendreau P, Sarfarazi M, Mendola R, Dalsky G. Predictors of axial and peripheral bone mineral density in healthy children and adolescents, with special attention to the role of puberty. J Pediatr.1993; 123 :863 –870 Warner JT, Bell W, Webb DKH. Daily energy expenditure and physical activity in survivors of childhood malignancy. Pediatr Res.1998; 43 :607 –613 Warner JT, Bell W, Webb DKH, Gregory JW. Relationship between cardiopulmonary response to exercise and adiposity in survivors of childhood malignancy. Arch Dis Child.1997; 76 :298 –303 Reilly JJ, Brougham M, Montgomery C, Richardson F, Kelly A, Gibson BES. Effect of glucocorticoid therapy on energy intake in children treated for acute lymphoblastic leukemia. J Clin Endocrinol Metab.2001; 86 :3742 –3745 Wheeler DL, Vander Griend RA, Wronski TJ, Miller GJ, Keith EE, Graves JE. The short and long term effects of methotrexate on the rat skeleton. Bone.1995; 16 :215 –221 Crofton PM, Ahmed SF, Wade JC, et al. Bone turnover and growth during and after continuing chemotherapy in children with acute lymphoblastic leukaemia. Pediatr Res.2000; 48 :490 –496 Mohnike KL, Kuble U, Mittler U. Serum levels of insulin-like growth factor-I, -II and insulin-like growth factor binding proteins 2 and 3 in children with acute lymphoblastic leukaemia. Eur J Pediatr.1996; 155 :81 –86 Arguelles B, Barrios V, Pozo J, Munoz MT, Argente J. Modifications of growth velocity and the insulin-like growth factor system in children with acute lymphoblastic leukemia: a longitudinal study. J Clin Endocrinol Metab.2000; 85 :4087 –4092...查看详细 (32605字节)
☉ 11333128:Factors Associated With Parental Readiness to Make Changes for Overweight Children
Department of Pediatrics, Division of General Pediatrics Department of Emergency Medicine, Boston University School of Medicine, Boston Medical Center, Boston, Massachusetts Department of Pediatrics, Drexel University School of Medicine, St Christopher’s Hospital for Children, Philadelphia, Pennsylvania Drexel University School of Public Health, Philadelphia, Pennsylvania ABSTRACT Objective. The prevalence of childhood obesity is increasing in the United States. However, it has been difficult to help children successfully lose weight and maintain weight loss. Parental involvement in this effort is important. Currently, little is known about parents’ readiness to make behavior changes to help their children lose weight. The objective of this study was to describe demographic factors and parental perceptions associated with parents’ readiness to make weight-reducing lifestyle changes for their overweight and at-risk-for-overweight children. Methods. A total of 151 parents of children who were aged 2 to 12 years and had BMIs 85th percentile for age and gender completed a 43-item self-administered questionnaire. Parental stage of change, defined as precontemplation stage, contemplation stage, and preparation/action stage, was determined using an algorithm involving current parental practices and future intentions. Parents in the preparation/action stage were considered to be ready to make behavior changes to help their child lose weight. Maximum-likelihood multinomial logistic regression was used to identify demographics and perceptions associated with parental stage of change. Results. Sixty-two percent of the children had a BMI 95th percentile. Their mean age was 7.5 years, and 53% were male. Of the 151 parents, 58 (38%) were in the preparation/action stage of change, 26 (17%) were in the contemplation stage, and 67 (44%) were in the precontemplation stage. Factors associated with being in the preparation/action stage of change were having overweight or older (8 years) children, believing that their own weight or child’s weight was above average, and perceiving that their child’s weight was a health problem. After controlling for multiple factors, having an older child (odds ratio [OR]: 2.99; 95% confidence interval [CI]: 1.18–7.60), believing that they themselves were overweight (OR: 3.45; 95% CI: 1.36–8.75), and perceiving that their child’s weight was a health problem (OR: 9.75; 95% CI: 3.43–27.67) remained significantly associated with being in the preparation/action stage of change. Conclusions. Several demographic factors and personal perceptions are associated with a parent’s readiness to help his or her child lose weight. Knowledge of these factors may be beneficial to providers and program developers when addressing pediatric overweight with parents and initiating new interventions. Key Words: childhood obesity stage of change parental perceptions Abbreviations: OR, odds ratio CI, confidence interval Approximately 10% of children who are aged 2 to 5 years and 15% of children who are aged 6 to 11 years in the United States are overweight (defined as having a BMI 95th percentile for age and gender).1 In the past 30 years, these rates have doubled for children aged 2 to 5 and nearly tripled for children aged 6 to 11. Among black and Hispanic children, these rates are even higher.2,3 Although some interventions have been successful in initiating weight loss in children, most interventions have had limited success with long-term maintenance.4,5 Assessing a person’s readiness to change his or her behaviors and targeting the intervention to this level of readiness may improve these rates. Behavior modification techniques are often used in weight management programs to promote lifestyle changes around diet, exercise, and sedentary activities.6–8 Because mothers typically play an important role in determining what food is available for their children and shaping eating and activity-related behaviors,9–11 it is not surprising that behavior modification programs that involve parents, particularly mothers, have more of an impact than those that do not.12,13 Assessing a parent’s readiness to make lifestyle and dietary changes therefore may be an important step toward helping children lose weight. The concept of "readiness to change" was first described by Prochaska and colleagues in the transtheoretical model and its stages of change.14,15 According to this model, there are 5 stages of behavior change that categorize the transition from having no interest in changing behavior to maintaining such changes after they are made (Table 1). People who are in the preparation stage are defined as "ready to change" because they are more likely to initiate change for themselves in the following month compared with people who are in the precontemplation or contemplation stages. This model has been validated in adults across a variety of health behaviors, including weight control and reducing dietary fat,16,17 smoking cessation,15,18 alcohol use,19 and preventive health behaviors.20 Although this model has been applied to individual patients, it has never been used to examine a parent’s readiness to change behaviors for his or her child. This study is the first to examine parents’ stage of change as it relates to changing behaviors for their child. We focused on parents of children aged 2 to 12 years because of the increased parental involvement in a child’s growth and development during this period. We were specifically interested in the sociodemographic factors and parental perceptions that were associated with being in the preparation and action stages of change. By understanding the factors associated with being more ready to change, physicians and other health care providers may be able to adjust their interactions with patients and intervene more appropriately. In addition, interventions that target the different levels of parental readiness to change can be developed. METHODS Study Design and Population We conducted a cross-sectional survey of a convenience sample of parents/guardians of children who attended an inner-city, hospital-based pediatric practice in North Philadelphia between September 1 and December 31, 2003. Parents of children who were between the ages of 2 and 12 and were at risk for overweight (BMI 85th percentile but 1 child per family had a BMI 85th percentile, the parent was asked to complete the survey for the child who was scheduled to see the doctor first. Parents were excluded when the child required gastric-tube feeds; had a chronic medical condition that affected his or her weight or ability to eat independently; or was being treated with chronic steroids, chemotherapy, or immune suppressants. A 43-item self-administered questionnaire, available in English and Spanish, was developed and piloted by the investigators (available on request). Patients were enrolled consecutively, during all 5 days of the workweek, when investigators were available. Trained study investigators also obtained consent from parents/guardians and assent from children who were older than 5 years. The study was approved by the institutional review boards at Drexel University College of Medicine and St Christopher’s Hospital for Children. Study Measures The survey was designed to obtain demographic information about the child and the parent as well as information about parental beliefs and behaviors. Parental perceptions regarding the child’s weight and their own weight were rated on a 5-point Likert scale ranging from "very underweight" to "very overweight." Additional questions determined whether parents thought that their child’s weight was a health problem or obesity in general was a health problem. Finally, parents were asked to recall whether their doctor had had any discussions with them about their child’s weight. The outcome measure was parent’s stage of change. An algorithm based on that presented by Kristal et al.21 was used to determine parent’s stage of change (see Fig 1). Questions in the algorithm included whether parents were "thinking about making lifestyle changes to help [their] child lose weight" and "how likely [they were] to make changes in the next 6 months." Questions regarding specific behavior changes, for example, decreasing fruit juice consumption, changing to low-fat or skim milk, increasing fruit and vegetable consumption, increasing physical activity levels, and decreasing the amount of time spent watching TV or playing on the computer, were used to determine which parents were actively making changes. Parents who were consistently making behavior changes, defined as >50% of the time, in any of the previously listed areas were categorized as being in the action stage of change. On the basis of the transtheoretical model and its stages of change, parents who were in the preparation stage of change were considered "ready to make a change." Data Analysis Analyses were performed using Stata 7.0 for Windows (College Station, TX). All categorical data were analyzed using 2 tests and logistic regression. Maximum-likelihood multinomial logistic regression was used to examine the relationship among demographic characteristics, parental perceptions, and stage of change. The referent group consisted of parents who were in the precontemplation stage of change. Stratified analysis by child gender was also performed. Standard demographic variables and all variables that were significant at the P .10 level in the contemplation and preparation/action stages of change were placed in a multivariate multinomial logistic-regression model. In addition, 2-way interaction terms of parental perceptions of their own weight and either perceptions of their child’s weight or whether this was a health problem for their child were tested for statistical significance. Backward stepwise regression with maximum-likelihood ratio testing was performed for model selection. Variables were retained when they had a P value of .10. RESULTS Between September 1 and December 31, 2003, 1708 children who were aged 2 to 12 presented to the clinic for a health maintenance visit. Among them, 545 (32%) were identified as having a BMI 85th percentile for age and gender. During the study period, 187 children and their parents were approached for enrollment. Thirty-two (17%) parents refused for reasons listed in Fig 2. Of the 155 parents who were recruited for the study, 4 did not respond to the questions that assessed readiness to change and were excluded from the analysis, thus leaving 151 parent-child dyads. More than half (62%) of the children in the study were overweight (Table 2). The mean age of the children was 7.5 years, and there were slightly more boys than girls (53% vs 47%). Most children in this study were black (44%) or Latino (51%). Most parental respondents were female (88%); had a high school degree or less (82%); and received public assistance in the form of food stamps, the Special Supplemental Nutrition Program for Women, Infants, and Children or the Temporary Assistance for Needy Families Program (72%). Approximately half (47%) of the parents viewed themselves as being overweight. Nine parents were in the action stage of change, and 49 were in the preparation stage. These groups were combined for analysis because interventions and discussions with health care professionals would have similar characteristics. Thus, 38% of parents were in the preparation/action stage of change. Twenty-six (17%) parents were in the contemplation stage, and 67 (44%) were in the precontemplation stage. Numerous significant associations were found among sociodemographic variables, parental perceptions, and parent’s stage of change (Table 3). Parents of overweight children, compared with parents of at-risk-for-overweight children, had an odds ratio (OR) of 4.54 (95% confidence interval [CI]: 2.07–9.93) for being in the preparation/action stage of change versus the precontemplation stage. Parents of older children (8–12 years), compared with parents of younger children, also had significantly higher odds (OR: 3.73; 95% CI: 1.77–7.86) of being in the preparation/action stage of change rather than the precontemplation stage. There were no differences on the basis of child gender, ethnic/racial group, or parental receipt of federal assistance. Stratified analysis by child gender also revealed no effect modification. When parental perceptions were examined, parents who thought their child’s weight was a health problem had 16.0 times the odds of being in the preparation/action stage (95% CI: 6.33–40.33). Parents who perceived themselves to be overweight had higher odds of being in the contemplation stage (OR: 7.39; 95% CI: 2.66–20.51) than being in the preparation/action stage of change (OR: 3.86; 95% CI: 1.82–8.18). Finally, when the child’s doctor had commented that the child’s weight was a health problem, the odds that the parent would be ready to make a change increased to 10.80 (95% CI: 3.78–30.86). In the multivariate multinomial logistic-regression analysis, the odds of being in the preparation/action stage of change were increased when the child was 8 years of age (OR: 2.99; 95% CI: 1.18–7.60) or the parents thought that their child’s weight was a health problem (OR: 9.75; 95% CI: 3.43–27.67; Table 4). The odds of being in the preparation/action stage were also increased when the parents rated themselves as being overweight (OR: 3.45; 95% CI: 1.36–8.75). Whether the doctor made a comment about the child’s weight was not statistically significant in the multivariate analysis. However, among parents who thought that their child’s weight was a health problem, 56% reported that their doctor had made a comment about their child’s weight, whereas only 8% of parents who did not think that their child’s weight was a health problem reported that the doctor had made a comment (P < .001). The remaining variables and interaction terms were not statistically significant. Overall, this model explained 24.6% of the variance in parental stage of change. DISCUSSION In this study, we examined the relationship among sociodemographic factors, parental perceptions, and a parent’s readiness to make lifestyle changes for his or her overweight or at-risk-for-overweight child. Important factors associated with parental readiness to make changes included older age of the index child and beliefs that their child’s weight was a health problem. With as much as 30% of the patient population being overweight or at risk for overweight,1 interventions that emphasize the immediacy of the health problems associated with childhood obesity may have more of an impact on parents. Physicians and program developers can also use this information to encourage parents to take action sooner, when children are more amenable to change. Another factor that had an impact on parents’ readiness to change was whether they perceived themselves to be overweight. However, the odds of being in the preparation/action stage was half that of being in the contemplation stage. One can hypothesize that other, more personal factors, such as failed experiences with diets and exercise programs, detracted from parents’ motivations and prevented them from moving on to a more active stage of change. In addition, overweight parents may believe that their child’s overweight status has a genetic cause and therefore is not amenable to change. Discovering why these parents are not ready to make a change may help clinicians to assist parents to become more active in their child’s weight loss efforts and eventually break the cycle of familial overweight. It is also interesting to note that physician’s comments were not significant in the multivariate analysis. Nevertheless, many parents who thought that their child’s weight was a health problem also reported that their doctor had made a comment about their child’s weight. This result suggests that doctors and other health care providers may have a strong influence on whether parents understand the health risks associated with childhood overweight. We cannot specify, however, the causal relationship between these variables because of the cross-sectional nature of the study; parents may have realized that their child’s weight was a health problem only after the doctor had made a comment, or the doctor’s comments simply may have reinforced what they were beginning to recognize or already knew. Although providers are likely to play an important role in helping parents to understand the health risks of childhood overweight, future prospective studies will be better able to evaluate the influence of a doctor’s involvement in motivating parents to change. In our study, we examined factors that were associated with parental readiness to make a change. Knowledge of these factors can help providers and program developers tailor their interactions and interventions more appropriately, but other factors or perceptions that may act as barriers to change also need to be addressed. Baughcum et al22 showed that low-income mothers believe that having a larger child indicates that the child is healthy and that they are good parents. Other low-income mothers believe that children can outgrow their overweight status and that a child is not overweight unless he or she is inactive or having social problems in school.23 Cultural attitudes may also play a role. Fitzgibbon et al24 showed that black and Hispanic women do not become dissatisfied with their body image until they are well above the Centers for Disease Control and Prevention’s standards of overweight. Although not studied specifically, these beliefs and cultural references most likely have a negative impact on a parent’s readiness to change behaviors. To be more effective, interventions should address these misperceptions and work within different cultural frameworks to help parents become ready to make behavior changes. In addition to family and cultural beliefs, situational barriers that prevent parents from becoming more active in their child’s weight loss efforts may exist. Haas et al25 showed that children of parents with less education and lower income levels are more likely to be overweight. Other studies suggest that these demographic factors are associated with an adult’s real and perceived ability to carry out behavior changes, such as eating more fruits and vegetables.26,27 Providers may find that exploring situational barriers to change and working with parents to overcome them may help to move parents through the stages of change. There are several limitations in this study. First, the study population consisted of a convenience sample of eligible parents and children, leading to selection bias. However, the majority (83%) of parents who were approached agreed to participate, and parents were enrolled consecutively during all 5 days of the workweek. In addition, the cross-sectional design of the study was a limitation, prohibiting any inferences of causality. Yet several factors were significant, and future prospective studies may be able to clarify the causal relationship of these and other factors. Third, the study population was predominately inner-city Latino and black, therefore limiting the generalization of these results to other populations. However, published literature regarding minority parents’ understanding and approach to weight loss is limited. Additional knowledge about motivating factors in these at-risk populations may help health care providers to communicate the problem and solutions more effectively. Finally, the multivariate multinomial logistic-regression model could explain only 24.6% of the variance. This indicates that variables that were not measured in the study contribute to a parent’s readiness to change. This study sheds light on some of the factors associated with a parent’s readiness to help his or her child lose weight. Frequently, providers broach this subject with their patients and parents without determining whether the parents are ready to make behavior changes or even think that their child is overweight. From previous literature, it is known that physicians do not always feel confident in their skills when addressing this matter with parents.28 Understanding whether a parent is ready for this discussion can be key to creating a nonantagonistic and productive interaction. Moreover, understanding which factors are associated with parental behavior change may help physicians feel more confident when trying to motivate parents. Finally, parental perceptions of their own weight, not only their child’s weight, are important in the process of change. By assessing a parent’s thoughts on this matter, providers will understand whether there are other, more personal issues that are influencing the parent’s view of being overweight and readiness to make changes. CONCLUSIONS To date, no published studies have investigated parental readiness to make changes to help their child lose weight. In this study, we found that parents are more likely to be ready when the child is 8 years of age. Furthermore, belief that their child’s weight is a health problem or recognition that they as parents are overweight is associated with readiness to make changes for their child. Because pediatricians and other health care providers are uniquely positioned to influence parental perceptions, understanding the factors that are associated with a parent’s readiness to make environmental changes to help his or her child lose weight will help them to communicate more effectively with their patients’ parents. In addition, knowledge of these factors may inform the development of more focused public health campaigns and interventions in the future. ACKNOWLEDGMENTS This work was supported in part by National Research Service Award training grant 2 T32 HP10014 10. We acknowledge Howard Bauchner, MD, who is supported by the National Institutes of Health grant K24 HD042489, for careful review of this manuscript. We thank Pierre Chanoine, MD, for involvement in the survey development. We also thank Wendy Bernatavicius for assistance in subject recruitment. FOOTNOTES Accepted Jan 20, 2005. No conflict of interest declared. REFERENCES Ogden C, Flegal K, Carroll M, Johnson C. Prevalence and trends in overweight among US children and adolescents, 1999–2000. JAMA.2002; 288 :1728 –1732 Crawford P, Story M, Wang M, Ritchie L, Sabry Z. Ethnic issues in the epidemiology of childhood obesity. Pediatr Clin North Am.2001; 48 :855 –878 Strauss R, Pollack H. Epidemic increase in childhood overweight, 1986–1998. JAMA.2001; 286 :2845 –2848 Schmitz M, Jeffery R. Public health interventions for the prevention and treatment of obesity. Med Clin North Am.2000; 84 :491 –512 Summerbell C, Ashton V, Campbell K, Edmunds L, Kelly S, Waters E. Interventions for treating obesity in children. Cochrane Database Syst Rev.2003; (3):CD001872 Epstein L, Roemmich J, Raynor H. Behavioral therapy in the treatment of pediatric obesity. Pediatr Clin North Am.2001; 48 :981 –993 Drohan S. Managing early childhood obesity in the primary care setting: a behavioral modification approach. Pediatr Nurs.2002; 28 :599 –610 Saelens B, Sallis J, Wilfley D, Patrick K, Cella J, Buchta R. Behavioral Weight control for overweight adolescents initiated in primary care. Obes Res.2002; 10 :22 –32 Birch L, Fisher J. Development of eating behaviors among children and adolescents. Pediatrics.1998; 101 :539 –549 Birch L, Davison K. Family environmental factors influencing the developing behavioral controls of food intake and childhood overweight. Pediatr Clin North Am.2001; 48 :893 –907 Kohl H, Hobbs K. Development of physical activity behaviors among children and adolescents. Pediatrics.1998; 101 :549 –554 Epstein L, Wing R, Koeske R, Andrasik F, Ossip D. Child and parent weight loss in family-based behavior modification programs. J Consult Clin Psychol.1981; 49 :674 –685 Golan M, Weizman A, Apter A, Fainaru M. Parents as the exclusive agents of change in the treatment of childhood obesity. Am J Clin Nutr.1998; 67 :1130 –1135 Prochaska J, Velicer W. The transtheoretical model of health behavior change. Am J Health Promot.1997; 12 :38 –48 Prochaska J, DiClemente C. Stages and processes of self-change of smoking: toward an integrative model of change. J Consult Clin Psychol.1983; 51 :390 –395 Ounpuu S, Woolcott D, Greene G. Defining stage of change for lower-fat eating. J Am Diet Assoc.2000; 100 :674 –679 Greene G, Rossi S. Stages of change for reducing dietary fat intake over 18 months. J Am Diet Assoc.1998; 98 :529 –534 Prochaska J, DiClemente C, Velicer W, Rossi J. Standardized, individualized, interactive, and personalized self-help programs for smoking cessation. Health Psychol.1993; 12 :399 –405 Heather N, Rollnick S, Bell A. Predictive validity of the Readiness to Change Questionnaire. Addiction.1993; 88 :1667 –1677 Prochaska J, Velicer W, Rossi J, et al. Stages of change and decisional balance for 12 problem behaviors. Health Psychol.1994; 13 :39 –46 Kristal A, Glanz K, Curry S, Patterson R. How can stages of change be best used in dietary interventions J Am Diet Assoc.1999; 99 :679 –684 Baughcum A, Burklow K, Deeks C, Powers S, Whitaker R. Maternal feeding practices and childhood obesity: a focus group study of low-income mothers. Arch Pediatr Adolesc Med.1998; 152 :1010 –1014 Jain A, Sherman S, Chamberlin L, Carter Y, Powers S, Whitaker R. Why don’t low-income mothers worry about their preschoolers being overweight Pediatrics.2001; 107 :1138 –1146 Fitzgibbon M, Blackman L, Avellone M. The relationship between body image discrepancy and body mass index across ethnic groups. Obes Res.2000; 8 :582 –589 Haas J, Lee L, Kaplan C, Sonneborn D, Phillips K, Liang S. The association of race, socioeconomic status, and health insurance status with the prevalence of overweight among children and adolescents. Am J Public Health.2003; 93 :2105 –2110 Campbell M, Symons M, Demark-Wahnefried W, et al. Stages of change and psychosocial correlates of fruit and vegetable consumption among rural African-American church members. Am J Health Promot.1998; 12 :185 –191 Glanz K, Basil M, Maibach E, Goldberg J, Snyder D. Why Americans eat what they do: taste, nutrition, cost, convenience, and weight control concerns as influences on food consumption. J Am Diet Assoc.1998; 98 :1118 –1126 Story M, Neumark-Sztainer D, Sherwood N, et al. Management of child and adolescent obesity: attitudes, barriers, skills, and training needs among health care professionals. Pediatrics.2002; 110 :210 –214...查看详细 (27238字节)
☉ 11333129:The relation between c-myc expression and interferon sensitivity in uveal melanoma
1 RAFT Institute of Plastic Surgery, Mount Vernon Hospital, Northwood, Middlesex, HA6 2JR, UK 2 Gray Cancer Institute, Mount Vernon Hospital, Northwood, Middlesex, UK 3 Institute of Opthalmology, City Road, London, UK ABSTRACT Background/aim: Interferons (IFN) are currently being used to treat melanoma, including some patients with uveal melanoma. IFN is thought to inhibit tumour growth through downregulation of the c-myc oncogene; the overexpression of which has been shown to be associated with resistance in cell lines. The aim of this study was to investigate the relation between c-myc gene expression and IFN sensitivity in a series of uveal melanomas in a short term chemosensitivity assay. Methods: Tumours from 45 patients with uveal melanoma who had undergone enucleation were studied. The ATP chemosensitivity assay was used to study sensitivity to IFN--2b in freshly isolated cells from each tumour. Flow cytometry was used to assess c-myc expression in formalin fixed material from the primary specimens. Results: There was a wide range of IFN sensitivity between the specimens whereas c-myc expression was universal and present in 80% of the tumour cells in 80% of the specimens. Higher c-myc expression was associated with IFN- resistance as measured by the maximum percentage of inhibition (p = 0.05) and there was a trend with the IFN sensitivity index (p = 0.07). Conclusions: These results demonstrate that tumours with high c-myc expression are also associated with IFN resistance. Future research is required to explore the potential of c-myc gene manipulation combined with IFN therapy. Abbreviations: CAM, complete assay medium; CTL, cytotoxic T lymphocyte; FITC, fluorescein isothiocyanate; HLA, histocompatibility antigen; IFN, interferons; LTR, long terminal repeat; MI, maximal inhibitor; NK, natural killer; PBS, phosphate buffered saline; RLU, relative light units Keywords: c-myc; uveal melanoma; interferon; chemosensitivity The clinical course of uveal melanoma is unpredictable. Most patients with uveal melanoma have no demonstrable evidence of metastatic disease at the time of initial diagnosis. However, up to 50% of patients will develop secondary disease. Systemic chemotherapy that is effective in cutaneous melanoma has failed to show activity in uveal melanoma.1,2 The BOLD chemotherapy regimen (dacarbazine, lomustine, vincristine and bleomycin) combined with interferon alfa has been shown to have modest activity against metastatic uveal melanoma in hepatic and extrahepatic sites.3,4 Recent results suggest that fotemustine and GeT (gemcitabine + treosulfan) may be effective.5 Controversy still surrounds the use of interferon alfa in cutaneous melanoma6,7 but it remains the subject of clinical investigation. In uveal melanoma, experimental studies in vitro8 and in vivo9 have also indicated a potential role for interferons. Interferon alfa and interferon gamma treatment inhibited cell growth and upregulated the expression of class I and II histocompatibility antigen (HLA) antigens in two primary uveal melanoma cell lines8 while treatment with IFN--2b resulted in decreased hepatic metastases from intraocular melanoma in a murine model.9 The mechanisms by which interferon alfa exerts its anti-tumour effect have not been fully established. Several lines of evidence have suggested that c-myc has an important role in the action of interferon alfa. Administration of interferon alfa to tumours has been shown to lead to downregulation of c-myc oncoprotein expression and upregulation of p21/WAF gene expression, together leading to G1/S phase delay and a reduction in tumour proliferation.10,11 Studies in Balb/c 3T3 fibroblasts demonstrated that parental cells were sensitive to the antimitogenic effects of interferon alfa and beta but that cell cycle arrest was abolished by the transfection of a construct that linked the two coding exons of c-myc to the long terminal repeat (LTR) of Ha-MS virus producing steady state levels of exogenous c-myc mRNA which were 3–10-fold higher than the endogenous mRNA levels.12 A similar effect was noted in M1 myeloblastic cells transfected with an SV-40 driven c-myc plasmid.13 These studies suggest that overexpression of the c-myc gene, and the subsequent failure to downregulate its expression, is associated with interferon resistance. IFN mediated downregulation of c-myc has been shown to occur by a reduction in the half life of its mRNA and not through an effect on transcription rate.14 Further evidence has suggested that the selective reduction in the half life of c-myc mRNA occurs through an increase in the activity of the 2',5'-oligoadenylate synthetase/RNase L (2',5'-oligo (A) synthetase) pathway.15 Another pathway linking IFN and c-myc is the modulation of HLA expression. Interferon is known to increase the level of class I HLA mRNA10 and surface expression of HLA molecules.8 Conversely, overexpression of c-myc oncogene expression is associated with decreased HLA expression on the surface of tumour cells16,17 reducing their antigenicity. We have previously shown that c-myc overexpression predicts for poor outcome in a series of cutaneous melanomas18,19 and other variants including subungual20 and acral lentiginous melanoma.21 Interestingly, overexpression of c-myc oncoprotein was associated with better outcome in uveal melanoma.22 This study was undertaken to directly relate c-myc oncoprotein expression with sensitivity of primary uveal melanomas to interferon alfa assessed using an ex vivo ATP chemosensitivity assay. MATERIALS AND METHODS Tumour material The surgical specimens were obtained from patients who had undergone enucleation for uveal melanoma at Moorfields Eye Hospital and St Bartholomew’s Hospital, London. Uveal melanomas were detected in patients presenting with reduced visual acuity, a field defect, or by an associated retinal detachment or vitreous haemorrhage. All patients were treated by surgical enucleation of the affected eye performed as an in-patient procedure under general anaesthesia. All patients presented with only primary disease as confirmed by a preoperative metastatic evaluation consisting of clinical examination, routine liver function tests, and a liver ultrasound test. Patients with tumours demonstrating extrascleral extension at the time of resection and histopathological diagnosis were treated subsequently with orbital radiotherapy. Those developing distant metastases at the time of this study were treated with chemotherapy as for metastatic cutaneous melanoma. Each uveal melanoma specimen was divided into two portions under sterile conditions. One underwent conventional histopathological examination and the other was used to assess its sensitivity to interferon. Measurement of the c-myc oncogene expression in each tumour was subsequently performed from material obtained from the paraffin blocks. ATP chemosensitivity assay The sensitivity of each uveal melanoma specimen to interferon alfa was assessed using the ATP chemosensitivity assay, which we have previously reported for uveal melanoma.23 A portion of each fresh uveal melanoma specimen was removed under sterile conditions. The samples were then cut into small cubes, 10 ml of collagenase blend H (0.375 mg/ml Sigma) was added, and the mixture incubated overnight to allow digestion to occur. The digest was washed with 10 ml of PBS, centrifuged at 1100 rpm for 5 minutes and the pellet resuspended in 10 ml of complete assay medium (CAM-DCS Innovative Diagnostik Systeme, Hamburg, Germany). The live cell count was assessed using a trypan blue exclusion method. A volume of 5x103 live cells were subsequently added to each well of a 96 well plate in 100 μl of CAM. The cells were incubated for 6 hours to allow them to attach to the plate. Intron-A (IFN -2b, Schering Plough) was then added to each well at a number of concentrations corresponding to 6.25%, 12.5%, 25%, 50%, 100%, or 200% of the standard therapeutic dose (100% = 1000 IU/ml). Each combination was tested in triplicate. One row of 12 wells received CAM only, and no interferon, and was termed M0 as the negative control. One further row of 12 wells in each plate acted as the positive control (M1) and received the maximal inhibitor of cell survival (MI; DCS Innovative Diagnostiik Systeme). The plate was incubated for 6–7 days at 37°C in 5% CO2 and high humidity. The cells were checked every 2–3 days for infection or overgrowth by microscopy. Following the incubation, ATP was extracted from the cells using 50 μl of TCER (DCS Innovative Diagnostik Systeme). A volume of 50 μl from each well was transferred to another 96 well plate and 55 μl of luciferin-luciferase (DCS Innovative Diagnostik Systeme) added to each well to hydrolyse the ATP. The plate was loaded into a Dynateh ML1100 luminometer and the light emitted from each well measured and expressed as relative light units (RLU). This measure of total ATP has been shown to be a surrogate for a clonogenic assay24 and superior to assays based on MTT (3-(4,5-cimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide).25 The mean percentage inhibition of cell growth/survival for the triplicate wells was calculated using the formula: The IFN sensitivity index was calculated by adding the mean percentage growth inhibition, for all six drug concentrations, together and subtracting this figure from 600. A sensitivity index of less than 600 corresponds to tumour sensitivity to IFN and above 600 to resistance. The maximum percentage inhibition of IFN for each tumour was the maximum inhibitory percentage produced on the dose-response curve at any dose. Flow cytometric analysis of c-myc oncoprotein Measurement of the c-myc oncogene expression in each tumour was subsequently performed from material obtained from the paraffin blocks as described previously.20 Two 35 μm sections were cut from the block used for diagnosis, dewaxed in xylene, and rehydrated through a series of alcohols. Nuclei extraction was achieved by incubation with pepsin solution (4 mg/ml in 0.1 M HCl, Sigma Chemicals, Poole, UK) for 45 minutes at 37°C. The extracted nuclei were filtered through a 35 μm mesh and divided into two samples, one of which acted as a control while the other was used for c-myc staining. The nuclei concentration was adjusted to 106 cells/ml in phosphate buffered saline (PBS) and stained for c-myc using a rabbit polyclonal antibody to the human oncoprotein (Cambridge Research Biomedicals Ltd, Cambridge). A pellet of each test sample was incubated in a volume of 100 μl of dilution buffer (PBS + 0.5% normal goat serum + 0.5% Tween 20) containing 4 μl of the c-myc antibody (final dilution 1:25) for 1 hour at room temperature. The control sample was incubated with the corresponding rabbit immunoglobulin fraction as negative control and baseline for flow cytometry. After washing in PBS, both samples were incubated with a 1:20 dilution of the secondary fluorescein isothiocyanate (FITC) conjugated goat anti-rabbit IgG antibody (Sigma) for 45 minutes at room temperature. The samples were washed in PBS and resuspended in 1 ml PBS containing 1 mg/ml ribonuclease A (Sigma), to which 20 μl of propidium iodide (Sigma) was then added. Stained samples were analysed on a FACScan flow cytometer (Becton Dickinson, San Jose, CA, USA) by assessment of 10 000 events from each sample. The percentage of cells expressing c-myc protein was defined by setting a region on the control sample containing less than 1% of the events. This region was then superimposed on the c-myc stained sample to define the percentage positivity. Data analysis Clinicopathological features including age, sex, and histological parameters of the primary tumour were obtained from each patient’s records. The histological parameters of the tumours available were the largest tumour diameter, the mitotic index, and the predominant cell type (spindle cell, epithelial or mixed). Data were analysed using JMP (SAS Institute) and the statistical relations between parameters assessed using the Anova t test and the Spearman rank correlation. RESULTS Patient characteristics The median age at presentation was 59.5 years (range 25–85 years). Twenty six patients were male and 19 female. All patients in the study group presented with only primary disease at the time of enucleation. The mean largest tumour diameter, measured from the histological section, was 13.8 mm (range 8–22 mm). Sixteen tumours were of spindle cell morphology, 19 tumours were of mixed cell type, and nine tumours exhibited epithelioid cell type. Three tumours were necrotic and therefore unclassifiable. Chemosensitivity profiles Examples of typical interferon alfa dose-response curves for four uveal tumours are displayed in figure 1. There was a range of responses from specimens that were relatively resistant to the action of interferon alfa such as one case that had a maximum percentage of inhibition of 5.5% and an interferon alfa sensitivity index of 593.8. In contrast another specimen was relatively sensitive to interferon alfa with a maximum percentage of inhibition of 64.1% and an interferon sensitivity index of 296.8. The dose-response curves tended to be quite shallow such as seen in figure 1C. Figure 1 Typical dose-response curves of uveal melanoma cells to interferon alfa (IFN-). The distributions of maximum percentages of inhibition and interferon alfa sensitivity indices for the series of tumours are shown in figure 2. The mean maximum percentage of inhibition by interferon alfa was 17.3% (SD 36.3%) and ranged from –97.9% (that is, growth) to 99.8%. There were 10 tumours which showed apparent stimulation of growth and this was particularly evident in four patients which had a more than 40% increase in ATP levels. The mean interferon sensitivity index for the series of tumours was 617.5 (224.5) and ranged from 133 to 1269. Using the criterion of a score of 600 as the cut off between more and less sensitive, 56% were classified into the sensitive group. As expected there was a strong correlation (r2 = 0.84, p>0.0001) between the two parameters of sensitivity. Figure 2 The distribution of (top) sensitivity index to interferon alfa (IFN-) and (bottom) maximal percentage inhibition among the 45 uveal melanoma tumours in this study. Chemosensitivity profiles and clinicopathological parameters There was a statistically significant difference (p = 0.048) in maximum inhibitory index between the younger patients (mean 30.8%) and the older patients (mean 11.3%) when the patients were stratified according to age, above and below the median for the whole group (61 years). A similar trend (p = 0.058) was seen with the interferon alfa sensitivity index being lower in the younger patients (mean 527.7) than the older patients (mean 643.5) Although the trend was for larger tumours to be less sensitive (interferon alfa sensitivity index 582.9, maximum inhibition 16.9%) than smaller tumours (546.9 and 28.6%), this did not reach statistical significance. There was no difference in response to interferon alfa when comparing the tumours between male and female patients or between tumours with high or low mitotic indices using either of the interferon alfa sensitivity indices. Tumours of mixed cell type tended to be more resistant (630.8, 8.5%) than epithelial (567.6, 24.2%) and spindle tumours (574.5, 28.6%) but this was not statistically significant. These differences reached statistical difference (p = 0.041) if maximal growth inhibition was compared between the mixed cell type and the other two histologies. C-myc oncoprotein and clinicopathological features All 45 uveal melanomas analysed in this study showed evidence of staining for the c-myc oncoprotein. The median positivity for the series was 92.0% and the mean 85.1% (range 11.8–100%). The distribution of c-myc positivity in the series of tumours is shown in figure 3. The variation in c-myc between tumours was relatively small (coefficient of variation 25%) as 80% of specimens had a positivity rate of greater than 80%. Figure 3 The distribution of c-myc oncoprotein positivity within the 45 tumours in this study. There was no significant difference between oncoprotein positivity in the younger (<61 years) patients (84.8%) compared with the older patients (80.5%). However, there was a trend (p = 0.074) towards higher c-myc positivity in uveal melanomas from male patients (88.5%) compared with those from females (76.3%). Similarly, there was a trend (p = 0.073) towards higher oncoprotein positivity levels in the larger tumours (89.7%) compared to the smaller tumours (75.7%) using a stratification above and below the median diameter for the group as a whole (13 mm). There was no difference in c-myc positivity between those tumours with a high mitotic index compared to those with a low index. Unlike the interferon alfa sensitivity, there was no significant difference in c-myc positivity between tumours demonstrating a predominantly spindle cell, mixed, or epithelial cell type. Interferon alfa sensitivity and c-myc expression Correlation analysis revealed no direct correlation between interferon alfa sensitivity and c-myc oncoprotein expression. However, this may be because of the preponderance of high c-myc expressing tumours. When the series of tumours were divided into two groups above and below the median c-myc positivity value (92%) some associations were observed. Figure 4 (top) shows that the mean maximal inhibitory percentage for the low c-myc expression group was 28.1%. The mean maximal inhibitory percentage for the high c-myc expression group was 7.0% and this just reached significance (p = 0.049). Correspondingly (fig 4, bottom), the mean interferon sensitivity index for the lower c-myc expression group was 553.4 (in the sensitive range) while the mean interferon sensitivity index for the high c-myc expression group was 673.5 (in the resistant range); this did not quite reach significance (p = 0.073). Figure 4 The association between c-myc positivity and maximal percentage growth inhibition (top) and interferon alfa sensitivity index (bottom). The symbol represents the mean value in each group while the bars are the standard deviation. DISCUSSION Irrespective of primary treatment with eye conserving therapies or enucleation, up to 50% of uveal melanomas will develop metastases during the next decade. Uveal melanoma is notable for its haematogenous dissemination and its tendency to metastasise into the liver.1,26 Once metastasised, life expectancy is short because of the refractory nature of the disease to conventional chemotherapeutic approaches.26 Evidence from tumour doubling times suggests that micrometastases lie dormant in many cases and do not progress until after removal of the primary lesion and that treatment can impact on the growth of the secondary lesion.27 There is a clear need for an effective adjuvant therapy for patients at high risk of metastasis from ocular melanoma as there is also for patients with other high risk melanoma types. Despite some controversy regarding its efficacy in cutaneous melanoma, chemoimmunotherapy has been used in the treatment of disseminated uveal melanoma.4,28 A key component of these schedules is the inclusion of interferons. However, uveal melanoma presents a paradox in that, unlike cutaneous melanoma, lack of expression of MHC class I on primary uveal melanoma has been found to be correlated with a better patient survival and, conversely, overexpression with poorer survival.29,30 MHC class I upregulation appears to be one of the mechanisms involved in IFN activity.10 In cutaneous melanoma, downregulation of HLA class I in primary lesions is associated with increased thickness of the lesion, tumour progression, and reduced survival. Cutaneous melanoma metastases have been shown to exhibit a lower HLA class I expression than primary tumours31 and this is associated with a worse survival.31,32 This evidence presents a clear rationale to pursue immunotherapeutic approaches in cutaneous melanoma but is counterintuitive for uveal melanoma. However, the biology of uveal melanoma is complex and represents a distinct entity from its cutaneous relative in many aspects even though they share a common cell of origin; our studies on c-myc are an example of this paradigm. In cutaneous melanoma we have found overexpression of the proto-oncogene to be associated with poor survival in primary, secondary, and variant lesions of this disease18–21,33 and like others16 to be associated with downregulation of class I HLA expression.17 In contrast, c-myc overexpression in uveal melanoma predicts for better survival,22 yet the inverse relation between c-myc and class I HLA expression is similar to cutaneous melanoma.34 In a further study we explored the relation between c-myc, bcl-2, and p53 in uveal melanoma and speculated that overexpression of c-myc in the presence of an intact p53 pathway would render the tumour cells susceptible to apoptosis and possibly less capable of metastasis, resulting in a better prognosis. In cutaneous melanoma, p53 mutation is a late event35 and may predispose to metastasis. Tumours would have a higher mitotic and apoptotic rate than uveal melanoma, but their p53 mutation may make apoptosis during metastasis less likely. High c-myc in such cases would result in faster growth and metastasis, resulting in a poor prognosis. The paradox of class I HLA overexpression being associated with poor outcome in uveal melanoma has also been the subject of speculation.29,30,36 HLA class I molecules are essential for cytotoxic T lymphocyte (CTL) responses against malignant cells, and loss of HLA class I expression may lead to immune silent tumour cells. However, loss of HLA class I antigens makes cells more sensitive to natural killer (NK) cell mediated lysis. This might suggest that CTL mediated control of tumour growth does not have a major role in the clinical course of uveal melanoma and that the data are compatible with a potential role of NK cell mediated control of haematogenic metastatic spread. Another tantalising aspect of interferon alfa activity is a potential anti-angiogenic effect at repeated low doses,37 which might be particularly effective considering the mode of spread of uveal melanoma. The data presented in this study show a modest overall response, although with considerable inter-tumour variation, of uveal melanoma cells to interferon alfa; this is similar to a previous study in cutaneous melanoma.38 The tumours expressing the highest levels of c-myc were the least sensitive to interferon. These results support the concept that c-myc downregulation is associated with the cell growth inhibition produced by interferon alfa and that resistance is associated with tumour c-myc overexpression. This has important implications for the use of interferon as adjuvant therapy in melanoma. The patient groups which would gain most from effective adjuvant therapy—that is, those with the worst prognosis and the highest c-myc expression levels when considering cutaneous melanoma, are the least sensitive to interferon. This may explain why the efficacy of interferon as an adjuvant agent in melanoma has been questioned. It suggests that the use of interferon alone as adjuvant therapy in cutaneous melanoma is unlikely to be beneficial as has been demonstrated by the majority of clinical trials.39–42 The link between c-myc overexpression and interferon alfa resistance supports the use of therapeutic strategies to block the effects of the c-myc gene, such as antisense gene therapy,43 to overcome tumour resistance to interferon alfa. The combination of these two therapies may therefore offer a potential method to increase the efficacy of interferon and offer the prospect of more successful adjuvant therapy in the future. The caveat would be whether modulation of c-myc expression in uveal melanoma would lead to a phenotype that may be intrinsically less susceptible to apoptosis. The interplay between interferon alfa, c-myc, and biological processes is clearly complex in uveal melanoma and a fertile and a challenging area for future research. ACKNOWLEDGEMENTS This work was supported by The RAFT Institute of Plastic Surgery and Moorfields Eye Hospital (including in part an EU CRAFT grant BMH4-CT98-9522 and an unrestricted educational grant from Schering Plough Ltd). REFERENCES Woll E , Bedikian A, Legha SS. Uveal melanoma: natural history and treatment options for metastatic disease. Melanoma Res 1999;9:575–81. Pyrhonen S . The treatment of metastatic uveal melanoma. Eur J Cancer 1998;34 (Suppl 3) :S27–30. Nathan FE, Berd D, Sato T, et al. BOLD+interferon in the treatment of metastatic uveal melanoma: first report of active systemic therapy. J Exp Clin Cancer Res 1997;16:201–8. Pyrhonen S , Hahka-Kemppinen M, Muhonen T, et al. Chemoimmunotherapy with bleomycin, vincristine, lomustine, dacarbazine (BOLD), and human leukocyte interferon for metastatic uveal melanoma. Cancer 2002;95:2366–72. Cree IA. Cytokine therapy and ocular melanoma. In: Zierhut M, Jager MJ, Ksander BR, eds. Immunology of ocular tumours. Lisse: Swets and Zeitlinger, 2002:147–55. Eggermont AM. Critical appraisal of IFN-alpha-based adjuvant therapy in stage II-III malignant melanoma. Expert Rev Anticancer Ther 2002;2:563–9. Gray RJ, Pockaj BA, Kirkwood JM. An update on adjuvant interferon for melanoma. Cancer Control 2002;9:16–21. De Waard-Siebinga I , Creyghton WM, Kool J, et al. Effects of interferon alfa and gamma on human uveal melanoma cells in vitro. Br J Ophthalmol 1995;79:847–55. Dithmar S , Rusciano D, Lynn MJ, et al. Neoadjuvant interferon alfa-2b treatment in a murine model for metastatic ocular melanoma: a preliminary study. Arch Ophthalmol 2000;118:1085–9. Dron M , Modjtahedi N, Brison O, et al. Interferon modulation of c-myc expression in cloned Daudi cells: relationship to the phenotype of interferon resistance. Mol Cell Biol 1986;6:1374–8. Subramaniam PS, Kominsky S, Johnson HM, et al. Type I interferon induction of the Cdk-inhibitor p21WAF1 is accompanied by ordered G1 arrest, differentiation and apoptosis of the Daudi B-cell line. Oncogene 1998;16:1885–90. Einat M , Kimchi A. Transfection of fibroblasts with activated c-myc confers resistance to antigrowth effects of interferon. Oncogene 1988;2:485–91. Resnitzky D , Kimchi A. Deregulated c-myc expression abrogates the interferon- and interleukin 6-mediated G0/G1 cell cycle arrest but not other inhibitory responses in M1 myeloblastic cells. Cell Growth Differ 1991;2:33–41. Dani C , Mechti N, Piechaczyk M, et al. Increased rate of degradation of c-myc mRNA in interferon-treated Daudi cells. Proc Natl Acad Sci USA 1985;82:4896–9. Chatterjee D , Savarese TM. Posttranscriptional regulation of c-myc proto-oncogene expression and growth inhibition by recombinant human interferon-beta ser17 in a human colon carcinoma cell line. Cancer Chemother Pharmacol 1992;30:12–20. Versteeg R , Noordermeer IA, Kruse-Wolters M, et al. c-myc down-regulates class I HLA expression in human melanomas. EMBO J 1988;7:1023–9. Grover R , Ross DA, Richman PI, et al. C-myc oncogene expression in human melanoma and its relationship with tumour antigenicity. Eur J Surg Oncol 1996;22:342–6. Ross DA, Wilson GD. Expression of c-myc oncoprotein represents a new prognostic marker in cutaneous melanoma. Br J Surg 1998;85:46–51. Grover R , Ross DA, Wilson GD, et al. Measurement of c-myc oncoprotein provides an independent prognostic marker for regional metastatic melanoma. 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☉ 11333130:Factors influencing visual acuity after intravitreal triamcinolone acetonide as treatment of exudative age related macular degeneration
Department of Ophthalmology, Faculty of Clinical Medicine Mannheim of the University Heidelberg, Germany ABSTRACT Aim: To evaluate factors influencing change in visual acuity (VA) after intravitreal injection of triamcinolone acetonide as treatment of exudative age related macular degeneration (AMD). Methods: This prospective, interventional, comparative non-randomised clinical case series study included 94 patients (99 eyes) showing progressive exudative AMD with occult (n = 61 eyes), minimally classic (n = 18), predominantly classic (n = 1), or totally classic (n = 8) subfoveal neovascularisation. Mean follow up was 8.5 (SD 4.7) months (median, 7.3 months; range 3.1–24.5 months). All patients received an intravitreal injection of 20–25 mg of triamcinolone acetonide. Results: An increase in best VA of at least one line on the Snellen charts was found in 63 (63.1%) eyes. Correspondingly, mean VA increased significantly (p50%) in one (1.0%) eye which did not show a subretinal haemorrhage. The subfoveal neovascularisation was totally classic (>50%) in eight (8.1%) eyes of which two (25%) showed a subfoveal and parafoveal haemorrhage. A detachment of the retinal pigment epithelium was detected in 11 (11.1%) eyes. For the patients with the predominantly classic type and the totally classic of subfoveal neovascularisation, photodynamic therapy had been recommended but was refused by the patients for various reasons such as cost and immobility. The intravitreal injection of triamcinolone acetonide was performed under sterile conditions in the operation theatre using an operating microscope. Under topical anaesthesia, a paracentesis was performed to puncture the anterior chamber and to release some aqueous humour. After that, the patients received transconjunctivally an intravitreal injection of 20–25 mg of triamcinolone acetonide. The triamcinolone acetonide was usually prepared by the pharmacy by extracting 0.625 ml from the ampoule (Volon A, Bristol-Myers-Squibb, Germany) containing 40 mg of triamcinolone acetonide in 1 ml. The withdrawn volume was filled into a tuberculin syringe (1 ml) or a 2 ml syringe. The syringe was filled up with Ringer’s solution. A millipore filter (pore size, 5 μm; Sterifix Pury, Braun Melsungen AG, Melsungen, Germany) was placed on top of the syringe, and the content of the syringe was pressed through the filter with the triamcinolone acetonide crystals remaining in the syringe. The syringe was refilled with Ringer’s solution, and the same procedure was repeated three times. At the end, 0.2 ml of solution in the tuberculin syringe was left and, using a 27 gauge needle, the content was injected transconjunctivally into the vitreous cavity. At baseline of the study and in repeated intervals afterwards, all patients underwent a routine ophthalmological examination including standardised VA measurement using Snellen charts, slit lamp biomicroscopy, Goldmann applanation tonometry, and ophthalmoscopy. The examinations were routinely performed at the first day after the injection, 1 week after the injection, 1 month after the injection, and at roughly monthly intervals from then on. Thirty three patients skipped at least one follow up examination within the first three months after the injection and returned for a later re-examination (table 1). For all patients included in the study, the results of at least one examination performed at least 3 months or more after the intravitreal injection were available. Table 1 Visual acuity (VA) before and after an intravitreal injection of triamcinolone acetonide For statistical analysis, the non-parametric Wilcoxon test was used to compare the changes in VA during the study period. To compare between the subgroups of the study, the Wilcoxon-Mann-Whitney test was applied. RESULTS After the injection, mean VA significantly (p0.20) (table 5). For all subgroups except for the subgroup with predominantly classic subfoveal neovascularisation (n = 1 eye), the correlation between gain in VA after the injection and preoperative VA was significant (p0.20) difference in gain in VA after the injection between the two study subgroups. DISCUSSION For patients with exudative AMD, recent investigations have proved that photodynamic therapy is of benefit in the treatment of the classic type of subfoveal neovascularisation.43–45 Treatment of exudative AMD with minimally classic subfoveal neovascularisation, however, has been inconclusive so far because studies have not shown a marked therapeutic effect of photodynamic therapy. Consequently, other treatment modalities have been investigated of which one is the intravitreal application of triamcinolone acetonide. Gillies and colleagues, who injected 4 mg of triamcinolone acetonide intravitreally, did not find a pronounced effect of intravitreal triamcinolone acetonide on VA.46 Danis and colleagues performed a comparative study and reported a beneficial effect of 4 mg of triamcinolone acetonide in their study group compared with the control group.31 A recent investigation including 71 eyes with exudative AMD showed a significant increase in VA after an intravitreal injection of 20–25 mg of triamcinolone acetonide.41 The improvement in VA was significant for the examinations performed 1 month (p = 0.04) and 2 months (p = 0.04) after the injection. About 3–5 months after the injection, VA declined so that VA measurements obtained at the end of the follow up period of that study did not differ significantly (p = 0.17) from the baseline values. Overall, 48 (66.2%) eyes gained in VA during the follow up period.41 Based on these preceding studies, the purpose of the present investigation was to evaluate which factors may be associated with an increase or decrease of VA after an intravitreal injection of triamcinolone acetonide in patients with exudative AMD. Preoperative VA significantly influenced VA after the injection. Patients with a relatively high preoperative VA showed a more pronounced loss of VA than patients with a relative low preoperative VA (tables 2–4; fig 4). It suggests that for eyes with a preoperative VA of less than 0.20, intravitreal injection of triamcinolone acetonide can result in an increase in VA. Eyes with a preoperative VA of higher than 0.20 may loose VA after the injection. It does, however, not necessarily mean that the loss in VA after the intravitreal injection is caused by the intravitreal injection itself. It may be that the eyes with loss in VA after the injection would have lost more in VA if the intravitreal injection had not been performed. The type of subfoveal neovascularisation was another factor influencing gain in VA after the intravitreal injection. Eyes with a detachment of the retinal pigment epithelium showed a significantly higher increase in VA than eyes with a minimally classic subfoveal neovascularisation in which VA did not markedly change after the intravitreal injection (table 5). It may have clinical importance, as photodynamic therapy has not been shown to increase VA in patients with retinal pigment epithelium detachment. There are limitations of the present study, one of which is the design as a non-randomised case series investigation. As it was not the purpose of the study to examine whether intravitreal triamcinolone has a therapeutically beneficial effect on VA but to evaluate which factors are associated with a positive or negative change in VA after the intravitreal injection, a randomised prospective study design may not have been necessary. Another limitation may be that, although intravitreal triamcinolone will have increased cataract, cataract surgery was not performed in combination with, or after the intravitreal injection. The vision reducing effect of progressive cataract, however, may have hidden parts of a vision improving effect of triamcinolone so that this limitation of the study may serve to support the conclusion of the investigation. An additional limitation of the study may be the relatively high dosage of triamcinolone acetonide injected into the eye. In all preceding studies of other study centres applying intravitreal triamcinolone acetonide as treatment of exudative AMD, a dosage of 4 mg was used.31,32,46 We chose to use 20–25 mg of triamcinolone acetonide because, from the very beginning of our ongoing triamcinolone investigations (now involving more than 400 patients with various diseases), we have used the same dosage of 20–25 mg triamcinolone acetonide and have not seen yet the side effects normally attributed to that high dosage. An additional reason for the high dosage in the present study was that in preceding studies on the intravitreal use of 4 mg of triamcinolone acetonide for patients with exudative AMD, the therapeutic effect has not been quite clear.46 In several preceding studies, a single intravitreal injection of triamcinolone acetonide has already been used as treatment for exudative AMD. In 1998, Challa et al32 evaluated safety and efficacy of intravitreal triamcinolone after 18 months of follow up in patients with exudative AMD considered unsuitable for laser photocoagulation. In the non-randomised clinical pilot study, 30 eyes of 28 patients were treated with an intravitreal injection of triamcinolone (4 mg). Of the 20 eyes with initial VA of 0.10 or better, vision was maintained in 11 eyes (55%), and six eyes (30%) suffered severe visual loss (six or more lines). VA improved in three of 10 eyes with initial vision of 3/60 or worse. The authors concluded that a single intravitreal injection of 4 mg triamcinolone may be reasonably well tolerated and may be helpful in the treatment of exudative AMD. In a randomised clinical trial, Danis and colleagues examined the effects of intravitreal injection of 4 mg triamcinolone acetonide on the visual and clinical course of exudative AMD in 27 patients who were compared with a non-treated control group.33 The authors found that VA was significantly (p<0.005) better in the treated group compared with control subjects at 3 and 6 months follow up. An increase in intraocular pressure was seen in 25% of treated patients, but was controlled with topical medications. Progression of cataract was more frequently detected in the treated group. The authors concluded that intravitreal triamcinolone acetonide may provide improvement in VA in exudative AMD. These clinical studies were supported by experimental studies on the effect of intravitreal cortisone on experimental subretinal neovascularisation and other types of intraocular blood vessel proliferation.26–29 The results of the present study and of the other investigations mentioned above are partially in contrast to a recent study by Gillies and colleagues, who found no effect of 4 mg of intravitreal triamcinolone acetonide on the development of severe visual loss over a follow up period of one year.46 One of the reasons for the discrepancy between the investigation performed by Gillies and colleagues and the present study may be the difference in the dosage of triamcinolone acetonide injected. Another reason may be that in the study by Gillies and colleagues, re-injections were not performed. At the end of the follow up, VA was no longer better than before the intravitreal injection. Interestingly, Gillies et al found a statistically significant and therapeutically positive effect of intravitreal triamcinolone on the size of the subfoveal neovascularisation 3 months after the injection. It is in agreement with experimental studies on an angiostatic effect of intravitreal cortisone on experimental subretinal neovascularisation and other types of intraocular blood vessel proliferation.26–29 An additional reason for the discrepancy between the study by Gillies et al and the present and other preceding studies may be that Gillies’ investigation included patients with the classic type of subfoveal neovascularisation which is associated with a worse prognosis compared with the occult type. The most recent study on the intravitreal use of triamcinolone acetonide in eyes with exudative AMD was reported by Spaide and colleagues who combined photodynamic therapy with intravitreal triamcinolone acetonide and found an unexpectedly low frequency of photodynamic retreatments as compared with data in the literature.47 In conclusion, the data of the present pilot study suggest that the gain in VA after an intravitreal injection of 20–25 mg of triamcinolone acetonide in patients with exudative AMD is significantly better in eyes with low preoperative acuity than in eyes with high preoperative VA, and that the gain in VA may be higher for eyes with retinal pigment detachment than in eyes with minimally classic subfoveal neovascularisation. Table 3 Visual acuity (VA) before and after an intravitreal injection of triamcinolone acetonide in eyes with a preoperative VA of higher than 0.08 and less than, or equal to, 0.20 REFERENCES Jonas JB, S?fker A. 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☉ 11333131:Coronary Artery Dilation Among Patients Presenting With Systemic-Onset Juvenile Idiopathic Arthritis
Rheumatology Program, Division of Immunology Department of Cardiology, Children's Hospital Boston, Boston, Massachusetts Section on Immunology and Immunogenetics, Joslin Diabetes Center, Boston, Massachusetts Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital, Boston, Massachusetts Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire ABSTRACT Objective. To evaluate coronary artery diameters among patients presenting with systemic-onset juvenile idiopathic arthritis (SoJIA). Methods. Fifty cases of SoJIA were reviewed. At the time of initial presentation with fever, 12 patients had echocardiograms that included a complete evaluation of the coronary arteries. A single reviewer measured the diameters of the left main, proximal left anterior descending, and proximal right coronary arteries. Body surface area-adjusted z scores were calculated with respect to a normative population. Results. Coronary artery dilation (z score: >2) was observed for 5 of the 12 patients with SoJIA who had echocardiograms performed at the time of presentation with fever. No patient developed a coronary artery aneurysm, and all of the coronary artery z scores normalized within 4 months. Only 2 of the 5 patients with coronary artery z scores of >2 fulfilled the clinical criteria for Kawasaki disease, the most commonly recognized cause of coronary artery dilation among children. Conclusions. Children presenting with SoJIA may have coronary artery dilation similar to that observed for children with Kawasaki disease. These data suggest that the presence of coronary artery dilation on initial echocardiograms for patients with fever does not exclude the diagnosis of SoJIA. Key Words: juvenile rheumatoid arthritis Still's disease Kawasaki disease fever Abbreviations: IVIG, intravenously administered immunoglobulin KD, Kawasaki disease SoJIA, systemic-onset juvenile idiopathic arthritis Systemic-onset juvenile idiopathic (or rheumatoid/chronic) arthritis (SoJIA) (Still's disease) is characterized by hectic daily fevers and arthritis. These symptoms may be accompanied by evanescent rashes, lymph node enlargement, hepatomegaly, splenomegaly, or serositis.1 The disease is associated with elevation of inflammatory indices and circulating levels of proinflammatory cytokines, especially interleukin-6.2 Aggressive immunosuppressive therapy is often required to achieve disease control. Reported cardiac complications of SoJIA include pericarditis, pericardial effusion, myocarditis, and rarely endocarditis.3–5 Diagnosis of SoJIA is often challenging, especially before children have had symptoms for 6 weeks (as required by International League of Associations for Rheumatology criteria for SoJIA and American College of Rheumatology criteria for systemic-onset juvenile rheumatoid arthritis) or 3 months (as required by European League Against Rheumatism criteria for systemic-onset juvenile chronic arthritis).1,6,7 Infectious diseases and other inflammatory conditions, including childhood vasculitides, may mimic SoJIA. Children with early SoJIA are often treated for Kawasaki disease (KD) when it cannot be excluded by the tenth day of fever and when caregivers think that presumptive therapy of a child who may have KD is necessary.8,9 This is more likely to occur when children have other symptoms common to both KD and SoJIA, such as rash, cervical lymphadenopathy, or extremity swelling. Although mucosal changes and isolated cervical lymphadenopathy are more typical of KD, these factors alone may not distinguish KD from SoJIA adequately. In an attempt to differentiate KD and SoJIA, clinicians often rely on ophthalmologic evidence of uveitis or echocardiographic evidence of coronary artery dilation.10 Either finding would typically favor the diagnosis of KD, although the incidence of coronary artery dilation in SoJIA is not known. In fact, we observed dilation of the coronary arteries in several patients who were diagnosed eventually as having SoJIA. On the basis of this observation, we evaluated retrospectively the dimensions of the coronary arteries among patients during the initial febrile episodes leading to the diagnosis of SoJIA. METHODS We reviewed the medical records of the 50 patients with SoJIA who were treated in the outpatient rheumatology clinic at Children's Hospital Boston in 2002–2003. Nineteen of these 50 patients had prior echocardiograms. Echocardiograms for 7 of the 19 patients were limited and did not include images sufficient for measurement of the coronary arteries; 6 were obtained for patients with previously diagnosed SoJIA, to evaluate possible pericarditis or endocarditis, and 1 was obtained at the time of presentation with fever of unknown origin, to evaluate possible endocarditis. Therefore, 12 of the 19 patients had echocardiograms obtained at the time of their initial febrile presentation that included coronary artery imaging adequate for measurement of the diameters of the left main, proximal left anterior descending, and/or proximal right coronary arteries. These 12 echocardiograms were evaluated more thoroughly, with review of all echocardiograms except for those for patient 1 by a single pediatric echocardiographer (J.C.L.) who was blinded to the original measurements. The studies for patient 1 were not reviewed because they had been reviewed previously, to reach a consensus regarding the coronary artery dimensions, by multiple pediatric cardiologists, including other investigators in this study (S.N.W. and J.W.N.). Measurements of the internal lumen diameters of the coronary arteries were made by using previously described methods.11 These diameters were compared with measurements for a large sample of normal subjects with body surface area-adjusted z scores. A z score is defined as the number of SDs a measurement lies from the mean for the normal subjects; a z score of >2 indicates that a measurement lies >2 SDs above the mean. Following standard practice, coronary arteries with dimensions >2 SDs above the mean (ie, z scores of >2) were defined as abnormally dilated.11 Our review of the patients' medical records and echocardiograms was approved by the institutional review board of Children's Hospital Boston. RESULTS Review of the 12 echocardiograms allowed measurement of the coronary artery dimensions for all 3 coronary arteries for 8 patients and for 2 of the 3 coronary arteries for the remaining 4 patients, leading to a total of 32 vessels. The coronary artery z scores for these 12 patients with SoJIA are depicted in Fig 1. Our main finding was that, at the time of initial febrile presentation, 5 patients with SoJIA had 1 coronary artery z score of >2 and 2 patients had 2 vessels with z scores of >2. The 5 patients with SoJIA with coronary artery z scores of >2 are described in greater detail in Table 2, with particular attention to features of their presentations that were clinically similar to features of KD. Three patients with SoJIA (including the 2 meeting KD criteria) had a left anterior descending or right coronary artery z score of 2.5; 1 of those patients had a right coronary artery z score of >3. The coronary artery dilations normalized within 4 months after disease onset, and no patient developed a coronary artery aneurysm. Arthritis was present for 3 of those 5 patients at the time of presentation with fever, and arthritis developed within 1 month after disease onset for the other 2 patients. All 5 of the patients were treated with corticosteroids early in the disease course, for either presumed intravenously administered immunoglobulin (IVIG)-resistant KD (patients 1–4) or presumed SoJIA (patient 5). The corticosteroids were tapered subsequently and discontinued for 4 of the 5 patients, with the addition of other immunomodulatory medications. DISCUSSION Both KD and SoJIA should be considered when a child with prolonged fever, rash, and cervical lymphadenopathy is evaluated. In view of our findings for these 5 children and the frequent occurrence of pericarditis in SoJIA and coronary arteritis in KD, echocardiograms often should be included in the evaluation of children for whom these diagnoses are being considered. Documentation of coronary artery dilation typically would favor the diagnosis of KD. As we have demonstrated, however, similar changes in coronary artery dimensions may occur among children presenting with SoJIA. With this small sample, we were not able to identify any echocardiographic variables that would distinguish patients with acute KD from patients with early SoJIA. Although arthritis may occur in the acute febrile or convalescent phase of KD, our patients had more persistent signs of systemic inflammation than are usually seen in KD. Furthermore, our patients required aggressive, prolonged, immunosuppressive therapy. In contrast, arthritis during the convalescent phase of KD is typically self-limited and may be controlled with short courses of nonsteroidal antiinflammatory drugs. In the absence of pathognomonic physical examination or laboratory findings, clinical criteria are used to establish diagnoses of both SoJIA and KD.1,9 Four of the 5 patients we report with coronary artery z scores of >2 were treated for KD. Patients 1 and 2 fulfilled KD diagnostic criteria, whereas patients 3 and 4 did not. The simplest explanation for multiple diagnoses among these children is that they had SoJIA but their symptoms could not be distinguished from those of KD early in the disease course. Indeed, many patients treated for KD do not fulfill the diagnostic criteria and are considered to have "incomplete" KD, particularly if coronary artery abnormalities are demonstrated echocardiographically.12 Although it is possible that some of our patients had both KD and SoJIA, it is statistically unlikely that we would encounter 5 children with the simultaneous onset of both KD and SoJIA at a single institution in a period of 3 years, because both conditions have annual incidence rates of 10 cases per 100000. Another possibility is that KD may trigger or evolve into SoJIA. These 2 systemic inflammatory disorders could share common triggering agents, susceptibility factors, or immunopathogenic pathways. Elevation of circulating levels of inflammatory cytokines, including tumor necrosis factor- and interleukin-6, occurs in both KD and SoJIA.2,13–15 For most patients, KD is a self-limiting illness. It may be hypothesized that, for individuals with immunologic and/or genetic risk factors for the development of SoJIA, KD may trigger a self-perpetuating inflammatory cascade through abnormal immunoregulatory mechanisms. This hypothesis is particularly intriguing in view of the tendency of our patients with SoJIA with coronary artery dilation to present with features suggesting KD (Tables 1 and 2). It should be noted, however, that we have not observed coronary artery aneurysms typical of KD for any of our patients with SoJIA. The design of our study does introduce important limitations. First and most importantly, in our retrospective study, several patients with SoJIA did not have prior echocardiograms. It is likely that echocardiograms were obtained more commonly for patients with SoJIA presenting with clinical features suggestive of KD, potentially leading to an increased likelihood of detecting dilated coronary arteries. A prospective study to estimate coronary artery z scores for all patients presenting with SoJIA would be necessary to eliminate this type of ascertainment bias. Second, the normative data used to determine coronary artery z scores were obtained for an afebrile population of children. It is possible that prolonged fever alone causes transient coronary artery dilation. Despite these limitations, we have documented that coronary artery dilation can be observed among febrile children shortly before the diagnosis of SoJIA is established. Until more is understood about the cause and pathogenesis of both KD and SoJIA, diagnosis and therapy will continue to rely on clinical criteria and acumen. Our findings have implications for the treatment of patients presenting with features of KD and SoJIA. If a patient meets the criteria for KD, then appropriate therapy with IVIG and acetylsalicylic acid (aspirin) should be instituted.9,16 However, our report suggests that rare patients in this category may have or may develop SoJIA. Therefore, careful follow-up monitoring is necessary to document the resolution of symptoms after treatment for KD. Persistence of fever with the development of frank arthritis should alert physicians to the possibility of SoJIA. The finding of coronary artery dilation should not dissuade physicians from the diagnosis of SoJIA. Rather, our data suggest that transient coronary artery dilation may occur early in the course of SoJIA. Should all patients with a systemic inflammatory syndrome and coronary artery dilation be treated with IVIG regardless of whether KD diagnostic criteria are met Should patients with SoJIA and coronary artery dilation be treated with IVIG Providing answers for these interrelated questions is difficult. One of our patients with SoJIA (patient 5) with a coronary artery z score of >2 did not meet the criteria for KD and was not treated with IVIG or aspirin. Her coronary artery dimensions normalized after treatment with orally administered corticosteroids. Furthermore, none of our patients with SoJIA developed coronary artery aneurysms, and all of the coronary artery z scores normalized. Although these findings are reassuring, the number of patients with SoJIA with documented coronary artery dilation was small, and 4 of 5 of our patients were treated with IVIG. Given the risks associated with not treating patients with KD, we continue to recommend IVIG therapy for patients with significant coronary artery dilation and systemic inflammation when an experienced clinician believes that the child could have KD. It seems that coronary artery dilation supports a diagnosis of KD but is not specific for the condition. Our findings also suggest that vigilance is necessary during the long-term treatment of patients with SoJIA. It is possible and even likely that the coronary artery dilation we observed results from vascular inflammation. The link between vascular inflammation and atherosclerosis17 is highlighted by the increased risk of coronary artery disease and myocardial infarction among adults with rheumatoid arthritis or systemic lupus erythematosus.18–21 Furthermore, longer disease duration seems to increase the risk of coronary artery disease among these patients, whereas aggressive disease control decreases it.22 By extension, it is conceivable that children with SoJIA are at increased risk for coronary artery disease as adults, perhaps because of coronary inflammation that is usually subclinical at presentation. The relative risk of premature atherosclerotic coronary artery disease among adults with a history of SoJIA or KD is unknown.21 One case report linked fatal postpartum coronary thrombosis to localized coronary artery dilation for a 27-year-old woman with a nearly lifelong history of SoJIA.23 Our report opens important avenues to explore the pathogenesis, management, and consequences of coronary artery dilation among patients with SoJIA. FOOTNOTES Accepted Jan 11, 2005. No conflict of interest declared. REFERENCES Petty RE, Southwood TR, Manners P, et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol. 2004;31 :390 –392 Yokota S. Interleukin 6 as a therapeutic target in systemic-onset juvenile idiopathic arthritis. Curr Opin Rheumatol. 2003;15 :581 –586 Svantesson H, Bjorkhem G, Elborgh R. Cardiac involvement in juvenile rheumatoid arthritis: a follow-up study. Acta Paediatr Scand. 1983;72 :345 –350 Yancey CL, Doughty RA, Cohlan BA, Athreya BH. Pericarditis and cardiac tamponade in juvenile rheumatoid arthritis. Pediatrics. 1981;68 :369 –373 Goldenberg J, Ferraz MB, Pessoa AP, et al. Symptomatic cardiac involvement in juvenile rheumatoid arthritis. Int J Cardiol. 1992;34 :57 –62 Brewer EJ Jr, Bass J, Baum J, et al. Current proposed revision of JRA criteria: JRA Criteria Subcommittee of the Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Section of the Arthritis Foundation. Arthritis Rheum. 1977;20 (suppl):195 –199 Rheumatism ELA. EULAR Bulletin 4: Nomenclature and Classification of Arthritis in Children. Basel, Switzerland: National Zeitung AG; 1977 Newburger JW, Takahashi M, Burns JC, et al. The treatment of Kawasaki syndrome with intravenous gamma globulin. N Engl J Med. 1986;315 :341 –347 Dajani AS, Taubert KA, Gerber MA, et al. Diagnosis and therapy of Kawasaki disease in children. Circulation. 1993;87 :1776 –1780 American Academy of Pediatrics. Kawasaki syndrome. In: Pickering LK, ed. Red Book: 2003 Report of the Committee on Infectious Diseases. 26th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2003: 392–395 de Zorzi A, Colan SD, Gauvreau K, Baker AL, Sundel RP, Newburger JW. Coronary artery dimensions may be classified as normal in Kawasaki disease. J Pediatr. 1998;133 :254 –258 Newburger JW, Takahashi M, Gerber MA, et al. Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Pediatrics. 2004;114 :1708 –1733 Suzuki H, Uemura S, Tone S, et al. Effects of immunoglobulin and gamma-interferon on the production of tumour necrosis factor- and interleukin-1 by peripheral blood monocytes in the acute phase of Kawasaki disease. Eur J Pediatr. 1996;155 :291 –296 Okada Y, Shinohara M, Kobayashi T, Inoue Y, Tomomasa T, Morikawa A. Effect of corticosteroids in addition to intravenous gamma globulin therapy on serum cytokine levels in the acute phase of Kawasaki disease in children. J Pediatr. 2003;143 :363 –367 Chien YH, Chang KW, Yang YH, Lu MY, Lin YT, Chiang BL. Association between levels of TNF- and TNF- promoter –308 A/A polymorphism in children with Kawasaki disease. J Formos Med Assoc. 2003;102 :147 –150 Sundel RP. Update on the treatment of Kawasaki disease in childhood. Curr Rheumatol Rep. 2002;4 :474 –482 Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med. 1999;340 :115 –126 Asanuma Y, Oeser A, Shintani AK, et al. Premature coronary-artery atherosclerosis in systemic lupus erythematosus. N Engl J Med. 2003;349 :2407 –2415 Fischer LM, Schlienger RG, Matter C, Jick H, Meier CR. Effect of rheumatoid arthritis or systemic lupus erythematosus on the risk of first-time acute myocardial infarction. Am J Cardiol. 2004;93 :198 –200 Roman MJ, Shanker BA, Davis A, et al. Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus. N Engl J Med. 2003;349 :2399 –2406 Thomas E, Symmons DP, Brewster DH, Black RJ, Macfarlane GJ. National study of cause-specific mortality in rheumatoid arthritis, juvenile chronic arthritis, and other rheumatic conditions: a 20 year follow-up study. J Rheumatol. 2003;30 :958 –965 Choi HK, Hernan MA, Seeger JD, Robins JM, Wolfe F. Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study. Lancet. 2002;359 :1173 –1177 Parry G, Goudevenos J, Williams DO. Coronary thrombosis postpartum in a young woman with Still's disease. Clin Cardiol. 1992;15 :305 –307...查看详细 (19852字节)

☉ 11333132:Refractive adaptation in amblyopia: quantification of effect and implications for practice
1 Department of Visual Neuroscience, Imperial College London, UK 2 Department of Mathematics, Imperial College London, UK ABSTRACT Aim: To describe the visual response to spectacle correction ("refractive adaptation") for children with unilateral amblyopia as a function of age, type of amblyopia, and category of refractive error. Method: Measurement of corrected amblyopic and fellow eye logMAR visual acuity in newly diagnosed children. Measurements repeated at 6 weekly intervals for a total 18 weeks. Results: Data were collected from 65 children of mean (SD) age 5.1 (1.4) years with previously untreated amblyopia and significant refractive error. Amblyopia was associated with anisometropia in 18 (5.5 (1.4) years), strabismus in 16 (4.2 (0.98) years), and mixed in 31 (5.2 (1.5) years) of the study participants. Mean (SD) corrected visual acuity of amblyopic eyes improved significantly (p0.10 logMAR) occurred beyond this time. The occlusion phase was of variable duration depending upon an algorithm to detect "stability" of visual outcome (that is, the best visual outcome likely to have been achieved for any given child). Here, we report only upon visual outcome at the end of the of refractive adaptation phase. Prescription of spectacle correction was based on a strict refraction protocol (table 1). Refractive adaptation began approximately 14 days after the initial assessment and determination of stable baseline measures (allowing for delivery of spectacles from the child’s own dispensing optician). At the first visit of the refractive adaptation phase (week 0), visual performance was recorded with and without refractive correction. Previous instruction had been given that spectacles were not to be worn in the intervening period between delivery and clinic attendance. Children and parents were advised of the need for spectacles to be worn full time and a schedule of three vision assessments at 6 weekly intervals instigated (weeks 6, 12, and 18). Table 1 Criteria for clinically significant refractive error The primary visual function outcome measure was logMAR visual acuity.9,10 Three logMAR visual acuity charts were employed: ETDRS (manufacturer precision vision), crowded (Keeler Ltd), and uncrowded (Keeler Ltd) logMAR charts. Standard protocols for visual acuity testing were used and were scored by letter. The type of chart used depended on the reading ability of the child, and was generally age dependent. If a child was able to undertake a more difficult test as they progressed through the trial, the initial test(s) remained in that child’s test battery. The outcome measure of most importance was considered to be the visual acuity of the amblyopic eye, hence this was recorded first at the start of every visit in case the child became fatigued. Kruskal-Wallis one way analysis of variance on ranks was used to detect differences in response to refractive adaptation with respect to age, type of amblyopia, and refractive error. Classification of strabismus was not used as a factor as the numbers of each group were too small. Multiple testing dictated that only p values <0.01 were deemed significant. Visual acuities are expressed in logMAR and change in acuities in log units. Power of 80% is given to detect a significant difference of 0.20 log units with n 16 (smallest n in analysis), variance 0.20, and = 0.01. It should be noted therefore with the numbers of subjects in each age, amblyopia type, and refractive error group that there is less power to detect differences <0.20 log units. RESULTS With parental written consent, 65 children of mean (SD) age 5.1 (1.4) years with previously untreated amblyopia and significant refractive error were recruited. Amblyopia was associated with anisometropia in 18 (mean age 5.5 (1.4) years) participants, strabismus in 16 (mean age 4.2 (0.98) years), and both anisometropia and strabismus in 31 (mean age 5.2 (1.5) years). For amblyopic eyes, mean (SD) visual acuity at recruitment was 0.77 (0.41) and ranged from 0.1 to 1.6 logMAR. Mean (SD) visual acuity in the fellow eyes was 0.15 (0.1) and ranged from –0.05 to 0.4. The number of data sets at the 0, 6, 12, and 18 weeks assessment were 49, 50, 47, and 52, respectively. Distribution of refractive errors Mean (SD) (spherical error (dioptres) for the amblyopic and fellow eyes was +4.0 (2.1) and +2.7 (1.8), respectively. Astigmatism was present in 41 (63%) with a mean (SD) cylindrical error of –0.91 (1.00) for amblyopic eyes and –0.45 (0.62) for fellow eyes. Distribution of refractive error according to amblyopia type is shown in table 2. Mean (SD) anisometropia was 1.47 (1.56) for the whole group and 1.97 (1.03), 0.32 (0.34) and 1.66 (2.11) for amblyopia associated with anisometropia, strabismus, and mixed amblyopia, respectively. Table 2 Mean (SD) refractive error and cylinder axis range Participants were categorised according to type of refractive error: anisometropic hypermetropia, anisometropic astigmatism, isometropic. Details of the classification scheme are shown in table 3, and the mean refractive error of each group is provided in table 4. Table 3 Classification of refractive error Table 4 Mean (SD) refractive error and cylinder axis range for refractive error categories Distribution of strabismus Details of the classification of strabismus for those in the strabismic amblyopia and mixed amblyopia groups are provided in table 5. Table 5 Classification of subjects with manifest strabismus (includes those with mixed amblyopia). Mean (SD) of angle of deviation at near and distance fixation with and without correction at week 0 Response to spectacle wear Amblyopic eyes The mean (SD) uncorrected vision of amblyopic eyes at week 0 refractive adaptation was 0.77 (0.40). Mean (SD) corrected visual acuity of amblyopic eyes improved significantly (p<0.001) from 0.67 (0.40) at week 0 to 0.43 (0.37) after 18 weeks of spectacle wear: a mean improvement of 0.24 (0.18), range 0.00 to 0.60 log units (fig 1 and table 6). Eight (12%) children demonstrated less than 1 log line (0.1) of improvement (six mixed; one anisometropic; one strabismic). Five of the eight children had worn spectacles (range 8–14 weeks) before study entry, although significantly different prescriptions were ordered at the start of the refractive adaptation phase of the study. Figure 1 Change in mean (SD) logMAR visual acuity of the amblyopic eye during refractive adaptation. Table 6 Mean (SD) logMAR visual acuity during refractive adaptation by amblyopia type Mean (SD; range) interocular difference reduced significantly (p = 0.01) from 0.53 (0.4; 0.1–1.54) to 0.36 (0.37; 0–1.33) a mean reduction in the amblyopic deficit of 0.17 (0.17; 0.00–0.60) log units. Change in mean (SD) logMAR visual acuity (from week 0 refractive adaptation to best VA measurement) did not differ significantly by amblyopia type (anisometropia 0.29 (0.17); mixed 0.19 (0.15); strabismus 0.30 (0.24), table 6) p = 0.29, by age ("under 4 years" (n = 19) 0.23 (0.18); "4–6 years" (n = 29) 0.24 (0.20); "over 6 years" (n = 17) 0.16 (0.23)) p = 0.38, or by refractive status (anisometropic hypermetropia 0.24 (0.14), anisometropic astigmatism 0.15 (0.19), isometropic 0.18 (0.22), p = 0.35, table 7). Table 7 Mean (SD) logMAR visual acuity during refractive by category of refractive error The mean number of weeks taken to achieve best visual acuity of the amblyopic eye did not differ significantly between amblyopia groups (anisometropia 15.6 (SD 5.6), mixed 14.0 (6.2), and strabismic 15.1 (4.3) p = 0.52), or with age ("under 4 years" 14.0 (5.6); "4–6 years" 15.6 (5.9); "over 6 years" 14.4 (5.9)) p = 0.63). Mean (SD) visual acuities at each 6 weekly stage for each group are shown in table 6. Fellow eyes Mean (SD) visual acuity in the fellow eyes improved significantly (p<0.001) from 0.15 (0.13) to 0.07 (0.07) logMAR during refractive adaptation, a mean (SD) change in visual acuity of 0.09 (0.08) log units. Children with less significant refractive errors in the fellow eye (1.5D or less) demonstrated a 0.04 (0.05) log unit improvement. Those with significant refractive errors (1.75D or more) demonstrated a 0.1 (0.07) log unit improvement. Resolution of amblyopia with spectacles alone During refractive adaptation the mean (SD), visual acuity of the amblyopic eye in 14 study participants (mean age 5.49 (1.46)) improved from 0.48 (0.20) to 0.1 (0.08). These children had an average interocular difference of 0.02 (0.05) at the end of refractive adaptation and therefore no longer met the study entry inclusion criteria. On this basis they left the study (that is, did not progress to the occlusion phase). Of these 14, nine did not require any further treatment; five had strabismus, five anisometropia, and four had both strabismus and anisometropia; 13 of the 14 had a significant refractive error in their fellow eye. DISCUSSION This study has quantified the gains in visual acuity attributable to refractive correction and a subsequent period of refractive adaptation as a function of amblyopia type and age of child. Clinically and statistically significant improvements in the acuity of amblyopic eyes were observed subsequent to 18 weeks of refractive adaptation, which did not differ as a function of type of amblyopia or age (3–8 years). Our study does not allow us to rule out the possibility of further improvement beyond 18 weeks. A significant proportion of children attained acuity in their amblyopic eye such that occlusion therapy was not required. Acuity gains accrued gradually over time taking, on average, 14 weeks and were slightly less (by around one line) than we reported in a much smaller (n = 12) cohort.4 In contrast, a recent randomised controlled trial of the treatment of unilateral visual impairment reported similar gains in the spectacle only group to those of our present study but only from an initially uncorrected baseline, suggestive of a much smaller effect.5 Current clinical practice involves the use of a mainstream therapy (that is, occlusion or penalisation) simultaneously with or in close conjunction (after 4 weeks) with the prescription of spectacles. However, our findings suggest that all children with amblyopia and a significant refractive error will benefit from a longer period of refractive adaptation before any further treatment—which in some cases would no longer be necessary. In others, occlusion could be started with improved visual acuity, possibly enhancing concordance with the treatment. The full benefit of refractive correction is not immediate, ruling out a simple optical explanation; and a previous study has indicated that practice effects or repeated testing are not a contributory factor.4 Refractive correction effectively extends upwards the range of spatial frequency information previously available to the retina and anterior visual pathway and, at least in theory, this could facilitate improvement by promoting, non-competitive, activity dependent recovery.6 An analogous effect has been observed consequent upon the removal of monocular infantile cataract.11 The pathophysiological mechanisms contributing to the amblyopic deficit differ according to amblyopia type.12 In anisometropic amblyopia unilateral blur causes foveal form deprivation and reduced cortical neuronal sensitivity. In strabismic amblyopia there is cortical inhibition of impulses from the fovea of the deviating eye.13 For anisometropic amblyopia the correction of refractive error eliminates the unilateral blur which should improve neuronal sensitivity and therefore stimulate visual recovery (see above). However, in the case of the strabismic amblyope with identical refractions in each eye, correction of refractive error may reduce the angle of strabismus but this is unlikely to change cortical inhibition and therefore the mechanism(s) of improvement is unclear. Possibly, in-focus peripheral visual input has a part to play. Significant gains were also seen in the fellow eyes of children; however, in most participants this was predictable given the presence of a significant refractive error in their fellow eye. Those with none or insignificant refractive errors showed a minimal change within the limits of normal test-retest variability.14 Although it is a long held clinical belief that amblyopia therapy is more successful in the earlier stages of visual development,15–17 (in accord with the presumed end of the visual sensitive period around 6–7 years18), the evidence is not conclusive. Recent ATS studies of the Pediatric Eye Investigator Group demonstrated greater gains in visual acuity of those less than 5 years of age for children with severe amblyopia19 but no difference for children of another study that had moderate amblyopia.20 However, here we demonstrate equal gains for all age groups between 3 and 8 years of age. This is the first time that the visually sensitive period for refractive correction has been examined. REFERENCES Reeves B . Taxonomy and epidemiology of amblyopia. In: Moseley MJ, Fielder AR, eds. Amblyopia: a multidisciplinary approach. Oxford: Butterworth-Heinemann, 2002. Kivlin JD, Flynn JT. Therapy of anisometropic amblyopia. J Paediatr Ophthalmol Strabismus 1981;18:47–56. Clarke WN, Noel LP. Prognostic indicators for avoiding occlusion therapy in anisometropic amblyopia. Am Orthopt J 1990;40:57–63. Moseley MJ, Neufeld M, McCarry B, et al. Remediation of refractive amblyopia by optical correction alone. Ophthal Physiol Opt 2002;23:1–4. Clarke MP, Hrisos S, Wright CM, et al. Randomised controlled trial of treatment of unilateral impairment detected at preschool vision screening. BMJ 2003;327:1251–5. Mitchell DE, Gingras G. Visual recovery after monocular deprivation is driven by absolute, rather than relative, visually evoked activity levels. Curr Biol 1998;8:1179–82. Stewart CE, Fielder AR, Stephens DA, et al. Design of the Monitored Occlusion Treatment of Amblyopia Study (MOTAS). Br J Ophthalmol 2002;86:915–19. Stewart CE, Moseley MJ, Stephens DA, et al. Treatment dose-response in amblyopia therapy: the Monitored Occlusion Treatment for Amblyopia Study (MOTAS). Invest Ophthalmol Vis Sci. Bailey IL, Lovie JE. New design principles for visual acuity letter charts. Am J Optom Physiol Opt 1976;53:740–5. McGraw PV, Winn B. Glasgow Acuity Cards: a new test for the measurement of letter acuity in children. Ophthal Physiol Opt 1993;13:400–3. Maurer D , Lewis TL, Brent HP, et al. Rapid improvement in the acuity of infants after visual input. Science286:108–10. Hess RF. Sensory processing in human amblyopia. In: Moseley MJ, Fielder AR, eds. Amblyopia: a multidisciplinary approach. Oxford: Butterworth-Heinemann, 2002. Von Noorden CK. Examination of patient—III Sensory signs, symptoms, and adaptations in strabismus. In: von Noorden GK. Binocular vision and ocular motility: theory and management of strabismus. 5th ed. St Louis: Mosby, 1996:217–223. Kheterpal S , Jones HS, Moseley MJ, et al. Reliability of visual acuity in children with reduced vision. Ophthal Physiol Opt 1996;16:447–9. Massie H . Fixing eye for occlusion: survey of 1,000 cases of patients receiving occlusion of the fixing eye. Trans Ophthalmol Soc Aust 1965;24:39–46. Flynn JT, Woodruff G, Thompson JR, et al. The therapy of amblyopia: an analysis comparing the results of amblyopia therapy utilising two pooled sets. Trans Am Ophthalmol Soc 1999;97:373–90. Fulton AB, Mayer DL. Esotropic children with amblyopia: effects of patching on acuity. Graefe’s Arch Clin Exp Ophthalmol 1988;226:309–12. Banks MS, Aslin RN, Miyake S. Sensitive period for the development of human binocular vision. Science 1975;190:675–7. The Pediatric Eye Disease Investigator Group. A randomized trial of prescribed patching regimens for treatment of severe amblyopia in children. Ophthalmology 2003;110:2075–87. The Pediatric Eye Disease Investigator Group. A randomized trial of patching regimens for treatment of moderate amblyopia in children. Arch Ophthalmol 2003;121:603–11....查看详细 (20896字节)
☉ 11333133:Olfactory Evaluation in Children: Application to the CHARGE Syndrome
General Pediatrics Unit Pediatrics Radiology Unit Biostatistics Unit, Hpital Necker Enfants Malades, Paris, France Department of Otolaryngology Head Neck Surgery, Unité Centre National de la Recherche Scientifique UPRESSA 7060, Hpital Europeen Georges Pompidou, Paris, France ABSTRACT Objective. To find an efficient tool for testing olfactory function in children and use it to investigate a group of children with CHARGE (coloboma, congenital heart disease, choanal atresia, mental and growth retardation, genital anomalies, and ear malformations and hearing loss) syndrome. Methods. We adapted for children an olfaction test that had just been validated in an adult French population and investigated a control group of 25 healthy children aged 6 to 13 years. We then tested the olfactory capacity of a group of 14 children with CHARGE syndrome, aged 6 to 18 years. A questionnaire was completed with the parents about their children's feeding difficulties and their ability to recognize odors in everyday life. We recorded and scored the histories of feeding behavior anomalies, the visual and auditory status, and current intellectual levels. MRI of the olfactory tracts and bulbs was analyzed for 9 of 14 children. Results. We showed that healthy children have similar olfactory function to that of the adult control group, which was representative of the general population, without any difference for either gender or age. We also showed that all children with CHARGE syndrome had olfactory deficiency. Half of them were anosmic, and the others had olfactory residual function (hyposmic). We found no association between olfactory deficiency and feeding behavior, visual or auditory impairment, or intellectual level. Parental subjective evaluations were accurate for only half of the group. All of the MRIs showed anomalies of the olfactory tracts and bulbs varying from moderate hypoplasia to complete aplasia, without any relation between the radiologic and the functional results. Conclusions. Olfaction can be assessed in children, even the young and disabled. Our results support the proposition that rhinencephalon anomalies should be included as a major criterion for the diagnosis of CHARGE syndrome. Key Words: CHARGE syndrome olfaction in children olfactory deficiency Abbreviations: CHARGE, coloboma, congenital heart disease, choanal atresia, mental and growth retardation, genital anomalies, and ear malformations and hearing loss PEA, phenylethylalcohol Olfaction has always been and remains the most neglected sense in studies of child development and behavior, the main reasons being the poor knowledge concerning the role of olfaction in human development and behavior and the lack of available tools for investigating olfaction, in particular in children. Development of the olfactory system begins very early in the human embryo; olfactory bulbs have their definitive structure at day 56. Then, cells of the olfactory placode differentiate to gonadotropic cells and migrate to the hypothalamic region along the terminal nerve (cranial nerve 0), the olfactory nerve (cranial nerve 1), and the vomeronasal nerve. One part of the olfactory system projects to the anterior part of the hypothalamus for odor perception and discrimination; the other projects to the limbic system and the hippocampus for the behavioral impact of olfaction and olfactory emotional memory.1 The Jacobson vomeronasal organ is a fetal structure that reduces after birth and that allows the transmission of odors through aqueous middles, in particular amniotic fluid.2 Several data have shown that olfaction is functional during prenatal life.3–6 At birth, newborns have highly efficient olfactory abilities, allowing them to discriminate the odor of their mother's skin or milk from those of other mothers7,8 and to modify their feeding behavior according to the milk flavor.9,10 In mice, olfaction is crucial at birth to lead the pups to their mother's nipples, and anosmic mice die shortly after birth because they cannot find them.11 All of these data suggest that human neonatal olfaction probably plays a role both in mother-child bonding and in newborns' feeding behavior. During the first years of life, the role of olfaction is probably important, although few studies have demonstrated this, principally because olfaction evaluation is difficult in this age range. Nevertheless, in a previous study, we showed that reproducible behavioral modifications (breathing rhythm, mobility, and sight) indicate that healthy infants and toddlers (3 months to 3 years) have good olfaction abilities.12 Several studies have shown that olfaction improves from the age when it becomes testable (7–8 years of age) until the age of 40 years.13–16 These observations may be attributable to the methods of olfaction testing and are discussed later. After puberty, girls have better olfaction abilities than boys.17,18 From the age of 40 years, olfaction abilities decrease, which partly explains anorexia in the elderly.18 The role of olfaction in adults is likely involved in several fields, such as appetite, emotional memory, and sexual bonding. However, few studies can prove these roles. Studies on behavior in adults with olfaction disorders, in particular patients with Kallmann syndrome, are rare and do not show major effects of hyposmia, suggesting that hyposmic patients compensate for their deficit by other sensorial and cognitive means.19–21 Moreover, in humans, especially in Western and so-called developed cultures, the sense of smell is not well taught or stimulated. CHARGE syndrome (coloboma, congenital heart disease, choanal atresia, mental and growth retardation, genital anomalies, and ear malformations and hearing loss) is a congenital malformative picture that was described 25 years ago.22,23 In addition to the defects cited in the acronym, other anomalies have been described. Some of them have a high frequency, such as vestibular anomalies, facial dysmorphism, asymmetrical facial palsy, and brainstem dysfunction, whereas others have a lower frequency, such as renal, esophageal, osseous, and cerebral malformations.24–26 Once the structural anomalies are repaired, children with CHARGE have to overcome multiple sensory impairments, such as visual, auditory, and balance impairments. Olfaction has never been investigated in patients with CHARGE syndrome, although several arguments suggest that olfaction dysfunction is crucial in this malformative condition. First, most children with CHARGE syndrome have initial, severe, and long-lasting feeding disorders that are poorly explained by their swallowing disorders alone. Second, children with CHARGE syndrome may have genital anomalies as a result of hypothalamic luteinizing hormone-releasing hormone deficit.27 Some radiologic and anatomic data have already shown arhinencephaly in CHARGE syndrome.23,28 Finally, children with CHARGE syndrome often have peripheral orofacial anomalies that may impair olfaction, such as choanal atresia, cleft palate, or upper airway anomalies that sometimes lead to tracheotomy. We wanted to evaluate an additional sense (olfaction) in children with other multiple sensorial deficits. Thus, the aims of this study were dual: first, to explore an olfactory test adapted to young children (>5 years of mental age) or disabled children, and, second, to apply this test to a series of children with CHARGE syndrome. METHODS Patients Control Group A control group of 25 healthy children who were aged 6 to 13 years and had no known history of olfactory disturbance were investigated. The group was composed of 14 girls aged 7 to 13 years (mean ± SD: 10.6 ± 2.2) and 11 boys aged 6 to 13 years (mean ± SD: 9.5 ± 1.9). Three girls had adenoidectomy, 1 boy had adenoidectomy and tonsillectomy, and 1 girl was born prematurely without intellectual sequelae. To compare these children's olfactory test results with those of adults, we used the results of 52 normal adults tested by Bonfils et al.29 Patients With CHARGE Syndrome Fourteen children with CHARGE syndrome were included. The group consisted of 8 girls aged 7.5 to 18 years (mean ± SD: 12.5 ± 4) and 6 boys aged 6 to 10 years (mean ± SD: 7.8 ± 1.4). The diagnosis of CHARGE syndrome was made according to Blake and Amiel's criteria (5 major criteria or 4 major criteria and 3 minor criteria30,31). We asked the families to participate when their child had speech and mental age corresponding to a 5- or 6-year level. Their visual ability had to be good enough to allow them to recognize drawings representing the odors on 10 10-cm pictures. Six patients had peripheral risk factors for olfaction deficit: patients 2 and 3 had cleft lip and palate; patients 2, 3, 8, and 9 had transient tracheostomy; and patients 5, 9, and 14 had unilateral choanal atresia. Patient 14 had previously been tested with a different method. She was excluded from the results but included in the association calculation and the discussion. Parents and children of both groups all were volunteers for this prospective study. Consent of all of the families was obtained in accordance with the ethics rules of our hospital. Olfactory Tests The French Biolfa olfactory test, recently validated in healthy young adults, was adapted to children.29 The Biolfa test uses 2 series of 30-mL glass sniff bottles that contain odorous chemical substances. The first series measure the olfactory thresholds of 3 different substances (eugenol, aldehyde C14, and phenyl ethyl alcohol [PEA; quantitative trial]). The second series is an odor identification test to determine quality of olfactory function using a large panel of odors that are common to Southern European countries (qualitative trial). Olfactory Thresholds The threshold test consisted of aqueous dilutions of 3 components (eugenol, aldehyde C14, and PEA), the mean detection thresholds of which (0.5, 0.15, and 7.5 ppm, respectively) were published by the French Association for Normalization in 1989.32 These concentrations defined the level 3 on the difficulty scale of 9 concentration levels used in the test (Table 1). The lowest concentration at which 1 of these odors was detected was termed "detection threshold." In each test, we asked the child which of 2 stimuli (an odor or a blank), presented sequentially and in random order, smelled stronger (the forced-choice procedure). The first test began at the third level of difficulty. When a child failed to detect an odor, the next test was performed at the next higher concentration level. For normal patients, the threshold results are expressed in concentration (parts per million). This calculation cannot be used for anosmic patients because they cannot detect any odor (infinite threshold). Then, for analyzing the olfactory function in such cases, a test score was calculated for each component (eugenol, aldehyde C14, and PEA). For each child, the eugenol score was the value [1/eugenol threshold], the PEA score was the value [1/PEA threshold x 100], and the aldehyde C14 score was the value [1/aldehyde C14 threshold]. In anosmic patients, the olfaction threshold concentration tends to the infinite; thus, the test score tends to 0 and was estimated as 0. Odor Quality Identification The second part of the test is a qualitative evaluation in which the patient was asked to recognize an odor presented at a concentration corresponding to his or her own olfactory detection threshold previously measured. Among the 8 odors proposed for adults, we chose the 6 that are most familiar to children, to be sure that we were specifically testing olfaction and not the cognitive processes of the children: citronella (lemon), cis-3-hexenol (grass), L-carvone (mint), 1-octene-3-ol (mushroom), vanillin (vanilla), and paracresyl acetate (horse dung). Moreover, drawings representing 10 odors were systematically presented to the child to help his or her memory and oral expression. The test was scored as the number of olfactory items out of 6 correctly identified. The same investigator performed all of the tests. For children with CHARGE, 1 parent was present during the test, to avoid communication difficulties with the investigator. Clinical Investigation in Patients With CHARGE Syndrome In addition to the olfaction test, a questionnaire was discussed with the parents on their child's feeding difficulties and ability to smell and recognize odors in everyday life. This subjective evaluation of their olfactory capacity was scored at 3 levels: normal olfaction, residual olfaction, and no olfaction. Factors that are likely to decrease olfactory capacities, such as tracheostomy, choanal atresia, and cleft palate, were noted (even when they were no longer present at the study time). The severity of 2 other sense impairments (auditory and visual) was noted. Because the group was small, they were scored in 2 grades. For visual ability, "minor" impairment meant no coloboma, or unilateral coloboma, or bilateral coloboma but outside the macula and the papilla; "major " impairment meant large, bilateral coloboma, including the macula. For auditory ability, "minor" impairment meant hearing loss 60 dB. The severity of the feeding disorders was scored after analysis of the medical history, taking into account both the duration of artificial feeding (nasogastric tube or gastrostomy) and the abnormal feeding behavior (poor appetite and delay before achieving normal chewing and swallowing). Feeding disorders were scored in 4 grades: absent, minor, moderate, and major. The current intellectual status of the children with CHARGE was evaluated according to their school level, school system, and rehabilitation programs. They were scored in 5 classes, using a previous protocol, from class 0 (the best) to class 4 (the worst).33 Radiologic Data For ethical reasons, brain MRI was not performed only for this study. However, we reanalyzed previous MRIs, only 9 of which pass through thin sections of coronal planes, correctly showing the olfactory tracts and bulbs. Olfactory bulb and tract anomalies were scored as follows: normal, moderate, or major hypoplasia or absent. The radiologist was blinded to the results of the olfactory tests. Statistical Methods To compare the olfactory thresholds of the children of the control group (n = 25) with the series of normal adults previously investigated (n = 52), we used the nonparametric Wilcoxon test. To compare children with CHARGE syndrome with the control group, because our sample was small, we used nonparametric tests, the Wilcoxon test for continuous data, and Fisher's exact test for categorical data. Fisher's exact tests were performed to test the relation among the olfactory deficiency and feeding disorders, current intellectual levels, and radiologic results. Concordance between objective olfaction test results and familial subjective evaluations was evaluated using the coefficient. RESULTS Control Group We first showed that healthy children have olfactory capacities similar to a control group of adults, representative of the general population. Comparison between the children's and adults' threshold concentrations for the 3 components (eugenol, aldehyde C14, and PEA) showed no difference (Table 2). There were no differences between girls' and boys' detection thresholds (Fig 1). For the qualitative test, children tended to have better results than adults (Fig 2). The 2 odors that are the most familiar in infancy (vanilla and mint) were recognized by 84% and 88%, respectively, of the healthy children, although they were recognized by only 55% and 51% of the adults, respectively. Sixty-eight percent of healthy children recognized lemon (63% for adults), which was better recognized by the older children, and 56% of all children (42% for adults) recognized horse dung (they all were city dwellers!). Overall, we found no difference between boys and girls, and the younger children had results similar to older children. Results of children with a history of ears, nose, and throat problems were similar to those without such a history. Children of the control group had a very good understanding of the test whatever their age, showing that it was suitable for young children and suggesting that it was valid for disabled children, provided that they have reached speech and intellectual levels of 5 years. CHARGE Group The control group and the group of children with CHARGE did not differ for age or gender. Quantitative Evaluation All children with CHARGE syndrome, except for 1, had severely decreased olfactory thresholds. One child has a detection threshold in the normal range for aldehyde C14 and PEA (7.5 and 0.15 ppm, respectively) but no detectable threshold for the third component. Nine of the 13 children who were tested by Biolfa (70%) had 0 detection scores. Detection scores differed highly between CHARGE and control children (Table 3). Qualitative Evaluation All children with CHARGE syndrome had severe olfactory discrimination difficulties. Only the patient who had correct detection threshold at the quantitative evaluation had a qualitative score (4 of 6) in the normal range. All of the others had lower scores. Seven of the 9 children who had a null detection threshold could not recognize any odor. These 7 children can clearly be considered anosmic (7 of 13 = half of the series). The other 2 children (with a null detection threshold) were able to recognize only 1 and 2 odors, respectively. The children who had residual abilities in the quantitative evaluation could identify from 2 to 5 odors. The difference in scores between children with CHARGE syndrome and control subjects is shown in Fig 3. Comparison of these discrimination tests between children with CHARGE syndrome and control subjects showed highly significant differences except for horse dung (Table 4). To grade olfactory deficit is difficult because both threshold and discrimination have to be considered and because the olfactory stimulus is not a linear variable. Nevertheless, results for our group of children with CHARGE syndrome can be summarized as follows: half of the children were anosmic (n = 7), the other half were hyposmic (n = 6 + the child who was previously tested with another test and who was considered hyposmic). Of the 6 children who had hyposmia, 2 were severe, 3 were moderate, and 1 was mild. To search for associations with the clinical parameters, because the sample was small, we divided the results of the children with CHARGE syndrome into 2 groups: anosmic and hyposmic. We did not find any statistical relation between olfactory test and clinical parameters. Comparison between subjective evaluation (parents' opinion) and objective results of the Biolfa test showed a poor concordance ( < 0). The parents' assessments agreed with the Biolfa results for only 6 of 13 children (patient 14 tested with another technique). Of the 6 children with peripheral risk factors for olfaction deficit, 3 were anosmic and 3 were hyposmic. This ratio was not different from that for the whole group. Surprising, we found no relation between the olfactory deficits and the severity of the feeding disorders. We found no association between the olfactory deficits and the current intellectual levels of the children, despite that all of the children of the low intellectual level groups were anosmic. However, children of the high intellectual level group could also have severe hyposmia or anosmia. We found no relation between the olfactory deficit and either visual or auditory impairment. All 9 MRIs showed anomalies of the rhinencephalon. The olfactory tract and bulb anomalies varied from moderate hypoplasia to complete aplasia. No association could be found between the radiologic and the functional results. DISCUSSION Olfactory evaluation of children is now possible using the French Biolfa test, which has been adapted and validated in healthy children. We found no statistical difference between the results of the healthy children and those of adults, although the qualitative part of the test had been simplified for children. The results of children were better than those of adults for the 2 infantile odors. We found no differences for either age or gender. Our results differ from those of Richman et al,15 who tested children aged 3 to 17 years. They showed better olfactory abilities in older children than in younger and in girls than in boys. These differences may be attributable to methodologic bias. Because the wider the age range is and the more complex the test, the more likely differences between the youngest and oldest children are. Even in our simplified procedure, we observed that the less usual odors, such as lemon or dung, were the least well recognized by normal children. This suggests that the main problem in child olfaction testing is to determine whether the test evaluates olfaction or cognitive function. No girl of our control group was pubescent, whereas some of the Richman's group may have been because they were older than ours. This may also explain the lack of difference between genders in our study. The Biolfa test is an interesting tool for evaluating olfaction in normal children as well as in children with disabilities. Olfaction certainly has more influ-ence than we know on children's development and behavior, especially on feeding behavior and maybe on affective and psychological behavior. Olfaction is a primitive sense that is efficient early in life but receives no training and must be forgotten or neglected when higher methods of communication, especially speech, set in. Nevertheless, it might be interesting to look for olfactory dysfunction in children with disorders that affect appetite or behavior, such as nonorganic failure to thrive, for which the decrease in ingested food is often not understood, attention-deficit/hyperactivity disorder, and autism. Finally, the olfactory system could be impaired in children with congenital or acquired lesions of the forebrain or of the brain midline. Having an efficient test for olfactory evaluation may now change the pediatrician's approach to this question and lead to additional studies on the effects of introducing olfaction stimulation in rehabilitation programs for children with disabilities. In CHARGE syndrome, olfaction seems to be a crucial question. In this series, olfactory deficiency and rhinencephalon radiologic anomalies were always present. Our sample of MRIs is small, but the results are very coherent. If this high frequency of radiologic rhinencephalon anomalies is confirmed in larger series, then this radiologic feature could become a major criterion for the diagnosis of CHARGEsyndrome. Rhinencephalon anomalies have already been described in CHARGE syndrome, at autopsy or in brain imaging, but these anomalies are not yet systematically sought.28 Thin sections of coronal planes, showing olfactory bulbs and tracts, are now recommended in brain imaging of patients who are suspected to have CHARGE syndrome. Rhinencephalon congenital anomalies are rare and are mostly observed in isolated congenital anosmia, holoprosencephaly spectrum, Kallmann de Morsier syndrome, and Johnson-McMillin syndrome. Isolated congenital anosmia is usually described in adults who complain of smell disorders late in life, and very few cases have been published in children.34,35 In this situation, the patients are otherwise healthy and the differential diagnosis of CHARGE syndrome is not considered. Johnson-McMillin is a rare autosomal dominant syndrome associated with alopecia, hypogonadotrophic hypogonadism, atresia of the external auditory canal, tooth defects, cardiac defects, and mental retardation. It induces embryologic anomalies of the ectoderm and neuroectoderm of the first and second brachial arches, Rathke's pouch, and the diencephalon.36,37 Overlaps between Johnson-McMillin and CHARGE syndrome exist because CHARGE syndrome also induces anomalies of neuroectoderm development and neural crest migration. Overlaps between CHARGE and Kallmann syndromes are interesting for several reasons. Kallmann syndrome, in its typical phenotype, is associated with hypogonadotropic hypogonadism and olfaction deficit. Some cases of Kallmann syndrome have been described with additional features such as hearing loss, choanal atresia, and mental retardation.38,39 In these situations, searching for semicircular canal anomalies could be useful to confirm or not CHARGE diagnosis. Moreover, endocrinologic anomalies of Kallmann syndrome are useful for understanding and investigating genital anomalies of patients with CHARGE syndrome. The lack of relationship that we found between functional and radiologic anomalies in CHARGE syndrome is not surprising, because the same observation has already been made in Kallmann neuroradiologic studies.40 Finally, several autosomal genes have been implicated in Kallmann syndrome and may be candidate regions when a mutation in the CHD7 gene has been excluded (40% of the patients with CHARGE).41–43 Our results suggest that olfactory deficiency of CHARGE syndrome is attributable not only to central anomalies but also to peripheral ones, which worsen olfactory function. We observed children with associated choanal atresia and different types of rhinencephalon radiologic anomalies. No child of this series had bilateral and complete choanal atresia, explaining why 2 of the 3 children with choanal atresia had residual olfactory abilities. Only bilateral choanal atresia has been shown to be responsible for anosmia in a small sample, suggesting that choanal atresia plays a deleterious role by its reduction of airflow through the olfactory nasal epithelium.44 Similarly, tracheotomy and cleft palate in children without central olfactory system anomalies have been incriminated in olfaction disorders.45,46 The consequences of olfactory deficiency in children with CHARGE syndrome are difficult to quantify because these children have multiple causes explaining their disabilities. That is probably why we did not find any association between olfactory deficiency and most clinical aspects of our series. A more subtle analysis than ours that focuses on the description of feeding behavior and cognitive function could provide more information. Hence, it is possible that olfactory deficiency participates in the phenotype of the affected children, especially regarding their feeding disorders, mother-child attachment, behavior disturbance, communication difficulties, and maybe cognitive outcome. When it becomes possible, evaluation of olfactory abilities of children with CHARGE syndrome should be included in the investigations that are used to analyze their disabilities. Even if olfactory deficiency cannot be measured in children who have CHARGE syndrome and whose mental age and speech level are below 5 years, radiologic data could suggest functional anomalies and lead to various suitable actions. First, olfactory deficiency has to be taken into account in the understanding of the abnormal feeding behavior of most children with CHARGE syndrome. For those who have major difficulties in achieving normal feeding behavior, especially difficulties in swallowing solids even after improvement of their organic swallowing disorders, it is likely that food texture plays an important role. Healthy children recognize and appreciate food by its visual aspect, taste, texture, and smell. If vision and olfaction are impaired, then children surely give more value to taste and texture. Their preference for salty or spicy tastes becomes understandable, as well as their preference for smooth textures. Moreover, children with olfaction dysfunction may benefit from rehabilitation programs. Sense of smell does not pass exclusively via olfactory bulbs, tracts, and nerve. Specific odors, such as lemon and vinegar, pass through the sensory branch of the fifth cranial nerve. In CHARGE syndrome, these odors should be preferred to odors that pass exclusively through the classical olfactory system. From early in life, olfactory residual capacities need to be stimulated by increasing the concentration of the fragrances that surround the child by giving him or her tasty food. Stimulation by games may educate their olfactory memory. Finally, olfaction must be part of the multisensorial stimulation programs that are essential for children with CHARGE syndrome. ACKNOWLEDGMENTS We thank Professor Lyonnet and Dr Amiel from the genetics department for advice; all the patients, children, and parents, control and CHARGE, who participated in this study; and Alan Strickland for help in preparing the manuscript. FOOTNOTES Accepted Nov 22, 2004. No conflict of interest declared. REFERENCES Bossy J. Development of olfactory and related structures in staged human embryos. Anat Embryol.1980; 161 :225 –236 Berliner DL, Monti-Bloch L, Jennings-White C, Diaz-Sanchez V. The functionality of the human vomeronasal organ (VNO): evidence for steroid receptors. 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☉ 11333134:Corneal and conjunctival sensitivity to air stimuli
1 Cornea and Contact Lens Research Unit, School of Optometry and Vision Science and Vision CRC, University of New South Wales, Sydney, New South Wales, 2052, Australia 2 CCLR, School of Optometry, University of Waterloo, Canada ABSTRACT Aims: To determine the repeatability of ocular surface sensitivity to mechanical stimulation using air stimuli and the effect of contact lens (CL) wear on sensitivity. Methods: Repeatability: 14 subjects (24–39 years) participated. Mechanical sensitivity to warmed (34°C) and ambient (20°C) air was measured for the central cornea (CC), inferior cornea (IC), and inferior conjunctiva (ICON). Measurements were taken on 12 days; six morning and six afternoon measurements. Differences between sites, time of day, and stimulus temperature were evaluated. CL wear: 10 subjects (22–30 years) participated. Measurements were taken at the same time of day, either following no wear, wear of a CL of oxygen permeability of 28x10–9 or wear of a CL of Dk 140x10–9 . Differences between sites and wear conditions were evaluated. Results: Repeatability: Sensitivity varied between sites (p0.05) and there was no demonstrable reduction in temperature or increased variability with increased flow rates for 1 second and 2 second pulse durations. The stimulus temperatures were selected to provide a mechanical stimulus without a thermally cooling effect (34°C) and a mechanical stimulus with maximum cooling effect (20°C). Using the current instrument design without an additional cooling device, air pulses could not be delivered at temperatures lower than 20°C. Figure 1 A schematic view of the modified gas aesthesiometer. Figure 2 Temperature variation with flow rate for nominal on-eye temperatures of 20°C and 34°C. During stimulation, the gas is transiently directed towards the tip of the probe by means of a pulse generator that changes the direction of flow in the electronic valve. This produces a pulse of gas in the tip of the probe with a defined duration, CO2 concentration, temperature, and flow rate. Stimulus duration ranged between 1–3 seconds with a precision of 0.1 second. The optical range finder in the probe housing was modified to maintain an alignment distance between the probe and the eye of 4 mm. Two laser pointers assist with finding the correct working distance when stimulating non-reflective locations on the ocular surface and moveable fixation lights mounted on the instrument housing enabled alteration of stimulus location. Using a flow rate of 240 ml/minute, using air at 34°C with a 1 second pulse duration, the stimulus size at 4 mm from the probe was 0.5 mm central diameter corresponding to the region of highest pressure. The pressure profile across the cornea appeared to show a Gaussian distribution, with decrease in pressure outside this region. Disturbance in the fluorescein pattern on the eye was detectable in the surrounding region to a diameter of 1.5 mm. The effect of stimulus delivery for these conditions on the eye is shown in figure 3; however, the precise characteristics of the stimulus footprint on eye under a range of flow rate and temperature conditions are yet to be fully elucidated. Figure 3 Aesthesiometer stimulus delivery on the eye for 240 ml/minute flow rate and 1 second delivery. The probe tip is visible and the stimulus location is shown by the disruption in the tear film shown with fluorescein. Subjects For the repeatability study, 14 normal non-contact lens wearers participated. Subjects were 12 females and two males, with a mean age of 32 (SD 6) years (range 24–39). Ten subjects participated in the contact lens wear study. This group comprising five males and five females with a mean age of 24 (3) years (range 21–30) participated. No subject had a history of ocular pathology or systemic disease. This investigation was conducted in accordance with the tenets of the Declaration of Helsinki. Written consent was obtained following explanation of the study procedures. University of New South Wales ethics committee approval for the procedures was also obtained before the investigation. Procedures One second air pulses (flow rates 21–240 ml/min) with an on-eye temperature of either 20°C or 34°C were delivered to the right eye of each subject to the corneal apex (central cornea), to the inferior cornea at a position 2 mm vertically above a tangent to the inferior limbus, and to the inferior conjunctiva, 2 mm vertically below a tangent to the inferior limbus. The inferior cornea and conjunctiva were selected as being the regions potentially susceptible to the effects of exposure or tear film instability in contact lens wear or dry eye disease. Thresholds to mechanical stimulation were determined by the method of constant stimuli and by using a logistic response function (Curve Expert 1.3, Daniel Hyams). Subjects were asked to respond verbally as to whether the stimulus had been detected or not. The flow rate corresponding to 50% positive response rate was determined (T50). The order of presentations for different flow rates and ocular sites was randomised within each occasion, and a minimum of 1 minute was allowed between repeated stimulation of the same site, to limit summation or adaptation. Randomisation for temperature of stimulus presentation was not possible within occasions, since a 20 minute period is required for full equilibration following change of stimulus temperature. The subject was masked to the order of stimulus presentation, but not to location tested. For the repeatability study, measurements were taken on 12 separate occasions, six in the morning (10 am plus or minus 1 hour) and six in the afternoon (3 pm plus or minus 1 hour). Temperature and humidity of the laboratory were recorded for each measurement. Mean (SD) humidity and temperature was 40.0% (8.3%) and 24.2 (0.6)°C, respectively. In the CL wear study, measurements were taken on three separate occasions, each in the afternoon. Stimuli were delivered as above; however, ocular sites for the right eye were examined with stimuli delivered at 34°C only. On one occasion, subjects were tested without previous CL wear, and on the remaining two occasions, testing followed either 6 hours bilateral wear of disposable Etafilcon A lenses (Vistakon, Johnson & Johnson, Jacksonville, FL, USA) of power –1.00 dioptres, back optic zone radius of 8.80 mm, diameter 14.0 mm, water content 58%, and material oxygen permeability of 28x10–9 or bilateral wear of Lotrafilcon A silicone hydrogel lenses (CibaVision, Duluth, AT, USA), of power –1.00 dioptres, back optic zone radius 8.60 mm, diameter 13.80 mm, water content 24% and material oxygen permeability of 140x10–9 . The order of testing (lens type or no lens wear) was randomised. Mean (SD) humidity and temperature was 54% (7%) and 24 (0.6)°C (CL wear study). Data analysis Analysis of variance (ANOVA) was carried out on the entire data set using time of day and day as within subject factors and location and stimulus temperature as between subject factors (SPSS for windows, version 10.0.07, Chicago, IL, USA). A multiple comparisons test with Bonferroni adjustment was used to determine differences between ocular sites. Coefficients of repeatability (1.96x within subjects standard deviation) were estimated for each ocular site. One way ANOVA was carried out on the CL wear data to determine differences between CL wear conditions and a multiple comparisons test with Bonferroni adjustment was used to determine differences. RESULTS General results Mean and standard deviations for T50 measurements at each ocular site for the two stimulus temperatures for morning and afternoon measurements are shown in table 1. Table 1 Mean (SD) threshold values (ml/min) and coefficients of repeatability for each ocular site and stimulus temperature Day to day and diurnal variability The sensitivity data were seen to meet the assumptions for ANOVA, such that the data exhibited a normal distribution and the sensitivity measurements taken on different occasions showed similar variance. ANOVA revealed no significant difference in sensitivity between days (p>0.05, power to detect differences was 0.52). Time of day significantly affected sensitivity for the central and inferior cornea for stimuli delivered at 34°C (p<0.001), with higher sensitivity found for afternoon measurements. Conjunctival sensitivity was unaffected by time of day and all measurements taken at 20°C did not demonstrate diurnal variations. The majority of variation in sensitivity measurements occurred between subjects and coefficients of repeatability ranged between 16–36 ml/min (table 1). In general, better repeatability was observed for afternoon measurements and for the lower stimulus temperature. Ocular site and stimulus temperature ANOVA showed significant differences in sensitivity between ocular sites and between stimulus temperatures (p<0.01, table 2). Sensitivity for low temperature stimuli was higher than for the eye temperature stimuli. Post hoc testing showed that corneal sensitivity was significantly higher than conjunctival sensitivity (p<0.01); however, differences between the central and inferior cornea were not significant. Table 2 ANOVA results for between subjects effects Effects of short term contact lens wear The sensitivity data were seen to meet the assumptions for ANOVA, such that the data exhibited a normal distribution and the sensitivity measurements for different conditions showed similar variance. However, there were interactions between ocular site and lens factors, hence one way ANOVAs between lens wear conditions were carried out for each site. Table 3 shows the summary data for each site and lens type. Lens wear conditions did not affect corneal sensitivity; however, there were differences in conjunctival sensitivity between wear conditions (ANOVA, p<0.05). The conjunctiva was significantly more sensitive following wear of Lotrafilcon lenses compared to either no lens wear or Etafilcon lens wear (p<0.05). Table 3 Mean threshold values (ml/min) for lens wear conditions DISCUSSION This study reports for the first time, the repeatability of ocular surface sensitivity to mechanical stimulation of the ocular surface, using air stimuli delivered at eye and room temperature using a modified Belmonte aesthesiometer and the effects of short term contact lens wear on ocular surface sensitivity. Diurnal variations in sensitivity were shown for both inferior and central corneal locations, with a higher sensitivity demonstrated in the afternoon compared to the morning for stimuli delivered at eye temperature. Diurnal variation was not observed for measurement of conjunctival sensitivity or for any stimuli delivered at room temperature. The diurnal variation in central corneal sensitivity in the present study was 13% compared with 28% in a study using the Cochet-Bonnet aesthesiometer.22 Diurnal variation to stimuli delivered using an air jet aesthesiometer was 35% over a 24 hour period.23 Reduced sensitivity upon awakening has been attributed to reduced oxygen tension at the epithelial surface during eye closure, and the degree of reduction in sensitivity is related to the duration of eye closure.24 Animal studies have shown that a similar relation and corneal sensitivity reduction following overnight eye closure appear to occur in conjunction with a reduction in corneal epithelial acetylcholine and choline acetyltransferase activity.25 The conjunctiva is likely to be less susceptible to the effects of hypoxia because of its vascular nature; therefore, the lack of a demonstrable hypoxia induced diurnal variation in mechanical sensitivity is not unexpected. However, the power to detect diurnal variations in conjunctival sensitivity was low in the present study. Day to day variations in corneal and conjunctival sensitivity were small using this technique. There were no significant differences in mechanical thresholds between days and no obvious learning effect occurred; however, the observed power to detect differences was small (0.20 to 0.52). This lack of day to day variation is consistent with other gas aesthesiometry techniques.18,26 Significant differences were shown between the ocular sites, with the cornea showing higher sensitivity than the conjunctiva. Multiple range testing showed that the site differences were significant only for eye temperature stimuli. Similar findings have been reported using comparable gas aesthesiometry techniques.27 Site related differences have been demonstrated using the Cochet-Bonnet aesthesiometer, where regions of the conjunctiva have been shown to be up to 3 log units less sensitive than the central cornea.11,28 However, the magnitude of the difference between the sites in sensitivity to air jet mechanical stimuli in the present study and in earlier reports18,27 appears to be reduced in comparison. This may be the result of site related differences in the type and distribution of nociceptors and stimulus characteristics. Animal electrophysiological studies suggest that high pressure mechanoreceptors, which would be exclusively stimulated by a pure mechanical stimulus, tend to be located in the central cornea.3,29,30 Human and animal ultrastructural studies have shown that corneal free nerve endings show structural and functional specialisation.30,31 A fibres responding to mechanical stimulation have small receptive fields, elongated structure running parallel to the ocular surface, and exhibit directional selectivity. Conversely, polymodal receptors and low pressure mechanoreceptors with larger receptive fields are distributed throughout the cornea and conjunctiva. C fibres responding to polymodal stimuli run perpendicular to the ocular surface. Differences in sensitivity between the ocular sites were not significant for stimuli delivered at room temperature in this study. Mechanical thresholds for stimuli delivered at ambient temperature were significantly lower than those delivered at eye temperature, which is consistent with previous reports.20 Limited18 or no differences32 in sensitivity between the cornea and conjunctiva have been reported previously for gas aesthesiometers delivering thermally cooling stimuli, which effect cooling of the tear film. Energy transfer from the underlying tissue to the tear film is detected by the sensory nerves.33 Both the cornea and conjunctival sensory nerves appear to have high sensitivity to stimuli with both thermally cooling and mechanical effects (table 2). Using a pure thermal stimulus, the cornea appears to be less sensitive than the conjunctiva.34 However, the intensity of perceived sensation with suprathreshold thermal stimuli appears to be similar in the cornea and conjunctiva.35 C fibres responding to thermal stimuli are found in exposed areas of the eye, such as the cornea, limbus, and bulbar conjunctiva and tend to have large overlapping receptive fields.3,36 In ocular sites not exposed to external temperature changes, such as the sclera and episclera, sensory fibres appear to respond to change in temperature associated with increased or decreased blood flow.37 It is conceivable that fibres in the limbus and conjunctiva have a similar role. Significant differences in threshold were observed between the two stimulus temperatures tested (tables 1 and 2). Thresholds were lower, indicating that the ocular surface was more sensitive to stimuli delivered at a lower temperature. This finding is entirely consistent with the expectation that lower temperature stimuli elicit both a mechanical and thermally cooling response,18,26 through stimulating mechanical, polymodal and cold nociceptors and resulting in a lower air pressure being required to elicit a threshold response. Short term wear of hydrogel and silicone hydrogel lenses in unadapted subjects appears to have no effect on corneal sensitivity in this study. Previous reports on the effects of short term wear in adapted daily contact lens wearing subjects have indicated that corneal sensitivity is either slightly reduced following 8–12 hours wear of hydrogel lenses6,38 or shows no change.39 The observed reduction has been attributed to corneal oedema causing a metabolic alteration.6,38 One interesting observation not previously reported is the increased sensitivity of the bulbar conjunctiva following short term wear of silicone hydrogel lenses. A similar change was not observed with hydrogel lenses. Conjunctival and limbal sensitivity is mediated primarily through the low threshold mechanical and polymodal fibres.2 In response to sustained mechanical pressure, unmyelinated C polymodal fibres will continue to fire, with an irregular tonic discharge.36 It is conceivable that lenses of high modulus may provide a chronic low grade stimulus to the inferior ocular surface, possibly as a result of mechanical pressure or lens edge configuration effects; however, further study with a larger sample size is required to confirm this effect and to examine the impact of lens wear on regional conjunctival sensitivity. In summary, the modified Belmonte aesthesiometer permits reasonably repeatable measurement of the mechanical sensitivity of the cornea and conjunctiva, Mechanical threshold measurements are consistent with previously reported techniques; however, we believe that this technique allows elucidation of mechanical fibre responses both with and without the influence of thermal component. ACKNOWLEDGEMENTS This study was supported by the Australian Government through the Australian Research Council Collaborative Grants Scheme, the Cooperative Research Centres Scheme and by Allergan Ltd. REFERENCES Bron AJ, Tripathi RC, Tripathi BJ. The cornea and sclera. In: Bron AJ, Tripathi RC, Tripathi BJ, eds. Wolff’s anatomy of the eye and orbit. 8th ed. London: Chapman and Hall, 1997:233–71. Belmonte C , Garcia-Hirschfeld J, Gallar J. Neurobiology of ocular pain. Prog Ret Eye Res 1997;16:117–56. Tanelian DL, Beuerman RW. Responses of rabbit corneal nociceptors to mechanical and thermal stimulation. Exp Neurol 1984;84:165–78. Beuerman RW, McCulley JP. Comparative clinical assessment of corneal sensation with a new aesthesiometer. Am J Ophthalmol 1978;86:812–15. Kanellopoulos AJ, Pallikaris IG, Donnenfield ED, et al. Comparison of corneal sensation following photorefractive keratectomy and laser in situ keratomileusis. J Cataract Refract Surg 1997;23:34–8. Millodot M . Effect of soft lenses on corneal sensitvity. Acta Ophthalmol 1974;52:603–8. Millodot M . Effect of long-term wear of hard contact lenses on corneal sensitivity. Arch Ophthalmol 1978;96:1225–7. Von Frey M . Berichte uber die verhaindlungen der koniglich sachsichen. Ges Wiss 1894;46:185–96. Boberg-Ans J . Experience in clinical examination of corneal sensitivity and the nasolacrimal reflex after retrobulbar anaesthesia. Br J Ophthalmol 1955;39:705–26. Cochet P , Bonnet R. L’esthesie corneenne. La Clin Ophtalmol 1960;4:3–27. Norn MS. Conjunctival sensitivity in normal eyes. Acta Ophthalmol 1973;51:58–66. Millodot M , Larson W. Effect of bending the nylon thread of the Cochet Bonnet aesthesiometer upon the recorded pressure. Contact Lens 1967;1:5–7. Brennan NA, Bruce AS. Aesthesiometry as an indicator of corneal health. Optom Vis Sci 1991;68:699–702. Murphy PJ, Patel S, Marshall J. A new non-contact corneal aesthesiometer (NCCA). Ophthal Physiol Opt 1996;16:101–7. Beuerman RW, Maurice DM, Tanelian DL. Thermal stimulation of the cornea. In: Anderson, Matthews, eds. Pain in the trigeminal region. Amsterdam: Elsevier/North-Holland, Biomedical Press, 1977. Brennan NA, Maurice DM. Corneal aesthesiometry with a carbon dioxide laser. Invest Ophthalmol Vis Sci 1989;30:S148. Weinstein S , Drozdenko R, Weinstein C. A new device for corneal esthesiometry: clinical significance and application. Clin Eye Vis Care 1992;4:123–8. Vega JA, Simpson TL, Fonn D. A noncontact pneumatic esthesiometer for measurement of ocular sensitivity: a preliminary report. Cornea 1999;18:675–81. Dupuy B , Thompson H, Beuerman R. Capsaicin: a psychophysical tool to explore corneal sensitivity. Invest Ophthalmol Vis Sci 1988;29:454. Belmonte C , Acosta MC, Schmelz M, et al. Measurement of corneal sensitivity to mechanical and chemical stimulation with a CO2 esthesiometer. Invest Ophthalmol Vis Sci 1999;40:513–19. Stapleton F , Tan ME, Vega J, et al. Repeatability of measurement of corneal and conjunctival sensitivity. Invest Opthalmol Vis Sci 1999;40:S338. Millodot M . Diurnal variation of corneal sensitivity. Br J Ophthalmol 1972;56:844–7. Du Toit R , Vega JA, Fonn D, et al. Diurnal variation of corneal sensitivity and thickness. Cornea 2003;22:205–9. Millodot M , O’Leary DJ. Loss of corneal sensitivity with lid closure in humans. Exp Eye Res 1979;29:417–21. Mindel JS, Szilagyi PIA, Zadunaisky JA, et al. The effects of blephorrhaphy induced depression of corneal cholinergic activity. Exp Eye Res 1979;29:463–8. Murphy PJ, Lawrenson JG, Patel S, et al. Reliability of the non-contact corneal aesthesiometer and its comparison with the Cochet-Bonnet aesthesiometer. Ophthal Physiol Opt 1998;18:532–39. Feng Y , Simpson TL. Nociceptive sensation and sensitivity evoked from the human cornea and conjunctiva stimulated by CO2. Invest Ophthalmol Vis Sci 2003;44:529–32. Drager J . Corneal sensitivity: measurement and clinical importance. Vienna: Springer Verlag, 1984. Belmonte C , Gallar J, Pozo MA, et al. Excitation by irritant chemical substances of sensory afferent units in the cat’s cornea. J Physiol 1991;437:709–25. MacIver MB, Tanelian DL. Structural and functional specialisation of A delta and C fiber free nerve endings innervating rabbit corneal epithelium. J Neurosci 1993;13:4511–24. Muller LJ, Pels L, Vrensen GFJM. Ultrastructural organization of human corneal nerves. Invest Ophthalmol Vis Sci 1996;37:476–88. Murphy PJ, Armstrong E, Woods LA. A comparison of corneal and conjunctival sensitivity to a thermally cooling stimulus. Adv Exp Med Biol 2002;506:719–22. Murphy PJ, Morgan PB, Patel S, et al. Corneal surface temperature change as the mode of stimulation of the non-contact corneal aesthesiometer. Cornea 1999;18:333–42. Kenshalo DR. Comparison of thermal sensitivity of the forehead, lip, conjunctiva and cornea. J Appl Physiol 1960;15:987–91. Acosta MC, Tan ME, Belmonte C, et al. Sensations evoked by selective mechanical, chemical and thermal stimulation of the conjunctiva and corrnea. Invest Ophthalmol Vis Sci 2001;42:2063–7. Gallar J , Pozo MA, Tuckett RP, et al. Response of sensory units with unmyelinated fibres to mechanical, thermal and chemical stimulation of the cat’s cornea. J Physiol 1993;468:609–22. Gallar J , Acosta MC, Belmonte C. Activation of scleral cold thermoreceptors by temperature and blood flow changes. Invest Ophthalmol Visual Sci 2003;44:697–705. Velasco MJ, Bermudez FJ, Romero J, et al. Variations in corneal sensitivity with hydrogel contact lenses. Acta Ophthalmol 1994;72:53–6. Knoll HA, Williams J. Effects of hydrophilic contact lenses on corneal sensitivity. Am J Optom Am Arch Optom 1970;47:561–3....查看详细 (28942字节)
☉ 11333135:Effects of Atomoxetine on Growth After 2-Year Treatment Among Pediatric Patients With Attention-Deficit/Hyperactivity Disorder
Massachusetts General Hospital, Boston, Massachusetts Mount Sinai Medical Center, New York, New York University of Nebraska Medical Center, Omaha, Nebraska Lilly Research Laboratories, Indianapolis, Indiana Indiana University School of Medicine, Indianapolis, Indiana ABSTRACT Objective. Treatment for attention-deficit/hyperactivity disorder is maintained typically over periods of months or years and, as a result, the potential effects on growth of pharmacotherapy for this disorder have been an area of concern. This meta-analysis examined the effect on growth of atomoxetine, now approved in the United States for the treatment of attention-deficit/hyperactivity disorder. Methods. Patients (N = 412) were 6 to 16 years of age at the start of the treatment period and received atomoxetine treatment (maximal dose: 1.8 mg/kg per day) for 2 years. Weight and height measurements were analyzed both as actual values and after conversion to percentiles and z scores with growth charts from the Centers for Disease Control and Prevention. Expected weight and height at the end point were calculated through extrapolation from patients' baseline percentiles with the growth charts. Results. Results indicated that, after 2 years, observed weight and height were close to those predicted on the basis of the patients' baseline weight and height. Weight increased an average of 10.8 kg, a decrease relative to baseline normative weight of 2.7 percentiles, corresponding to 0.87 kg. Height increased an average of 13.3 cm, a decrease relative to baseline normative heights of 2.2 percentiles, corresponding to 0.44 cm. For both weight and height, the quartile of patients who were smallest at baseline had an increase in end-point percentile, whereas patients in the highest quartile had a decrease. Conclusions. These findings suggested that, at the group level, there was only a minimal effect on height after 2 years of treatment with atomoxetine and, for patients most at risk (the lowest quartile), there seemed to be no effect. Key Words: atomoxetine attention-deficit/hyperactivity disorder growth children adolescents Abbreviations: ADHD, attention-deficit/hyperactivity disorder MTA, Multimodal Treatment Study of children with attention-deficit/hyperactivity disorder Attention-deficit/hyperactivity disorder (ADHD) is among the most common psychiatric disorders of childhood, and pharmacotherapy is now widely regarded as the most effective intervention for most patients.1,2 Because ADHD is a chronic disorder, typically treatment is maintained for periods of months or years; as a result, the potential effects of pharmacologic treatments for ADHD on developmental outcomes, particularly growth, have been an area of interest and concern for many clinicians. Until recently, however, only limited systematic data about the effects of ADHD treatments on growth have been available.3–8 In recent years, more efforts have been made to investigate the issue of whether growth in height and weight is affected by long-term pharmacologic treatment, and the recent Multimodal Treatment Study of children with ADHD (MTA) results,9 together with the introduction of regulatory requirements for systematic investigations of drug effects during long-term treatment, have created a growing body of data to address this question. Several recent studies have suggested that the initiation of psychostimulant treatment is associated with a modest decline in growth rates that abates with time and that, over longer periods, both weight and height gains are at or close to expected values.6,8 Data from the MTA trial of methylphenidate, dosed 3 times per day, showed somewhat more pronounced effects on growth by early adolescence.10 Atomoxetine, a nonstimulant, selective, norepinephrine reuptake inhibitor, was approved by the US Food and Drug Administration as a treatment for ADHD.11–14 The clinical development of atomoxetine was conducted primarily in pediatric populations and included a provision for children and adolescents who completed short-term studies (typically 6–12 weeks) to continue to receive treatment in an ongoing, long-term, extension study for up to 5 years. As part of all of these studies, weight and height were measured and recorded regularly, providing an opportunity to evaluate systematically the effects of long-term treatment with atomoxetine on growth. We report data on weight and height for patients who completed 2 years of treatment with atomoxetine. METHODS Patient Group and Study Design Data were pooled from 13 multicenter trials conducted at 90 sites across North America as part of the clinical development program for atomoxetine. Patients included children and adolescents between the ages of 6 and 16 years at the time of initial assessment. ADHD (as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) was assessed clinically and confirmed with the Kiddie Schedule for Affective Disorders and Schizophrenia.15 The studies allowed patients who entered and completed a short-term study the option to continue treatment for up to 5 additional years in an extension study. The studies that fed into the extension ranged from 6 weeks to 2 years in length and used similar dose ranges, with a target dose of 1.2 mg/kg per day and a maximal dose of 1.8 mg/kg per day in most studies. The total daily dose was administered either once daily or as a divided twice-daily dose. Each study was reviewed and approved by the institutional review boards for the participating study sites. After complete explanation of the procedures and risks of the studies, each patient's parent or legal guardian signed written informed consent forms and each patient signed assent forms. These studies were conducted in accordance with the ethical standards of the Declaration of Helsinki (1975, as revised in 2000).16 All patients underwent medical history recording and a complete physical examination at entry into the initial study and again at entry into the extension study. Routine laboratory examinations, including serum electrolyte assays, liver function tests, and complete blood counts, and electrocardiography were performed at the initial study entry and periodically thereafter, to monitor safety. Patients with serious medical illnesses were excluded, and administration of psychotropic medications other than atomoxetine was not allowed except for one 187-patient study in which some of the patients had an 8-week period of fluoxetine coadministration. Weight was measured at every study visit in all studies. Height was measured at the initial and final study visits for all studies. In the extension study and in the 2 initial studies that lasted >6 months, height was measured at study entry and then at regular intervals that did not exceed 6 months. Statistical Analyses Two study populations were defined for analytical purposes. The first population included all patients who completed 2 years of treatment and had a weight or height measurement performed after 2 years of drug exposure. For these patients, changes in weight and height and changes in weight and height percentiles, relative to population normative values for age and gender,17 were calculated for the overall period of drug exposure and for selected time points up to 2 years. Two additional analyses were performed with a second population, which included all patients who received atomoxetine therapy. This was done to assess the effect of treatment discontinuation on the results of the analyses that included only patients with 2 years of drug exposure. These analyses included t tests, comparing results for patients who discontinued treatment after 0 to 3, 3 to 6, 6 to12, or 12 to 18 months of exposure with results for patients with 2 years of exposure, and repeated-measures analyses. These repeated-measures analyses modeled weight and height z scores (taking into account both the mean and the SD of the sample to provide information about the relative weight and height of subgroups) and included effects of the duration of atomoxetine exposure and the duration of exposure squared. Changes from baseline to end point in weight, height, and BMI z scores were summarized separately for subgroups of patients, on the basis of gender, age, and modal atomoxetine daily dosage. Subgroup differences were analyzed with an analysis of covariance model with effects for baseline value and subgroup. Repeated-measures analyses with data for all patients were also performed and included effects for subgroup, duration of atomoxetine exposure, and duration of exposure squared and interaction terms for subgroup, duration of exposure, and duration of exposure squared (a model arrived at through backward selection from models with higher-order polynomial terms). RESULTS A total of 2551 patients received atomoxetine and had baseline weight and height measurements. Of these, 2327 had 1 other height measurement and 2532 had 1 other weight measurement. A total of 419 patients received atomoxetine for 2 years. Of these, 412 had a weight measurement recorded after 2 years and 382 had a height measurement recorded after 2 years. The numbers of patients included in the weight and height analyses are different because weight was measured at every visit but height was measured less frequently. Therefore, some patients in these ongoing trials had not yet had a height measurement after passing the 2-year treatment date at the cutoff time for inclusion in these data analyses. Patient characteristics for those receiving atomoxetine therapy (N = 2551) are summarized in Table 1. Mean changes in weight, height, and BMI after 2 years of treatment are summarized in Table 2. At baseline, the mean weight percentile was 60.1 (z score: 0.41) and the mean height percentile was 51.8 (z score: 0.06). As is typical in the North American population (from which the patients were drawn), the patients weighed more than expected, given their height (mean BMI percentile: 62.2; z score: 0.44). For the 412 patients with weight measurements recorded after 2 years, there was a marked absolute mean weight gain of 10.79 kg at the end point. These values corresponded to slight mean decreases, relative to baseline normative weights (–2.7 percentiles, P = .002). Compared with final height, however, final weight was still slightly above that expected (mean BMI percentile: 59.6; z score: 0.35). The decrease from the predicted weight, assuming maintenance of the baseline weight percentile, was 0.87 kg at the end point. Weight percentiles plotted against time (a measure of growth velocity) are shown in Fig 1, A. These data points reveal an initial decrease followed by maintenance of weight percentiles over time. A repeated-measures analysis of z scores that included data for all enrolled patients with 1 postbaseline weight measurement showed results similar to those observed in the completer analysis (Fig 1, B). For the 382 patients with height measurements after 2 years, there was a marked absolute mean height gain (13.3 cm at the end point) (Table 2). This value corresponded to a slight decrease, relative to the baseline mean normative height value (–2.2 percentiles, P = .02). The decrease from the height predicted by assuming maintenance of the baseline height percentile was 0.44 cm at the 2-year end point. Height percentile changes from baseline plotted against time are shown in Fig 2, A. These data points reveal an initial decrease but maintained height percentiles over time. A repeated-measures analysis of z scores that included data for all enrolled patients with 1 postbaseline height measurement showed results similar to those observed in the completer analysis (Fig 2, B). Analyses of weight and height according to baseline normative quartile are shown in Table 3. For both weight and height, the quartile of patients who were smallest at baseline increased in final percentile, whereas patients in the highest quartile had a decrease in end-point percentile. A concomitant change occurred in BMI, such that patients in the lower quartiles at baseline had an increase at the end point, whereas patients in the upper quartiles at baseline had a decrease at the end point. Overall, weight and height changes from baseline to end point (z scores) were correlated significantly, even when baseline weight and height z scores were taken into account (partial correlation: 0.56; P 1.4 mg/kg per day), revealed no statistically significant effects of atomoxetine dose on changes from baseline to final standardized weight, height, or BMI (data not shown). There were also no statistically significant gender differences in changes from baseline to final standardized weight, height, or BMI. However, repeated-measures analyses with all patient data showed a statistically significant difference between genders in normative weight values, suggesting that, at least initially, female patients showed greater decreases in normative weight but this difference was made up for with time (data not shown). Analysis of standardized growth data according to age at first atomoxetine dose is shown in Table 5 and indicates, for weight, a significant effect of age (P = .005), such that 13-year-old patients were not affected at all (z = 0.0). For height, there was also a significant effect of age (P = .048), such that 13-year-old patients actually showed increases (z = 0.07). For BMI, there was not a statistically significant effect of age. Repeated-measures analyses with all patient data showed a statistically significant difference between age groups in both normative weight and height values, with younger children at least initially showing greater decreases in normative values. All age groups resumed normal growth velocity as treatment progressed. To assess the impact of patients who discontinued treatment, normative weight and height observations at the time points described below for patients who discontinued treatment at selected time points were compared with observations at the same time points for patients who completed 24 months of treatment with a 2-sample t test. The last weight measurements obtained before the start of a time interval for patients who discontinued treatment were compared with weight measurements taken at a similar time point for 24-month exposure patients (data not shown). The only statistically significant change was seen when patients who discontinued treatment after 3 to 6 months of exposure were compared with the 24-month exposure patients; 24-month exposure patients showed a greater decrease in normative weight. This observation does not suggest a clinically meaningful trend. The last height measurements for patients who discontinued treatment after various intervals were compared with height measurements taken at similar time points for patients who completed 24 months of treatment (data not shown). One statistically significant difference was observed between groups (12–18 months); however, this difference was minimal and was not observed at any other time point. There was no pattern suggesting meaningful differences between patients who completed 24 months of treatment and those who discontinued treatment at earlier time points. DISCUSSION Among patients treated for 2 years with atomoxetine at usual doses, mean growth rates slowed moderately for weight and slightly for height during the initial 6 months of treatment; however, during the subsequent 18 months, rates were as expected for weight and height. After 2 years of treatment, mean weight and height increased to values close to those predicted by age and gender normative values. There was only a 2-percentile change in height, from the mean 52nd percentile to the 50th percentile, and this was related largely to effects early in treatment. This change would correspond to a mean decrease from the height predicted by the initial height of only 0.44 cm. In addition, the analyses of changes according to quartile for both weight and height suggested that the smallest patients, who were presumably most at risk for clinically important effects, were least affected. These data suggest that atomoxetine has a modest initial effect on growth rates that does not persist during periods of extended treatment. Interestingly, the analyses of changes relative to baseline quartiles for weight and height suggested some regression to the mean, with the most marked changes being observed for the patients in the highest and lowest quartiles. Similar findings were reported for children treated with methylphenidate18 and amphetamine,19 with long-term treatment of children <13 years of age. We cannot fully account for this finding but speculate that it may be related to inherent variability in growth processes. Growth curves represent average growth and do not fully reflect individual growth trajectories. This problem may be exacerbated by issues of pubertal tempo among adolescents. In our study, the mean age at study entry was 10.6 years. Therefore, the 2-year period of observation coincided with the onset and development of puberty for many patients. Tanner and Davies20 suggested that children who experience relatively early onset of puberty tend to reach their final height faster and are thus tall for their age early but not later. Similarly, children who reach puberty later tend to be short for their age early but not later. It is likely that the sample distribution of weight and height was affected at the beginning of the study because of early or late pubertal development and, over the course of the study, moved back toward the population mean as the group became older and differential effects related to the timing of puberty decreased. Results indicated a statistically significant difference between genders, suggesting a slightly greater effect on growth velocity for weight among boys (consistent with a recent report by Lisska and Rivkees4). However, the overall patterns of responses, with modest early decreases in growth velocity followed by resumption of normal growth rates during ongoing treatment, were similar for the 2 genders. Similarly, there was a statistically significant change across age groups for both weight and height, with greater slowing of growth velocity early in treatment among younger children. However, all groups resumed normal growth velocity as the length of treatment increased. Because the observed differences between groups (male/female, younger/older) for these effects were small and because all growth velocity returned toward a normal trajectory over time, these findings, although statistically significant, seem unlikely to represent clinically meaningful differences. Also of interest, the modal dose did not seem to be related to outcomes. This could reflect confounding related to pharmacokinetic variability, because low doses could be associated with high plasma drug exposures for some patients, whereas other patients could receive higher doses but have relatively low plasma drug exposures. However, the lack of relationship of dose to apparent growth effects provides additional evidence of the generally benign relationship of atomoxetine to growth processes. The finding of an acute effect that resolved during chronic treatment could be related to several factors. Initiation of treatment with atomoxetine is associated with a decrease in appetite, which could result in decreased caloric intake and lead to the initial decrease in weight. This hypothesis is consistent with the observation in clinical studies that, over time, decreased appetite tends to diminish as a reported adverse effect. It also suggests that the addition of a caloric supplement for a period of time when treatment is initiated could blunt the initial deceleration in growth velocity. This is consistent with a previous report on hypopituitarism that suggested that changes in appetite modulate changes in growth rates.21 Alternatively, because it is known that norepinephrine affects neuroendocrine systems that modulate growth,22–24 it is possible that increased noradrenergic tone related to atomoxetine could affect the regulation of the hypothalamic-pituitary-growth axis. Because neuroendocrine systems are quite resilient and tend to return to homeostatic set-points, this mechanism could also be consistent with the observed pattern of early effects on growth that diminish with time. Several factors limit the interpretation of these data. The comparison data used for prediction of expected growth rates were taken from normative population growth data, rather than from a matched, randomized sample. This choice reflects the fact that randomizing a matched group of patients to placebo or to a psychosocial intervention for an extended period for comparison purposes would have been unacceptable to most clinicians, particularly in view of the results of the MTA that demonstrated superior outcomes for children randomly assigned to pharmacologic treatment, compared with those randomly assigned to a psychosocial intervention. The study also cannot control for effects on growth related to ADHD itself, which were reported by some researchers.6,7 It is noted that collection of weight and height data at multiple sites over a long period of time might have resulted in variability related to measurement errors, which could have affected the observed outcomes. However, given the size of the sample and the likelihood that most measurement errors were random, errors would likely increase the random noise in the sample but not systematically bias the results. Errors made consistently across visits (for example, weighing patients with their shoes on) would not affect greatly examinations of changes over multiple visits. Therefore, we consider it unlikely that measurement errors seriously affected the results. Finally, it is possible that the patients who did not remain in the study for the full 2 years (either because they discontinued treatment or because the original study protocol was <2 years) would have had an effect on this analysis had they been included. The dropout analysis, however, indicated that this would not have been the case. For weight, in the only dropout time interval that showed a significant difference, if the patients who dropped out had been included, then actually the weight loss noted in this study would have decreased. For height, there was a statistically significant difference at 1 isolated time point, but this was not indicative of a clinically significant trend. CONCLUSIONS The data presented here suggest that, at the group level, there was only a minimal effect on height after 2 years of treatment with atomoxetine; for those most at risk (those in the lowest quartile), there seemed to be no effect. Individual patients, however, could show more (or less) pronounced effects. Therefore, it is important for clinicians to assess growth periodically during treatment and, for patients who seem to be growing more slowly than expected, to consider whether treatment with atomoxetine is a factor. ACKNOWLEDGMENTS This research was funded by Eli Lilly and Company. We thank Dr Rodney Moore for contributions to the preparation of this manuscript. FOOTNOTES Accepted Dec 29, 2004. Conflict of interest: Drs Spencer, Newcorn, Kratochvil, and Biederman have functioned as paid consultants and/or investigators for studies sponsored by Eli Lilly and Company. Drs Ruff and Michelson are employees and shareholders of Eli Lilly and Company. REFERENCES MTA Cooperative Group. A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. Arch Gen Psychiatry. 1999;56 :1073 –1086 American Academy of Pediatrics. Clinical practice guideline: treatment of the school-aged child with attention-deficit/hyperactivity disorder. Pediatrics. 2001;108 :1033 –1044 Biederman J, Faraone SV, Monuteaux MC, Plunkett EA, Gifford J, Spencer T. Growth deficits and attention-deficit/hyperactivity disorder revisited: impact of gender, development, and treatment. Pediatrics. 2003;111 :1 –6 Lisska MC, Rivkees SA. Daily methylphenidate use slows the growth of children: a community based study. J Pediatr Endocrinol Metab. 2003;16 :711 –718 Poulton A, Cowell CT. Slowing of growth in height and weight on stimulants: a characteristic pattern. J Paediatr Child Health. 2003;39 :180 –185 Spencer TJ, Biederman J, Harding M, O'Donnell D, Faraone SV, Wilens TE. Growth deficits in ADHD children revisited: evidence for disorder-associated growth delays J Am Acad Child Adolesc Psychiatry. 1996;35 :1460 –1469 Spencer T, Biederman J, Wilens T. Growth deficits in children with attention deficit hyperactivity disorder. Pediatrics. 1998;102 :501 –506 Sund AM, Zeiner P. Does extended medication with amphetamine or methylphenidate reduce growth in hyperactive children Nord J Psychiatry. 2002;56 :53 –57 MTA Cooperative Group. National Institute of Mental Health Multimodal Treatment Study of ADHD follow-up: changes in effectiveness and growth after the end of treatment. Pediatrics. 2004;113 :762 –769 Swanson J, Elliott G, Greenhill L, Newcorn J, Jensen P. 24-month stimulant effects on growth in MTA follow-up. Presented at the 50th Annual Meeting of the American Academy of Child and Adolescent Psychiatry; October 14–19, 2003; Miami, FL Michelson D, Buitelaar JK, Danckaerts M, et al. Relapse prevention in pediatric patients with ADHD treated with atomoxetine: a randomized, double-blind, placebo-controlled study. J Am Acad Child Adolesc Psychiatry. 2004;43 :896 –904 Michelson D, Allen AJ, Busner J, et al. Once-daily atomoxetine treatment for children and adolescents with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled study. Am J Psychiatry. 2002;159 :1896 –1901 Kaufman J, Birmaher B, Brent D, Rao U, Ryan N. Kiddie-SADS-Present and Lifetime Version (K-SADS-PL): Version 1.0 of October 1996 Edition. Pittsburgh, PA: University of Pittsburgh Press; 1996 World Medical Association. Declaration of Helsinki: Recommendations Guiding Medical Doctors in Biomedical Research Involving Human Subjects. Ferney-Voltaire, France: World Medical Association; 2000 Kuczmarski RJ, Ogden CL, Grummer-Strawn LM, et al. CDC growth charts: United States. Adv Data. 2000;(314) :1 –27 Spencer TJ. Treatment for ADHD with OROS methylphenidate: long-term effect on growth. Presented at the 156th Annual Meeting of the American Psychiatric Association; May 21, 2003; San Francisco, CA Biederman J, Faraone S, Spencer TJ. Extended release mixed amphetamine salts in ADHD: growth parameter analysis. Presented at the 156th Annual Meeting of the American Psychiatric Association; May 17–22, 2003; San Francisco, CA Tanner JM, Davies PS. Clinical longitudinal standards for height and height velocity for North American children. J Pediatr. 1985;107 :317 –329 Kaplowitz PB, Jennings S. Enhancement of linear growth and weight gain by cyproheptadine in children with hypopituitarism receiving growth hormone therapy. J Pediatr. 1987;110 :140 –143 al Damluji S. Adrenergic control of the secretion of anterior pituitary hormones. Baillieres Clin Endocrinol Metab. 1993;7 :355 –392 Laakmann G, Schoen HW, Blaschke D, Wittmann M. Dose-dependent growth hormone, prolactin and cortisol stimulation after i.v. administration of desimipramine in human subjects. Psychoneuroendocrinology. 1985;10 :83 –93 Lovinger R, Holland J, Kaplan S, et al. Pharmacological evidence for stimulation of growth hormone secretion by a central noradrenergic system in dogs. Neuroscience. 1976;1 :443 –450...查看详细 (29536字节)
☉ 11333136:Plasma vascular endothelial growth factor, angiopoietin-2, and soluble angiopoietin receptor tie-2 in diabetic retinopathy: effects of laser
1 Haemostasis, Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham, UK 2 Birmingham and Midland Eye Centre, City Hospital, Birmingham, UK ABSTRACT Background: Proliferative diabetic retinopathy (PDR) may be a response to abnormal angiogenic growth factors such as vascular endothelial growth factor (VEGF), angiopoietin-2 (Ang-2), and the soluble angiopoietin receptor tie-2. The authors hypothesised the following: (a) there are differences in plasma levels of these growth factors in different grades of diabetic retinopathy; and (b) that the effects of intervention with panretinal laser photocoagulation (PRP) for PDR, and angiotensin receptor blockade (using eprosartan) for patients with other grades of diabetic retinopathy will be to reduce levels of the growth factors. Methods: Cross sectional and interventional study (using PRP and eprosartan) in diabetic patients. VEGF, Ang-2, and tie-2 were measured by ELISA. Results: VEGF (p80 mm Hg and/or systolic blood pressure >130 mm Hg. Patients with type 2 diabetes with background diabetic retinopathy who had not received previous laser therapy were also studied. The diagnosis of proliferative retinopathy was made on slit lamp biomicroscopy with the aid of fluorescein angiography in doubtful cases. Trained photographers took fundus photographs of two 50° fields of each eye centred on the macula temporal and disc nasal. The diabetic retinopathy was graded according to the worse affected eye by masked expert observers using retinal photographs. Based on the modified Airlie House photographic classification, retinopathy was graded as grade 1 or non-proliferative retinopathy, grade 2 or preproliferative retinopathy, and grade 3 or proliferative retinopathy.15 Twenty eight patients with proliferative retinopathy underwent PRP, and were re-examined at 2 months. Nineteen patients with pre-proliferative retinopathy, and background diabetic retinopathy, who are not taking an ACE inhibitor or angiotensin receptor antagonist at baseline, were treated with eprosartan 600 mg daily, and the dose increased over 2 weeks to 800 mg, if diastolic blood pressure was more than 80 mm Hg at a 1 week visit. Patients were also re-examined and had repeat blood samples for research indices at 2 months. Exclusion criteria for all subjects were a history of renal or liver impairment, malignancy, cardiovascular disease (previous myocardial infarction, stroke, peripheral artery disease), uncontrolled hypertension (>160/95 mm Hg), connective tissue disease, deep vein thrombosis, or pulmonary embolism (confirmed, where appropriate, by laboratory tests). Baseline blood samples were compared to healthy control subjects recruited from those attending hospital for non-acute minor surgical conditions, such as cataract surgery and hernia surgery, and from members of the hospital staff. None of the patients or healthy controls had a history of renal or liver disease, malignancy, connective tissue disease, deep vein thrombosis, or pulmonary embolism. The project had the approval of the ethics committee of West Birmingham Health Authority and all patients gave informed consent to the study. A 20 ml blood sample was taken at baseline and in those undergoing with intervention with PRP or eprosartan, at 2 months. VEGF, tie-2, and Ang-2 were measured by ELISA using commercial reagents.9,10 Power calculations and statistical analysis Based on our pilot study,13 we calculated that 18 patients and 18 controls would have 90% power at the p0.05) (table 1). Table 1 Plasma vascular endothelial growth factor, angiopoietin-2, and soluble angiopoietin receptor tie-2 in diabetic retinopathy Correlations In the patients and controls, VEGF levels were significantly correlated with Ang-2 (r = 0.587, p<0.001) and tie-2 (r = 0.27, p = 0.004). However, the correlation between Ang-2 and tie-2 levels was not significant (r = 0.178, p = 0.065). Age only significantly correlated with Ang-2 levels (r = 0.234, p = 0.013). Among diabetic patients only, VEGF levels were significantly correlated with Ang-2 (r = 0.442, p<0.001) and tie-2 (r = 0.518, p<0.001). The correlation between Ang-2 and tie-2 levels was significant (r = 0.509, p<0.001). There were no correlations with age among the diabetic subgroup. Effects of intervention There were no statistically significant effects of laser photocoagulation on plasma VEGF, Ang-2, and tie-2 levels in the 19 patients with proliferative diabetic retinopathy (table 2). Similarly, there were no statistically significant effects of eprosartan in the 28 patients with non-proliferative diabetic retinopathy (table 3). Table 2 Effects of laser photocoagulation in 19 patients with proliferative diabetic retinopathy Table 3 Effects of eprosartan in 28 patients with non-proliferative diabetic retinopathy DISCUSSION In this study, we have confirmed previous observations of increased plasma VEGF levels in diabetic patients, as well as previous observations of higher plasma VEGF levels in patients with more severe retinopathy,13 with the highest median VEGF levels among patients with pre-proliferative and proliferative retinopathy (grades 2 and 3). We also show, for the first time, that Ang-2 levels are increased in diabetics, with the highest levels among patients with grade 2 and 3 retinopathy. Furthermore, we also demonstrate that soluble tie-2 levels are lower among diabetics than controls, with no relation to the severity of retinopathy. VEGF correlated with both Ang-2 and tie-2 among diabetics and in the whole study cohort, in keeping with these three indices being possible indices of angiogenesis. Interestingly, the correlation between Ang-2 and tie-2 was only significant in the diabetic patients, as has previously been shown in cancer patients.10 We have previously reported plasma tie-2 levels to be higher in patients with coronary artery disease compared to healthy controls, as well as a significant correlation between tie-2 and VEGF in this patient group (Spearman r = 0.59, p<0.001).15 That levels of tie-2 correlate with other angiogenic markers is consistent with work suggesting interactions between the VEGF and angiopoietin families of growth factors and receptors.10 Certainly, Ang-2 appears to be an antagonist to tie-2, and in tumour models, high expression of Ang-2 coincides with vessel regression and high levels of VEGF at the tumour margin—in keeping with robust angiogenesis.16 Indeed, Ang-2 may cause destabilisation of the vascular network, promoting the greater expression of VEGF. In contrast with our previous pilot study,14 there was no significant reduction in VEGF levels after panretinal photocoagulation in the present study. Our previous pilot study included patients with proliferative retinopathy secondary to both diabetes and retinal vein occlusion, while the present study was confined to diabetic patients only and significant cardiovascular disease or hypertension were exclusion criteria. Many patients in the present cross sectional study were also treated with ACE inhibitors at baseline (reflecting current clinical practice), and pre-intervention VEGF levels were also much lower that than reported in our pilot study, making a substantial change secondary to intervention more difficult to show. These reasons may also account for the corresponding lack of effect of panretinal photocoagulation on Ang-2 and tie-2 levels. Similarly, we failed to show a significant effect of eprosartan on our research indices in patients with pre-proliferative diabetic retinopathy. In our previous study in hypertensive patients (a minority of whom had concomitant diabetes), treatment with either an ACE inhibitor or losartan resulted in a significant reduction in plasma VEGF levels,17 although we are not aware of any previous published data on the effect of angiotensin receptor blockers on Ang-2 or tie-2 in diabetes. This study is limited by its cross sectional design and numbers in the intervention arms are relatively small. It is possible that patients with diabetes had significant underlying atherosclerotic vascular disease, although we attempted to exclude such patients to minimise confounding effects. In conclusion, we have shown increased plasma levels of VEGF and Ang-2, as well as lower soluble tie-2, in diabetic patients. The highest median VEGF and Ang-2 levels were seen among patients with pre-proliferative and proliferative retinopathy, but there was no relation of tie-2 to the severity of retinopathy. As the majority of previous research into Ang-2 and tie-2 has been in relation to angiogenesis in malignancy, and the present study would suggest that Ang-2 and tie-2 may be used as a potential indices of angiogenesis in diabetes mellitus (in addition to VEGF) and may help elucidate the role of the angiopoietin/tie-2 system in this condition. ACKNOWLEDGEMENTS We acknowledge the support of the Sandwell and West Birmingham Hospitals NHS Trust Research and Development Programme for the Haemostasis, Thrombosis and Vascular Biology Unit. This project is supported by the Royal Blind Asylum and School/Scottish National Institute for the War Blinded Award of the Royal College of Surgeons of Edinburgh, as well as an educational non-promotional grant from Solvay Healthcare Limited, which also provided the eprosartan. REFERENCES Witmer AN, Vrensen GF, Van Noorden CJ, et al. Vascular endothelial growth factors and angiogenesis in eye disease. Prog Retin Eye Res 2003;22:1–29. Caldwell RB, Bartoli M, Behzadian MA, et al. Vascular endothelial growth factor and diabetic retinopathy: pathophysiological mechanisms and treatment perspectives. Diabetes Metab Res Rev 2003;19:442–55. Lu M , Adamis AP. Vascular endothelial growth factor gene regulation and action in diabetic retinopathy. Ophthalmol Clin North Am 2002;15:69–79. Lauren J , Gunji Y, Alitalo K. Is angiopoietin-2 necessary for the initiation of tumor angiogenesis? Am J Pathol 1998;153:1333–9. Metheny-Barlow LJ, Li LY. The enigmatic role of angiopoietin-1 in tumor angiogenesis. Cell Res 2003;13:309–17. Takagi H , Koyama S, Seike H, et al. Potential role of the angiopoietin/tie2 system in ischemia-induced retinal neovascularization. Invest Ophthalmol Vis Sci 2003;44:393–402. Holash J , Wiegand SJ, Yancopoulos GD. New model of tumor angiogenesis: dynamic balance between vessel regression and growth mediated by angiopoietins and VEGF. Oncogene 1999;18:5356–62. Holash J , Maisonpierre PC, Compton D, et al. Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science 1999;284:1994–8. Chung NA, Makin AJ, Lip GY. Measurement of the soluble angiopoietin receptor tie-2 in patients with coronary artery disease: development and application of an immunoassay. Eur J Clin Invest 2003;33:529–35. Chaturvedi N , Sjolie AK, Stephenson JM, et al. Effect of lisinopril on progression of retinopathy in normotensive people with type 1 diabetes. The EUCLID Study Group. EURODIAB Controlled Trial of Lisinopril in Insulin-Dependent Diabetes Mellitus. Lancet 1998;351:28–31. Caine GJ, Blann AD, Stonelake PS, et al. Plasma angiopoietin-1, angiopoietin-2 and Tie-2 in breast and prostate cancer: a comparison with VEGF and Flt-1. Eur J Clin Invest 2003;33:883–90. Aeillo LP, Avery RL, Arigg PG, et al. Vascular endothelial growth factor in ocular fluids of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 1994;331:1480–7. Yang Q , Zwijsen A, Slegers H, et al. Purification and characterisation of VEGF/VPF secreted by human retinal pigment epithelial cells. Endothelium 1994;2:73–85. Lip PL, Belgore F, Blann AD, et al. Plasma VEGF and soluble VEGF receptor Flt-1 in proliferative retinopathy: relationship to endothelial dysfunction and laser treatment. Invest Ophthalmol Vis Sci 2000;41:2115–19. Sjolie AK, Stephenson J, Aldington S, et al. Retinopathy and vision loss in insulin-dependent diabetes in Europe. The EURODIAB IDDM complications study. Ophthalmology 1997;104:252–60. Zhang L , Yang N, Park JW, et al. Tumor-derived vascular endothelial growth factor up-regulates angiopoietin-2 in host endothelium and destabilizes host vasculature, supporting angiogenesis in ovarian cancer. Cancer Res 2003;63:3403–12. Belgore FM, Blann AD, Li-Saw-Hee FL, et al. Plasma levels of vascular endothelial growth factor and its soluble receptor (SFlt-1) in essential hypertension. Am J Cardiol 2001;87:805–7, A9....查看详细 (20408字节)
☉ 11333137:Visual acuity and the ability of the visually impaired to read medication instructions
1 Specialist Registrar in Ophthalmology, Tennent Institute of Ophthalmology, Gartnavel General Hospital, Glasgow, UK 2 Chest Heart & Stroke Scotland Research Fellow, British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow Division of Medicine and Cardiovascular Sciences, Glasgow, UK 3 Consultant Ophthalmologist, Tennent Institute of Ophthalmology, Gartnavel General Hospital, Glasgow, UK ABSTRACT Background/Aims: Although medical information is often communicated in writing, little attention is given as to whether patients can read it—for example, the miniscule writing on the side of the medication bottles (equivalent to 6/6 reduced Snellen). The authors wished to determine a distance visual acuity threshold, using routine assessments of visual acuity (VA), beyond which patients are unable to read their instructions. Methods: 180 patients, subgrouped according to the best line of Snellen acuity (from 6/9 to 6/60) achieved in either eye were recruited. Subjects were asked to read the printed manufacturer’s instructions on the side of the drops box without magnification. Results: Those subjects with best corrected VA of lower than or equal to 6/24 showed a significantly diminished ability to read the instructions on their eye drops bottles (p0.05 in each case). However, when these subjects were grouped and compared with subjects with "best" VAs of 6/24, 6/36, and 6/60, the latter three groups showed a significantly diminished ability to read the instructions on their eye drop bottles (p0.05; **p<0.001. Moreover when these latter groups were able to select the font used the mode for preferred Arial font sizes were 16 for the 6/24 group, 18 for 6/36, and 22 for 6/60. DISCUSSION To our knowledge, this is the first study to document the inability of patients with visual impairment to read the instructions on their bottle of eye drops. Furthermore there is evidence of a distance VA threshold effect such that although the majority of patients with 6/18 VA are able to read their instructions, patients whose VA is worse cannot. As it is common for patients to leave a consultation without remembering what was discussed,2 including how to take their medication, this has significant implications in clinical practice as it provides evidence that we need to include enlarged print instructions for patients with a VA of 6/24 or less to enable them to self medicate safely and effectively. This is particularly true for elderly patients for whom hearing impairment and memory problems can compound the difficulties.3 Furthermore, in line with the Disability Discrimination Act (1995),4 we need to provide a "level playing field" for people who otherwise face obstacles and barriers in their everyday lives. Part 3 of the Act (starting October 2004) requires the provider of a service to take such steps as it is reasonable to enable disabled people to make use of a service, or to facilitate the use by disabled persons of such a service. For a person with visual impairment as described above, the provision of enlarged print would enable the correct usage of medications. We wished to provide an easy, inexpensive method of assessing whether patients would require enlarged print. Although near VA can be assessed using the near test types and reduced Snellen charts, this requires extra time and personnel. As we have shown and as one would expect, the median near VA decreases as the best distance VA decreases. Therefore, to judge whether a patient will need enlarged print to read their medication instructions, the distance VA can suffice. As all ophthalmology patients have their distance VA assessed as a matter of course, it does not provide an increased workload. In the provision of enlarged print instructions, we found that the affected group with distance VA of 6/24 to 6/60 was able to read an Arial font size of 22 and thus this size is effective for all affected groups with an acuity of 6/60 or better. The small number of patients with VA of 6/24 or less who were able to read the small writing tended to be younger patients (age 40 or less), mostly suffering with congenital conditions, whose youth presumably facilitated accommodation. We would recommend that a copy of instructions, printed in enlarged print of Arial font 22, be distributed with all bottles of medication when the patient is found to have a best distance VA of 6/24 or less, particularly if the patient is elderly. This recommendation is probably applicable for all information given to patients with reduced VA. REFERENCES World Health Organization. International Statistical Classification of Diseases and Related Health Problems, Tenth Revision. Vol 1. Geneva, Switzerland: World Health Organization, 1992. Fletcher C . Listening and talking to patients. BMJ 1980;281:994–6. Menon GK, Dutton GN. Writing to our patients. Br J Ophthalmol 1999;83:765. Disability Discrimination Act 1995 (c. 50), Part III, (21), 4....查看详细 (10853字节)
☉ 11333138:Elevated plasma levels of interleukin 8 in patients with acute anterior ischaemic optic neuropathy
1 Department of Ophthalmology, Schneider Children’s Medical Center of Israel, Petah Tiqwa, Israel 2 Department of Ophthalmology, Rabin Medical Center, Petah Tiqwa, Israel 3 Department of Immunology, Rabin Medical Center, Petah Tiqwa, Israel ABSTRACT Background/aim: Alterations of the immune system may have a role in thrombogenesis. Artery sites occluded with thrombi apparently release pro-inflammatory cytokines. Non-arteritic anterior ischaemic optic neuropathy (NAION) results from occlusion of the blood supply to the optic nerve. The aim of this study was to analyse levels of pro-inflammatory cytokines in patients with acute event of NAION. Methods: Study participants included 10 patients (12 eyes) with NAION and 20 age matched controls with the same risk factors for atherosclerosis disease. Peripheral blood samples were obtained immediately at the acute onset of NAION. Plasma interleukin 8 (IL-8), IL-6, and tumour necrosis factor alpha (TNF-) levels were measured immediately following diagnosis and during the follow up intervals. Results: The plasma levels of IL-8 were significantly higher in NAION patients at the time of diagnosis in comparison to the control group (p = 0.002), and decreased during the follow up period (6–12 months) (p = 0.05). There were no differences in plasma levels of IL-6 and TNF- between NAION patients and controls, either in the acute phase or during the follow up period. Conclusion: Plasma levels of IL-8 are elevated during the acute phase of NAION, but not IL-6 and TNF-. These elevated levels are in accordance with other acute vascular thrombosis. The clinical significance of these findings should be further evaluated. Abbreviations: AAION, arteritic AION; AION, anterior ischaemic optic neuropathy; CRP, C reactive protein; CVA, cerebral vascular accidents; ELISA, enzyme linked immunosorbent assay; ESR, erythrocyte sedimentation rate; IL-8, interleukin 8; NAION, non-arteritic AION; NIDDM, non-insulin dependent diabetes; TNF-, tumour necrosis factor alpha Keywords: interleukins; tumour necrosis factor; anterior ischaemic optic neuropathy Alterations of the immune system appear to have a crucial role in the pathogenesis of thrombosis.1,2 Thrombosis superimposed on atherosclerotic plaque is a major cause of occlusive vascular disease.3 Researchers believe that arterial sites occluded with thrombi release local proinflammatory secretory polypeptides, termed cytokines, such as tumour necrosis factor alpha (TNF-), interleukin (IL) 6, and IL-8, via several types of cells (lymphocytes, monocytes, macrophages, vascular endothelial cells, smooth muscle cells and fibroblasts).4,5 A systemic increase in plasma IL-6 and IL-8 levels after ischaemia and reperfusion processes has so far been confirmed clinically in patients with acute coronary arteries occlusion and cerebral vascular accidents (CVA).6,7 Anterior ischaemic optic neuropathy (AION) results from interruption of the blood supply to the anterior part of the optic nerve.8,9,10 It may be arteritic AION (AAION) or non-arteritic AION (NAION). NAION is essentially caused by transient hypoperfusion or non-perfusion of the posterior ciliary artery circulation in the optic nerve head.11 NAION is characterised by small vessel occlusion as a result of atherosclerotic disease, as opposed to AAION in which giant cell vasculitis is pathognomonic. NAION has the same classic risk factors of atherosclerosis—namely, hypertension, diabetes mellitus, hyperlipidaemia, and older age.12 NAION is the leading cause of sudden optic nerve related vision loss in the United States, affecting 2.3–10.2 per 100 000 people over 50 years old.13 Patients typically present with sudden, painless unilateral loss of vision associated with swelling of the optic nerve head in the affected eye.14–16 The diagnosis may be made immediately or weeks to months following the acute event. Unfortunately, 15–40% of patients experience another event in the fellow eye within a short period.12 The mechanism underlying involvement of the fellow eye is not understood. Identification of the factors that trigger the evolution of NAION associated thrombosis may result in better diagnosis and treatment. The aim of this study was to determine changes in plasma levels of proinflammatory cytokines in patients with acute NAION. METHODS Patients The study group consisted of 10 patients (12 eyes) who presented with acute NAION at the Department of Ophthalmology of Rabin Medical Center between January 1998 and June 2000 and agreed to participate in the study. Arteritic AION patients, diagnosed by clinical and laboratory tests, and patients with either elevated erythrocyte sedimentation rate (ESR), C reactive protein (CRP), or positive temporal biopsy were excluded. Blood for cytokine levels (IL-6, IL-8, and TNF-) was drawn from all patients immediately at diagnosis, during the acute event, and in majority of the patients during the follow up interval. Control serum samples were obtained from 20 age matched subjects with similar atherosclerosis risk factors and without visual symptoms. All were candidates for elective cataract surgery with no history of optic neuropathy, unilateral visual loss, or history suggestive for giant cell arthritis. The study was approved by the institutional review board and was performed in accordance with the Declaration of Helsinki for research involving human subjects. Laboratory tests Serum samples from patients and controls were kept at –20°C until analysis. Levels of IL-6, IL-8, and TNF- were measured by enzyme linked immunosorbent assay (ELISA) kits (R & D Systems, MN, USA). Statistical analysis The data were analysed statistically with the SPSS-X package. The 2 test and Fisher’s exact test were used to compare nominal data between the groups, and Mann-Whitney test was used to compare cytokine levels between groups. Analysis of the change in cytokines levels during the follow up period of each patient was performed with the aparametric Wilcoxon test. RESULTS Patient characteristics The study group included 10 patients, three men and seven women, mean age 67.8 years (range 56–85 years, SD 7.5 years), with mean follow up of 2.3 years (range 1–3.2 years). NAION was diagnosed in the right eye in five cases and in the left eye in the other seven cases. All 10 patients had plasma cytokine levels sample on diagnosis. Repeat plasma cytokines levels were checked at 3, 6, 9, and 12 months for three, six, two, and three patients respectively. Of 10 patients with NAION, eight had a unilateral event whereas two had bilateral events, with one being evaluated in both acute episodes. The time interval between the two episodes was 12 months in one patient (with blood samples in the two episodes) and 9 months in the other. All patients had normal ESR values at diagnosis (mean, 31 mm in the first hour) and CRP levels within normal range (mean 0.4 mg/dl). All patients started aspirin treatment (325 mg once a day) on diagnosis. Underlying systemic diseases in the patient group included hypertension (five patients), ischaemic heart disease (two patients), CVA (one patient), and non-insulin dependent diabetes (NIDDM) (three patients). Two patients were on low dose aspirin at the time of the acute event, and none was treated with coumadin or corticosteroids. The control group included eight men and 12 women, mean age 70.2 years (range 53–85 years, SD 8.9 years). Underlying systemic diseases included hypertension (eight subjects), ischaemic heart disease (two subjects), and seven had NIDDM. In addition, five of the control group were receiving low dose aspirin. None was treated with coumadin or corticosteroids. Serum cytokines IL-8 Plasma levels of IL-8 were examined at the acute onset of NAION in all patients, and another 14 samples during the follow up interval. Elevated plasma levels of IL-8 in NAION patients at the time of diagnosis (84.6 (SD 69.1) pg/ml) were significantly higher in comparison with the control group (20.2 (12.8) pg/ml; p = 0.002) (fig 1A), and decreased during the follow up period (3–12 months) (p = 0.05). Three months after the acute phase, plasma levels of IL-8 were similar to those of controls (p = 0.63) (fig 1B). Figure 1 (A) Plasma levels of cytokines (IL-8, IL-6, TNF- ) during acute non-arteritic ischaemic optic neuropathy (NAION). Note the significant elevation of IL-8 in the patient group. (B) Plasma levels of cytokines 3–12 months following NAION event. No differences in plasma levels of cytokines IL-8, IL-6, TNF- between patients and control groups. Note that IL-8 levels return to normal range. Patient 3 was found to have significantly higher levels of IL-8 (100 pg/ml) during the acute NAION event, compared with the average levels of the control group (18 pg/ml). During his follow up interval, the levels of IL-8 decreased gradually (21 pg/ml and 9 pg/ml at 6 and 9 months, respectively). However, significantly increased IL-8 levels reappeared when the patient developed an acute event of NAION in his fellow eye (484 pg/ml) after 12 months of follow up. Patient 7 also had bilateral NAION, but no blood samples for cytokines were taken during the fellow eye NAION, which appeared after 9 months of follow up. IL-6 Plasma levels of IL-6 were examined at the acute onset of NAION, and after 3, 6, 9, and 12 months. Plasma levels of IL-6 in acute NAION (3.4 (SD 3.1) pg/ml) were similar to the control group (3.88 (5.17) pg/ml; p = 0.6) (fig 1A). Plasma levels of IL-6 did not change significantly and were similar to those of the control group during the follow up at 3, 6, 9, and 12 months (fig 1B). TNF- Plasma levels of TNF- were examined at the acute onset of NAION, and after 3, 6, 9, and 12 months. Plasma levels of TNF- in acute NAION (0.8 (SD 1.2) pg/ml) were similar to the control group (1.4 (1.5) pg/ml; p = 0.93) (fig 1A). Plasma levels of TNF- did not change significantly and were similar to those of the control group during the follow up at 3, 6, 9 and 12 months (fig 1B). DISCUSSION The present clinical study revealed significant elevations of IL-8 during the acute phase of NAION. In accordance with this study, studies in baboons have shown elevations in IL-8 levels after induction of a thrombus, suggesting that the thrombotic event could contribute to the increased IL-8 concentration.17 In addition, thrombotic events in patients with paraneoplastic syndrome were found to be associated with elevated IL-8 levels.18,19 IL-8 is a potent neutrophil chemotactic cytokine (chemokine) known to have a role in inflammation and host defence.20–22 As a product of different types of cells, it may be present in any tissue and be produced during infections, ischaemia, trauma, and other disturbances of tissue homeostasis. It is likely to be the main cause of the local accumulation of neutrophils.21,23 Recently, locally increased levels of IL-8 were detected in the lumen of the coronary arteries following myocardial infarction.7 During acute NAION, no change in plasma levels of TNF- or IL-6 could be detected. TNF- is an important induction agent of IL-8. During acute myocardial infarction, increased plasma IL-6 and IL-8 levels were accompanied by increased plasma IL-1? and TNF- levels. However, the peak of the TNF- concentration occurs in the late phase.7,24,25 Therefore, TNF- might serve as a negative control in the early stages of myocardial infarction, as well as in acute NAION. However, IL-8 resistance to inactivation and its slow clearance may prolong the presence of IL-8 in active form beyond that of most other mediators in the immediate environment of the cells from which it is released.20 Recent studies of thrombotic syndromes have shown that inflammation may stimulate coagulation activity and thereby enhance the risk of thrombosis. Atherosclerotic plaques, which are rich in soft extracellular lipids and macrophages, may be more vulnerable to plaque rupture and consequent cytokine secretion. These data suggest that NAION might occur secondary to atherosclerotic plaque rupture and the resulting increase in production of IL-8 by the macrophages. Cytokines are non-antibody proteins, secreted by inflammatory leucocytes and some non-leucocytic cells that act as intercellular mediators. Treatment of NAION traditionally consists of aspirin, a non-steroidal anti-inflammatory drug, mainly because of its anticoagulant effect. However, a better understanding of the cytokine response may lead to new therapeutic possibilities.26 Experimental studies in a cerebral perfusion injury model has found that rabbits given a neutralising anti-IL-8 antibody had significantly reduced brain oedema and infarct size compared to rabbits receiving a control antibody.27 Although many types of cells, including lymphocytes,28 fibroblasts,29 monocytes,30 macrophages,31 smooth muscle cells, and endothelial cells4,5 are capable of producing IL-6 and IL-8 in cell culture, the cell source of production of IL-8 in NAION remains to be established. So far, endothelial cells are the most likely.4,5 Our findings may also have important diagnostic implications. The most common presenting symptom in AION is sudden painless visual loss. In some cases, the acute event goes unnoticed, and the patient appears later when he or she suddenly discovers the visual loss. To date, the only diagnostic index for discriminating acute from long standing visual loss was the optic nerve head appearance. Disc pallor cannot be detected before 6 weeks from the event. On the basis of this study, we propose measuring IL-8 plasma levels as a possible laboratory tool to discriminate acute onset from long standing or slowly progressive visual loss. Although human studies revealed plasma IL-8 elevations following brain ischaemia, rabbit models of ischaemia reperfusion showed only a local increase in the brain tissue.27 Other models of coronary artery occlusion demonstrated both local and systemic elevations in IL-8 levels.3,7,32 In this study we evaluated the systemic levels of IL-8 only, as ocular fluid is not routinely obtained in patients with acute visual loss secondary to NAION. In summary, this study demonstrated remarkable elevation of IL-8 plasma levels in optic nerve related infarct (NAION). In the absence of histological confirmation of the small vessel occlusion, these findings support the pathophysiology of microvascular thrombosis causing NAION. The clinical significance of these findings should be further evaluated. REFERENCES Esmon CT. Inflammation and thrombosis. J Thromb Haemost 2003;1:1343–8. Tousoulis D , Davies G, Stefanadis C, et al. Inflammatory and thrombotic mechanisms in coronary atherosclerosis. Heart 2003;89:993–7. Miya Y , Kanda T, Tamura J, et al. A new murine model of coronary artery thrombosis and role of interleukin-8 in the development of coronary thrombosis. Res Commun Mol Pathol Pharmacol 2000;108:108–15. Hoch RC, Schraufstatter IU, Cochrane CG. In vivo, in vitro, and molecular aspects of interleukin-8 and the interleukin-8 receptors. J Lab Clin Med 1996;128:134–45. Luster AD. Chemokines—chemotactic cytokines that mediate inflammation. N Engl J Med 1998;338:436–45. Kanda T , Hirao Y, Oshima S, et al. 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☉ 11333139:Obesity Rather Than Severity of Sleep-Disordered Breathing as the Major Determinant of Insulin Resistance and Altered Lipidemia in Snoring C
the Division of Pediatric Sleep Medicine and Kosair Children’s Hospital Research Institute, Department of Pediatrics, University of Louisville, Louisville, Kentucky ABSTRACT Objective. Sleep-disordered breathing (SDB) is associated with insulin resistance and dyslipidemia in adults and in obese children. However, the prevalence of such metabolic abnormalities among snoring children is unknown. This study was done to prospectively assess the relative contribution of SDB and obesity to metabolic disturbances in a large cohort of snoring children. Methods. Measurements of fasting serum glucose, insulin, and lipids were obtained after polysomnographic evaluation in 116 snoring children and in 19 control subjects. Insulin resistance was assessed using the insulin/glucose ratio (I/G ratio) and homeostasis model assessment (HOMA). Results. A total of 135 children (79 boys; mean age: 8.9 ± 3.5 years) were studied. Sixty-four children had moderate to severe SDB (AHI = 5 per hour of total sleep time [TST]), 52 had mild SDB (AHI = 1 but 50% with a corresponding decrease in Sp2 of >4% and/or terminated by a 3-second electroencephalogram arousal.44 The obstructive apnea/hypopnea index (AHI) was defined as the number of apneas and hypopneas per hour of total sleep time (TST). Children with an AHI = 1 but 25 μIU/mL or I/G ratio >0.33) was present in 16 or 12 children, respectively, only 1 of whom was not obese. Because the severity of SDB did not seem to contribute to the occurrence and/or severity of metabolic disturbances, we reexamined these issues by partitioning our cohort into obese and nonobese categories (Table 2). Obese children were significantly older and had more SDB problems. Furthermore, significant differences in insulin levels, I/G ratio, HOMA, TG, and HDL levels (P 95% may have accounted for the higher risk for SDB in the context of obesity.50–52 Indeed, we have observed progressively an increasing prevalence of obesity during the past decade among snoring children who presented at a large pediatric sleep center (Gozal D, unpublished observations, 2003), such that 40% to 50% of the patients fulfill the criteria for obesity, as opposed to 17% obesity prevalence in the metropolitan area of Louisville. This increased representation of obese children among symptomatic snoring children is not surprising considering the effect of excessive fat deposition on upper airway collapsibility53 and the overall higher prevalence of SDB among obese children.54,55 Therefore, to account for such disparate overrepresentation of obesity, we included a relatively high number of control subjects who also fulfilled obesity criteria (37%). The present study strongly concurs with previous publications demonstrating a high prevalence of insulin resistance among obese children10,56 and also supports changes in insulin sensitivity as a function of age.18,40,57,58 Moreover, the significant correlations among obesity, increased I/G ratio, and serum lipid profile alterations support the notion that risk factors for cardiovascular disease tend to cluster in childhood and are strongly associated with obesity.59,60 In contrast with some of the reports on adult patients with SDB, SDB in children does not seem to impose an added risk for development of insulin resistance. Although the exact reasons of this discrepancy are currently unknown, differences in the overall duration of SDB and in SDB severity could account for at least some of the contributing factors to the added risk for metabolic syndrome among adult patients with SDB. Indeed, adult patients with SDB are much more likely to present after SDB has gone undiagnosed over prolonged periods of time, and higher AHI, deeper falls in SpO2, and more severe sleep fragmentation are usually observed in the average adult patient compared with the pediatric SDB patient.61 Our findings do not lend support to the conclusions by de la Eva et al40 in obese children with SDB. These investigators showed that significant correlations were present between AHI and fasting insulin levels independent of BMI. However, this study included only obese children; therefore, separation of the preponderant role of obesity from the putative role of SDB on glucose homeostasis would be difficult, if not altogether impossible. Moreover, all of the patients who were studied by de la Eva et al had abnormal insulin levels, suggesting a potentially skewed population in that study. As shown above, additional analyses using only obese individuals in our cohort (n = 70) failed to reveal the presence of any significant association between SDB severity and insulin resistance. In this context, it is noteworthy that even in adult populations, the effect of CPAP on insulin resistance has yielded conflicting results,25,26,29–32,62,63 thereby raising the possibility that although SDB may induce an adverse effect on glucose regulatory mechanisms, this effect is small at most. Indeed, the effect of CPAP on insulin sensitivity was found to be smaller in obese patients than in nonobese patients, suggesting that in obese individuals, insulin sensitivity is determined primarily by obesity and to a smaller extent by respiratory disturbances during sleep.26 However, the experimental evidence linking components of SDB to glucose dysregulation supports the notion that both exposure to hypoxia62,63 and sleep loss can induce insulin resistance.64 It therefore is possible that for the average nonobese pediatric population with SDB, much larger sample sizes will be needed to reveal the putative, albeit small, size effects of respiratory and sleep disturbances on the homeostatic control of glycemic levels. Furthermore, such future studies will require incorporation of a treatment arm (tonsillectomy and adenoidectomy) to establish irrevocably the contribution of SDB to insulin resistance in the pediatric population. The present study supports the previously suggested association between obesity and altered lipid profiles.14,65,66 Dyslipidemia, characterized by high plasma concentrations of TGs and low concentrations of HDL, is a potent risk factor for coronary heart disease.67 This "atherogenic" lipid profile is of particular significance in a population such as that of children with SDB, who show plasma elevations of the cardiovascular risk factor marker CRP.39 However, in contrast with CRP levels, which correlate with SDB severity even after controlling for obesity, dyslipidemia in our cohort was determined primarily by obesity and degree of the insulin resistance. Indeed, stepwise linear regression analysis showed I/G ratio and relBMI as the major contributing factors for high levels of TGs and low levels of HDL. A technical issue that pertains to this study deserves comment. We consistently sampled all of the study participants in the morning after a sleep study so as to ensure standard fasting collection procedures as well as an identical timing in relation to their sleep period. Thus, we did not examine whether SDB imposes any acute effects on homeostatic glycemic control during sleep. On the basis of the absence of any obvious differences in the morning levels of HOMA among the children when divided according to the degree of SDB, it is unlikely that sleep-to-waking differences might be present. Exercise training favorably affects insulin sensitivity in both adults and children.68–70 Thus, lack of physical activity in obese children could account for the higher I/G found in obese children compared with the nonobese children in our cohort. We are unable to examine this potential confounder, however, because information regarding physical activity was not collected in our cohort. Similarly, we did not specifically obtain information on the dietary habits and body fat distribution of our population, and these factors have been shown to modify the propensity for insulin resistance and the occurrence of dyslipidemia.71–74 The absence of a significant difference between boys and girls in insulin resistance does not exclude the effect of puberty on glucose homeostasis in our cohort. Because Tanner staging was not performed, this is a limitation of the current study. Notwithstanding such limitations, our findings do not support a major role for SDB in the emergence of insulin resistance or altered lipid metabolism in children. Thus, in contrast with adults, insulin resistance and dyslipidemia seem to be determined primarily by adiposity in snoring children, suggesting that weight loss should be encouraged aggressively as part of the management of SDB in obese children. 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☉ 11333140:Genotype-phenotype correlation in a family with Arg135Leu rhodopsin retinitis pigmentosa
1 Department of Ophthalmology, University of North Carolina, Chapel Hill, NC, USA 2 Chapel Hill, NC, USA 3 Casey Eye Institute, Oregon Health and Science University, Portland, OR, USA 4 Department of Ophthalmology and Visual Sciences, University of Iowa Hospitals and Clinics, Iowa City, IA, USA ABSTRACT Aim: To describe the clinical characteristics and disease course of a large family with retinitis pigmentosa (RP) from an Arg135Leu change in rhodopsin. Methods: 29 patients in this family were evaluated. Goldmann visual fields were performed on 14 affected individuals, Ganzfeld electroretinography (ERG) on eight individuals (11–56 years), and blood samples collected on 10 individuals (11–58 years). Patient visual field data were compared with previously reported patients with different rhodopsin mutations using linear regression. Results: An Arg135Leu mutation was identified in rhodopsin. Distinct stages of clinical evolution were identified for this family ranging from normal, white dots, classic bone spicules and, finally, ending with extensive retinal pigment epithelium (RPE) atrophy. 9/16 patients over the age of 20 years also demonstrated marked macular atrophy. All patients who underwent full field ERG testing demonstrated non-recordable ERGs. The overall regression model comparing solid angles of visual fields from patients with rhodopsin mutations (Pro23His, Pro347Ala, Arg135Leu) shows significant effects for age (p = 0.0005), mutation (p = 0.0014), and interaction between age and mutation (p = 0.018) with an R2 of 0.407. Conclusions: An Arg135Leu change in rhodopsin results in a severe form of RP that evolves through various fundus appearances that include white dots early in life and classic appearing RP later. This transmembrane change in rhodopsin proves to be more severe than in a family with an intradiscal change and a family with a cytoplasmic change. Abbreviations: ADRP, autosomal dominant retinitis pigmentosa; ARMS, amplification refractory mutation system; GVF, Goldmann visual fields; mfERG, multifocal electroretinography; RP, retinitis pigmentosa; RPA, retinitis punctata albescens; RPE, retinal pigment epithelium Keywords: multifocal electroretinography; retinitis pigmentosa; retinal dystrophy; retinitis punctata albescens; rhodopsin Retinitis pigmentosa (RP) is characterised by clinical findings of bone spicules, arteriolar attenuation, and optic nerve atrophy. However, there is a wide range of presentation and severity. The clinical appearance of any given patient with RP depends on the stage of the patient in the disorder and the molecular basis of disease. Of the approximately 100 000 patients with RP in the United States, 15–20% of patients have autosomal dominant retinitis pigmentosa (ADRP).1–3 The most common molecular causes of ADRP are changes in rhodopsin. Rhodopsin related RP tends to have a milder disease course than other forms of RP.1,4 However, Sandberg demonstrated that the severity of rhodopsin related RP was dependent on the site of the sequence variation.5 An Arg135Leu mutation in rhodopsin was reported by Sung.4,6,7 We describe the clinical characteristics of this mutation in a 13 generation family. This change in rhodopsin demonstrates a very severe course with widespread white dots early that fade into a more classic appearance of RP in adulthood. SUBJECTS AND METHODS This study had approval of the institutional review board of the University of North Carolina (UNC). A total of 24 affected patients, all members of a 13 generation family with ADRP (fig 1), were examined at UNC. Five additional affected and multiple unaffected patients were examined at a family reunion by the author. Patients clearly reported nyctalopia from early childhood and this symptom was used to determine disease status. Affected patients from four different generations and two separate branches of the family came to UNC. Patients underwent a standard eye examination, Goldmann perimetry, electroretinographic testing, and fundus photography. Patients with hand movement or worse vision did not undergo ancillary testing. Full field electroretinography and multifocal electroretinography (mfERG) were performed according to ISCEV standards.8,9 Eight patients underwent full field ERG testing with an LKC Veritas system (Gaithersburg, MD, USA). Three patients underwent mfERG using a Veris system (ElectroDiagnostics, Inc, San Mateo, CA, USA). Goldmann visual fields (GVF) were converted to solid angle (in steradians) using described methods.10,11 A linear regression model was performed from patients with Arg135Leu, Pro23His and Pro347Ala mutations in rhodopsin11 (JMP SAS, Cary, NC, USA). Figure 1 Pedigree. The family, which clearly demonstrates an autosomal dominant pattern of inheritance, could be traced back 13 generations. The branches of the family that participated in the current study are boxed. From the left box, one woman from generation X, five patients from generation XI, and two patients from generation XII were examined. From the right box, seven patients from generation XI, seven patients from generation XII, and two patients from generation XIII were examined at UNC. The majority of living affected and unaffected members of these two branches of the family were examined at the family reunion in western North Carolina. Molecular analysis and findings Ten patients at various disease stages ranging in age from 11–58 years had blood samples sent to the Carver Molecular Ophthalmology Laboratory for analysis. Screening using an amplification refractory mutation system (ARMS)12 disclosed neither the Pro23His nor Arg135Trp changes in rhodopsin. Samples that had aberrant migration patterns of polymerase chain reaction products, using single stranded conformational polymorphism analysis,11,13,14 were sequenced bidirectionally with fluorescent dideoxynucleotides on an ABI model 377 automated sequencer. An Arg135Leu change in rhodopsin was identified in all samples. RESULTS Clinical findings All affected patients in this study, ranging in age from 7–64 years of age, reported symptoms of nyctalopia before 5 years of age. No unaffected patients demonstrated white dots or other signs of RP. Visual acuity ranged from 20/20 to light perception and remained stable until the development of posterior subcapsular cataracts in the third to fourth decade of life (fig 2). Nearly all patients over the age of 16 who were evaluated had cataracts or intraocular lenses with maintained central visual acuity until the fourth to fifth decade of life. However, 9/16 patients over the age of 20 years demonstrated some degree of macular atrophy that compromised central vision (fig 3A). Six of seven patients under the age of 20 years who were examined, demonstrated widespread white dots and minimal RPE changes with only the youngest patient (age 7 years) not demonstrating any definite signs (fig 3B and 3C). In the second to third decades, the white dots fade and are replaced by RPE atrophy and bone spicules (fig 3D) and, finally, the fundus shows marked RPE atrophy and choroidal sclerosis (fig 3E and F). Figure 2 Visual acuity. The central visual acuity of the better seeing eye of each patient is plotted against their age at examination. From this distribution, there is a notable drop off in central visual acuity by the fourth decade of life. Outliers who maintain central visual acuity beyond the fourth decade of life notably have minimal macular atrophy. Figure 3 Fundus appearance. (A) Fundus image of affected man, aged 41 years. Note the parafoveal atrophy of the retinal pigment epithelium (RPE). There is RPE atrophy and bone spicules beyond the arcades. Arterioles are attenuated. (B) Fundus image of affected boy, aged 9 years. Note the relative lack of fundus findings. This patient has some pallor to the optic nerve and attenuation of his arterioles. Periphery demonstrated no evidence of RPE atrophy, bone spicules, or white dots. (C) Fundus image of affected girl, aged 11. Note the extensive white dots and RPE mottling in the mid-periphery. Bone spicules are notably absent. (D) Fundus image of affected girl, aged 16. Note the presence of white dots and RPE atrophy. Bone spicules are beginning to develop in the mid-periphery. (E) Fundus image of affected woman, aged 45 years. Note the extensive RPE thinning and atrophy both in the mid-periphery and the macula. The optic nerve is pale and there is arteriolar attenuation. (F) Fundus image of affected man, aged 57 years. Note the extensive RPE clumps in the mid-periphery and visible sclerotic choroidal vessels. Electroretinographic findings We evaluated eight patients with full field electroretinography (ages 11–50 years) and three patients with mfERG. All patients undergoing full field electroretinography showed non-recordable responses. For mfERG testing, only the 16 year old demonstrated recordable retinal function, though no other patients younger than 40 years were tested. Repeat mfERG for this patient 13 months later found considerable further loss of recordable amplitude. Perimetric findings Fifteen patients underwent Goldmann perimetry. There was no measurable field with the I4e isoptre by the fourth decade of life. The V4e test target became undetectable by the sixth decade of life (fig 4). When the solid angle of I4e isoptre was compared to the clinical characteristics of the Pro23His and the Pro347Ala change in rhodopsin, there was a significant difference in the loss of visual field for patients with an Arg135Leu change in rhodopsin compared with the other mutations. The difference between visual field data for patients with the rhodopsin Arg135Leu RP and those with either other change remained significant at the 0.0005 level after Bonferroni correction (fig 5). The overall regression model comparing patients with rhodopsin mutations (Pro23His, Pro347Ala, Arg135Leu) shows significant effects for age (p = 0.0005), mutation (p = 0.0014), and interaction between age and mutation (p = 0.018) with an R2 of 0.407. Comparison of Arg135Leu change and Pro23His change demonstrated a significant difference in these populations (p = 0.0002) but no significance in the effect of age or the interaction of age and mutation. Comparison of Arg135Leu change and Pro347Ala change shows significant effect of age (p = 0.0001), mutation (p = 0.0001), and the interaction of age with mutation (p = 0.0003). Figure 4 Graph showing solid angle of visual field for patients for II4e and V4e isoptres at their particular age. II4e isoptres are depicted by diamonds and the V4e isoptres are depicted by squares. Note that the II4e isoptre is essentially unrecordable in patients over the age of 35 years and the V4e isoptre is minimally recordable by 50 years of age. Figure 5 Graph comparing the solid angle of visual field for the I4e isoptre of three mutations in rhodopsin: Pro23His, Pro347Ala, and Arg135Leu. Note that patients with the intradiscal change (Pro23His) have the most recordable visual field over time and that those with the transmembrane change (Arg135Leu) have the worst overall visual fields. DISCUSSION Rhodopsin related disease may present with a wide spectrum of severity and clinical features, including regional and diffuse RP,15–17 sectoral RP,18–23 and congenital stationary night blindness.24–27 Sandberg previously identified the importance of the locus of mutations in rhodopsin to a specific patient’s disease course, showing that intradiscal variations such as Pro23His carried the mildest course of disease and cytoplasmic variations such as at codon 347 carried the most severe prognosis.5,28 The severity of mutations in the intracytoplasmic region of rhodopsin is well documented though only a few clinical studies exist for changes in the transmembrane region.29 Pannarale described one family with an Arg135Trp mutation in rhodopsin with a very severe course. That family demonstrated non-recordable electroretinographic responses by the third decade of life but low, recordable wave forms for younger patients.17 Thus, changes associated with codon 135 may result in a more severe course.30 The appearance of white dots in association with rhodopsin and, specifically, Arg135Trp rhodopsin related RP, was described by Souied as an early finding in that form of RP.31 The term retinitis punctata albescens (RPA) was originally used to denote a specific form of RP.32 Although some have questioned in the past whether RPA was a specific disorder or simply a phenotype or stage of classic RP,33 recently, RPA has been recognised as a specific autosomal recessive retinal degeneration that results from mutations in the gene RLBP1.34–36 Admittedly, though, the white dots in RPA, although similar, are clinically different from those observed in our family. In summary, we present a family with RP caused by an Arg135Leu mutation in rhodopsin. This family demonstrated a particularly severe course that was worse than families with cytoplasmic or intradiscal mutations in rhodopsin. From a cross sectional study of patients, we inferred the progression of disease for this family. In the first decade of life, affected patients will be symptomatic without clinical signs on fundus examination. By the second decade, patients develop extensive fine white dots at the level of the retinal pigment epithelium in the absence of extensive RPE atrophy or bone spicules. The white dots fade by the third decade of life leaving bone spicules with widespread RPE atrophy. This appearance steadily worsens with increasing age and is associated with progressive decrease in visual field area. Patients uniformly developed cataracts by the second decade of life and appeared to respond favourably to cataract extraction. However, macular atrophy, as observed in our patients, is not uncommon in patients with changes at codon 135 of rhodopsin.7,17,30 Central acuity appeared to be closely related to the degree of macular atrophy.17 Description of disease natural history is becoming increasingly important with the future of hereditary retinal degenerations directed towards intervention. This family demonstrates how a specific phenotype may be present only for a brief period in a patient’s life. While this is not the first paper to describe the association of a white dot phenotype with rhodopsin, we are the first to clearly document that this clinical appearance is largely dependent on the age of the subject. We also further demonstrated the importance of age and genotype for the modelling of disease course as previously described.37 The R2 value predicts that up to 40.7% of disease variation may be predicted on the basis of patient age and specific genotype. While other factors will influence disease course, this value calls attention to the importance of these two variables. The severity of this particular form of retinitis pigmentosa and the careful understanding of its natural history will be important considerations in the inclusion of patients with this condition in future clinical trials. ACKNOWLEDGEMENTS Supported in part by a career development award from the Foundation Fighting Blindness (KTO) and unrestricted grants from the Foundation Fighting Blindness (RGW and EMS), Research to Prevent Blindness (RGW and EMS). The authors thank the assistance of Gary Weaver, MD, Donald Bowden, PhD, and Joan Winnicki from Wake Forest University in identifying this family for further studies. The authors would also like to thank Cassandra Janowski, Andrea Billingslea, and Azadeh Rohanian Perry for their assistance in manuscript preparation and patient care. REFERENCES Sohocki MM, Daiger SP, Bowne SJ, et al. 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☉ 11333141:Aerobic Capacity, Strength, Flexibility, and Activity Level in Unimpaired Extremely Low Birth Weight(800 g) Survivors at 17 Years of Age Co
Neonatal Follow-Up Programme, Children's and Women's Health Centre of British Columbia, Vancouver, British Columbia, Canada Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada Centre for Community Child Health Research, BC Research Institute for Children's and Women's Health, Vancouver, British Columbia, Canada ABSTRACT Objectives. To compare aerobic capacity, strength, flexibility, and activity level in extremely low birth weight (ELBW) adolescents at 17 years of age with term-born control subjects. Methods. Fifty-three ELBW teens of birth weight 800 g were assessed at 17.3 years (16.3–19.7 years; birth weight: 720 g [520–800 g]; gestation: 26 weeks [23–29 weeks]) along with term-born control subjects (n = 31) at age 17.8 years (16.5–19.0 years; birth weight: 3506 g [3068–4196 g]; gestation: weeks 40 [39–42 weeks]). ELBW and control teens were assessed by a pediatric physiotherapist and completed components of the Canadian Physical Activity, Fitness and Lifestyle Appraisal and a self-assessment fitness and activity questionnaire. Continuous data were analyzed using MANOVA (group, gender) followed by t tests; categorical data were analyzed using the 2 test. Results. ELBW teens had lower aerobic capacity, grip strength, leg power, and vertical jump; could do fewer push-ups; had less abdominal strength as measured by curl-ups; had less lower back flexibility; and had tighter hamstrings. ELBW teens reported less previous and current sports participation, lower physical activity level, and poorer coordination compared with term-born control subjects. ELBW teens were also found to have more difficulty with maintenance of rhythm and cadence. Although ELBW teens rated themselves lower on all measures of sporting activity, they were as happy with their level of fitness as the control subjects. Conclusions. Compared with term-born control subjects, there are significant differences in motor performance in unimpaired ELBW survivors in late adolescence, reflected in aerobic capacity, strength, endurance, flexibility, and activity level. We conclude that these differences in fitness and physical activity are related to the interaction of effects of premature birth on the motor system together with a more inactive lifestyle. These findings have potential implications for later adult health problems. Key Words: premature infants extremely low birth weight infants follow-up studies motor development strength flexibility Abbreviations: ELBW, extremely low birth weight DCD, developmental coordination disorder VLBW, very low birth weight mCAFT, Modified Canadian Aerobic Fitness Test CPAFLA, Canadian Physical Activity Fitness and Lifestyle Appraisal test Variations in muscle tone and problems with motor coordination are common in children of extremely low birth weight (ELBW; 800 g),1–5 but there are few data describing motor functioning and fitness in late adolescence in teens who are free of severe sensorimotor or cognitive impairments. Long-term motor sequelae of prematurity have been documented extensively3,6–9 and predate the survival of extremely small and sick infants resulting from high-technology neonatal intensive care. A study by our group on the same cohort of ELBW children at 9 years of age found that 51% of the ELBW children who did not have neurosensory handicaps, ambulatory cerebral palsy, and/or low IQ were classified as having developmental coordination disorder (DCD) compared with 5% of the control children.6 Parents of ELBW teens have reported more clumsiness and below average performance in sports,10,11 and in self-report studies, ELBW teens have reported more clumsiness and less athletic competence.12,13 The majority of follow-up studies throughout childhood and the early teen years have shown that ELBW and very low birth weight (VLBW) children are significantly shorter and lighter and have lower BMI and smaller head circumference than normal birth weight children.11,14–17 Muscle strength may also be reduced,18 although differences become less apparent as teens get older. However, some studies of ELBW and VLBW survivors in late teens and early adulthood found no height or weight differences19,20 with catch-up growth to puberty in ELBW16 and VLBW children.21 Various studies have also shown that small for gestational age ELBW infants who did not experience catch-up growth throughout childhood remained smaller as adults,21 with 1 study finding that small for gestational age VLBW boys show the least catch-up growth.22 This study was undertaken to examine differences in physical activity, aerobic capacity, flexibility, and grip and trunk strength between ELBW (800 g) teens and term-born control teens at the end of the adolescent growth spurt at 17 years of age. Participation in regular physical activity is a contributor to good overall health, whereas inactivity and poor physical fitness are now recognized as significant health risks. Lack of physical activity is a significant contributor to the increasing rate of childhood obesity in developed countries.23 Establishing early, adequate levels of fitness and activity may be particularly important in former tiny infants, who may be at risk for early-onset adult diseases such as diabetes, hypertension, ischemic heart disease, and strokes. METHODS Participants ELBW Study Group Between January 31, 1981, and February 9, 1986, 250 infants of birth weight 800 g were admitted to the provincial NICU in British Columbia. A total of 148 died in the neonatal period and 4 died after neonatal discharge, leaving 98 (39%) who survived to late adolescence. Nineteen of the children in this birth cohort were identified as having 1 or more major impairments at age 8.5 years and were excluded from the present study. For this purpose, major impairments were defined as IQ <70, nonambulatory cerebral palsy, visual impairment worse than 20/200 in the better eye with optimal refractive correction, or sensorineural hearing loss with hearing aids requiring educational adaptation for the hearing impaired. Of the 79 eligible ELBW teens, 53 (67%) consented to a psychoeducational and motor study and participated at 17 years of age. The results of the psychoeducational portion are presented in a separate paper.24 The characteristics of the ELBW group are given in Table 1. Control Group A group of 31 teens who were born at born between October 1, 1983 and August 31, 1984 and have participated as longitudinal control subjects for our studies of the ELBW group since 3 years of age served as control subjects at 17 years. The characteristics of the control group are also given in Table 1. Measures ELBW and control teens received the same battery of tests and questionnaires. The assessment included height, weight, and head circumference measurements and components of the Canadian Physical Activity, Fitness and Lifestyle Appraisal (CPAFLA),25 an established standardized test produced by the Canadian Society for Exercise Physiology and Health Canada, which was administered by the physiotherapist (M.R.). Our assessment included the following components: BMI: the BMI score is a relationship between weight and height that is associated with body fat and health risk: BMI = body weight in kg/height in m2. Modified Canadian Aerobic Fitness Test (mCAFT): aerobic fitness is a measurement of an individual's ability to deliver oxygen to working muscles. Oxygen consumption increases parallel to the increase in energy demand until the limit of the aerobic system has been reached. Subjects conducted a stepping sequence in time to preset recorded music, to generate a stepping rate specific for gender and age, using standardized criteria. For example a 15- to 19-year-old female individual would begin at stage 3, which has a step cadence of 102 footplants per minute. The subjects practiced the stepping sequence before the start of the test with and without the music. As the test began, the subjects lifted their body weight up and down the steps at the set rhythm and cadence using the mCAFT prerecorded CD that provided both music and voice instructions for the first 3 minutes. When the music stopped, the subjects stood motionless while a resting heart rate was recorded with an electronic heart rate monitor. Additional 3-minute block stepping sessions were repeated following a standardized protocol of increasing speed increments until the subject's heart rate reached the ceiling postexercise target rate, determined as 85% of aerobic power in a person of average fitness of the appropriate age and gender. The Aerobic Fitness Score was derived using an equation developed by laboratory tests on a large sample of Canadians at various ages. The Aerobic Fitness Score equation is as follows: 10 [17.2 + (1.29 x O2 cost) – (0.09 x weight in kg) – (0.18 x age in years)]. The O2 cost variable is measured in ml/kg/min and is drawn from a chart based on stepping cadence in footplants/min. For example, a 17-year-old girl who weighed 58 kg and completed stage 4 by reaching the ceiling heart rate would have a stepping cadence of 114 footplants/min and a corresponding O2 cost of 24.5 mL/kg/min; therefore, her Aerobic Fitness Score on the mCAFT would be 10 [17.2 + (1.29 x 24.5) – (0.09 x 58) – (0.18 x 17)] = 385.25. The health-benefit zones associated with the Aerobic Fitness Score for 15- to 19-year-old male individuals are categorized based on the test as follows: excellent, 574+; very good, 524 to 573; good, 488 to 523; fair, 436 to 487; needs improvement, <436. The health-benefit zones associated with the Aerobic Fitness Score for 15- to 19-year-old female individuals are defined as follows: excellent, 490+; very good, 437 to 489; good, 395 to 436; fair, 368 to 394; needs improvement, <368. Musculoskeletal fitness tests Muscle strength: upper limb strength was measured as grip strength for each hand independently using a hand-grip dynamometer. Lower limb strength was measured by determination of leg power in a vertical jump, incorporating the height to which the body mass was raised. Dynamic muscle endurance: this was measured for upper limb muscles by number of completed push-ups and for abdominal muscles (core strength) by number of partial curl-ups. Flexibility: trunk flexion was assessed using a flexometer; hamstring length was determined as the popliteal angle measured using a goniometer. In addition, data were collected by questionnaire by the physiotherapist about orthotic use; level of sports participation in the past and present, occurrence of musculoskeletal pain in the past and present, frequency of activity, enjoyment of physical activity, coordination compared with their peers, and happiness with fitness level. The ability of the ELBW and control teens to maintain rhythmic movement was assessed by the physiotherapist during the step tests from the mCAFT. Difficulty with maintenance of rhythm was defined as the inability to establish and maintain rhythm during the mCAFT stepping by 1 minute. Procedures In accordance with the protocol approved by the Clinical Research Ethics Board of the University of British Columbia and the Research Review Committee of the Children's and Women's Health Centre of British Columbia, ELBW and control subjects were contacted by mail. Written informed consent was obtained from each teen and from a parent. ELBW and control teens were seen individually in the Neonatal Follow-Up Program at British Columbia's Children's Hospital by a qualified physiotherapist and data collected centrally as part of a larger study of this cohort. Data Analysis Multivariate analysis of variance (MANOVA) was used on the set of continuous measures (group [ELBW, control] x gender). Overall significance on MANOVA was followed by univariate tests. Statistical significance was set at P < .05. Categorical data from the questionnaires (eg, orthotic use, sports participation, back and/or leg pain) were analyzed by using 2 analysis. There were no significant differences in perinatal and sociodemographic characteristics between ELBW teens that were studied at 17 years of age (N = 53) and the remaining ELBW teens from the original regional birth cohort who could not be located or refused to participate in the study (N = 26). However, there were significantly more boys than girls who did not participate in the study (P = .012). RESULTS Height, Weight, and Head Circumference The results of growth measurements of the 2 groups are given for boys and girls in Table 2. ELBW teens had significantly lower weight (P = .009), height (P = .0001), and head circumference (P = .0001). Statistically significant gender differences appeared in height (P = .0001) and head circumference (P = .001), whereas there were no gender x group interactions. Fitness Test (CPAFLA) BMI and Aerobic Fitness The results of the CPAFLA fitness test are presented in Table 3. There were no group or gender differences in BMI. ELBW teens had lower aerobic fitness capacity as measured by the mCAFT step test (P = .035), and boys had a better aerobic fitness score than the girls overall (P = .0001). Muscle Strength The ELBW group scored lower than control subjects on combined grip strength (P = .0001), right-hand grip strength (P = .001), and left-hand grip strength (P = .0001). Overall, boys scored higher than girls for right, left, and combined grip strength (P = .0001). In addition, group x gender interactions were found for combined (P = .009), right (P = .032), and left grip strength (P = .003). The ELBW group scored lower than the control group on lower limb strength in vertical jump (P = .0001) and leg power (P = .0001). There were overall gender differences, with boys having more leg power (P = .0001) and higher vertical jump (P = .0001) than the girls. Dynamic Muscle Endurance ELBW teens could do fewer push-ups (P = .014) and partial curl-ups (P = .033) than the control teens, and boys performed better than girls at both the push-ups (P = .006) and the partial curl-ups (P = .027). Flexibility ELBW teens were less flexible than the control teens on measurements of trunk-forward flexion (P = .002) and right (P = .001) and left popliteal angle (P = .001). There were no gender differences in trunk-forward flexion, but girls had better flexibility than boys in right (P = .001) and left popliteal angle (P = .009; Figs 1 and 2). Reported Pain, Sports/Activity Participation, Coordination, and Rhythm The results of the motor questionnaire are presented in Table 4. Overall, more boys participated in sports compared with girls (P = .014). ELBW teens participated less in sports than control subjects (P = .0001). In addition, ELBW teens reported less frequent participation in physical activity (P = .0001; Fig 3), with the boys being more active than the girls (P = .02). There were no differences between the ELBW and control groups in orthotic use, reported leg pain, or reported back pain. There were no differences between the groups in how much the teens reported that they enjoyed physical activity or their degree of satisfaction with their level of fitness. However, ELBW teens did report that they were less coordinated than their peers (P = .023), and the physiotherapist rated ELBW teens as having more difficulty establishing and maintaining rhythm and cadence during the step test compared with the control subjects (P = .0001). DISCUSSION This is the first study to examine multiple measures of motor and physical ability in late adolescence in ELBW survivors who were born at 800 g birth weight. Our ELBW teens were smaller than their peers and had specific areas of weakness in aerobic capacity, strength, endurance, flexibility, and general fitness as well as lower rates of general activity. Growth Measurements and BMI The differences that were found in weight, height, and head circumference between the ELBW and control groups are not surprising as many VLBW and ELBW studies have shown differences in growth throughout childhood and into adulthood.11,14,15,17,18 However, this is one of the first studies that followed both ELBW teens and an age-matched cohort longitudinally, demonstrating that these differences persist past childhood into late adolescence. Comparison of height, weight, and BMI with a peer group matched for age and socioeconomic status is very important as population standards for growth change over time and are influenced by racial and socioeconomic variables, with a tendency for each generation to grow taller in the developed world. We did not find differences in BMI, suggesting that although the ELBW teens were generally smaller than the control teens, they still scored within their expected weight for their height. However, this finding is in contrast to Saigal's study of ELBW teens at 12 to 16 years of age11 and a recent study by Doyle et al19 showing that ELBW teens at 20 years of age attained a height that was consistent with their parents height but that their weight was comparatively heavy for their height as measured by the BMI. We examined the weight outliers in our groups and did not find significant differences between the ELBW and control groups. We therefore did not find a tendency to higher BMI in ELBW young adults in this study. This could be attributable to the relatively small sample size, a difference being masked by a recent tendency toward obesity in the pediatric and adolescent population as a whole, or our group may not yet be old enough. There was also no significant difference in blood pressure between the 2 groups (using 1 clinical recording for each patient during the visit). Aerobic Capacity, Sports Participation, and Activity Level Recent and continued participation in physical activity is an important determinant of current measurable fitness and flexibility. At the outset, therefore, it is difficult to know whether the lower scores on multiple measures in this study are attributable to fundamental differences as a result of extreme prematurity (eg, cardiorespiratory, muscular, or neurobiological compromise) or these findings partly or even predominantly reflect the lower physical activity lifestyle that the ELBW teens tend to choose. Lower aerobic capacity found in the ELBW teens could be a result of teens' participating less in physical activity as a result of physical limitations, such as coordination difficulties and clumsiness, less social acceptance, or specific experience (eg, knowledge of the rules), or could be a consequence of parents' limiting the participation of ELBW teens in physical activity because of perceived disability or potential injury. In a psychosocial study on the same group,24 ELBW teens viewed athleticism as having less personal and social importance compared with term-born control subjects, perhaps in an attempt to reconcile poorer athletic abilities. We found that very few ELBW teens have participated in organized sports in the past compared with control teens; for example, 62% of the ELBW teens participated in organized sports in the past compared with nearly all (94%) of the control teens at 17 years of age. Even fewer ELBW teens (34%) were currently participating in some type of sports activity at the time of the assessment compared with 74% of the control teens. In the British Columbia public school system, there is no curricular requirement to participate in physical education or organized sports beyond the end of grade 10 (age 16), so the lower rate of participation by the ELBW group reflects a lifestyle choice free of curricular obligation. In addition to participating less in organized sports, ELBW teens reported lower activity level overall, with 47% of ELBW teens participating in some type of physical activity at least once per week compared with 87% of the control teens. Surprising, more than half (53%) of the ELBW teens engaged in a type of physical activity less than twice per month. It is interesting that, despite these findings, there were no differences in how much the teens reported enjoying physical activity or their degree of satisfaction with their level of fitness. Perhaps this reflects a tendency of the less physically active to want to seem more accepting of physical activity when questioned specifically by a physiotherapist. Supporting our findings, a study of ELBW children at 11 years of age found that ELBW children had a lower level of fitness compared with normal birth weight children on a treadmill task, and the parents of ELBW children also identified their teens as being less active than the normal birth weight group.26 It is interesting that the investigators in the treadmill study were unsure of whether the ELBW children's diminished effort on the task was limited by subtle pulmonary difficulty or poor exercise tolerance. Our findings of lower aerobic capacity may also be attributable to subtle subclinical functional pulmonary compromise; however, this question was not specifically addressed. Because of small sample size and gender differences, it was not possible in this study to evaluate the effect of being small for gestational age at birth or severity of neonatal lung disease on aerobic capacity at 17 years of age. Strength and Endurance No studies have examined strength in ELBW teens in late adolescence. In many occupations, physical strength and endurance are important attributes. As there were differences in growth measurements between the ELBW and control teens, we expected to find differences in strength between the 2 groups. Once again, the marked differences may be a result of the reduced participation in physical activity in the ELBW group, especially in push-ups, curl-ups, vertical jump, and leg power. This may also explain the differences in handgrip strength found between our groups, as handgrip strength is also strongly associated with levels of physical activity and health.27,28 As expected, boys in both groups had greater strength than the girls, yet the strength measurements of the ELBW boys were strikingly different from the same-age control boys. Flexibility The incidence of cerebral palsy is increased in the ELBW population; however, for this study, we excluded teens with nonambulatory cerebral palsy. Previous studies have demonstrated coordination and motor difficulties in ELBW children (eg, refs 3 and 6–8), but no studies to our knowledge have examined flexibility specifically in ELBW children and teens. Our findings of decreased flexibility in the ELBW teens compared with the control teens may be a result of less participation in physical activity but could also be attributed to an ongoing tendency to muscular tightness and minor tone abnormalities, seen frequently in ELBW preschoolers and potentially contributing to a diagnosis of DCD in some ELBW children at school age. The muscle tone and posture abnormalities in infancy described as transient dystonia of prematurity, by definition, are expected to decrease and eventually resolve with maturation; however, the persistent tightness in the hamstrings and lower back seen in ELBW teens suggests that some subtle features may persist and be related to prematurity per se. As expected, girls showed better overall flexibility than the boys, but the ELBW girls performed in a similar flexibility range as the control boys, indicative of decreased flexibility compared with the normal range of a female adolescent. Coordination and Rhythm Our findings that ELBW teens had more difficulty with establishing and maintaining cadence and rhythm may be an indication of ongoing coordination difficulties. Our current sample of ELBW children was composed of 15 (28%) teens who received a diagnosis of DCD at 9 years of age. However, after examining ELBW teens who received a diagnosis of DCD against ELBW teens who were in the original DCD sample at 9 years (N = 22) but did not receive a diagnosis of DCD, there were no significant differences in the way in which the DCD ELBW teens performed on the physiotherapy measures or the way in which they responded to the physiotherapy questions, with the exception of 1 question, which specifically addressed coordination. The teens who received a diagnosis of DCD at 9 years of age believed that they were not as coordinated as their peers compared with the teens who did not receive a diagnosis of DCD (P = .027). Motor clumsiness has been well documented in preterm infants (eg, refs 3 and 6–8), and it has been assumed that this was related to subtle perinatal brain injury. However, some recent MRI studies of VLBW children in their early to middle teens have found that although they had smaller brain volumes, there was no relationship found between brain measurements and motor neurologic or coordination scores.29–31 Difficulties with movement integrated with rhythm are probably multifactorial in origin, reflecting subtle difficulties with integrative brain functions that are not yet identifiable on current methods of neural imaging. Poor early coordination combined with low self-confidence may contribute to lack of establishment of healthy levels of physical activity in childhood as well as lack of common knowledge of and skills for group sports and activities (eg, how to swim, catch a ball). This carries into young adulthood, contributing to poor self-image and lack of association with more socially and physically active peers. This may add to the overall tendency of ELBW teens to be more sedentary compared with their peers. Limitations One of the principal limitations of this study is the loss of 33% of the eligible patients. We believe that this reflects the change in consent procedure, as in previous follow-up studies of the same cohort our recruitment numbers were much higher. For this study, because of the age of the subjects, the participation and "appointment contract" was with the teen, rather than the parent as in previous studies on this cohort. We excluded children with major neurosensory impairment evident at 9 years, as the objective of this study was to compare ELBW teens who were free of impairment with those with whom they would be competing in the adult world. However, these results are not generalizable to the complete ELBW survivor cohort in their late teens as the data obtained from this cohort excluded teens with serious neurosensory impairments. The ELBW cohort in this study comprised the smallest survivors of neonatal intensive care in the 1980s. Although these results may be broadly applicable to current tiny infant survivors of similar birth weight and gestational age in our NICUs, changes in intensive care techniques, survivors of lower birth weight and gestational age, access to neonatal care, and changing sociodemographic factors make direct application to the current tiny infant survivors difficult. CONCLUSIONS In late adolescence, ELBW teens remain smaller than their peers; participate less in physical activities; and have specific areas of weakness in terms of aerobic capacity, limb and core strength, and flexibility of the lower back and hamstrings compared with term-born control teens. These findings have potential implications for later health problems in the ELBW survivors. Recommendations for early intervention of former extremely low birth weight youths and teens should include early encouragement to be active and participate in noncompetitive physical activities with family and peers. This should contribute to the establishment of a foundation for a healthy, active lifestyle that will support establishing peer relationships, social skills, and self-confidence in this vulnerable population. ACKNOWLEDGMENTS This study was supported by British Columbia Medical Services Foundation operating grant BCM99-0010 and a Senior Scholar Award (to R.E.G.) from the Michael Smith Foundation for Health Research. We thank the families and staff of the Neonatal Follow-up Program, in particular Julie Petrie-Thomas, who, along with J.T., facilitated the attendance of the teens in the clinic. FOOTNOTES Accepted Nov 22, 2004. No conflict of interest declared. 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☉ 11333142:Identification of monosomy 3 in choroidal melanoma by chromosome in situ hybridisation
1 Department of Ophthalmology, Gartnavel General Hospital, Glasgow, UK 2 Department of Pathology, Royal Infirmary, Glasgow, UK 3 University Department of Pathology, Western Infirmary, Glasgow, UK ABSTRACT Background/aims: In uveal melanoma monosomy 3 is emerging as a significant indicator of a poor prognosis. To date most cytogenetic studies of uveal melanoma have utilised fresh tissue or DNA extracted from tissue sections. In this study chromosome in situ hybridisation (CISH) was used to study monosomy 3 in tissue sections. The copy number of chromosome 3 was determined and related to patient survival. Methods: Archival glutaraldehyde or formalin fixed, paraffin embedded material was obtained from 30 metastasising and 26 non-metastasising choroidal melanomas. Hybridisations were performed using centromere specific probes to chromosomes 3 and 18. Chromosome 18 was included as a control as previous abnormalities in uveal melanoma have not been described. Chromosomal imbalance was defined on the basis of changes in both chromosome index and signal distribution. Results: CISH was successfully performed on both glutaraldehyde and formalin fixed tissue. Four cases were unsuccessful because of extensive tumour necrosis. All cases were balanced for chromosome 18. Monosomy 3 was detected in 15 of the 26 cases of metastasising melanoma; the 26 non-metastasising tumours were all balanced for chromosome 3. Monosomy 3 was significantly associated with metastases related death. Conclusion: CISH can successfully identify monosomy 3 in archival glutaraldehyde or formalin fixed, paraffin embedded tissue sections. Similar to previous studies monosomy 3 is a significant predictor of metastases related death. Abbreviations: CI, chromosome index; CISH, chromosome in situ hybridisation; FF, formalin fixed; FISH, fluorescence in situ hybridisation; GF, glutaraldehyde fixed; MM, metastasising melanoma; NMM, non-metastasising melanoma Keywords: choroidal melanoma; monosomy 3 Uveal melanoma is the most common primary intraocular malignancy in adults with an estimated incidence of 4.3 per million per year in North America.1 With modern imaging there have been significant improvements in the accuracy of diagnosis as well as advances in the treatments available. Despite this the overall mortality of 16–53% remains unchanged owing to the propensity of uveal melanoma to metastasise to the liver.2,3 After clinical diagnosis of hepatic metastases life expectancy is extremely poor and the median survival time is only 7 months.4 It is generally accepted that the peak mortality from metastatic disease occurs within 3 years of diagnosis.2 However, the clinical course of patients with uveal melanoma is unpredictable and metastases may present up to 36 years later.5 Recently cytogenetic analyses of uveal melanomas have shown that loss of an entire chromosome 3 homologue (monosomy 3) often associated with an increased chromosome 8q shows a significant correlation with metastases and decreased survival.6,7,8,9,10,11,12,13,14 Many of the techniques used in these studies require fresh tissue—for example, for cell culture used in standard cytogenetics15,16 and fluorescence in situ hybridisation (FISH)10,11 on dissociated tumour cells. Alternatively, DNA can be extracted from fresh or paraffin embedded tissue for analysis.7,17 None of the techniques described, however, has identified the presence or absence of monosomy 3 within tissue sections. For this study we have used the alternative approach of interphase cytogenetics. In interphase cytogenetics, probes specific to individual chromosomes can be hybridised to cell nuclei in their resting state between divisions as well as metaphase nuclei within a tissue section. The aim of this study was to adapt this technique to enable the identification of monosomy 3 in tissue sections from glutaraldehyde or formalin fixed, paraffin embedded archival melanomas and to correlate this analysis with patient survival. PATIENTS AND METHODS Study population Archival specimens of choroidal malignant melanoma were obtained from the Western Infirmary Pathology files. The specimens included local resection and enucleation specimens from 30 patients who had died from metastatic melanoma and 26 patients who were either alive or had died from other causes after a minimum period of 7 years (mean 21 years, range 7–30 years). For patients with metastatic melanoma surgery was performed between 1975 and 1992 and for patients with non-metastasising melanoma surgery was performed between 1973 and 1991. Patients with metastatic melanoma were identified either from the cancer registry or case notes as having proved liver metastases by imaging, biopsy or postmortem examination. Patients without metastatic melanoma were both alive and well or had a cause of death other than metastatic melanoma and no evidence of metastatic disease at last follow up. All tissues had been previously fixed in glutaraldehyde or formalin and embedded in paraffin wax. Eight of the 26 cases of metastasising melanoma (MM) and four of the 26 cases of non-metastasising melanoma (NMM) had been formalin fixed (FF). The remaining tumours had all been fixed in glutaraldehyde fixed (GF). The FF and GF specimens were of similar ages. In 14 enucleation specimens (three FF and 11 GF) normal retina was used as an internal control. In addition, eight cases of normal human skin (all glutaraldehyde fixed) were included as an external control. After identification of cause of death all samples were anonymised and full ethical approval in accordance with local policy was obtained for the use of these tissue samples. Tissue section preparation Sections, 4 μm thick, were mounted on aminopropyltriethoxysilane coated glass slides. Before use, the slides were baked at 65°C for 4–24 hours. The tissue sections were dewaxed in 100% xylene and rehydrated in graded ethanol to water. Sections were microwaved in TRIS-EDTA (4.5 mM TRIS, 1 mM EDTA, pH 8) at full pressure for 5 minutes. After rapid cooling the sections were then digested with pepsin (0.4% pepsin in 0.2 M hydrochloric acid) for 30 minutes at 37°C and post fixed for 10 minutes in tissue fixative (Streck Laboratories Inc, Omaha, NE, USA). Finally, sections were dehydrated in 100% ethanol and air dried. DNA probes Chromosome specific repetitive sequence probes for chromosome 3 (D3Z1) and chromosome 18 (D18Z1) were purchased from Q-Bio gene (Illkirch, France). Chromosome 18 was selected as a control chromosome as, to our knowledge, there are no reports describing alterations in uveal melanoma. Both commercial probes were ready labelled with digoxigenin. Probes were diluted 1:10 in a hybridisation mix consisting of 70% formamide, two times the standard concentration of standard saline citrate (SSC) (1xSSC is 0.15 M sodium chloride and 0.015 M sodium citrate, pH 7), 500 μg/ml salmon sperm DNA, and 10% dextran sulphate. In situ hybridisation The probe in the hybridisation mix and DNA in the tissue sections were co-denatured together using the Omnislide modular system (ThermoLife Sciences, Hampshire, UK) at 80°C for 5 minutes and then incubated at 37°C overnight. After hybridisation, slides were washed twice in 2x SSC at room temperature for 5 minutes and then in 1xSSC at 70°C for 5 minutes. Before immunohistochemical detection of hybridised probe the slides were washed in 4xSSCT (4xSSC, 0.05% Tween-20) and blocked for 30 minutes at room temperature in 4x SSCT, 10% blocking reagent (Roche, USA). The slides were then incubated with anti-digoxigenin alkaline phosphatase (AP) Fab fragments (Roche, USA) 1:500 dilution in 4xSSCT, 10% blocking reagent for 30 minutes at room temperature. Slides were washed in 4xSSCT for 5 minutes, and then rinsed in distilled water. The slides were then incubated in NBT/BCIP solution (0.4 mM nitroblue-tetrazolium (NBT), 0.38 mM 5-brom-4-chloro-3-indolylphosphate (BCIP), 1.25 M levamisole in 100 mM HCl pH 9.5, 100 mM NaCl, 50 mM magnesium chloride) overnight. The sections were rinsed in tap water and counterstained with haematoxylin. Sites of binding were identified as blue-black dots. Quantification of hybridisation signals Chromosome specific centromeric probes were hybridised to sections of choroidal melanoma. In order to obtain control values, centromeric copy numbers for the two chromosomes were assessed using retina where present in the tissue sections and normal skin. The evaluation and interpretation of in situ hybridisation signals were carried out as previously described.18,19 Briefly, tissue sections were examined by light microscopy using an oil immersion lens (magnification x1000) and an eyepiece graticule to prevent recounting of nuclei. Overlapping nuclei and minor hybridisation signals were not analysed and only nuclei with the histological appearance of tumour cells were evaluated. Poor quality hybridisations were excluded. For each section the number of signal spots per nucleus was recorded for 200 nuclei and the assesser was masked to the outcome of the patient. The hybridisation data were analysed in two ways to assess the degree of chromosome imbalance for each sample and each chromosome. Firstly, the chromosome index (CI), which gives an average chromosome copy number, was calculated by dividing the total number of hybridisation spots counted by the total number of nuclei counted. The CIs are shown in figure 1. For chromosome 3 the mean CI for retina and skin was 1.66 and 1.56 respectively. For chromosome 18 the mean CI for retina and skin was 1.63 and 1.51. A tumour was defined as monosomic for chromosome 3 if its CI was less than 3 SD from the mean (that is, less than 1.37). Figure 1 Scattergram showing distribution of chromosome index (CI) for chromosomes 3 (A) and 18 (B) in skin (solid diamond), retina (solid square), non-metastasising melanoma (NMM solid triangle); formalin fixed (FF, open triangle), glutaraldehyde fixed (GF, open square), and metastasising melanoma (MM solid circle; FF, open circle; GF, open triangle). The lines denotes the mean CI (solid line) (SD 3) (black broken lines) or 2.58 SD (grey broken lines) for retina. Values falling 3 SD below the mean were classified as chromosome loss. The second method used to identify monosomy was the signal distribution, which can potentially detect relatively small populations with chromosomal numerical imbalances. To define the signal distribution the percentage of the nuclei counted with one, two or more than two hybridisation sites was calculated. A tumour was described as monosomic for chromosome 3 if the percentage of nuclei with one hybridisation site was greater than 60% of the nuclei counted. The criteria for both signal distribution and CI were based on published estimates and previous experience of the technique and take into account nuclear truncation.18–20 Nuclear truncation is an important aspect of interphase cytogenetic analysis of 4 μm sections because a proportion of nuclei will lose DNA based on the diameter of the nucleus. Tumours had to show chromosome loss by both CI and signal distribution to be regarded as monosomic. Statistical analysis Differences in chromosomal indices between tumour and retina, GF and FF cases, and older and newer tissues were compared using the two sided Mann-Whitney test with a priori level of statistical significance set at p<0.05. The log rank test was used to compare survival with presence of monosomy 3, which was represented by a Kaplan-Meier survival curve. RESULTS In situ hybridisation for chromosome 3 and 18 was successfully performed on 52 choroidal melanomas. Four cases were excluded because of heavy tumour pigmentation and large areas of necrosis. There was no apparent visual difference in hybridisation reactions in FF tumours when compared with GF tumours. Examples of choroidal melanomas and normal retina hybridised with chromosome 3 and 18 are shown in figure 2. Figure 2 Chromosome in situ hybridisation (CISH). (A) Glutaraldehyde fixed normal retina, hybridised with chromosome 18, showing two copies (double arrow) in most cells of the outer nuclear layer (onl). The photoreceptors (pr) are towards the bottom of the picture. (B) Glutaraldehyde fixed, metastasising epithelioid (e) melanoma, hybridised with chromosome 18, showing two copies (double arrow) in most cells. (C) Formalin fixed, non-metastasising epithelioid (e) melanoma, hybridised with chromosome 3, showing two copies (double arrow) in most cells. (D) Glutaraldehyde fixed, metastasising spindle (s) melanoma with moderate pigmentation (p), hybridised with chromosome 3, showing one copy in most cells (single arrow) (magnification x1000). Assessment of chromosome index The CI for chromosome 3 and 18 in MM, NMM, and controls is shown in figure 1. There was no significant difference between the CI for FF tissues when compared with the corresponding GF tissues. There was no significant differences between the CI for tumours removed more than 20 years ago when compared with those removed less than 10 years ago. For both MM and NMM the CIs for chromosome 18 were not significantly different compared with that of normal retina and all lay within 2.75 SD of the mean CI for normal retina. For MM the CIs for chromosome 3 were significantly different compared with normal retina (p = 0.0013) and 15 of the 26 (58%) tumours had a CI more than 3 SD from the mean. For NMM the CIs for chromosome 3 were not significantly different compared with that of normal retina and all lay within 2 SD of the mean. Assessment of signal distribution For chromosome 18 the mean signal distribution for two or more hybridisation sites per nucleus was 64% for retina, 62% for skin, 52% for NMM (FF 52%; GF 52%), and 63% for MM (FF 62%; GF 64%). Therefore, by signal distribution all the samples were balanced for chromosome 18. For chromosome 3 the mean signal distribution for two or more hybridisation sites per nucleus was 63% for retina, 54% for skin, 55% for NMM (FF 53%; GF 56%), and 31% for MM (FF 30%; GF 32%). By signal distribution all the cases of normal retina, skin, and NMM were balanced for chromosome 3. However, by signal distribution 15 of the 26 cases of MM had more than 60% of nuclei with only one hybridisation site and were therefore defined as monosomic for chromosome 3 by this parameter (see table 1). Table 1 Signal distribution for chromosome 3 showing the percentage of nuclei with 40%, 50%, 60%, and 70% of nuclei with only one hybridisation site Assessment of monosomy 3 Tumours had to show chromosome loss by both CI and signal distribution to be regarded as monosomic and therefore the data for CI and signal distribution were combined to assess monosomy 3. The results are summarised in table 2. Using both criteria 15 of the 26 cases of MM were defined as monosomic for chromosome 3. All the NMM were balanced for chromosome 3. In all cases both parameters agreed and there were no cases where either the CI or signal distribution indicated monosomy but the other parameter did not. Table 2 Summary of chromosomal changes in choroidal melanoma as defined by agreement in both chromosomal index and signal distribution Relation between monosomy 3 and survival In patients who had died of metastatic disease the average time to death was 1349 days (range 120–4619 days). Monosomy 3 was significantly associated with metastasis related death (p<0.0001). This is shown in the Kaplan-Meier survival curve (fig 3). Figure 3 Kaplan-Meier survival curve comparing survival with copy number for chromosome 3 as defined by agreement in both chromosome index and signal distribution. DISCUSSION This is the first study in which interphase cytogenetics has been applied to define the presence or absence of monosomy 3 in tissue sections of paraffin embedded choroidal melanomas. The main advantages of chromosome in situ hybridisation (CISH), used in this study, over other techniques are that it allows the direct assessment of chromosomal gains and losses in interphase and metaphase nuclei within a tissue section. This ensures that the nuclei assessed are indeed tumour cells and that the chromosomal changes within the tumour cells can be directly compared with adjacent normal tissue. CISH can be performed on archival tissue that is either formalin or glutaraldehyde fixed and we have already successfully performed CISH on glutaraldehyde fixed tissue samples up to 30 years old. In our laboratory CISH has previously been used to assess chromosomal gains and losses in other formalin fixed tumours such as adrenocortical tumours.21 In these tissues good hybridisation signals could be obtained when slides were simply pre-digested with pepsin for up to 1 hour. This method of tissue preparation worked for formalin fixed choroidal melanomas but we were unable to obtain signal with glutaraldehyde fixed tissues. However, by introducing a more rigorous pretreatment of microwaving under pressure in TRIS-EDTA buffer, before pepsin digestion, we were able to obtain good hybridisation signals. Interestingly, this additional step did not affect tissue preservation of formalin fixed cases and there were no significant differences between results obtained for CI and signal distribution between glutaraldehyde and formalin fixed cases. This pretreatment was therefore adopted for all cases in this study. Using this technique we identified monosomy 3 in 15 of 26 (58%) of MM. All 26 NMM were balanced for chromosome 3. Both MM and NMM were balanced for chromosome 18. This chromosome was selected as a control as, to our knowledge, there are no reports indicating loss or gain of chromosome 18 in uveal melanoma. Using our criteria the results obtained for CI and signal distribution agreed in all cases of monosomy 3. Our cut-off points were selected in accordance with our laboratory’s previous experience of the technique. We defined a normal chromosome complement as 3 SD from the mean CI. Other researchers have used a value of 2.58 SD.22 If this value was applied to our study one case would not have been defined as monosomic by CI. However, for signal distribution we used a strict cut-off point of 60% of cells showing fewer than two hybridisation sites to define chromosomal loss compared with 40% or less used in other studies.23,24 In table 1 we have also shown the number of nuclei with 40%, 50%, and 70% of nuclei with only one hybridisation site. It is clear that in our laboratory a cut-off point of less than 60% would identify many normal tissues as monosomic. The identification of cells with only one hybridisation site in normal tissue reflects the effects of nuclear truncation and ultimately will be affected by the thickness of sections used, which may vary between studies. In this study we used 4 μm sections as this gave the best hybridisation signal. Using the higher cut-off point of 70% we would have excluded one case. This is the same case that would have been excluded by defining a cut-off point for CI 2.58 SD from the mean. This does not significantly alter our results but indicates that the cut-off points may have to be reassessed as more cases are studied. It is difficult to compare the number of cases of monosomy 3 identified in this study with other studies. In these studies monosomy 3 has been identified in 50–73% of choroidal melanomas but not all these studies differentiated non-metastasising from metastasising tumours and the follow up was shorter than in our study. In this small study monosomy 3 was significantly associated with death from metastatic disease confirming the work of previous studies.6,7,11–14 Other techniques used for the assessment of non-random chromosomal abnormalities in uveal melanoma include standard cytogenetics,15,16 comparative genomic hybridisation,6,25 microsatellite analysis,7,12,26 and FISH.10,11,27 In standard cytogenetics, fresh tissue is required and disaggregated tumour cells are cultured and chromosomes analysed in metaphase. It has, however, been suggested that the cells which grow in culture may not be representative of the total tumour population.17 Comparative genomic hybridisation and polymerase chain reaction based microsatellite analysis have been undertaken on both fresh7,12 and archival paraffin embedded tissue.26 Both these techniques involve the extraction of DNA from the tissue samples. In comparative genomic hybridisation differentially labelled tumour and normal DNA samples are simultaneously hybridised to normal metaphase chromosomes. Regions of gains or losses within the tumour DNA can be identified by an increased or decreased colour ratio of the two fluorochromes used for the detection of hybridised DNA sequences along these reference chromosomes. In microsatellite analysis paired primers are used to amplify microsatellite markers on chromosomes of interest. Both these techniques are performed using DNA isolated directly from many tumour cells without culture and theoretically should more accurately represent the tumour cell population in vivo. However, tissue samples can be contaminated with non-tumour DNA that may be preferentially amplified during polymerase chain reaction. FISH has been used to describe cytogenetic abnormalities in uveal melanomas10,11,27 and by utilising different fluorochromes several chromosomes or chromosomal regions can be assessed simultaneously. The studies described, however, have utilised only fresh tissue and stained slides prepared from disaggregated tumour cells. FISH analysis for other chromosome regions has been performed on tissue sections of choroidal melanoma.28 In the study by Patel et al11 the authors comment that glutaraldehyde fixed tissue is not suitable for FISH analysis. CISH avoids the requirement for fresh tissue and the potential examination of non-representative tumour populations or non-tumour DNA. A further advantage of CISH is that different regions within a tumour, with, for example, different cell types may be analysed. This may help identify the emergence of subclones within a tumour and provide information on the role of monosomy 3 in tumour development. Direct comparisons are not possible between the results of interphase cytogenetic studies and techniques that involve DNA extraction such as microsatellite analysis and comparative genomic hybridisation.29 Unlike these techniques the main disadvantage of the CISH technique described is that fine mapping of changes cannot be achieved with alpha repeat centromeric probes. Microsatellite analysis and comparative genomic hybridisation have shown that in the majority of cases chromosome 3 loss of heterozygosity involves an entire chromosome homologue; however, in a small number of tumours regional losses on chromosome 3 have been identified and such regional losses cannot be detected with this technique as it stands.7,17 However, probes for other chromosome regions are available and the technique could be adapted to detect regional losses. The technique could also be adapted to detect other chromosomes known to show gains or losses in uveal melanoma such as 8q14 and 6q,6 respectively. It is also not possible to characterise specific tumour suppressor genes that may be involved. None the less, CISH represents a valuable additional technique that will allow the study of monosomy 3 in tissue sections and therefore takes into account tumour heterogeneity allowing the correlation of genotype with phenotype. With CISH it will be possible to screen a large archival series and define a group of tumours for more detailed study using alternative cytogenetic techniques. Furthermore, it may refine the prognostic implications of monosomy 3 as regards short or long time to death from metastatic disease. Finally, the technique can easily be applied to routine pathology specimens without special treatment and could therefore identify high risk patients who may benefit from close monitoring. ACKNOWLEDGEMENTS We are grateful to Mr Jim Ralston for his technical expertise and to Dr Ian McKay for his advice on statistics. REFERENCES Singh AD, Topham A. 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Patel KA, Edmondson ND, Talbot F, et al. Prediction of prognosis in patients with uveal melanoma using fluorescence in situ hybridisation. Br J Ophthalmol 2001;85:1440–4. Scholes AG, Damato BE, Nunn J, et al. Monosomy 3 in uveal melanoma: correlation with clinical and histologic predictors of survival. Invest Ophthalmol Vis Sci 2003;44:1008–11. Prescher G , Bornfeld N, Hirche H, et al. Prognostic implications of monosomy 3 in uveal melanoma. Lancet 1996;347:1222–5. Sisley K , Rennie IG, Parsons MA, et al. Abnormalities of chromosomes 3 and 8 in posterior uveal melanoma correlate with prognosis. Genes Chromosomes Cancer 1997;19:22–8. Horsman DE, White VA. Cytogenetic analysis of uveal melanoma. Consistent occurrence of monosomy 3 and trisomy 8q. Cancer 1993;71:811–19. Sisley K , Rennie IG, Cottam DW, et al. Cytogenetic findings in six posterior uveal melanomas: involvement of chromosomes 3, 6, and 8. Genes Chromosomes Cancer 1990;2:205–9. Speicher MR, Prescher G, du Manoir S, et al. 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☉ 11333143:Multidrug resistant proteins: P-glycoprotein and lung resistance protein expression in retinoblastoma
1 Department of Ocular Pathology, Vision Research Foundation, Chennai,Tamil Nadu, India 2 Brown Medical School, Providence, RI, USA 3 Feinberg Northwestern School of Medicine, Chicago, IL, USA 4 Department Ocular Oncology, Medical and Vision Research Foundations, Sankara Nethralaya, Chennai, India ABSTRACT Background/aim: Retinoblastoma is the commonest primary intraocular tumour in children. Chemotherapy now plays a big part in the treatment of these tumours. There is not much information about the role of the multidrug resistance proteins (MDR)—P-glycoprotein (P-gp) and vault protein lung resistance protein (LRP)—in retinoblastoma. The authors investigated the expression of P-gp and LRP in retinoblastoma and correlated them clinicopathologically. Methods: Among 60 retinoblastomas, 40 tumours were not subjected to preoperative or postoperative chemotherapy and 20 tumours were subjected to postoperative chemotherapy. In this cohort 27 tumours had no invasion and 33 tumours had invasion of choroid, optic nerve, and orbit. P-gp and LRP expression were studied by immunohistochemistry. Immunoanalysis was done semiquantitatively. Results: Among the 60 tumours P-gp was expressed in 23 (38%) tumours and LRP was expressed in 35 (58%). P-gp was expressed in 11/27 (40%) tumours with no invasion and in 12/33 (36%) tumours with invasion. LRP was expressed in 15/27 (55%) tumours with no invasion and in 20/33 (60%) tumours with invasion. Both P-gp and LRP were negative in three tumours with invasion, which had later developed bone marrow metastasis. There was no correlation between P-gp and LRP expression with invasion, differentiation and laterality of the tumours and response to treatment. Conclusion: Retinoblastoma expresses P-gp and LRP intrinsically before chemotherapy and none of these proteins predicted the response to chemotherapy. Thus, further studies are needed to understand the significance of the expression of the P-gp and LRP proteins in retinoblastoma. Abbreviations: ATP, adenosine triphosphate; CSA, ciclosporin A; DLP, diode laser photocoagulation; EBRT, external beam radiation therapy; LRP, lung resistance protein; MDR, multidrug resistance proteins; P-gp, P-glycoprtein; TCC, transconjunctival cryopexy Keywords: lung resistance protein; P-glycoprtein; multidrug resistance; retinoblastoma; immunohistochemistry; chemotherapy Retinoblastoma is the most common primary intraocular tumour in children. Primary chemoreduction is used for intraocular retinoblastoma and systemic chemotherapy is used following enucleation in patients with optic nerve and deep choroidal invasion, orbital extension, and metastatic disease.1 Because most retinoblastomas showed an initial response to chemotherapy but eventually progressed, Chan and Galle2–6 observed that retinoblastoma that failed chemotherapy expressed the multidrug resistance protein—P-glycoprotein (P-gp) and they suggested the use of a chemosensitiser ciclosporin A (CSA).6 CSA theoretically blocked the multidrug resistant P-gp frequently found in retinoblastoma. They suggested that combining CSA with chemotherapy controls intraocular retinoblastoma without requiring radiation.7 However others have not used CSA in the chemotherapy protocol and have obtained good results.8,9,10,11 P-gp, is a 170 kD adenosine triphosphate (ATP) dependent transmembrane efflux pump.12 P-gp has been observed in a number of drug resistant cell lines. Undoubtedly, P-gp contributes to clinical drug resistance in patients with cancer; however, it clearly is not the sole mechanism of drug resistance. In 1993, Scheper et al13 first described lung resistance protein (LRP) in non-P-glycoprotein drug resistant cell lines. Since its original description, LRP has been identified as the major vault protein. Vaults are complex ribonucleoprotein particles containing at least two high molecular weight proteins and a small RNA molecule in addition to the 110 kd major vault protein. Clinical studies have reported that LRP expression predicts for drug resistance and poor outcome in patients with acute myelogenous leukaemia, ovarian cancer and other cancers.14,15 In retinoblastoma, LRP expression has not been studied. There is also not much information about the expression of P-gp in retinoblastomas from Asian Indian children. Thus, we studied the expression of the P-gp and LRP proteins in retinoblastoma and correlated them clinicopathologically. METHODS The study was reviewed and approved by the local ethics committee of our institute, and the committee deemed that it conformed to the generally accepted principles of research, in accordance with the Helsinki Declaration. Paraffin embedded tissue blocks from 60 patients with retinoblastoma between 1997 and 2003 were retrieved. Clinical and pathological information was obtained from medical records and surgical pathology reports. An ocular pathologist (SK) reviewed haematoxylin and eosin stained slides with a double headed microscope. Inclusion and exclusion criteria Inclusion criteria were that all the patients were treated by enucleation and patients had a minimum follow up for 24 months. Exclusion criteria included patients who had received preoperative chemotherapy and those who had received CSA in their chemotherapy protocol. Histopathology Retinoblastomas were microscopically graded into three groups according to the predominant pattern of differentiation.16 All tumour slides were reviewed and the choroidal invasion was classified as either focal invasion or diffuse invasion of choroid. For optic nerve invasion, prelaminar, postlaminar and the surgical end of the optic nerve were analysed. Invasion of the tumour cells into the orbit was also looked for in the sections. Clinical information regarding orbital recurrence and development of bone marrow metastasis were obtained from the files of the patients. Treatment All the 60 tumours were not subjected to preoperative chemotherapy. However, when the tumours had known risk factors for metastasis,16 such as diffuse invasion of choroid, invasion of the post-laminar portion of the optic nerve, surgical end of the optic nerve, and orbital invasion, the children received treatment with chemotherapy. In bilateral retinoblastoma the eye where the tumour was small was treated with focal therapy. The focal therapies employed were external beam radiation therapy (EBRT), diode laser photocoagulation (DLP), and transconjunctival cryopexy (TCC). The chemotherapy cycles ranged from two to eight cycles. The chemotherapy drugs included carboplatin, vincristine, and etoposide. Monoclonal antibodies P-glycoprotein (clone 5B12), a mouse monoclonal antibody and a prokaryotic recombinant protein corresponding to the C terminal cytoplasmic domain of the P-glycoprotein molecule, was used (Novocastra Laboratories, Newcastle upon Tyne, UK). It was used in a working dilution of 1:30. The immunoreactivity is membrane staining. Human lung resistance related protein (LRP) (110 kD), a mouse monoclonal antibody, was also obtained from Novacastra Laboratories. It was used in a working dilution of 1:200. The immunoreactivity is cytoplasmic staining. Immunohistochemistry Immunohistochemistry was performed on 4 μm thick formalin fixed, paraffin embedded sections mounted on 3-aminopropyltriethoxy silane coated slides. After conventional deparaffinisation and rehydration, endogenous peroxidase activity was quenched by incubation in 3% H2O2 (10 minutes) at room temperature. Pretreatment in a pressure cooker (20 minutes) with citrate buffer (0.1M citric acid and 0.1M trisodium citrate in distilled water; pH –6.0) for P-gp and LRP was performed to unmask epitopes. Next, samples were incubated (60 minutes) in normal rabbit serum (1: 50 in 1% phosphate buffered saline bovine serum albumin), and then with the optimally diluted specific antibody (overnight) at 4°C in a humidified chamber. The monoclonal antibody P-gp and LRP was detected by the Dako LSAB+ System horseradish peroxidase (Dako Corp, Glostrup, Denmark) for 45 minutes. Bound peroxidase was developed with diaminobenzidine (DAB) and hydrogen peroxide and counterstained with haematoxylin. As control tissues, colon was used for P-gp and lung for LRP. Immunoreactivity scoring Two observers without knowledge of the clinical data independently assessed the expression of P-gp and LRP. The distribution of P-gp and LRP expression was semiquantitatively assessed by estimating both the staining intensity and the percentage of positively stained cells. The staining intensity was graded as; + for bright staining, +/– for dull staining, and – for absent staining. Three staining categories were established: negative (absent staining), heterogeneous (bright staining in 10% of tumour cells and dull staining in >10% tumour cells), and positive (bright staining in >10% of the tumour cells).15 Statistical analysis Data were analysed for statistical significance using the 2 test. For statistical analysis heterogeneous expression was combined with positive expression and compared against negative expression in tumours with invasion and tumours with no invasion. Statistical analysis was performed correlating P-gp, LRP expression with laterality of tumours, differentiation and invasion and also correlating between P-gp and LRP expression in the overall cohort. For statistical analysis, moderately differentiated and well differentiated tumours were compared with poorly differentiated tumours. RESULTS Clinical information A total of 60 tumours were available from 60 eyes for the study. Among them, there were tumours from 34 males and 26 females. There were 47 unilateral retinoblastomas and 13 bilateral retinoblastomas. The age of the children ranged from 40 days to 7 years (median 2 years) There were 40 (in table 1: nos 1–40) tumours, which were not subjected to postoperative chemotherapy. There were 20 (in table 2: nos 41–60) tumours enucleated and then the children subjected to post operative chemotherapy because of invasion of choroid/optic nerve and orbit. Table 1 Retinoblastomas enucleated and not subjected to preoperative or postoperative chemotherapy Table 2 Retinoblastomas enucleated and subjected to postoperative chemotherapy Histopathological information There were 12 well differentiated, nine moderately differentiated, and 39 poorly differentiated tumours. Among the 60 tumours, 33 tumours had invasion and 27 tumours had no invasion. Among 33 tumours with invasion, 10 had diffuse choroidal invasion and post-laminar optic nerve invasion (of these, three also had associated orbital invasion), five had diffuse choroid alone, three had focal choroid and post-laminar portion of the optic nerve involved, one had focal choroidal invasion and surgical end of optic nerve, one had prelaminar alone, one prelaminar with focal retinal pigment epithelium (RPE) invasion, one RPE invasion alone, one iris invasion alone, one diffuse choroidal and surgical end involved, one surgical end of optic nerve alone, one prelaminar and post-laminar invasion of optic nerve, and seven had post-laminar portion of the optic nerve involved. Clinical outcome Tumours from cases 1–40 (shown in table 1), which were enucleated and not subjected to postoperative chemotherapy, did not recur. For treatment of cases 41–60 (shown in table 2), the children were subjected to postoperative chemotherapy because of the underlying choroidal invasion/optic nerve invasion/orbital invasion. Four children developed orbital recurrence of the tumour and three children developed bone marrow metastasis. P-gp expression in tumours with no invasion Among the 27 tumours with no invasion, P-gp was expressed in 11 (40%). There were 10 tumours positive for P-gp (five with 70%–80% cells stained with +intensity, three with 40% cells stained with +intensity) and three tumours heterogeneous (30–40% cells stained with +/– intensity). P-gp was negative in 16 tumours. LRP expression in tumours with no invasion Among the 27 tumours with no invasion, LRP was expressed in 15 (55%) tumours. There were 14 tumours positive for LRP (nine with 70%–90% cells stained with +intensity, five with 20%–40% cells stained with +intensity) and one tumour heterogeneous (30% cells stained with +/– intensity). LRP was negative in 12 tumours. P-gp expression and LRP expression in tumours with invasion, orbital recurrence, and metastasis Among 33 tumours with invasion, P-gp was expressed in 10. Among these, seven tumours showed positive staining (four with 50–70% cells stained and three with 20–40% cells stained with +intensity), heterogeneous in three tumours (three with 20% cells stained with +/– intensity). LRP was expressed in 20 tumours; 18 tumours were positive (10 with 60–90% cells stained and eight with 20–50% cells stained with +intensity), two tumours heterogeneous (one with 20% cells stained and one with 40% cells stained with +/– intensity). Among the four children with orbital recurrence P-gp and LRP were positive in two cases each. Among the three children who developed bone marrow metastasis both P-gp and LRP expression were negative. Comparison of P-gp and LRP expression with differentiation of the tumours Among the 12 well differentiated tumours, eight expressed P-gp and seven expressed LRP. Among the nine moderately differentiated tumours, two expressed P-gp, and four expressed LRP. Among the 39 poorly differentiated tumours, 13 expressed P-gp and 24 expressed LRP. There was no correlation between differentiation of the tumours with P-gp and LRP expression. P-gp and LRP expression in unilateral and bilateral tumours Among the 47 unilateral tumours, 17 (36%) expressed P-gp and 30 (64%) expressed LRP. Among the 13 bilateral tumours, four (30%) expressed P-gp and six (46%) expressed LRP. There was no correlation between laterality of the tumours with P-gp and LRP expression. Figure 1 shows the P-gp expression and figure 2 shows the LRP expression in retinoblastoma respectively. Figure 1 P-glycoprotein (P-gp) expression in retinoblastoma. (A) Microphotograph showing P-gp in the membrane of the tumour cells (in >10% of the tumour cells with bright intensity) in retinoblastoma with no invasion (DAB with haematoxylin and eosin counterstain, x200). (B) Microphotograph showing the P-gp in the membrane of the tumour cells (in >10% of the tumour cells with dull intensity) in a child who had orbital recurrence (DAB with haematoxylin and eosin counterstain, x100). (C) Microphotograph showing the P-gp in the membrane of the tumour cells (in 30–40% of the tumour cells with dull intensity) in retinoblastoma with no invasion (DAB with haematoxylin and eosin counterstain, x100). Figure 2 Lung resistance protein (LRP) expression in retinoblastoma. (A) Microphotograph showing the LRP in the cytoplasm of the tumour cells (>10% cells stained with bright intensity) in retinoblastoma with no invasion (DAB with haematoxylin and eosin counterstain, x200). Inset shows the lower magnification of the same). (B) Microphotograph showing the LRP (in >10% of the tumour cells with dull intensity) in retinoblastoma in with invasion (DAB with haematoxylin and eosin counterstain, x100). (C) Microphotograph showing the LRP (in >10% of the tumour cells with bright intensity) in the pretreatment tumour sample in a child with no invasion. (DAB with haematoxylin and eosin counterstain, x100). DISCUSSION Evidence for a clinically relevant role for multidrug resistance proteins in retinoblastoma is not readily available because these tumours are seldom tested before chemotherapy; moreover, in these bilateral cases, test results of tumours in the enucleated eye that do not require further treatment cannot be considered predictive of the P-gp or LRP expression of retinoblastoma in the retained eye undergoing chemotherapy, because each tumour arises as a result of different second mutation, although they share a common germ line RB1 mutation. Thus, the available data that correlate multidrug resistance proteins expression with outcome of chemotherapy in retinoblastoma are meagre and circumstantial. In our study P-gp was expressed in 38% (23/60) of tumours and LRP expressed in 58% (35/60) of tumours. Thus, this shows that retinoblastomas express P-gp and LRP intrinsically even previous chemotherapy. P-gp was expressed in 40% of tumours with no invasion and 36% of tumours with invasion. LRP was expressed in 55% of tumours with no invasion and 60% of tumours with invasion. Thus, there was no correlation of these proteins with invasiveness. There was also no correlation of these proteins with differentiation of the tumours and laterality. Regarding the correlation of these proteins with response to chemotherapy, since the 40 tumours (1–40), were not subjected to any chemotherapy, we cannot correlate the P-gp and LRP expression in the tumour samples with clinical outcome. In the 20 tumours that were subjected to postoperative chemotherapy 13 responded well to postoperative chemotherapy (P-gp was positive in five and LRP was positive in seven). There were seven children who did not do well despite postoperative chemotherapy (four developed orbital recurrence and three bone marrow metastasis; P-gp and LRP were positive in only two tumours). Thus, we were not able to use P-gp and LRP expression to predict the biological behaviour of the tumour. There is only one study on the expression of MDR proteins in retinoblastoma other than those of Galle and Chan et al.2–6 In a study17 on Rb cell line HXO-RB, the investigators observed that tumour cell lines expressed both multidrug resistance gene (MDR1) and multidrug associated protein P-gp. However it was only on cell lines, and there was no clinical correlation. Our study results are different from those of Gallie and Chan in that we did not find any correlation between the expression of P-gp and invasiveness of the tumours and response to treatment. Thus, whether P-gp protein has a rate limiting role in chemotherapy remains a challenging question. Few reports have attempted to correlate the high levels of P-gp found in carcinomas with outcome. Some studies of acute myelogeneous and acute lymphoblastic leukaemia, myeloma, lymphoma, rhabdomyosarcoma, and neuroblastoma have shown that the presence of detectable levels of P-gp correlated with poor prognosis and the absence of this protein with long term disease free survival. However, other studies on leukaemia, lymphoma, and neuroblastoma showed no such correlations.18 This is the first study on LRP expression in retinoblastoma. Our study shows that retinoblastoma expresses LRP intrinsically. The major vault protein/LRP was initially described in non-small cell lung cancer cell lines that lacked P-gp. Recently, it became evident that LRP is present in a variety of human cancer cell lines that have not previously been exposed to drugs. In these cell lines the expression of LRP correlated with intrinsic resistance to doxorubicin, vincristine, and platinum compounds.14 However, we were not able to correlate LRP expression with clinicopathological parameters or with chemotherapy. Then how do we explain the expression of P-gp in retinoblastoma? Firstly, the distribution of P-gp in normal tissue suggests a physiological role of detoxification, excretion, and protection of vital organs against toxic products and xenobiotics.19 P-gp expression has been observed in rabbit retina-choroid suggesting the involvement of a multidrug efflux transporter on the RPE and neural retina, which affects intraocular kinetics following systemic and intravitreal administrations of drugs.20 Thus, the expression of the P-gp by the tumour cells may help in transport of substrates intracellularly and this could be critical for tumour cell growth. Secondly, it could be that P-gp reflects an alternative antigenic marker of a primitive blast phenotype that, in this disease, represents only one of many redundant cell defence mechanisms or survival signals. Thus, in conclusion, our findings seem to reflect the existence of intrinsically resistant tumour cell clones in retinoblastoma before chemotherapeutic treatment. Interestingly, the presence of P-gp and LRP were unrelated to the response of the tumours to chemotherapy. This suggests that the role of these markers in tumour progression may be independent of their putative role in drug resistance.21 It is difficult to determine the exact contribution of these markers to clinical drug resistance, as most chemotherapeutic regimens consist of a combination of anticancer drugs with at least one drug not involved in the MDR phenotype. New treatment strategies, directed against those quiescent tumour cells that are not killed by the available drugs, are awaited. Thus, further studies are needed to understand the significance of the expression of the P-gp and LRP proteins in retinoblastoma. REFERENCES Rodriguez-Galindo C , Wilson MW, Haik BG, et al. Treatment of metastatic retinoblastoma. Ophthalmology 2003;110:1237–40. Chan HS, Thorner PS, Haddad G, et al. Multidrug-resistant phenotype in retinoblastoma correlates with P-glycoprotein expression. Ophthalmology 1991;98:1425–31. Chan HS, Canton MD, Gallie BL. Chemosensitivity and multidrug resistant to antineoplastic drugs in retinoblastoma cell lines. Anticancer Res 1989;9:469–74. Chan HS, Thorner PS, Haddad G, et al. Effect of chemotherapy on intraocular retinoblastoma. Int J Pediatr Hematol Oncol 1995;2:269–81. Chan HS, Lu Y, Grogan TM, et al. Multidrug resistance protein (MRP) expression in retinoblastoma correlates with the rare failure of chemotherapy despite cyclosporine for reversal of P-glycoprotein. Cancer Res 1997;57:2325–30. Gallie BL, Budning A, DeBoer G, et al. Chemotherapy with focal therapy can cure intraocular retinoblastoma without radiotherapy. Arch Ophthalmol. 1996;114: 1321–8, Erratum in: Arch Ophthalmol 1997;115:525. Chan HS, DeBoer G, Thiessen JJ, et al. Combining cyclosporin with chemotherapy controls intraocular retinoblastoma without requiring radiation. Clin Cancer Res 1996;2:1499–508. Shields CL, De Potter P, Himelstein BP, et al. Chemoreduction in the initial management of intraocular retinoblastoma. Arch Ophthalmol 1996;114:1330–8. Friedman DL, Himelstein B, Shields CL, et al. Chemoreduction and local ophthalmic therapy for intraocular retinoblastoma. J Clin Oncol 2000;18:12–17. Murphree L , Villablanca JG, Deegan WF 3rd, et al. hemotherapy plus local treatment in the management of intraocular retinoblastoma. Arch Ophthalmol 1996;114:1348–56. Greenwald MJ, Strauss LC. Treatment of intraocular retinoblastoma with carboplatin and etoposide chemotherapy. Ophthalmology 1996;103:1989–97. Gerlach JH, Kartner N, Bell DR, et al. Multidrug resistance. Cancer Surv 1986;5:25–46. Scheper RJ, Broxterman HJ, Scheffer GL, et al. Overexpression of a M(r) 110,000 vesicular protein in non-P-glycoprotein-mediated multidrug resistance. Cancer Res 1993;53:1475–9. Scheffer GL, Wijngaard PL, Flens MJ, et al. The drug resistance-related protein LRP is the human major vault protein. Nat Med 1995;1:578–82. Zurita AJ, Diestra JE, Condom E, et al. Lung resistance-related protein as a predictor of clinical outcome in advanced testicular germ-cell tumors. Br J Cancer 2003;88:879–86. Finger PT, Harbour JW, Karcioglu ZA. Risk factors for metastasis in retinoblastoma. Surv Ophthalmol 2002;47:1–16. Liu J , Tang L, Liu X, et al. A gene study on multidrug resistance of retinoblastoma. Zhonghua Yan Ke Za Zhi 2001;37. Fisher GA, Sikic BI. Drug resistance in clinical oncology and hematology. Introduction. Hematol Oncol Clin North Am 1995;9:xi–xii. Duhem C , Ries F, Dicato M. What does multidrug resistance (MDR) expression mean in the clinic? Oncologist 1996;1:151–8. Duvvuri S , Gandhi MD, Mitra AK. Effect of P-glycoprotein on the ocular disposition of a model substrate, quinidine. Curr Eye Res 2003;27:345–53. Pinedo HM, Giaccone G. P-glycoprotein—a marker of cancer cell behavior. N Engl J Med 1995;333:1417–19....查看详细 (24452字节)
☉ 11333144:Children With Idiopathic Short Stature Are Poor Eaters and Have Decreased Body Mass Index
Departments of General Pediatrics and Neonatology Pediatric Radiology, Center of Child and Adolescent Medicine, Justus Liebig University, Giessen, Germany Institute of Medical Biometry and Epidemiology, Philipps University, Marburg, Germany Eli Lilly and Company, Bad Homburg, Germany Department of General Pediatrics and Neonatology, University of the Saarland, Homburg, Germany Department of Child and Adolescent Psychiatry, Rheinische Kliniken Essen, Universitt Duisburg-Essen, Essen, Germany ABSTRACT Objective. In children with idiopathic short stature (ISS), studies investigating body mass index (BMI) or parameters of satiety regulation are scarce, and studies analyzing eating behavior are lacking. Methods. We recruited 214 children (123 index cases and 91 siblings) with ISS from 123 families. Affected children had to have a body height 3rd percentile for gestational age.13 Children with dysmorphic features or chronic diseases were excluded; this was ensured by tests for chronic inflammatory (erythrocyte sedimentation rate, blood count, C-reactive protein), celiac (gliadin and endomysium antibodies), hepatic (aspartate aminotransferase, alanine aminotransferase), or renal (creatinine) diseases and hypothyroidism (free thyroxin, thyrotropin). Growth-hormone deficiency was considered to be unlikely based on serum insulin-like growth factor I (IGF-I) and insulin-like growth factor–binding protein 3 (IGFBP-3) levels. Data Collection Medical histories of children and parents were recorded by using structured and standardized interviews. All interviews and clinical examinations were performed by the same physician (S.H.). Eating behavior was assessed by using the Child Eating Behavior Questionnaire14 (CEBQ), an instrument that allows the analysis of 8 dimensions of eating style developed in 400 British boys and girls. Daily energy and macronutrient intake was assessed according to the Leeds Food Frequency Questionnaire (LFFQ).15,16 Within a structured interview, we additionally asked mothers to characterize their children as "poor eaters" or "good eaters" by means of the following question: "Is or has your child been a poor eater (ie, has your child ever eaten or drunk poorly for at least 4 weeks)" The options provided for answering this question were "yes," "no," "unknown," or answer denied. Classification of the children as "poor" or "good" eaters was based on their current situation. Body height was measured to the nearest 0.1 cm by using an Ulm Stadiometer (Busse, Ulm, Germany). A Shnle type 7723 digital portable scale (capacity of 250 kg, precision of 0.1 kg) was used for measuring body weight. Pubertal development was characterized according to Tanner stage (pubic hair and breast development in girls, testicular volume and genital development in boys). Body height and BMI (kg/m2) were compared with the most current German reference data from >34000 children and adolescents.12 Target height was calculated according to Tanner et al.17 Bone age was assessed independently by 3 pediatric radiologists according to the method of Greulich and Pyle18 from radiograph films of the left hand. Bone-age determination was performed blinded for the patients' birth date, and the mean of 3 ratings for each radiograph was used. The interobserver agreement was very good as judged from pairwise Bland-Altman bias plots,19 in which mean differences between 2 raters were between 0.5 and 2.3 months and 95% limits of agreement were between 14 and 24 months. If available, radiograph films from earlier presentations at our outpatient clinic were considered as well (1–6 radiograph films were available per child), and the mean and maximal bone-age retardations at different time points were calculated. IGF-I, IGFBP-3,20 leptin,21 and total ghrelin (Linco Research Inc, St Charles, MO) were measured in our endocrinologic laboratory. All other parameters were measured by routine methods in our hospital's laboratory for clinical chemistry. For IGF-I and IGFBP-3, gender- and age-dependent standard deviation score (SDS) values were calculated,20 and leptin was transformed to SDS values according to gender, BMI, and pubertal stage.22 Data Analysis Because our sample comprised both single children and pairs of siblings, not all observations were independent; consequently, group means considering all children would give incorrect estimates of underlying population means. Therefore, to calculate the appropriate means (as well as means for subgroups, eg, good and poor eaters) for different variables, we used a linear model (analysis of variance), which included family as an independent fixed factor (with subgroup as an independent random factor if applicable) and calculated marginal means over families. Using the same model, we also tested for differences between subgroups. LFFQ data were available only for 103 index patients (who are independent) and were compared between subgroups by using an unpaired t test. Data analysis was performed by using SPSS 11.0 (SPSS Inc, Chicago, IL). RESULTS Our sample of 214 children included 56 cases (26.2%) with a bone-age delay of >1 year, 43 cases (20.1%) of FSS, 92 cases (43.0%) with a combination of both conditions, and 23 cases (10.7%) without pronounced bone-age retardation and with normal target height. A summary of clinical and anthropometric data of the 123 index patients and 91 siblings is given in Table 1. With respect to gender distribution, there was a striking imbalance in the group of index patients, with a majority of almost two thirds being male gender, whereas no difference could be found among siblings. Additionally, body height was considerably lower, by almost 1 SDS, in index patients. Bone-age retardation was clearly more pronounced in index patients compared with their siblings. Between male and female siblings there was no difference in height SDS (mean height SDS in male siblings: –1.57; mean height SDS in female siblings: –1.52; P = .58). BMI SDS was not correlated significantly with chronological age. The mean BMI SDS was –0.36 for children with pronounced bone-age delay (>1 year), which was slightly lower than in the group of children with no or a slight delay (1.96, compared with 5% expected from a general population sample. It was unexpected that patients with ISS have relatively high leptin levels for their BMI, a fact that may indicate alterations in endocrine mechanisms of satiety regulation in parallel to the observed altered eating behavior. Furthermore, our results are not in accordance with observations made by other investigators in smaller samples of children. Gill et al5 studied 23 boys with CDGP and found lower BMI values only in prepubertal children, whereas leptin was decreased only in pubertal children. In contrast, Bideci et al6 assessed 80 children with CDGP and also found decreased BMI values and decreased serum levels of leptin, but they did not adjust leptin for BMI. Ghrelin is a potent growth hormone secretagogue that exerts strong orexigenic effects. It has been shown to induce obesity in animals and stimulate appetite in humans.27 Increased levels of ghrelin in anorexia nervosa and weight loss, and reduced levels in obesity, have been reported.28,29 A comparison of the absolute ghrelin values of our study population with previously published data27,28 is not possible because different commercial assay kits provide different values. We used a new and recently developed procedure, for which reference data in healthy children are not yet available. The data reported in this article refer to the measurement of total serum ghrelin; bioactive, octanylated ghrelin could not be determined by our assay. Similar to leptin, total ghrelin did not show any differences between poor and good eaters. CONCLUSIONS Our clinical, behavioral, and endocrinologic findings in children with ISS point to an altered regulation of appetite and energy balance. It is possible that this altered regulation could contribute to the reduced height of these children. Alternatively, a currently unknown factor may induce both a reduced height growth and an altered eating behavior. ACKNOWLEDGMENTS This work was funded by German National Genome Research Network grant NGFN 01GSO118 and the European Union (Diet and Obesity; grant QLK1-2000-00515). We are grateful to the children and their parents for their participation in this study. FOOTNOTES Accepted Dec 29, 2004. No conflict of interest declared. REFERENCES Bierich JR. Constitutional delay of growth and adolescence. Baillieres Clin Endocrinol Metab. 1992;6 :573 –587 Pasquino AM, Albanese A, Bozzola M, et al. Idiopathic short stature. J Pediatr Endocrinol Metab. 2001;14(suppl 2) :967 –974 Lanes R, Lee P, Plotnick LP, Kowarski AA, Migeon CJ. Are constitutional delay of growth and familial short stature different conditions Clin Pediatr (Phila). 1980;19 :31 –33 Sedlmeyer IL, Palmert MR. Delayed puberty: analysis of a large case series from an academic center. J Clin Endocrinol Metab. 2002;87 :1613 –1620 Gill MS, Hall CM, Tillmann V, Clayton P. Constitutional delay in growth and puberty (CDGP) is associated with hypoleptinaemia. Clin Endocrinol. 1999;50 :721 –726 Bideci A, Cinaz P, Hasanoglu A, Tümer L. Leptin, insulin-like growth factor (IGF)-I and IGF binding protein-3 levels in children with constitutional delay of growth. J Pediatr Endocrinol Metab. 2002;15 :41 –46 Crowne EC, Shalet SM, Wallace WHB, Eminson DM, Price DA. Final height in boys with untreated constitutional delay in growth and puberty. Arch Dis Child. 1990;65 :1109 –1112 Wickman S, Sipil I, Ankarberg-Lindgren C, Norjavaara E, Dunkel L. A specific aromatase inhibitor and potential increase in adult height in boys with delayed puberty: a randomised controlled trial. Lancet. 2001;357 :1743 –1748 Papadimitriou A, Wacharasindhu S, Pearl K, Preece MA, Stanhope R. Treatment of constitutional growth delay in prepubertal boys with a prolonged course of low dose oxandrolone. Arch Dis Child. 1991;66 :841 –843 Thibault H, Souberbielle JC, Taieb C, Brauner R. Idiopathic prepubertal short stature is associated with low body mass index. Horm Res. 1993;40 :136 –140 Wright C, Birks E. Risk factors for failure to thrive: a population-based survey. Child Care Health Dev. 2000;26 :5 –16 Kromeyer-Hauschild K, Wabitsch M, Kunze D, et al. Perzentile für den Bodymass-Index für das Kindes- und Jugendalter unter Heranziehung verschiedener deutscher Stichproben. Monatsschr Kinderheilkd. 2001;149 :807 –818 Voigt M, Schneider KT, Jahrig K. Analysis of a 1992 birth sample in Germany. 1: New percent values of the body weight of newborn infants [in German]. Geburtshilfe Frauenheilkd. 1996;56 :550 –558 Wardle J, Guthrie CA, Sanderson S, Rapoport L. Development of the Children's Eating Behaviour Questionnaire. J Child Psychol Psychiatry. 2001;42 :963 –970 Cooling J, Blundell J. Differences in energy expenditure and substrate oxidation between habitual high fat and low fat consumers (phenotypes). Int J Obes Relat Metab Disord. 1998;22 :612 –618 Margetts BM, Cade JE, Osmond C. Comparison of a food frequency questionnaire with a diet record. Int J Epidemiol. 1989;18 :868 –873 Tanner JM, Goldstein H, Whitehouse RH. Standards for children's height at ages 2–9 years allowing for height of parents. Arch Dis Child. 1970;45 :755 –762 Greulich WW, Pyle SJ. Radiographic Atlas of Skeletal Development of the Hand and Wrist. 2nd ed. Stanford, CA: Stanford University Press; 1976 Bland JM, Altmann DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet. 1986;1 (8476):307–310 Blum WF, Schweizer R. Insulin-like growth factors and their binding proteins. In: Ranke MB, ed. Diagnostics of Endocrine Function in Children and Adolescents. Basel, Switzerland: Karger; 2003: 166–199 Blum WF, Englaro P, Hanitsch S, et al. Plasma leptin levels in healthy children and adolescents: dependence on body mass index, body fat mass, gender, pubertal stage, and testosterone. J Clin Endocrinol Metab. 1997;82 :2904 –2910 Blum WF, Juul A. Reference ranges of serum leptin levels according to body mass index, gender, and developmental stage. In: Blum WF, Kiess W, Rascher W, eds. Leptin—The Voice of Adipose Tissue. Heidelberg-Leipzig, Germany: Barth Verlag; 1997: 318–326 Horner JM, Thorsson AV, Hintz RL. Growth deceleration patterns in children with constitutional short stature: an aid to diagnosis. Pediatrics. 1978;62 :529 –534 Solans CV, Lifshitz F. Body weight progression and nutritional status of patients with familial short stature with and without constitutional delay in growth. Am J Dis Child. 1992;146 :296 –302 Blum WF, Englaro P, Attanasio AM, Kiess W, Rascher W. Human and clinical perspectives on leptin. Proc Nutr Soc. 1998;57 :477 –485 Kiess W, Müller G, Galler A, Reich A, Deutscher J, Klamm J, Kratzsch. Body fat mass, leptin and puberty. J Pediatr Endocrinol Metab. 2000;13 (suppl 1):717–722 Haqq AM, Farooqi IS, O'Rahilly S, et al. Serum ghrelin levels are inversely correlated with body mass index, age, and insulin concentrations in normal children and are markedly increased in Prader-Willi syndrome. J Clin Endocrinol Metab. 2003;88 :174 –178 Bellone S, Rapa A, Vivenza D, et al. Circulating ghrelin levels as function of gender, pubertal status and adiposity in childhood. J Endocrinol Invest. 2002;25 :RC13 –RC15 Hansen TK, Dall R, Hosoda H, et al. Weight loss increases circulating levels of ghrelin in human obesity. Clin Endocrinol. 2002;56 :203 –206...查看详细 (26343字节)
☉ 11333145:Is screening for interferon retinopathy in hepatitis C justified?
St James University Hospital, Beckett Street, Leeds LS9 7TF, UK ABSTRACT Background/aim: In the treatment of hepatitis C, the National Institute for Clinical Excellence advocates use of a combination of interferon alfa and ribavirin for selected patients. Retinopathy is a well recognised side effect of interferon therapy and is characterised by retinal haemorrhages, cotton wool spots, and macular oedema. The aim of this study was to document the incidence and natural history of the retinopathy in patients treated with a long acting (pegylated) interferon and ribavirin for hepatitis C and to assess the need to screen for retinal complications. Methods: All patients started on treatment from September 2002 to August 2003 were invited to participate in the study. The past medical and ocular history, visual symptoms, and the results of a full ophthalmological assessment performed 3 months after starting treatment were noted. Any patient with retinal changes was followed up at 3 month intervals until the changes resolved. Results: Of the 25 patients examined, four had evidence of retinopathy including deep retinal haemorrhage and cotton wool spots. Two of the patients were diabetic and one hypertensive. None had any visual symptoms and in all four the retinopathy resolved while the patients completed their course of treatment. Conclusions: The incidence of retinopathy with pegylated interferon is low. The retinal complications resolve while treatment is continued and are asymptomatic. This study does not support routine screening for retinopathy in patients treated with pegylated interferon and ribavirin for hepatitis C. Keywords: interferon; hepatitis C Hepatitis C is a blood borne RNA virus that can cause chronic liver disease. In the United Kingdom, the National Institute for Clinical Excellence (NICE)1 advocates treatment with a combination of interferon alfa and ribavirin for patients with moderate to severe hepatitis C infection. Treatment is recommended for all adults who have not had previous interferon alfa monotherapy, as well as for those who have had previous treatment leading to an initial response and have then relapsed. Interferon associated retinopathy was first described in 1990 by Ikebe et al.2 Features include haemorrhages and cotton wool spots around the disc and through the posterior pole, optic disc hyperaemia, and macular oedema.3,4 In addition, fluorescein angiography may demonstrate poorly perfused areas of retina.3,4 The reported incidence of retinopathy as a side effect of interferon varies widely in the literature. There is some evidence to suggest that the incidence of the retinopathy may be dose dependent.4 Treatment regimens with subcutaneous doses of interferon varying from 3x106 units three times a week to 9x106 units six times a week have been used for the hepatitis viruses, with higher doses used in the treatment of various malignancies.5,6 Case series and reports have shown an increased incidence of retinopathy in patients on higher and more frequent doses.7,8 Recently, a long acting form of interferon alfa has been developed, known as pegylated or polyethylene glycol conjugated interferon. This drug has slower absorption, a reduced volume of distribution, and lower elimination rates,9 as well as showing a more sustained virological response.10 Plasma levels of the drug are kept more stable, with a lower peak level. The local treatment protocol in our area uses pegylated interferon in combination with ribavirin. This encompasses a dose of 1.5 μg/kg of pegylated interferon, with an average 70 kg person receiving 105 μg per week. The dose of ribavirin used is also weight dependent with a total of 800 mg split over the day for people weighing 30–64 kg, 1000 mg for 65–86 kg, and 1200 mg over 86 kg. There are no previous reports in the literature relating to the incidence and severity of ocular side effects in patients treated with this regimen. Given the apparent dose dependent nature of interferon associated retinopathy and the altered pharmacokinetics of pegylated interferon, the aims of this study were to document the incidence and natural history of interferon associated retinopathy, to record any associated visual symptoms or systemic conditions, and to assess whether screening for this complication would be worthwhile. METHODS Patients started on combination treatment with pegylated interferon and ribavirin for hepatitis C during the study period were referred for ophthalmic examination by the hepatology team. Patients were normally examined by an ophthalmologist (FC) as close to 3 months after starting their treatment as possible. Patients with new visual symptoms were also seen sooner. Those patients with evidence of retinopathy at the 3 month stage were followed up at 3 month intervals until the retinopathy resolved. No changes to the interferon and ribavirin treatment regimen were made for these patients. Full ocular and past medical histories were taken, and ocular examination was performed. This consisted of visual acuity assessment, slit lamp examination, applanation tonometry, and dilated fundal examination. Fundal photographs to document any abnormal findings were taken where appropriate. Full blood count parameters, blood pressure, and viral genotype were also recorded. RESULTS Between August 2002 and August 2003 32 patients were referred for screening, of whom 25 attended for ophthalmic assessment. All the patients were on treatment with pegylated interferon alfa and ribavirin according to the local protocol. There were 15 men and 10 women, with ages ranging from 26 to 73 years (see table 1). Of the seven patients who did not attend for ophthalmological assessment, one died, two had their treatment stopped for unrelated reasons, and four failed to attend despite a number of appointments being offered. Table 1 Summary of patient details and findings At the 3 month examination, four of the 25 patients (16%) had evidence of retinopathy consisting of cotton wool spots and/or haemorrhages (fig 1). This was bilateral in three patients and unilateral in one. None of these patients had macular oedema, disc changes or visual symptoms. Of the patients reporting visual symptoms, none of these were attributable to interferon retinopathy. Figure 1 Retinopathy seen in patient 1 (A, B), patient 2 (C), and patient 3 (D). Diabetes mellitus was present in two of the 25 patients examined, both of whom had retinopathy. Systemic hypertension was present in four of the 25 patients, but only one had retinopathy. Full blood count abnormalities (haemoglobin 10 g/dl, white cell count 4 or platelets 100) were present in eight out of the 25 patients, only one of whom developed retinopathy. At the time of the 3 month examination when the retinopathy was noted, both the haemoglobin and platelets were back within normal limits. In the 25 patients examined, the most common viral genotype was 3a. The genotypes of the hepatitis C virus in affected patients were type 1 in one patient, type 2 in one patient, and type 3a in the remaining two. For the four patients with retinopathy at the 3 month visit, further visits were arranged. After an additional 3 months the retinopathy had disappeared in all patients except one, whose retinopathy had gone by 9 months after the initiation of treatment. All patients completed their planned courses of treatment without any dosage alteration. DISCUSSION Ocular side effects are well recognised complications of interferon and ribavirin therapy for hepatitis C, with the most common of these being an ischaemic retinopathy characterised by haemorrhages and cotton wool spots. Other features include optic disc hyperaemia and macular oedema. The incidence of reported retinopathy in patients on treatment with interferon for hepatitis viruses in the literature is very variable, with figures from fairly small scale studies ranging from 18% to 86%.4,7,11–18 Some of these studies have suggested that the retinopathy may be dose dependent or more common in patients with diabetes,4 hypertension,13 and abnormal full blood count parameters. It is notable that many of the previous studies looking at incidence of retinopathy were carried out with patients on high doses of interferon ranging from 6x106 to 10x106 units three times a week, which would be associated with high peak concentrations in tissues. Previous recommended treatment protocols have been based on the use of standard interferon alfa with ribavirin. They suggest that all patients receive 6 months of treatment initially, with a further 6 months offered to those with the type 1 viral genotype who have shown a good initial response to treatment with clearance of the virus. The dose of interferon used in standard treatment is 3 million (3x106) units subcutaneously three times a week. Following the recent availability of pegylated interferon, local treatment protocols have been adapted to use this. The advantages include less frequent injections, improved bioavailability but a lower total dose. The incidence of retinopathy in our patient population was four out of 25 (16%), which is lower than in any of the previously published studies. None of the four patients with retinopathy were symptomatic. In each case, the retinopathy resolved without long term sequelae. No patient had premature termination or alteration of their treatment regimen. Looking at the possible risk factors for developing interferon associated retinopathy, the presence of diabetes mellitus and systemic hypertension in this and other studies is similar. In this study, both the diabetic patients developed retinopathy but the number of cases is small. We found no convincing association of retinopathy with abnormal full blood count parameters or viral genotype. Although the incidence of interferon associated retinopathy may be dose dependent, the exact mechanism by which this retinopathy develops remains unknown. The similarity of the clinical features to diabetic and hypertensive retinopathy suggests an ischaemic mechanism. Others have suggested that the deposition of immune complexes in the retinal vasculature leads to capillary non-perfusion and the formation of cotton wool spots.5 By carrying out just one basic screening assessment at 3 months after starting the treatment it could be argued that there is potential to miss patients with retinal changes. Previous case series have commented on the time of onset of retinopathy in relation to the start of treatment. Most report onset of the retinopathy in the first 8–12 weeks following the start of treatment4,11,19,20 with just a few noticing retinopathy later. Our feeling was that there was sufficient evidence in previous studies to point to the most likely time for retinopathy to develop as being within the first 3 months, and that any earlier complications were unlikely to have resolved by then. It would theoretically be possible to miss earlier retinopathy that had remained asymptomatic and had resolved by the 3 month visit, but this is not likely to be of any clinical significance. Changes at a later date with a normal 3 month examination were unlikely. This study confirms previous reports that retinopathy is a temporary and asymptomatic complication of interferon therapy, but suggests that the incidence of retinopathy with pegylated interferon is less than with standard interferon. As there are no visual symptoms or sequelae, we feel that routine screening for interferon associated retinopathy is not justified. REFERENCES Dillon A . Guidance on the use of ribavirin and interferon alpha for hepatitis C. October 2000, from the National Institute of Clinical Excellence. www.nice.org.uk/article.asp?a=11676. Ikebe T , Nakatsuka K, Goto M, et al. A case of retinopathy induced by intravenous administration of interferon. Folia Ophthalmol Jpn (Ganka-Kiyo) 1990;41:2291–6. Tu KL, Bowyer J, Schofield K, et al. Severe interferon associated retinopathy. Br J Ophthalmol 2003;87:247–8. Hayasaka S , Nagaki Y, Matsumoto M, et al. Interferon associated retinopathy. Br J Ophthalmol 1998;82:323–5. Guyer DR, Tiedemann J, Yannuzzi LA, et al. Interferon-associated retinopathy. Arch Ophthalmol 1993;111:350–6. Esmaeli B , Koller C, Papedopoulos N, et al. Interferon-induced retinopathy in asymtomatic cancer patients. Ophthalmology 2001;108:858–60. Hayasaka S , Fujii M, Yamamoto Y, et al. Retinopathy and subconjunctival haemorrhage in patient with chronic viral hepatitis receiving interferon alfa. Br J Ophthalmol 1995;79:150–2. Hayasaka S , Okada M, Yamamoto S. Retinopathy in chronic hepatitis C patients treated by systemic interferon alfa-2b. J Rev Clin Ophthalmol (Ganka Rinsho Iho) 1996;90:1264–6. Lake-Bakaar G . Current and future therapy for chronic hepatitis C virus liver disease. Curr Drug Targets Infect Disord 2003;3:247–53. Medina J , Garcia BL, et al. Therapeutic advantages of pegylation on interferon alpha in chronic hepatitis C. Rev Esp Enferm Dig 2003;95:568–74, 561-7. Kawano T , Shigehira M, Woo H, et al. Retinal complications during interferon therapy for chronic hepatitis C. Am J Gastroenterol 1996;91:309–13. Jain K , Lam WC, Waseeb S, et al. Retinopathy in chronic hepatitis C patients during interferon treatment with ribavirin. Br J Ophthalmol 2001;85:1171–3. Saito H , Ebinuma H, Nagata H, et al. Interferon-associated retinopathy in a uniform regimen of natural interferon-alpha therapy for chronic hepatitis C. Liver 2001;21:192–7. Takikawa H , Kawakubo H, Yuzawa M, et al. Interferon associated retinopathy induced by interferon ?. Ganka 1994;36:189–93. Seki K , Itou Y, Nishi Y, et al. Interferon therapy for type C chronic active hepatitis and retinal haemorrhage. Acta Hepatol Jpn 1993;34:385–91. Soushi S , Kobayashi F, Obazawa H, et al. Evaluation of risk factors of interferon-associated retinopathy in patients with type C chronic active hepatitis. J Jpn Ophthalmol Soc (Nichigan Kaishi) 1996;100:69–76. Kadayifcilar S , Boyacioglu S, Kart H, et al. Ocular complications with high-dose interferon alpha in chronic active hepatitis. Eye 1999;13:241–6. Chuman T , Nao-i N, Sawada A, et al. Interferon-induced retinal changes. Nippon Ganka Gakkai Zasshi 1994;98:616–21. Sugano S , Yanagimoto M, Suzuki T, et al. Retinal complications with elevated circulating plasma C5a associated with interferon- therapy for chronic active hepatitis C. Am J Gastroenterol 1994;89:205–6. Manesis E , Moschol M, Borouzas D, et al. Neurovisual impairment: a frequent complication of alpha-interferon treatment in chronic viral hepatitis. Hepatology 1998;27:1421–7....查看详细 (14873字节)
☉ 11333146:Outcome of Extremely Low Birth Weight Infants With Leukemoid Reaction
the Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, East Lansing, Michigan; and Division of Neonatology, Sparrow Regional Children's Center, Lansing, Michigan ABSTRACT Background. Leukemoid reaction (LR) is defined as an absolute neutrophil count (ANC) of >30 x 103/mm3. No previous study has systemically examined the clinical and prognostic significance of this phenomenon in extremely low birth weight (ELBW) infants. Objective. The purpose of this study was to examine the effect of LR in morbidity, mortality, and long-term developmental outcome in ELBW infants. Method. Infants with gestational age of 30 weeks and birth weight 1000 g were included in the study (n = 152). The medical records were reviewed for the clinical characteristics and long-term developmental outcome of these infants. Serial complete blood cell count and ANC were calculated on day 1 and weekly thereafter until discharge. LR was defined as an ANC of >30 x 103/mm3. Results. LR was detected in 17% of the study infants (26 of 152). ANC increased postnatally in LR (n = 26) and no-LR (n = 126) infants during hospitalization, peaked in the second week of life (43 ± 3 vs 14 ± 1 x 103/mm3), and remained significantly higher in LR infants during the first 5 weeks of life. LR occurred more frequently during the first 2 weeks of life and lasted for 3 ± 1 days. There was no significant difference between the LR and no-LR infants in gestational age, birth weight, delivery mode, gender, Apgar scores, or incidence of respiratory distress syndrome, patent ductus arteriosus, necrotizing enterocolitis, intraventricular hemorrhage, and retinopathy of prematurity. LR infants required a significantly longer duration of ventilatory support (36 ± 4 vs 21 ± 2 days), longer duration of oxygen requirement (58 ± 6 vs 40 ± 3 days), and had a higher incidence of bronchopulmonary dysplasia (BPD) (54% vs 25%) compared with no-LR infants. Furthermore, the length of hospitalization was significantly longer in LR infants (69 ± 6 vs 54 ± 3 days). There was no significant difference between the groups in developmental outcome at 2 years of age including receptive/expressive language, fine/gross motor skills, and hearing. Incidence of abnormal neurodevelopment outcome was also similar between LR and no-LR infants. Conclusions. LR in ELBW infants is associated with a prolonged need for ventilatory and oxygen support, a higher incidence of BPD, and a tendency for lower mortality. The findings from our study suggest that LR is associated with conditions known to have an excess of proinflammatory cytokines. Additional prospective study is needed to understand the relationship between LR, proinflammatory cytokines, and development of BPD. Key Words: leukemoid reaction absolute neutrophil count extremely low birth weight infants bronchopulmonary dysplasia Abbreviations: LR, leukemoid reaction ANC, absolute neutrophil count ANS, antenatal corticosteroids BPD, bronchopulmonary dysplasia ELBW, extremely low birth weight CBC, complete blood cell PDA, patent ductus arteriosus RDS, respiratory distress syndrome PNS, postnatal corticosteroids NEC, necrotizing enterocolitis IVH, intraventricular hemorrhage PVL, periventricular leukomalacia ROP, retinopathy of prematurity LOH, length of hospitalization IL, interleukin G-CSF, granulocyte colony-stimulating factor Improvement in neonatal care has led to increased survival of premature infants with lower gestations at the cost of higher morbidity.1–4 The majority of morbidities occur as the result of immature adaptation to postnatal life, which can involve all major organs (including the hematologic system), with an increased prevalence of early- and late-onset neutropenia and neutrophilia.5 Neutrophilia with leukocyte a count of 50 x 103/mm3 associated with nonmalignant conditions has been described previously as leukemoid reaction (LR).6 Earlier studies of LR were done in an adult population. Holland and Maurer7 described the first case series of LR in a pediatric population, which included only 1 premature infant. A number of case reports have subsequently described the presence of neonatal LR.8,9 Because of differences in leukocyte and absolute neutrophil counts (ANCs) between the adult and infant populations, the LR during infancy has been defined as an ANC of >10 SD above the mean for gestational age or >30 x 103/mm3 during the first week of life.10–12 Neonatal LR has been described in a number of case reports in association with various clinical conditions including prematurity, chromosomal anomalies, exposure to antenatal corticosteroids (ANS), severe anemia, infections, and bronchopulmonary dysplasia (BPD).8,9,13–20 In the recent clinical studies by Calhoun et al10 and Rastogi et al,21 LR occurred in 1.3% to 15% of infants admitted to neonatal intensive care units, with no significant association demonstrated between LR and maternal and neonatal variables. In addition, Zanardo et al,20 in a retrospective case-controlled study of preterm infants with gestational age of 30 x 103/mm3.10–12 Maternal medical records were reviewed retrospectively for pregnancy and delivery characteristics including, age, gravida, parity, mode of delivery, course of delivery, timing of rupture of membrane, maternal-fetal conditions, chorioamnionitis, and perinatal infections. Medical records of the eligible premature infants were reviewed retrospectively for gestational age, birth weight, gender, Apgar score, patent ductus arteriosus (PDA), respiratory distress syndrome (RDS), early- and late-onset sepsis, exposure to ANS and postnatal corticosteroids (PNS), surfactant use, number of surfactant doses, type of ventilator use, ventilation index, oxygenation index (OI), alveolar-arteriolar oxygenation gradient, score of neonatal acute physiology II, ventilatory support, oxygenation requirement, BPD, necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), retinopathy of prematurity (ROP), length of hospitalization (LOH), and discharge status. Chorioamnionitis was defined based on a positive culture from the amniotic fluid. In the absence of a positive culture, chorioamnionitis was defined in the presence of organisms on Gram-stain, sheets of leukocytes, or low glucose in the amniotic fluid in the presence of any 2 of the following clinical symptoms: maternal fever, leukocytosis, uterine tenderness, pus from the cervix, and fetal tachycardia. RDS was diagnosed if infants had clinical respiratory distress and compatible radiologic findings.22 IVH was graded prospectively by using Papile's classification of cranial ultrasound finding of blood in the germinal matrix or ventricular system with or without ventricular and parenchymal extension.23 PDA was diagnosed clinically and confirmed by echocardiogram. NEC was defined as more severe than stage 3 according to Modified Bell's Staging System for NEC.24 BPD was prospectively diagnosed by the attending neonatologist for infants who required supplemental oxygen as their usual daily therapy at 36 weeks' postconceptional age in association with radiographic evidence of persistent parenchymal lung disease.25 ROP was classified by using the international classification of ROP.26 Early-onset sepsis in newborn infants was diagnosed clinically within the first 72 hours of life based on the signs and symptoms of infection such as meconium aspiration, poor peripheral circulation, respiratory distress, cyanosis, lethargy, irritability, increased or new apnea or bradycardia episodes, tachypnea, fever, hypothermia, poor feeding, abnormal glucose metabolism, and signs of localized infection, accompanied by abnormal laboratory studies such as neutropenia with an ANC of 10 SD above the mean for gestational age, which was chosen in accordance with definition used previously by Calhoun et al.10 The definition utilizes the normal reference range published by Manroe et al12 and Mouzinho et al.11 There are some limitations for using the similar definition in our study. First, the reference range of Manroe et al and Mouzinho et al were compiled by using data from before 1991.11,12 There have been several advances in the care of preterm infants since that time, with a significant increase in the survival of ELBW infants. The reference data before 1991 may not be adequately powered to represent this particular population of preterm infants. Furthermore, in the updated reference range published in 1994 by Mouzinho et al,12 the authors pointed out a significant trend of change in ANC distribution when compared with that of previous publications. They stated that the distribution of ANC is broader, but also the rise and fall after birth occurs more gradually and at a later time point. These observations suggested that there is a birth weight and/or gestational age–dependent effect on the distribution of ANC.12 With increasing survival of preterm infants of lower gestations, there is a likelihood that the above-mentioned trend will continue to escalade with peak ANC delayed beyond the first 60 hours of life and return to baseline at a much later time than previously observed. In our recent publication on late-onset neutropenia in very low birth weight infants, the peak ANC was noted to occur around the second week rather than within the first 60 hours of life and returned to baseline around the fifth to sixth week of life.28 A similar trend for delayed peak ANC and recovery to baseline was also observed in our unpublished data on the reference range of ANC in ELBW infants.29 Therefore, based on our findings and those from previous publications, the 30000/mm3 level was used to define LR for the duration of the hospitalization in our study infants. Inflammatory cytokine activation and cell recruitment occur early in the inflammatory response that persists over the first weeks of life in premature infants. The imbalance of anti-inflammatory cytokines (eg, interleukin [IL] 10) and proinflammatory cytokines (eg, IL-8, tumor necrosis factor , IL-1, IL-6, etc) has been implicated in the activation of inflammatory cascade associated with prematurity, RDS, cerebral white matter damage, IVH, NEC, BPD, and cerebral palsy.30–39 Various inflammatory cytokines are capable of initiating or stimulating production of granulocyte colony-stimulating factor (G-CSF) by several cell lines, including monocytes, macrophages, and epithelial and endothelial cells.40–45 G-CSF can accelerate the production of neutrophils, stimulate the activation of neutrophils, including respiratory burst activity, and produce a leukemoid-like reaction when administered in a sufficiently high dose.46,47 In a prospective series, Calhoun et al10 observed that neonatal LR was the result of a transient acceleration in neutrophil production and was associated with elevated serum G-CSF in 30% of the study infants. Growing evidence suggests that early activation and transendothelial migration of neutrophils has been found to be an important contributing factor in the pathogenesis of severe RDS and its progression to BPD in premature infants.48 Large numbers of inflammatory cells, predominantly neutrophils, were found in the bronchoalveolar specimens of preterm infants in various stages of developing BPD shortly after the initiation of mechanical ventilation.49–52 The elevated neutrophil count in airway secretions persisted for weeks in those infants who eventually developed BPD. The appearance of LR may represent a hematologic response from a unique group of premature infants with a genetic susceptibility for heightened response to the perinatal stress by increased production of inflammatory cytokines. The increased circulating neutrophils can readily migrate into various organs, including lung, through a complex interaction between endothelial cells and neutrophils facilitated by the presence of various inflammatory cytokines and local chemotactic and chemokinetic factors. Neutrophils are important in the immune response and repair process, but they may also cause localized tissue injury that leads to subsequent chronic inflammatory changes. Alternatively, the presence of LR in the study infants may be a reflection of the severity of neonatal lung disease and associated chronic lung changes in the early phase of inflammation. However, the likelihood of later speculation is low because of the similar baseline perinatal and pulmonary characteristics and severity of illness between the LR and no-LR groups. With the exception of pulmonary sequelae, the association of LR and prematurity-associated short- and long-term morbidities cannot be demonstrated in our current study or any previous publication to date.10,20,21 Absence of the relationship between LR and other prematurity-associated morbidities may attribute to the relatively low incidence and multifactorial nature of various events examined. The potential association can only be demonstrated with a carefully designed prospective study with an adequate sample size and particular attention to monitor and control various potential contributing factors that may lead to changes in the incidence of prematurity-associated morbidities. The absence of association between LR and sepsis in preterm infants has been described previously by Rastogi et al.21 However, ELBW infants with LR in our study population have demonstrated an increased tendency for a higher incidence of early- and late-onset sepsis. When we analyzed the diagnosis of each septic episode separately, a significant portion of septic episodes was diagnosed based on risk factors and clinical presentation rather than by cultures. However, because of the relatively low yield of the current culture method and low sensitivity of the currently available diagnostic hematologic and biochemical markers for neonatal sepsis evaluations, the diagnosis of sepsis, particularly early-onset sepsis, will inevitably rely on the clinical assessment of the physician, with emphasis on risk factors and clinical presentation. Therefore, the precise relationship between LR and early- or late-onset sepsis cannot be determined because of the retrospective design of the current study. On the other hand, the observed tendency between LR and sepsis in our study may provide added evidence to the earlier-stated speculation that the affected infants may represent a subgroup of premature infants with an exaggerated response to perinatal stress. Administration of ANS to pregnant mothers is a widely accepted obstetric practice before delivery of premature infants at risk for RDS. Corticosteroids are known to increase the leukocyte count by accelerating the release of neutrophils from bone marrow and decreasing egress from the circulation. The drug activity is detectable in cord blood as early as 1 hour after administration but undetectable by 72 hours.53,54 In this study, the LR and no-LR groups had similar exposure to ANS and exhibited a similar pattern of ANC changes, with the peak values occurring around the second week of life, which is beyond the theoretical range of ANS effect as observed in previous clinical studies.51,52 Therefore, the contribution of ANS to the occurrence of LR is limited, if any. The lack of association between ANS and LR in the current observation provided added evidence to the kinetic study by Calhoun et al,10 which concluded that the responsible mechanism for LR is increased neutrophil production rather than corticosteroid-induced leukocytosis. On the other hand, the relationship between the intravenously administered systemic PNS and LR is less clear. No significant difference in the overall exposure to PNS between the 2 groups was observed (84% vs 66%; P = .08). There were 3 infants in the LR group that demonstrated a LR within 2 weeks before or after the administration of PNS. The effect of PNS exposure on the occurrence of LR cannot be eliminated in those cases. The significance of this association remains to be determined by future kinetic study on the effect of corticosteroids on the occurrence of LR. In our study, there was a tendency for lower mortality in infants with LR compared with their no-LR counterparts, as reported previously by Rastogi et al.21 LR may be a manifestation of the immature inflammatory cascade activated in response to perinatal or neonatal insult and stress. Its presence in ELBW premature infants may confer a survival advantage at the expense of increased risk for morbidities, such as an increased demand for ventilation and/or oxygen support and a higher incidence of BPD. CONCLUSIONS LR in ELBW infants is associated with a prolonged need for ventilatory support and oxygen requirement, higher incidence of BPD, and a tendency for lower mortality. The findings suggest that LR may be associated with an excess of proinflammatory cytokines. Additional prospective study is needed to understand the relationship between LR, proinflammatory cytokines, and development of BPD. ACKNOWLEDGMENTS We thank Dr Ira Gewolb for constructive criticism and review of this manuscript. FOOTNOTES Accepted Jan 10, 2005. This work was presented in part at the Society for Pediatric Research meeting on May 1–4, 2004; San Francisco, CA. No conflict of interest declared. REFERENCES Rijken M, Stoelhorst GM, Martens SE, et al. Mortality and neurologic, mental and psychomotor development at 2 years in infants born less than 27 weeks' gestation: the Leiden follow-up project on prematurity. Pediatrics. 2003;112 :351 –358 Emsley HC, Wardle SP, Sims DG, Chiswick ML, D'Souza SW. Increased survival and deteriorating developmental outcome in 23–25 week old gestation infants, 1990–4 compared with 1984–9. Arch Dis Child Fetal Neonatal Ed. 1998;78 :F99 –F104 McElrath TF, Robinson JN, Ecker JL, Ringer SA, Norwitz ER. Neonatal outcome of infants born at 23 weeks' gestation. Obstet Gynecol. 2001;97 :49 –52 Jacobs SE, O'Brien K, Inwood S, Kelly EN, Whyte HE. Outcome of infants 23–26 weeks' gestation pre and post surfactant. Acta Paediatr. 2000;89 :959 –965 Krumbhaar EB. Leukemoid blood pictures in various clinical conditions. Am J Med Sci. 1926;172 :519 –533 Holland P, Maurer AM. Myeloid leukemoid reactions in children. Am J Dis Child. 1963;105 :568 –575 Hill JM, Duncan CN. Leukemoid reactions. Am J Med Sci. 1941;201 :847 –857 Teng RJ, Chen BW, Ho MM. Transient leukemoid reaction in an extremely premature infant. Acta Pediatr Sin. 1994;35 :225 –228 Calhoun DA, Kirk JF, Christensen RD. Incidence, significance and kinetic mechanism responsible for leukemoid reactions in patients in the neonatal intensive care unit: a prospective evaluation. J Pediatr. 1996;129 :403 –409 Mouzinho A, Rosenfeld CR, Sanchez PJ, Risser R. Revised reference changes for circulating neutrophils in very-low-birth weight neonates. Pediatrics. 1994;94 :76 –82 Manroe BL, Weinberg AG, Rosenfeld CR, Browne R. The neonatal blood count in health and disease. I. 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Leukemoid reaction and chronic lung disease in infants with very low birth weight. J Matern Fetal Neonatal Med. 2002;11 :396 –399 Zanardo V, Magarotto M, Rosolen A. Neonatal leukemoid reaction and early development of bronchopulmonary dysplasia in a very low-birth-weight infant. Fetal Diagn Ther. 2001;16 :150 –152 Zanardo V, Savio V, Giacomin C, Rinaldi A, Marzari F, Chiarelli S. Relationship between neonatal leukemoid reaction and bronchopulmonary dysplasia in low-birth-weight infants: a cross-sectional study. Am J Perinatol. 2002;19 :379 –386 Rastogi S, Rastogi D, Sundaram R, Kulpa J, Parekh AJ. Leukemoid reaction in extremely low-birth-weight infants. Am J Perinatol. 1999;16 :93 –97 Ruldoph AJ, Smith CA. Idopathic respiratory distress syndrome of the newborn. J Pediatr. 1960;57 :905 –921 Papile LA, Burstein J, Burstein R, Koffler H. Evaluation of subependymal and intraventricular hemorrhage. J Pediatr. 1978;92 :529 –534 Walsh MC, Kliegman RM. 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Undetectable interleukin (IL)-10 and persistent IL-8 expression early in hyaline membrane disease: a possible developmental basis for the predisposition to chronic lung inflammation in preterm newborns. Pediatr Res. 1996;39 :966 –975 Buron E, Garrote JA, Arranz E, Oyaguez P, Fernandez Calvo JL, Blanco Quiros A. Markers of pulmonary inflammation in tracheobronchial fluid of premature infants with respiratory distress syndrome. Allergol Immunopathol (Madr). 1999;27 :11 –17 Beresford MW, Shaw NJ. Detectable IL-8 and IL-10 in bronchoalveolar lavage fluid from preterm infants ventilated for respiratory distress syndrome. Pediatr Res. 2002;52 :973 –978 Duggan PJ, Maalouf EF, Watts TL, et al. Intrauterine T-cell activation and increased proinflammatory cytokine concentrations in preterm infants with cerebral lesions. Lancet. 2001;358 :1699 –1700 Minagawa K, Tsuji Y, Ueda H, et al. 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☉ 11333147:Cataract surgery and subtype in a defined, older population: the SEECAT Project
The Dana Center for Preventive Ophthalmology, Johns Hopkins University Schools of Medicine and Public Health, Baltimore, MD, USA ABSTRACT Aim: To describe the distribution of cataract subtypes present before surgery among a defined population of older, bilaterally pseudophakic individuals. Methods: This was a cohort study of bilaterally pseudophakic individuals participating in the Salisbury Eye Evaluation (SEE), and their locally resident siblings. Subjects underwent slit lamp and retroillumination photography and grading using the Wilmer Cataract Grading System. For all individuals determined to be bilaterally pseudophakic, an attempt was made to determine for each eye the type(s) of cataract present before surgery, based on previous SEE photographs (for SEE participants) and/or medical records obtained from the operating ophthalmologist (for both SEE participants and their siblings). Results: The mean age of 223 participants providing data in this study was 78.7 (SD 5.2) years, 19.3% of subjects were black and 60.1% female. The most common surgically removed cataract subtype in this population was pure nuclear (43.5%), followed by nuclear combined with posterior subcapsular cataract (PSC) (20.6%), and nuclear combined with cortical (13.9%); less common types were pure cortical (4.9%), pure PSC (4.5%), and PSC combined with cortical (2.7%). Factors such as sex and source of lens data (study photograph versus clinical record) did not significantly affect the distribution of lens opacity types, while PSC was significantly (p = 0.01) more common among younger people and nuclear cataract was significantly (p = 0.001) more common among white compared to black people. Conclusion: Epidemiological studies have suggested that the different subtypes of cataract are associated with different risk factors. As studies begin to identify new prevention strategies for cataract, it would appear likely that different strategies will be efficacious against different types of cataract. In this setting, it will be helpful to know which cataract types are most frequently associated with surgery. Among this older, majority white population, nuclear cataract showed a clear predominance among individuals having undergone surgery in both eyes. This may be contrasted with both clinic and population based studies of younger people, which have generally found PSC cataract to predominate. Abbreviations: PSC, posterior subcapsular cataract; SEE, Salisbury Eye Evaluation; SEECAT, SEE Cataract Genetics Study Keywords: Cataract surgery; older people Age related cataract is the leading cause of blindness in the world,1 and the most common cause of visual disability among older Americans.2 It is a treatable cause of decreased vision, accounting for visual impairment in more than 25% of women and 12% of men aged 75 years and older in a Beaver Dam (WI) population with ready access to cataract surgical services.3 Unoperated cataract is a particularly prevalent cause of blindness among African-American people.4 With changing indications for cataract surgery, cataracts are now removed more frequently, and earlier in a patient’s life than in previous decades.5 Klein et al6 suggest that age related cataract is not uncommon as early as the fifth decade of life, with 11.5% of people aged 43–54 years having some evidence of cortical opacity. The medical economic impact of cataract surgery is significant, as cataract care consumes 60% of the Medicare budget for vision.7 Payments for evaluation and surgical treatment of cataract consume two thirds of the total Medicare budget related to vision care.7 The demographic and other risk factors associated with lens opacities undergoing surgical removal have been addressed in several publications.3,8,9,10,11,12 However, the literature describing the specific cataract subtypes (nuclear, cortical, or posterior subcapsular cataract (PSC)) requiring removal in a defined population is relatively sparse. Adamsons et al report that PSC was present in nearly two thirds of lenses undergoing cataract surgery in a clinic based series,13 while Klein and colleagues3 similarly report PSC as the most important lens opacity in predicting incident cataract surgery in a population based study. The apparent high prevalence of PSC among cataracts undergoing extraction is in clear distinction to its prevalence in the population at large, where PSC represents the least common subtype in nearly all population based studies.14 We recently carried out a study of the genetics of age related cataract in an older population drawn from participants in the Salisbury Eye Evaluation (SEE) project15 in Salisbury, Maryland, and their siblings. Because of the age of the population involved, bilateral pseudophakia was quite common; in order to avoid loss of power, an effort was made to identify the type of cataract present in each eye for all such individuals, through use of previous photographs in the SEE project and/or records provided by the operative surgeon. Based on these data, we now report on the cataract subtype present before surgery in a well defined older population and their siblings. METHODS Between 1993 and 1995, the Salisbury Eye Evaluation (SEE) Project enrolled a random sample of 2520 residents of the Salisbury, Maryland area who were identified by Medicare records as 65–84 years old. Of the 1504 participants in the third round of the project, those with one or more siblings residing within 100 miles of Baltimore or Salisbury were invited to participate as "probands" in the SEE Cataract Genetics Study (SEECAT). After giving informed consent, all such probands and their siblings were examined at a central site, where a full ocular examination including dilatation of the pupil was carried out by an optometrist (HB), who determined if cataract surgery had occurred. Photographs from previous rounds of the SEE project (for "probands") and/or records of the preoperative clinical evaluation by the operating ophthalmologist (for both probands and siblings) were utilised in an attempt to determine the cataract subtype(s) present before surgery for one or both eyes in all subjects deemed to be bilaterally pseudophakic/aphakic. The Wilmer Cataract Grading System used in this study has been elaborated in detail elsewhere.16 Briefly, after dilatation of the pupil, standardised slit lamp photographs (Topcon SL-5D) were taken to assess nuclear change, and retroillumination photographs (Neitz camera) were taken to assess cortical and posterior subcapsular opacities.16,17 Slit lamp photographs were carried out with a 0.1 mm slit beam, at a height of 8–9 mm, set at an angle of 30°. A pair of retroillumination photographs, one focused on the anterior aspect of the lens and the other on its posterior aspect, were made for each eye. Nuclear cataracts were graded in decimal increments from 0.1 to 4.0 with reference to four standard photographs. A reference circle divided into 16 wedges was used to grade cortical cataracts from 0 to 16 out of 16, according to the proportion of the lens involved by cortical opacity. PSC was graded as present or absent.16,17 A subject was defined as "affected" by a particular cataract subtype if either eye: was affected by that subtype on a previously graded SEE photograph (nuclear grade 2 out of 4, cortical cataract grade 4 out of 16, PSC cataract present) or had cataract of that subtype graded by the operative surgeon as 2+ or greater (on a scale of 4), or characterised as "dense," "significant," or similar terminology in a clinical chart. Clinician grades might often come several years after the most recent previous study photograph, and so frequently provided new information. All cataract subtype designations were assigned by a single reviewing ophthalmologist (NGC). Presence of cataract subtypes was not mutually exclusive. Individuals affected in one eye by one subtype of cataract and in the other eye by another would be identified as affected by both subtypes. In those eyes where a determination of pseudophakia or aphakia was not consistent between the clinical examination and photographs, adjudication was carried out by the principal investigator (NGC) based on a review of photographs and clinical records. The protocol described above was reviewed in full by the joint committee on clinical investigation, the institutional review board for the Johns Hopkins University School of Medicine. Statistical methods Stata statistical software was used in the analysis of these data.18 Additionally, the GENMOD procedure in SAS (SAS Systems, Cary, NC, USA) was used to fit a GEE using maximum likelihood estimation of parameters to take into account the correlation in lens grades between siblings. Since the various cataract types were constrained to sum to 100%, and were thus not independent of one another, comparisons between cataract subtype distributions for race, sex, age, etc, were made only for one subtype at a time, treated as a "reference" type according to the binomial distribution. All analyses were carried out by a person, reflecting the presence of cataract type or pseudophakia/aphakia in either eye. RESULTS A total of 363 subjects (293 SEE participants and 70 siblings) were bilaterally pseudophakic/aphakic (fig 1). Among these subjects, previous photographs and/or preoperative clinical records were available for 223 people (61.4%), who are included in all further analyses. This number is composed of 65 SEE participants with a sibling participating in SEECAT, 104 SEE participants without a sibling participating in SEECAT, and 54 siblings. There were no statistically significant differences in race, age, or sex between the group of SEE participants with siblings (n = 65) and the group without siblings (n = 104); these two groups are combined in all further analyses. Figure 1 Subjects in the Salisbury Eye Evaluation (SEE) project and their locally resident siblings participating in a study of cataract subtype present before surgery in bilaterally pseudophakic individuals. As expected, among both SEE participants and siblings, bilaterally pseudophakic subjects were somewhat older and were less likely to be black compared to the group as a whole (table 1). The race, age, and sex characteristics of bilaterally pseudophakic subjects did not differ significantly for those with and without available lens data for either SEE participants or siblings (table 1). Table 1 Demographic characteristics of SEE participants and their locally resident siblings. 2 tests compared the group of bilateral pseudophakics with lens data to the population base of probands or siblings The distribution of age (p = 0.54), sex (p = 0.16), and race (p = 0.95) among bilaterally pseudophakic SEE participants with lens data (n = 169) did not differ from the group of bilaterally pseudophakic siblings with lens data (n = 54). The distribution of cataract subtype was similar between SEE participants and siblings, with nuclear cataract predominating in both groups (fig 2). When the two groups were combined, pure nuclear cataract was the most common subtype (43.5%), followed by nuclear in combination with PSC (20.6%), and nuclear combined with cortical opacity (13.9%). Cataracts composed of all three subtypes (PSC, cortical, and nuclear) were found among 9.9% of the entire group. The least common cataract subtype in this study population was posterior subcapsular combined with cortical (2.7%). The proportion of subjects with "any" significant nuclear cataract noted in the medical record or in a lens photograph in either eye was 87.5% (95% CI 83.6 to 92.2), while 37.9% had "any" PSC and 30.8% had "any" cortical opacity. Figure 2 Cataract subtype distribution among SEE participants, siblings, and all participants in a study of cataract subtype and cataract surgery. Nuclear cataract predominated for both male and female subjects, and the proportion of nuclear cataract did not differ by sex when adjusting for between sibling correlations (p = 0.12). Any PSC was significantly (p = 0.01, adjusted for between sibling correlations) more common among subjects younger than the mean age for the group (78.7 years) as compared to those at or above the mean age. Any nuclear cataract was significantly (p = 0.001, adjusted for between sibling correlations) more common among white persons compared to black people (fig 3). Figure 3 Sex, race, age, and cataract subtype distribution in a study of cataract subtype and cataract surgery. Although the small numbers involved precluded formal statistical testing, the source of lens data, whether from previous SEE photographs or the clinicians’ records, did not appear to affect the reported cataract subtype significantly. Pure nuclear cataract predominated among subjects with only photographs (n = 93), only clinician grades (n = 14), and those with both photographs and clinicians’ grades (n = 62) (fig 4). Note that, as only SEE participants (n = 169) had previous SEE photographs, only their data could be included in this analysis. Figure 4 Type of lens data available and cataract subtype distribution among SEE participants in a study of cataract subtype and cataract surgery. Nuclear cataract predominated among both first eye (n = 139) and second eye (n = 137) surgeries (fig 5). Note that only individuals for whom the dates of surgery for both eyes were known could be included in this analysis. Figure 5 Order of surgery (first eye versus second eye) and the distribution of cataract subtypes in a study of cataract subtype and cataract surgery. DISCUSSION In this well defined older population of bilaterally pseudophakic people, nuclear cataract clearly predominated as the subtype present before surgery, with pure nuclear and nuclear mixed with other subtypes accounting for nearly 90% of opacities. This pattern was observed regardless of whether the cataract subtype was identified by photographic grading, clinician assessment or both. There can be no doubt of the importance of obtaining information on cataract surgery among older populations such as this: it is estimated that some 62% of cataract surgery is performed in the United States on people aged 75 years and above.19 In contrast with our results, PSC has been identified as the type of cataract associated with the greatest risk for subsequent cataract surgery in population based studies from Blue Mountains in Australia20 and Beaver Dam in the United States.3 Additionally, clinic based studies have also reported a predominance of PSC in surgical series.13,21 One possible reason for this apparent disparity may relate to age differences in the populations studied. Several surgical series13,21 and population studies3 have reported that people developing or undergoing surgery for PSC cataract are on average significantly younger than those with nuclear cataract. Our own data show that PSC was significantly more common before cataract surgery among younger people compared to older participants. The younger group of siblings also appeared to have somewhat more PSC than the older group of SEE participants. The mean age in our study population was in the late 70s, a decade older, for example, than the mean for Adamsons et al’s subjects (67.5 years).13 The mean age at the time of surgery for our subjects was only 70.8 (SD 7.8) years, still several years older than the group reported by Adamsons et al. Although our subjects on average underwent surgery several years before the time when they presented to Round 3 of the SEE study, a similar time lag would also be present in other surgical incidence studies such as those from Blue Mountains20 and Beaver Dam, both of which reported on younger populations than ours.3 The possibility of bias, introduced by our inability to find older medical records pertaining to surgeries performed earlier in life, cannot be excluded, though information was obtained for some 62% of subjects. For example, nearly two thirds of the remaining 38% of subjects would have had to have pure PSC to have made PSC the most common form of cataract among all subjects (fig 2). The observed rate of pure PSC was only 4.5% (95% CI 1.8 to 7.2) among subjects with lens information. Alternatively, increased mortality associated with PSC might explain our failure to detect PSC or a history of cataract surgery for PSC in the older population we examined. In fact, all subtypes of cataract, not only PSC, have been associated with increased mortality, perhaps as a result of higher rates of accidents or complications from surgery.22–24 It has recently been suggested that increased mortality associated with cataract may actually be related to cataract risk factors such as diabetes, smoking, and cardiovascular disease, rather than cataract itself.24 Despite differences in subject age and methodology between the current study and those previously published it is, none the less, interesting to examine more closely the question of whether PSC cataract predominates in surgical studies. Adamsons et al, for example, conclude that "(PSC cataracts) cause more significant visual disability than do other types of cataracts." However, among 158 subjects undergoing a total of 198 cataract extractions in a general ophthalmology practice, Adamsons and colleagues report that preoperative clinical examination disclosed significant nuclear opacity in 65% of patients, as opposed to PSC in 61%.13 Summarising the Beaver Dam data on incident cataract surgery, Klein et al state that "Many factors are associated with cataract surgery, but the prior presence of posterior subcapsular cataract is the most important lens opacity." However, the age adjusted incidence of cataract surgery among 360 people with any nuclear cataract at baseline in the Beaver Dam study was 32.0%, compared to 28.0% for 112 people with any PSC. While the increased odds of undergoing incident cataract surgery associated with the presence of PSC (OR 15.51, 95% CI 8.27 to 29.09) was higher than for nuclear cataract (OR 4.0, 95% CI 2.40 to 6.66), the much higher prevalence of nuclear cataract appears to result in more people in the Beaver Dam population having undergone cataract extraction in association with nuclear as opposed to PSC opacity.3 Limitations of the current study must be clearly acknowledged. In the first place, both the SEE and SEECAT studies are relatively small ones, including 1500 and fewer than 800 subjects respectively. However, the advanced age of the study population guaranteed that the number of people undergoing cataract surgery was relatively high. For example, the total number of pseudophakic subjects for whom we were able to obtain lens information (n = 223) exceeds the number of incident cataract surgeries reported in the Blue Mountains Study (n = 126)20 and approximately equals that for Beaver Dam (n = 226).3 Secondly, the current report does not represent a truly population based sample. In order to participate, subjects had to be bilaterally pseudophakic, and have available preoperative records and/or old study photographs. Participants recruited from the parent SEE project were additionally subject to the survivor effect inherent in having lived to take part in the most recent round of a decade long study. Unlike the Blue Mountains and Beaver Dam studies, the current report does not describe all people in the population undergoing cataract surgery. However, it was possible to demonstrate demographic similarities between study participants and all subjects taking part in the population based SEE project, and all living siblings of SEE subjects. Furthermore, the current report provides unique data on cataract surgery in an older population, known to consume the large majority of cataract surgical resources, and also includes a substantial number of black people, not included in previous cataract surgical studies.3,13,20,21 Finally, there are inevitable limitations in our attempts to reconstruct lens opacities existing at the time of surgery from a combination of previous study photographs and clinician reports. Clinicians were not standardised in their reporting, and may have introduced substantial error into the reported cataract subtype distribution. Specifically, there is likely to be under-reporting by clinicians of cortical opacity as a subtype.4 Balanced against this concern is the fact that substantial time may have elapsed between the time of study photographs and cataract extraction. Introducing clinician reports may have allowed us to capture incident changes in the lens which would otherwise have been lost, especially for PSC, which may progress rapidly. This study of cataract subtype in a well defined, older population undergoing bilateral cataract extraction highlights the importance of nuclear cataract as a cause of visual impairment. While PSC appears to predominate in cataract surgical series including younger people, nuclear cataract assumes increasing importance in older groups. Our results suggest that nuclear cataract may convey a greater lifetime risk of cataract surgery. Given the ageing of the American population, and the fact that the very oldest segments of the population already consume the bulk of cataract surgical services, it is clear that nuclear cataract is a critical target for cataract prevention efforts. REFERENCES Thylefors B , Negrel AD, Pararajasegaram R, et al. Global data on blindness. Bull World Health Organ 1995;73:115–21. Eye Disease Prevalence Research Group. Causes and prevalence of visual impairment among adults in the United States. Arch Ophthalmol. (in press). Klein BEK, Klein R, Moss SE. Incident Cataract Surgery. Ophthalmology 1997;104:573–80. Munoz B , West SK, Rubin GS, et al. Causes of blindness and visual impairment in a population of older Americans: the Salisbury Eye Evaluation Study. Arch Ophthalmol 2000;118:819–25. Superstein R . Indications for cataract surgery. (Review) Curr Opin Ophthalmol 2001;12:58–62. Klein BEK, Klein R, Lee KE. Incidence of age-related cataract over a 10-year interval. Ophthalmology 2002;109:2052–7. Ellwein LB, Urato CJ. Use of eye care and associated charges among the Medicare population: 1991–1998. Arch Ophthalmol 2002;120:804–11. Cruickshanks KJ, Klein BEK, Klein R. Ultraviolet light exposure and lens opacities: The Beaver Dam Eye Study. Am J Public Health 1992;82:1658–62. Klein BEK, Klein R, Lee KE. Incident cataract after five-year interval and lifestyle factors: The Beaver Dam Eye Study. Ophthalmic Epidemiol 1999;6:247–55. Klein BEK, Klein R, Lee KE. Diabetes, cardiovascular disease, selected cardiovascular disease risk factors, and the 5-year incidence of age-related cataract and progression of lens opacities: the Beaver Dam Eye Study. Am J Ophthalmol 1998;126:782–90. Klein BEK, Klein R, Moss SE. Lens thickness and five-year cumulative incidence of cataracts. The Beaver Dam Eye Study. Ophthalmic Epidemiol 2000;7:243–8. Wong TY, Klein BEK, Klein R, et al. Refractive errors and incident cataracts: the Beaver Dam Eye Study. Invest Ophthalmol Vis Sci 2001;42:1449–54. Adamsons I , Munoz B, Enger C, et al. Prevalence of lens opacities in surgical and general populations. Arch Ophthalmol 1991;109:993–7. Congdon NC, Taylor HR. Age-related cataract. In: Johnson GJ, Minassian DC, Weale RA, West SK, eds. The epidemiology of eye disease. London: Arnold, 2003:106–7. Congdon NG, Broman K, Lai H, et al. Nuclear cataract shows significant familial aggregation in an older population after adjustment for possible shared environmental factors. Invest Ophthalmol Vis Sci. (in press). Taylor HR, West SK. The clinical grading of lens opactities. Aust NZ J Ophthalmol 1989;17:81–6. West SK, Rosenthal F, Newland HS, et al. Use of photographic techniques to grade nuclear cataracts. Invest Ophthalmol Vis Sci 1988;29:73–7. StataCorp: Stata Statistical Software: Release 7.0. Stata Corporation, College Station, TX 2000. Eye Disease Prevalence Research Group. The prevalence of cataract and pseudophakia among adults in the United States. Arch Ophthalmol. (in press). Panchapakesan J , Mitchell P, Tumuluri K, et al. Five year incidence of cataract surgery: the Blue Mountains Eye Study. Br J Ophthalmol 2003;87:168–72. Jahn CE, Janke M, Winowski H, et al. Identification of metabolic risk factors for posterior subcapsular cataract. Ophthalmic Res 1986;18:112–6. Wang JJ, Mitchell P, Simpson JM, et al. Visual impairment, age-related cataract, and mortality. Arch Ophthalmol 2001;119:1186–90. West SK, Munoz B, Istre J, et al. Mixed lens opacities and subsequent mortality. Arch Ophthalmol 2000;118:393–7. Borger PH, van Leeuwen R, Hulsman CA, et al. Is there a direct association between age-related eye diseases and mortality? The Rotterdam Study. Ophthalmology 2003;110:1292–6....查看详细 (25184字节)
☉ 11333148:Impact factors on intraocular pressure measurements in healthy subjects
Department of Ophthalmology, University Medical Centre Nijmegen, Nijmegen, Netherlands ABSTRACT Aim: To evaluate whether intraocular pressure (IOP) calculation by applanation tonometry is determined more essentially by the subject’s neck position or by neck constriction. Methods: 23 right eyes of 23 healthy subjects (12 male, 11 female) were included. IOP was measured by applanation tonometry with the TonoPen on sitting participants under four different conditions: with open collar upright (A) or with the head in the headrest of a slit lamp (B), with a tight necktie upright (C) or in slit lamp position (D). All measurements with neck constriction were performed 3 minutes after placing the necktie. Results: Mean IOP was 16.9 (SD 2.3) mm Hg (range 11–21 mm Hg) (A), 18.1 (SD 2.2) mm Hg (range 14–22 mm Hg) (B), 17.9 (SD 2.9) mm Hg (range 12–25 mm Hg) (C) and 18.7 (SD 2.7) mm Hg (range 13–24 mm Hg) (D). Mean IOP increased by 1.3 (SD 2.6) mm Hg (p = 0.028, paired t test, range +0.2 to +2.4 mm Hg) if subjects changed position from A to B. There was no statistically significant difference between measurements with or without neck constriction. Conclusion: Applanation tonometry may be inaccurate if performed in slit lamp position. In contrast, tight neckties do not significantly affect IOP evaluation in healthy subjects. Abbreviations: BCVA, best corrected visual acuity; BMI, body mass index; IOP, intraocular pressure; NC, neck circumference Keywords: intraocular pressure Elevated intraocular pressure (IOP) is generally accepted as one of the primary risk factors for glaucoma. Accuracy of IOP measurement may be altered by several factors, such as breath holding, Valsalva manoeuvres, and tight collars.1 Goldmann applanation tonometry is the calculation method used most widely. However, recent studies suggested that IOP would not be calculated adequately if Goldmann tonometry was applied on thin corneas.2 Tonometry by a portable electronic device (TonoPen), which appears to be of similar reliability as the Goldmann method, is less dependent on central corneal thickness because of a smaller area of applanation.3 In addition, a portable system can be used independent from the patient’s pose, which makes it particular useful for our present investigation. Recently, Teng et al postulated that a tight necktie might be a risk factor for increased IOP.4 The aim of our study was to determine whether the latter is dependent on different poses of the examined subject. SUBJECTS AND METHODS Twenty six subjects (14 male, 12 female) without diagnosis or family history of open angle glaucoma were enrolled in this prospective, observational trial. Each participant has given written informed consent before inclusion in the study and underwent complete ophthalmological examination, including best corrected visual acuity (BCVA), slit lamp examination, Goldmann applanation tonometry, and funduscopy with careful optic nerve head examination. In addition, body mass index (BMI) and neck circumference (NC) were evaluated. Three individuals were excluded because of probable glaucomatous changes of the optic disc. None of the eventually included participants had BCVA less than 20/40, IOP readings higher than 20 mm Hg, or any other ocular disorder that might be associated with glaucoma. Study IOP measurements of the right eye (study eye) were taken by TonoPen applanation tonometry under four different conditions: with open collar upright (A) and with the head on the headrest of the slit lamp (B), with a tight necktie upright (C) and in slit lamp position (D). Measurements with open collars were done first, followed by IOP readings with tightened neckties. The latter assessments were performed with the necktie tightened around the closed collar" to the point of slight discomfort," as proposed by Teng et al.4 For study measurements, subjects were seated in an examination chair. One drop of oxybuprocaine was instilled in the eye 3 minutes before the first tonometry. IOP was measured three times in primary gaze by the same masked examiner. Participants were allowed to blink between each individual measurement to prevent significant dehydration based variations of central corneal thickness. Successive measurements were performed 3 minutes after the participants had changed their positions. An independent reader recorded all the results and mean IOP values were calculated. To prevent bias, the TonoPen was recalibrated after each single alteration of the participant’s pose. The results were statistically analysed using SPSS 11.0 software for Windows (SPSS Inc, Chicago, IL, USA). Differences between IOP measurements in altered poses with and without necktie were put through paired samples t tests. Sex subjected divergences in IOP calculations were analysed by the independent samples t test. Pearson correlation coefficients were evaluated to analyse relations between IOP values and sex, BMI, or NC. We considered a p value of less than 0.05 statistically significant. RESULTS Twenty three right eyes of 23 normal subjects with a mean age of 21 (range 19–25) years participated in the study. Twelve participants were male and 11 female. Mean BMI was 23.99 (SD 2.39) and mean NC measured 362.4 (SD 23.9) mm. Mean IOP readings were 16.9 (SD 2.3) mm Hg (A), 18.1 (SD 3.0) mm Hg (B), 17.9 (SD 2.9) mm Hg (C), and 18.7 (SD 2.7) mm Hg (D). There was no significant correlation between the participants’ sex and IOP readings in either position (r2 = 0.094 (p = 0.67) (A), r2 = 0.232 (p = 0.29) (B), r2 = 0.095 (p = 0.67) (C), and r2 = 0.192 (p = 0.38) (D)). In addition, neither BMI nor NC was significantly correlated with IOP measurements in any of the four poses. Table 1 shows details about IOP changes between the different poses of the participants. IOP increased significantly when subjects had moved from (A) to (B) (p = 0.028). No significant difference appeared, when people changed from position (C) to (D) or between (B) and (D). There was a trend towards higher IOP if the participants wore tight neckties; however, this divergence was not statistically significant for any pose. Table 1 Mean IOP changes maintained by the participants’ poses DISCUSSION Broad information about significant risk factors for IOP elevation will facilitate the identification of subjects threatened by glaucoma.1 Within the scope of accurate IOP measurement, tight neckties have recently been blamed for inaccurate results of IOP calculation, thus being a risk factor for glaucoma.4 In the present study, we have evaluated IOP in two different poses under two diverse circumstances. The IOP of all participants, firstly, was measured in a comfortably seated, "daily life" position and, secondly, in slit lamp position as common in an ophthalmologist’s office. Both poses were evaluated with and without constricting necktie. We found a significant increase of mean IOP when normal subjects with open collars changed from erect to slit lamp position. However, this was not true when the participants wore tight neckties. We did not find significant IOP alterations in slit lamp position with or without a necktie. There was a trend to higher IOP if subjects wore tight neckties in an upright position; however, we were unable to find significant differences between open collars and astringent necktie measurements in any pose. Congestion of episcleral veins as a result of constriction of the craniocervical blood flow can cause a significant IOP rise.5 For comprehensive glaucoma care one has to consider various aspects of daily life as possibly increasing IOP. Of these, tight neckties have been proposed to be a risk factor for the development of glaucoma. In detail, men with thick necks, white collar professionals and men who prefer to wear tight neckties were considered to be endangered by increased IOP.4 Following this hypothesis, a considerable number of individuals in the industrialised world would be at risk for the development of glaucoma. However, the results of our present study do not suggest that astringent neckties are to be blamed for significant IOP increase. Furthermore, NC or BMI did not have impact on our IOP measurements with or without neck constriction. Hence it remains doubtful if tight neckties have to be considered as a risk factor for glaucoma. Besides aspects of the patient’s daily life, one has to look carefully at what may compromise correct IOP evaluation in the ophthalmologist’s office. When IOP is measured at the slit lamp by applanation tonometry, the patient will not be seated comfortably upright but slightly bent forward with the neck retroflexed. This may lead to internal constriction of the jugular vein, consequently causing elevation of intracranial blood pressure.6,7 Subsequent IOP elevation might then occur as a result of increased episcleral venous pressure. In accordance, we found a significant IOP increase when participants with open collars changed from an upright to a slit lamp position. To what extent blood flow physiology is altered under the latter circumstances is not known. In summary, neck retroflection can cause significantly increased IOP measurements in healthy subjects independent from BMI or NC. Consequently, applanation tonometry in the slit lamp position may not accurately reproduce IOP levels under everyday circumstances. In contrast with other investigators, we cannot confirm that tight neckties have a considerable impact on diagnosis and management of glaucoma. Presented in part as a poster at the 198th meeting of the Dutch Opthalmologic Society, Amsterdam, Netherlands, March 2004, and at the congress of the European Glaucoma Society, Florence, Italy, June 2004. REFERENCES American Academy of Ophthalmology. Intraocular pressure and aqueous humor dynamics. In: Liesegang TJ, Deutsch TA, Grand MG, eds. Basic and clinical science course. Section 10: Glaucoma. San Francisco: American Academy of Ophthalmology, 2003:14–24. Emara BY, Tingey DP, Probst LE, et al. Central corneal thickness in low-tension glaucoma. Can J Ophthalmol 1999;34:319–24. Viestenz A , Lausen B, Junemann AM, et al. Comparison of precision of the TonoPenXL with the Goldmann and Draeger applanation tonometer in a sitting and recumbent position of the patients—a clinical study on 251 eyes. Klin Monatsbl Augenheilkd 2002;219:785–90. Teng C , Gurses-Ozden R, Liebmann JM, et al. Effect of a tight necktie on intraocular pressure. Br J Ophthalmol 2003;87:946–8. Sultan M , Blondeau P. Episcleral venous pressure in younger and older subjects in the sitting and supine positions. J Glaucoma 2003;12:370–3. Mavrocordatos P , Bissonnette B, Ravussin P. Effects of neck position and head elevation on intracranial pressure in anaesthetized neurosurgical patients—preliminary results. J Neurosurg Anesthesiol 2000;12:10–14. Toole JF. Effects of change of head limb and body position on cephalic circulation. N Engl J Med 1968;279:307–11....查看详细 (11132字节)
☉ 11333149:A correlation of pregnancy term, disease activity, serum female hormones, and cytokines in uveitis
1 Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD, USA 2 Division of Epidemiology and Clinical Research, National Eye Institute, National Institutes of Health, Bethesda, MD, USA ABSTRACT Background/aims: Pregnancy and the postpartum period are associated with the activity of autoimmune diseases including uveitis. Although the exact mechanism is unknown, hormones are reported to alter inflammatory cytokines and influence disease activity. The authors studied ocular inflammation, female hormones, and serum cytokine levels during and after pregnancy. Methods: A prospective, observational case study was conducted. Four pregnant women in their first trimester with chronic non-infectious uveitis were followed monthly until 6 months after delivery. Serum female hormones (oestrogen, progesterone, prolactin) and various cytokines (IL-2, IL-4, IL-5, IL-6, IL-10, IFN-, and TGF-?) were measured by ELISA. Results: The four patients had five full term pregnancies. Uveitis activity decreased after the first trimester but flared in the early postpartum period. Serum female hormones, highly elevated during pregnancy, drastically dropped post partum. Cytokine levels except TGF-? were mostly undetectable. Conclusion: Female hormones and TGF-? may contribute to the activity of uveitis during pregnancy and the postpartum period. Abbreviations: CMO, cystoid macular oedema; EAU, experimental autoimmune uveitis; EIU, experimental induced uveitis; TGF-?, transforming growth factor beta Keywords: uveitis; female hormone; pregnancy; Th cytokine Many autoimmune diseases in females are known to improve during pregnancy but worsen in the postpartum period, because pregnancy induces in immune deviation promoting anti-inflammatory cytokines that prevent immunological rejection of the allogenic fetus.1,2 This immunological balance imposed by pregnancy seems to be an antithesis of the immunological imbalance that promotes cell mediated autoimmunity.3 Recent evidence indicates that there is a Th1, Th2, and transforming growth factor beta (TGF-?) shift during normal pregnancy and in the postpartum period resulting in a change in autoimmune disease activity.4–6 The relation between female hormones, cytokines, and disease activity during and after pregnancy has not been reported in human uveitis. The aim of this study was to assess serum female hormones, cytokines, and ocular inflammation during and after pregnancy. PATIENTS AND METHODS Four women (five full term pregnancies) in their first trimester of pregnancy with non-infectious uveitis for more than 2 years were enrolled in this National Eye Institute institutional review board approved clinical study after providing written informed consent. Patients had monthly ophthalmic examinations until 6 months post partum. At each assessment serum levels of the female hormones (oestrogen, progesterone, and prolactin) and Th1 (IL-2 and IFN); Th2 (IL-4, IL-5, IL-6, and IL-10); and Th3 (TGF-?) cytokine levels were measured with ELISA. The anti-human antibodies used in the ELISA assay were from the Quantikine kit (R & D Systems, Inc, Minneapolis, MN, USA). TGF-? assay measured only the active form. For examination and presentation of the data, hormone and TGF-? values were log10 transformed and averaged by month of gestation and after delivery over the total pregnancies. To quantify the severity of uveitis each eye received one point for the presence of each of the following conditions: keratic precipitates, anterior chamber cells, vitreous cells, vitreous haze, active uveal lesions, active retinal lesions, cystoid macular oedema (CMO), active retinal vasculitis, other inflammatory findings (for example, synechiae), disease flare, or treatment since last study visit. The totals for the patient’s eyes were then averaged to obtain the patient’s uveitis severity score, which could range from 0 (no conditions present) to a maximum of 11 (all conditions). To compare mean levels among the early phase of pregnancy (2–4 months), the late phase (5–9 months), and the postpartum phase (delivery to 6 months), a Monte Carlo of estimation of the p value from the permutation test of the hypothesis of no difference between the phases was conducted. Under this hypothesis the monthly sequence of values for each pregnancy is random and as likely to occur as any other. Within each of the five pregnancies the monthly values were randomly permuted. After permutation, mean values (hormone and TGF-? levels were log10 transformed before analysis) were calculated by phase for each pregnancy, and these means were then averaged over the five pregnancies by phase. This process was repeated for 100 000 iterations, and the fraction of times that the permutation induced difference exceeded the observed difference in absolute value was taken as the point estimate of the two sided p value. For 95% confidence against underestimating the p value, the upper 95% confidence limit was computed and reported as the p value. The testing level was two sided and set at 0.05. Since for each outcome variable there were three comparisons made, the Bonferroni criterion—that is, = 0.05/3, was applied to maintain the control of type I error for multiple comparisons. Trends in the scatter plots were traced by non-parametric local regression (loess) with the LOESS procedure of the Statistical Analysis System (SAS Institute, Inc, Cary, NC, USA). A local second degree least squares fitting at every point were made with the smoothing parameter (that is, fraction of data in the neighbourhood of a point) automatically selected according the Akaike information criterion. RESULTS The four patients were diagnosed with panuveitis secondary to sarcoidosis, idiopathic granulomatous panuveitis with retinal vasculitis, idiopathic anterior uveitis, and idiopathic posterior uveitis (table 1). The patient with sarcoidosis enrolled for two consecutive pregnancies. No patient developed any systemic medical or obstetric complications during pregnancy or in the postpartum period. Table 1 Clinical data of five pregnancies among four women An average of nine (range 7–12) clinical visits were recorded for each pregnancy. Overall, uveitis activity was slightly worse in the first trimester but became either inactive or milder in the late pregnancy, which allowed for reduction of immunosuppressive medications in all patients. However, a slight flare of the uveitis was likely in the first 3 postpartum months. Cases 1 and 4 had milder uveitis activity (uveitis scores in 0–7 range) while cases 2 and 3 had more severe uveitis (uveitis scores in 3–11 range). The ocular disease in patients with milder uveitis was characterised by trace to 2+ anterior chamber cells, trace to 1+ vitreal haze, CMO, inactive chroioretinal lesions, and vasculitis. In contrast, the ocular findings in the two patients with more severe uveitis included 3–4+ anterior chamber cells, 3–4+ vitreal haze, CMO, active chorioretinal inflammatory lesions, and retinal vasculitis. All four patients were on oral prednisone throughout their pregnancies. Two patients (cases 2 and 3) required an increased dose of prednisone in early pregnancy, one from 12.5 mg/day to 30 mg/day and the other from 30 mg/day to 40 mg/day. However, later in the pregnancies of these two patients their prednisone dose was decreased to 7.5 mg/day and 17.5 mg/day, respectively. During the late stage of pregnancy, the uvetis scores in these patients dropped into the milder range of 3–6. The two patients with mild uvetis were maintained on low dose prednisone throughout the pregnancy (case 1, 3 mg/day; case 4, 5 mg/day) (table 1). In the postpartum period following four of the five pregnancies, there was evidence of disease flare requiring increased immunosuppressive therapy. As expected, all three female hormones—oestrogen, progesterone, and prolactin—steadily and markedly elevated during pregnancy and drastically dropped in the postpartum period (table 2). Interestingly, most Th1 and Th2 cytokines were below detectable levels. Among a total of 270 assays from all five pregnancies, Th1 and Th2 cytokines were detected in only four assays from three patients with posterior uveitis; the Th2 cytokines during pregnancy (IL-5, 42 pg/ml; IL-6, 291 pg/ml; and IL-10, 40.7 pg/ml; respectively), and the Th1 cytokine (IL-2, 42 pg/ml) in the first month postpartum. TGF-?, a Th3 cytokine, was consistently detected in all patients throughout the study. Table 2 Mean of uveitis scores and geometric means of hormone levels Table 3 provides estimated p values for the comparisons of these means between phases, generated by the Monte Carlo permutation test. At the 0.0166 level of testing, uveitis scores dropped significantly from the early to late phase. All hormones decreased significantly from late phase to post partum. Progesterone in the postpartum phase was significantly lower compared to both early and late phases. Prolactin significantly increased from early to late while it significantly decreased from late to post partum. There were no significant differences between phases for TGF-?. Table 3 Estimated p values for comparisons between pregnancy phases Although uveitis scores did not vary freely, as they may have been controlled by immunosuppressive therapy, there was a discernible decrease in the female hormones with increasing uveitis score, but no change in TGF-? (fig 1). Figure 1 Figures 1 (A–D) Plots of monthly mean log10 of hormones and of TGF-? by monthly mean uveitis score. To quantify the severity of uveitis each eye received a point for the presence of each of the following conditions: keratic precipitates, anterior chamber cells, vitreous cell, vitreous haze, active uveal lesions, active retinal lesions, cystoid macular oedema, active retinal vasculitis, other inflammatory findings (for example, synechiae), disease flare, or treatment since last study visit. The totals for the patient’s eyes were then averaged to obtain the patient’s uveitis severity score, which could range from 0 (no conditions present) to a maximum of 11 (all conditions). The lines are loess fittings that non-parametrically track the relations between the variables. "E" designates early pregnancy, up to month 5 of gestation; "L," late gestation, from month 6 to delivery; and "P," postpartum period. DISCUSSION Pregnancy is associated with remediation of many autoimmune diseases including rheumatoid arthritis and multiple sclerosis, yet with exacerbation of other autoimmune conditions such as systemic lupus erythematosis.7,8,9,10,11 Few observational publications on non-infectious ocular inflammation have shown improvement during pregnancy and exacerbation after parturition.12–17 In a recent large series of 76 pregnancies among 50 women with Vogt-Koyanagi-Harada syndrome, Beh?et’s disease, and idiopathic uveitis, Rabiah and Vitale observed a flare up within the first 4 months of pregnancy, a relative inactivity in late pregnancy, and a rebound in activity within 6 months of delivery.12 We have reported a significantly lower incidence and severity of experimental autoimmune uveitis (EAU) due to higher elevation of circulating TGF-? and selective inhibition of Th1 responses in pregnant mice,18 as well as the effect of sex hormones on cytokine balance in EAU.19 This study agrees with other observations demonstrating amelioration of human non-infectious ocular inflammation in mid and late pregnancies and flare up during the postpartum period. Furthermore, we showed the relations among female hormones, TGF-?, a Th3 cytokine, and disease activity in a small heterogeneous group. These results are compatible with previous reports in EAU and experimental induced uveitis (EIU) models.18–20 Although other serum cytokine levels were mostly below the detectable levels, the four measurable Th2 cytokines were found in the pregnancy and the one measurable Th1 cytokine was in the postpartum period. The data suggest that physiological changes of sex hormones before and after delivery may polarise the immune response towards a Th2/Th3 response,6 which may counterbalance the augmented Th1 response observed in non-infectious uveitis. Data concerning the fluctuation in uveitis status is certainly quite complex. However, one of the main factors is associated with cytokine changes during pregnancy. In general, Th2 cytokines are associated with the downregulation of Th1 cytokines and may confer protection from Th1-mediated autoimmune diseases. During pregnancy, there is a shift from Th1 to Th2 that occurs both locally,21 at the fetal maternal interface, and systemically.22 This immune shift is thought to be necessary to avoid fetal rejection, since failure to achieve a Th1 to Th2 immune deviation has been associated with increased risk of spontaneous abortion.5 This naturally occurring, systemic shift in immune responses may underlie the improvement in Th1 mediated autoimmune diseases including most autoimmune meditated uveitis during pregnancy. Female patients with uveitis may require close follow up and treatment in the early postpartum period. Pregnancy and pregnancy related hormones including female hormones and cortisol influence the signs and symptoms of autoimmune diseases.4,23 The current study also suggests a correlation between uveitis severity and female hormone levels in the graphic display of the data, although the sample size was too small to achieve statistical significance. Recently oral oestriol therapy has been reported to benefit patients with relapsing remitting multiple sclerosis.24 The influence of female hormones on inflammatory cytokines and the interplay between circulating and cellular mechanisms causing uveitis remain to be further investigated. ACKNOWLEDGEMENTS Dr Grace Levy-Clark, Dr Ali Djalilian, and Ms Babilonia Ayukawa assisted with patient care. REFERENCES Raghupathy R . Th1-type immunity is incompatible with successful pregnancy. Immunol Today 1997;18:478–82. Wilder RL. Hormones, pregnancy, and autoimmune diseases. Ann N Y Acad Sci 1998;840:45–50. Makhseed M , Raghupathy R, El-Shazly S, et al. Pro-inflammatory maternal cytokine profile in preterm delivery. Am J Reprod Immunol 2003;49:308–18. Elenkov IJ, Chrousos GP. Stress hormones, proinflammatory and antiinflammatory cytokines, and autoimmunity. Ann N Y Acad Sci 2002;966:290–303. Marzi M , Vigano A, Trabattoni D, et al. Characterization of type 1 and type 2 cytokine production profile in physiologic and pathologic human pregnancy. Clin Exp Immunol 1996;106:127–33. Olivieri A , De Angelis S, Vaccari V, et al. Postpartum thyroiditis is associated with fluctuations in transforming growth factor-beta1 serum levels. J Clin Endocrinol Metab 2003;88:1280–4. Khamashta MA, Ruiz-Irastorza G, Hughes GR. Systemic lupus erythematosus flares during pregnancy. Rheum Dis Clin North Am 1997;23:15–30. Ostensen M . Sex hormones and pregnancy in rheumatoid arthritis and systemic lupus erythematosus. Ann N Y Acad Sci 1999;876:131–43 discussion 144. Barrett JH, Brennan P, Fiddler M, et al. Does rheumatoid arthritis remit during pregnancy and relapse postpartum? Results from a nationwide study in the United Kingdom performed prospectively from late pregnancy. Arthritis Rheum 1999;42:1219–27. Sicotte NL, Liva SM, Klutch R, et al. Treatment of multiple sclerosis with the pregnancy hormone estriol. Ann Neurol 2002;52:421–8. Whitaker JN. Effects of pregnancy and delivery on disease activity in multiple sclerosis. N Engl J Med 1998;339:339–40. Rabiah PK, Vitale AT. Noninfectious uveitis and pregnancy. Am J Ophthalmol 2003;136:91–8. Hyman BN. Postpartum uveitis. Ann Ophthalmol 1976;8:677–80. Steahly LP. Vogt-Koyanagi-Harada syndrome and pregnancy. Ann Ophthalmol 1990;22:59–62. O’Connor GR. Factors related to the initiation and recurrence of uveitis. XL Edward Jackson memorial lecture. Am J Ophthalmol 1983;96:577–99. Nohara M , Norose K, Segawa K. Vogt-Koyanagi-Harada disease during pregnancy. Br J Ophthalmol 1995;79:94–5. Chavis PS, Tabbara KF. Effects of pregnancy on the course of uveitis. In: Dodds EM, Couto CA, eds. Uveitis in the third millennium: Elsevier Science 2000:167–70. Agarwal RK, Chan CC, Wiggert B, et al. Pregnancy ameliorates induction and expression of experimental autoimmune uveitis. J Immunol 1999;162:2648–54. Buggage RR, Matteson DM, Shen DF, et al. Effect of sex hormones on experimental autoimmune uveoretinitis (EAU). Immunol Invest 2003;32:259–73. Miyamoto N , Mandai M, Suzuma I, et al. Estrogen protects against cellular infiltration by reducing the expressions of E-selectin and IL-6 in endotoxin-induced uveitis. J Immunol 1999;163:374–9. Wegmann TG, Lin H, Guilbert L, et al. Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon? Immunol Today 1993;14:353–6. Elenkov IJ, Wilder RL, Bakalov VK, et al. IL-12, TNF-alpha, and hormonal changes during late pregnancy and early postpartum: implications for autoimmune disease activity during these times. J Clin Endocrinol Metab 2001;86:4933–8. Langer-Gould A , Garren H, Slansky A, et al. Late pregnancy suppresses relapses in experimental autoimmune encephalomyelitis: evidence for a suppressive pregnancy-related serum factor. J Immunol 2002;169:1084–91. Soldan SS, Retuerto AI, Sicotte NL, et al. Immune modulation in multiple sclerosis patients treated with the pregnancy hormone estriol. J Immunol171:6267–74....查看详细 (17811字节)
☉ 11333150:Inflammatory cells in brush cytology samples correlate with the severity of corneal lesions in atopic keratoconjunctivitis
Department of Ophthalmology, Keio University, Tokyo, Japan ABSTRACT Background: Inflammatory cells infiltrating to the tarsal conjunctiva are thought to be involved in the pathogenesis of corneal lesions in severe allergic conjunctival diseases. The relation between such cells and the severity of corneal lesions was studied. Methods: Six patients with atopic keratoconjunctivitis (AKC) were enrolled in this study. Tarsal brush cytology findings and the severity of corneal damage at that point were recorded and analysed for correlation. Results: Four out of six patients exhibited correlation between eosinophils and corneal damage. Three out of six patients exhibited correlation between neutrophils and corneal damage. Two out of six patients exhibited correlation between both eosinophils and neutrophils and corneal damage. Analysis of all data from all patients taken together revealed that both eosinophils and neutrophils in brush cytology samples significantly correlated with corneal damage. Conclusions: Inflammatory cells in brush cytology samples correlated with corneal damage. Evaluation of the relative percentages of inflammatory cells in brush cytology samples is a useful method of assessing disease activity in allergic conjunctival disease. Abbreviations: AKC, atopic keratoconjunctivitis; ECP, eosinophil cationic protein; MBP, major basic protein; VKC, vernal keratoconjunctivitis Keywords: atopic keratoconjunctivitis; brush cytology; eosinophils; neutrophils; allergy Atopic keratoconjunctvitis (AKC) is a severe chronic allergic conjunctival disease and is often associated with corneal complications such as erosion and ulcers. Histologically, these diseases are characterised by the infiltration of lymphocytes, neutrophils, mast cells, eosinophils, and basophils to the conjunctiva. We have previously reported that the percentages of eosinophils and neutrophils in tarsal conjunctival brush cytology samples in patients with vernal keratoconjunctivitis (VKC) were significantly higher in subjects with severe corneal lesions such as ulcers.1 Inflammatory cells infiltrating from the tarsal conjunctiva are therefore thought to have an important role in the pathogenesis of corneal lesions. In this study we examined the relation between the percentage of each inflammatory cell in tarsal conjunctival brush cytology samples and the severity of corneal damage at that point in individual patients over a period of time. METHODS Six patients with AKC (range 520 years, all male) with severe corneal lesions including ulcers were enrolled in this study. All patients were diagnosed as atopic dermatitis by dermatologists and diagnoses of AKC were made from slit lamp examinations of the ocular surface findings. After informed consent was obtained, brush cytology was performed on the upper tarsal conjunctiva as previously described.2 After topical anaesthesia (0.4% oxybuprocaine hydrochloride), mucous discharge was carefully removed and the tarsal conjunctiva was scraped several times with Cytobrush-S (Medscand, Malm?, Sweden). The collected cells were suspended in Hanks solution and were then fixed onto glass slides by cytospin (28 g for 5 minutes, Sakura Seiki Co Ltd, Tokyo, Japan). The slides were stained by May-Giemsa and the numbers of various types of cells were counted up to a total of 500 under microscopic observation and the percentages of each cell type was recorded. All subjects were assessed by brush cytology at more than five time points. The severity of corneal lesions was assessed by fluorescein staining. The cornea was divided into three sections horizontally and each section was scored from 0 to 3 and the total score was recorded.3 Eyes with ulcers or erosions were scored as 10. The relation between the percentage of inflammatory cells and corneal epithelium score was plotted and statistically analysed for correlation. p Values of less than 0.05 were considered to be statistically significant. RESULTS Four out of six patients exhibited correlation between eosinophils and the severity of corneal damage. Three out of six patients exhibited correlation between neutrophils and the severity of corneal damage. Two out of six patients exhibited correlation between both eosinophils and neutrophils and the severity of corneal damage. Figure 1 shows the percentage of inflammatory cells and the severity of corneal lesions in a representative case. Eosinophils exhibited a tendency to parallel the severity of corneal lesions and decreased to almost zero when corneal lesions were not present. Neutrophils also tended to be increased in acute exacerbations; however, neutrophils were also present in many cases in decreased numbers even when there was little corneal damage. Figure 1 A case that exhibited positive correlation between the percentage of eosinophils and corneal damage. The percentage of eosinophils almost parallels corneal damage. Statistical analysis of all data from all cases obtained in this study taken together also revealed that eosinophils and neutrophils in brush cytology samples significantly correlated with corneal damage (r = 0.41, p<0.001 for both cell types). DISCUSSION Eosinophils are known to be important effector cells in the pathogenesis of corneal lesions in severe conjunctival allergies. Eosinophils and cytotoxic eosinophil granule proteins such as eosinophil cationic protein (ECP)4,5 and major basic protein (MBP)6 are present in the tears of patients with VKC. In a previous study, we detected large numbers of eosinophils and high concentrations of eotaxin, a potent chemoattractant for eosinophils, in tear samples of patients with severe corneal lesions.7 ECP and MBP have been shown to affect corneal epithelial cell viability and morphology in vitro.8 In contrast, the role of neutrophils in the pathogenesis of ocular allergies is less clearly defined. Neutrophils contain proteolytic enzymes such as collagenase, elastase, and myeloperoxidase that may cause primary tissue damage or may perpetuate the injurious process. We have previously reported that the percentage of neutrophils in brush cytology samples from patients with VKC were significantly higher in patients with corneal lesions.1 Brush cytology is a useful method of collecting cells including inflammatory cells from the conjunctival epithelium.2 In order to gain insights into the relative importance of each type of cell in the pathogenesis of such lesions, we investigated the relation between the number of each type of cell and the severity of the corneal lesions. In our study we found that eosinophils correlated with corneal damage in four out of six patients compared to three out of six patients in the case of neutrophils. In some cases (representative case shown in fig 1), the changes in the number of eosinophils paralleled corneal damage and decreased to almost zero when corneal lesions were not present. Neutrophils also tended to be increased in acute exacerbations; however, neutrophils were also present in many cases in decreased numbers even when there was little corneal damage. This difference in the relation of each type of cell to corneal damage may be because neutrophils not only cause primary tissue damage through their granular constituents but also have a critical role in the non-specific reactions of scavenging inflammatory stimuli and damaged connective tissue. To conclude, inflammatory cells, in particular eosinophils, exhibited a tendency to parallel corneal damage. Such cells may play an important part in the pathogenesis of corneal lesions in severe ocular allergies. Evaluation of the relative percentages of inflammatory cells in brush cytology samples is a useful method of assessing disease activity in allergic conjunctival disease. REFERENCES Miyoshi T , Fukagawa K, Shimmura S, et al. Interleukin-8 concentrations in conjunctival epithelium brush cytology samples correlate with neutrophil, eosinophil infiltration, and corneal damage. Cornea 2001;20:743–7. Tsubota K , Takamura E, Hasegawa T, et al. Detection by brush cytology of mast cells and eosinophils in allergic and vernal conjunctivitis. Cornea 1991;10:525–31. Shimmura S , Ono M, Shinozaki K, et al. Sodium hyaluronate eyedrops in the treatment of dry eyes. Br J Ophthalmol 1995;79:1007–11. Leonardi A , Borghesan F, Faggian D, et al. Eosinophil cationic protein in tears of normal subjects and patients affected by vernal keratoconjunctivitis. Allergy 1995;50:610–13. Montan PG, van Hage-Hamsten M. Eosinophil cationic protein in tears in allergic conjunctivitis. Br J Ophthalmol 1996;80:556–60. Udell IJ, Gleich GJ, Allansmith MR, et al. Eosinophil granule major basic protein and Charcot-Leyden crystal protein in human tears. Am J Ophthalmol 1981;92:824–8. Fukagawa K , Nakajima T, Tsubota K, et al. Presence of eotaxin in tears of patients with atopic keratoconjunctivitis with severe corneal damage. J Allergy Clin Immunol 1999;103:1220–1. Trocme SD, Hallberg CK, Gill KS, et al. Effects of eosinophil granule proteins on human corneal epithelial cell viability and morphology. Invest Ophthalmol Vis Sci 1997;38:593–9....查看详细 (9295字节)