Saturday, May 4
5:15pm – 7:15pm, Exhibit Hall F & G
4413     Late Breaker Poster Session

LB3       Poster Board 473
Elevated Creatinine Clearance and Altered Renal Prostaglandin Balance in Pre-Type I and Early After Onset of Type I Diabetes Mellitus
Vikas R. Dharnidharka, Gisette Seferina, Yancy van Patten, Rui-Hua Peng, Michael Clare-Salzler. Departments of Pediatrics and Pathology, University of Florida College of Medicine, Gainesville FL.
BACKGROUND: Diabetes mellitus (DM) nephropathy is influenced by multiple risk factors, including genetic predispositions. We have previously reported the aberrant expression of cyclooxygenase-2 (COX-2) in monocytes of subjects at-risk for and with Type I DM vs. healthy subjects (Litherland et al, JCI 1999).
OBJECTIVE: We hypothesized that altered prostaglandins (PGs) production through COX-2 mediated mechanisms may also affect renal hemodynamics and contribute to nephropathy.
METHODS: Our study groups were pediatric age subjects that a) were at-risk for Type I DM, siblings with islet cell autoantibodies + (pre-Type I); b) had established Type I DM < 1 year; or c) were normal age-matched controls. We analyzed peripheral blood and 24-hr urinary collections for creatinine clearance (CrCl, ml/min/1.73sq.m.), CD14+ monocyte COX-2 +ve (flow cytometry) and urinary metabolites of the main renal PGs: PGE2, PGI2 and TXA2 (PGE2, 6-ketoPGF1a and TXB2, respectively) by enzyme immunoassay (expressed as ng/mg/Cr or as ratios, mean + SE).
RESULTS: In this pilot study, pre-Type I DM subjects and patients with Type I DM had elevated 24-hr CrCl (Table), despite normal urinary 24-hr albumin excretions in all. Pre-Type I and Type I DM subjects had elevated percentages of CD14+ blood monocytes positive for COX-2. The mean urinary PGE2/TXB2 ratio was depressed in pre-Type I DM and early Type I DM but not in early pediatric age Type II DM, in comparison to healthy age matched controls.

CONCLUSIONS: Renal hyperfiltration begins before the onset of overt diabetes and may be mediated by a shift in renal prostaglandin balance in autoimmune diabetes.

LB4       Poster Board 474
Early vs Delayed Tube Placement for Persistent Middle-Ear Effusion in the First 3 Years of Life: Effects on Cognition, Language, and Speech Sound Production at Age 4 Years
J. L. Paradise, H. M. Feldman, C. A. Dollaghan, T. F. Campbell, D.K. Colborn, D. L. Pitcairn, H.E. Rockette, J. E. Janosky, M. Kurs-Lasky, D. L. Sabo, B. S. Bernard, C. G. Smith. Departments of Pediatrics, Children’s Hosp. of Pittsburgh and U. of Pittsburgh School of Medicine, Pittsburgh, PA.
BACKGROUND: To examine possible developmental effects of persistent early-life MEE and of tympanostomy-tube placement (TTP), we randomly assigned children with persistent MEE in the first three years of life to undergo TTP either promptly or after an extended period if MEE persisted. TTP markedly reduced subsequent MEE occurrence, but we found no differences between the two groups in measures of cognition, language, and speech sound production at age 3 yr (NEJM 2001;344:1179).
OBJECTIVE: To determine whether differences not present at age 3 yr were present at age 4 yr.
DESIGN/METHODS: We enrolled 6350 healthy infants aged < 2 mo and monitored them closely for MEE. 429 who reached specified thresholds for persistent MEE during the first 3 years of life were randomly assigned to undergo TTP either promptly or 6 months later if bilateral MEE persisted or 9 months later if unilateral MEE persisted. At ages 3, 4, and 6 yr we administered a battery of tests to the children; 397 (92.5%) were tested at age 4. Measures were: for cognition, McCarthy Scales of Children's Abilities, comprising General Cognitive Index (GCI) and Verbal, Perceptual Performance, and Quantitative subscales; for receptive language, Peabody Picture Vocabulary Test-Revised (PPVT-R); for expressive language, Number of Different Words (NDW) and Mean Length of Utterance in Morphemes (MLUm); and for speech, Percentage of Consonants Correct-Revised (PCC-R).
RESULTS: Mean (SD) values were as follows. None of the differences were statistically significant.

CONCLUSIONS: These results suggest that early TTP for persistent MEE in the first three years of life does not favorably affect cognition, receptive language, expressive language, or speech sound production at age 4 years. Funded by NICHD, AHRQ, GlaxoSmithKline, and Pfizer.

LB5       Poster Board 475
Implications of Recent Changes in the Global Landscape of Circulating Influenza A and B Viruses
Kanta Subbarao, Michael W. Shaw, Catherine B. Smith, Xiyan Xu, Henrietta Hall, Alexander Klimov, and Nancy J. Cox. Influenza Branch, Centers for Disease Control, Atlanta, GA
Background: Influenza A H1N1 and H3N2 viruses have co-circulated with influenza B viruses since 1977. Two antigenically and genetically distinct lineages of influenza B viruses, represented by the reference strains B/Victoria/2/87 and B/Yamagata/16/88 have co-circulated in humans since at least 1983. Between 1992 and 2000, Victoria lineage viruses were only detected in eastern Asia; young children outside Asia have had no exposure to these viruses. Influenza A H1N1 and B virus infections are seen more commonly in children than adults and can be associated with outbreaks among school age children.
OBJECTIVE: The goal of global influenza surveillance is to monitor the circulation of antigenic variants of influenza and the appearance of novel subtypes of influenza A.
RESULTSs: In the 2001-2002 influenza season we identified two significant changes among circulating influenza viruses. Influenza A viruses with an H1 hemagglutinin (HA) that derived the remaining gene segments from the circulating influenza A (H3N2) virus were identified in the US, Canada, Singapore, Malaysia, India, Oman and Egypt. This is the first instance of widespread circulation of such reassortants. In the same season, influenza B viruses of the Victoria lineage reappeared in several countries including Canada, USA, Philippines, India and Oman and have been associated with outbreaks on every continent except South America and Australia.
CONCLUSIONS: The H1N2 viruses likely arose by genetic reassortment between the 2 subtypes of circulating influenza A viruses. Although interesting as a virologic phenomenon, this event has not prompted concerns about vaccine composition because the recommended vaccine contains A/New Caledonia/20/99 (H1N1) and A/Panama/2007/99 (H3N2) viruses, with H1 and N2 antigens similar to those of the recent H1N2 viruses. In contrast, the majority of the B/Victoria-like isolates have poor cross reactivity to B/Sichuan/379/99-like viruses in current vaccines. Therefore, the reemergence of B/Victoria-like viruses has resulted in a World Health Organization recommendation for the inclusion of a B/Victoria-like strain in vaccines for the 2002-2003 season for the northern hemisphere.

LB6       Poster Board 476
Respiratory Burst Activity in Bronchopulmonary Dysplasia and Changes with Dexamethasone
Praveen Ballabh, M. Simm, C. Califano, Z. Aghai, C. Sison, A. N. Krauss, S. Cunningham-Rundles. Pediatrics, New York Presbyterian Hospital, Weill Medical College of Cornell University, New York; Division of New Born Medicine, Westchester Medical Center, Valhalla, New York.
BACKGROUND: Since development of Bronchopulmonary dysplasia (BPD) has been linked with increased oxidative stress and oxygen free radicals may play a significant role in pathogenesis of BPD, we hypothesized that respiratory burst activity is increased in the premature neonates who develop BPD.
OBJECTIVES: To evaluate longitudinal change in the respiratory burst activity (RBA) in neutrophils and monocytes in VLBW infants with respiratory distress syndrome (RDS) and to examine differences between non-BPD and BPD neonates, and also to investigate the effects of dexamethasone on RBA.
DESIGN AND METHODS: We measured RBA on neutrophils and monocytes in heparinized blood in response to E.Coli, fMLP (N-formyl-met-leu-phe) and PMA (phorbol 12 myristate) stimulation by flow-cytometry on days 3, 7, 14 and 21 of life, before and 2-3 days after initiating a 6-day course of dexamethasone treatment. Infants were followed until discharge and were classified as non-BPD (n=12, GA 28.7 ± 1.2 weeks, weight 1118 ± 137 grams) and either 1) BPD d28 reflecting their oxygen requirement at day of life 28 (n=16, GA 26.1± 1.2 weeks, weight 856 ± 112 grams), or 2) BPD 36 weeks reflecting oxygen dependence at 36 weeks’ corrected gestational age (n=11, GA 24.8 ± 0.9 weeks, weight 692 ± 105 grams). The diagnosis of BPD was supported by radiological changes of BPD.
RESULTS: The percentage of activated neutrophils producing a respiratory burst increased in all premature infants with increasing postnatal days during the first 21 days of life, when the physiological stimulus, E Coli was used as an activator (p < 0.02). There was no significant difference in the RBA measured either as percent activation or as mean fluorescence intensity between non–BPD and BPD infants after adjusting for the difference in weight and gestational age between the groups. The treatment with dexamethasone did cause decreased percent activation of neutrophils (p < 0.005) when E. Coli was used as a stimulus.
CONCLUSION: A significant increase in neutrophil respiratory burst activity occurs during the first month of life in VLBW infants. Greater pulmonary damage in BPD cannot be attributed to increased burst activity in either neutrophils or monocytes. Decreased neutrophilic burst activity on dexamethasone treatment may be a mechanism of corticosteroid to reduce lung inflammation in BPD.
Funded by NIH Grant # 06020

LB7 Poster Board 477
Discovery of A Previously Unreported Apparently Pervasive Error in Clinical Pulseoximetry
Dale R. Gerstmann. Utah Valley Regional Medical Center, Provo, UT; Office of Research and Education, Pediatrix Medical Group, Sunrise, FL.
BACKGROUND: Based on an NICU index case in which we were unable to reconcile disparate values between simultaneous pulseoximeter (SpO2) and oximeter (sO2) functional saturations, we hypothesized a possible systematic error in our clinical use of pulseoximetry or in blood gas oximetry.
OBJECTIVE: To identify the source of error in SpO2 or sO2 measurement.
METHODS: Critical observation by supervisors and industry scientists/engineers of device setup, sensor use practice, and blood gas timing and analysis; and, analysis of simultaneous SpO2 and arterial sO2 from a) 7 yr historical NICU data (N=30,918); b) prospective NICU data (N=632); c) verification data using 2 oximeters (N=50); d) adult critical care data (N=383); and e) NICU data from 2 remote centers (N=95, N=168). The error function (SpO2-sO2) was plotted and regressed against sO2, the measured standard.
RESULTS: No systematic technical or procedural errors were identified during intensive observation. Sensors and monitors functioned normally. A significant negative correlation between the error function and sO2 was found for each of the 4 local and 2 outside data sets. Plotted is the NICU historical data, which are typical of the other data sets (p<0.001). Error functions were similar for devices from Datex-Ohmeda, Nellcor, Massimo, Space Labs, Hewlett-Packard, and DataScope.
CONCLUSIONS: These data suggest pulseoximetry significantly overestimates true saturation as values decrease. If the error is also device independent, industry standard signal processing algorithms may need to be recalibrated for parameters thought to be patient or disease invariant.
(Dr. B. Yoder, Santa Rosa Children’s Hosp, San Antonio, and L. Greenway, PhD, LDS Hosp, Salt Lake City, kindly contributed their data. Scientific support provided by Datex-Ohmeda and Nellcor.)

LB8       Poster Board 478
A Novel Method of Reflectance Pulse Oximetry from Core Body in Neonates
Amir Kugelman, Yoram Wasserman, David Bader. Department of Neonatology, Bnai Zion Medical Center, B Rappaport Faculty of Medicine, Technion-IIT, Haifa, Israel.
BACKGROUND: Reflectance pulse oximetry (RPO) is a potential alternative to the traditional transmission oximetry. A novel RPO capable of measuring from the core body of neonates is presented. Its major advantage would be in infants in cardiovascular collapse, poor perfusion, or during motion artifacts when the transmission pulse oximetry signal is poor. The advantage of the reflectance method is demonstrated in a case of a premature infant with hypovolemic shock, where blood gas or transmission pulse oximetry  could not be obtained because of cardiovascular collapse.
OBJECTIVE: The aim of our study was to compare pulse oximetry data measured by the reflectance and transmission methods in neonates.
METHODS: We monitored 16 infants (birth weight 1484+830 gr., study weight 1852+843 gr., gestational age 31+4 weeks) by the two methods simultaneously, and data were collected on a computer placed at the bedside. The transmission oximetry (N395-Nellcor, Puritan Bennett, Inc.,CA, USA), was measured from the finger of the infant on the hand or the foot, while the reflectance oximetry (PRO2, Imagyn Medical Technologies, CA, USA) was measured on the upper back. Data were measured for 2-4 hours from each infant. We compared data obtained from the 2 methods. Informed consent was obtained from all parents whose infants participated in the study.
RESULTS: Mean oxygen saturation obtained from the reflectance method was 96.6+7.3 % and that measured by the transmission methods was 97.2+3.0 %. The mean difference between the methods was 0.55 %, and the standard deviation of the absolute errors was 6 %. No side effects were seen during the study.
CONCLUSIONS: The reflectance pulse oximetry method is comparable to the transmission methods in its accuracy and is safe to use in neonates. We speculate that the reflectance method might be advantageous in cases of poor peripheral perfusion in neonates.
This work was funded by Cybro Medical Ltd., Haifa, Israel.

LB9       Poster Board 479
Variation in Clinical Presentation of Pharyngitis Syndrome and Streptococcal Pharyngitis. A Multinational Study
Anne W. Rimoin; Antonio L.A. da Cunha; Rashmi Kumar; Mark C. Steinhoff. The International Group A Streptococcal Pharyngitis (GRASP) Study. Department of International Health, Pediatrics, Johns Hopkins Medical Institutions, MD.
BACKGROUND: Data on the clinical presentation of pharyngitis syndrome and group A beta hemolytic streptococcal (GABHS) pharyngitis derives largely from studies in high income countries. In low-income countries there are few prospective studies that provide data on pharyngitis syndrome and GABHS pharyngitis.
OBJECTIVES: To compare presenting signs and symptoms of pharyngitis syndrome and their association with GAHBS pharyngitis in children in 2 countries.
DESIGN/METHODS: Prospective, descriptive study to compare signs and symptoms associated with a) acute pharyngitis syndrome and b) throat culture. Participants were children age 2 – 12 years seeking care in pediatric outpatient clinics in Rio de Janeiro, Brazil (N=152) and Lucknow, India (N=206). Data on patient demographics and signs and symptoms were collected using a standard format. Data were recorded for each patient and compared with culture using χ² and student t-tests.
RESULTS: Mean age of patients was 8 vs. 5 years (India vs. Brazil for all comparisons). Patients were mostly male: 66 vs. 51%. GABHS culture positivity was: 9% vs.21%, p= .018. There were differences in pharyngitis syndrome presentation with cough (86% vs. 76%, p=.036), complaint of sore throat (38% vs. 60%, p=.000), tonsillar erythema (91% vs. 80%, p=.018), and tonsillar exudate (2% vs.15%, p=.000). There were no differences between countries for signs of hoarseness and nares excoriation or symptoms of fever, runny nose, disturbed sleep. Signs associated with GABHS in each country: tonsillar exudate (p=.05, Brazil) and enlarged cervical lymph nodes (p < .01 for both).
CONCLUSION: There appear to be substantial differences in clinical presentation of pharyngitis syndrome between these 2 countries. These differences may be due to etiologic spectrum, cultural, socio-economic, or other factors. Selected specific signs for GABHS were more similar. These data suggest that GABHS pharyngitis is a biological entity that is roughly similar in all humans, whereas presentation of pharyngitis syndrome varies among populations.
Funded by USAID.

LB10       Poster Board 480
Daily Physical Exercise Stimulates Growth in Premature Infants: A Randomized Controlled Trial
Sahar M. Hassanein, Mohamed F. Moustafa, and Hanna A. Amer. Ain Shams University, Cairo, Egypt
BACKGROUND: Premature infants have limited accretion of bone mass in utero. Limited physical activity during hospitalization increases bone resorption and demineralization. Mechanical loading on bone and joints increases activity of osteoblasts and stimulates bone formation and growth.
OBJECTIVE: To test the hypothesis that daily physical exercise (PE) can enhance the growth of the premature infant and shorten the length of hospital stay.
DESIGN/METHODS: A prospective randomized trial was conducted on 34 Preterm infants. Healthy premature infants who were on full enteral feeds and whom postconceptual age were <36 weeks were included in this study. Infants with congenital anomalies, sepsis, neurological and metabolic problems were not included. Infants were randomly assigned to one of two groups: Group I (n=16) subject to PE program, and Group II (n = 18) control. PE consisted of daily passive flexion and extensions of each joint of upper and lower extremities repeated 5 times each. Vital signs and oxygen saturation were recorded for an hour around the daily PE. Anthropometric measurements were done weekly until discharge. Serum minerals (Ca, P, Mg) and alkaline phosphatase enzyme levels were monitored. Trial continues until infants’ weight reaches 1700 g.
RESULTS: Mean gestational age (week) in Group I (31.4± 1.13), did not differ from Group II (32.5± 1.73); p>0.05. At enrolment, weight (kg), length (cm), head circumference (cm) and forearm length (cm) were comparable in Group I (1.46 ± 0.13, 39± 2.39, 29.1± 2.93 and 10.6± 1.1) vs. Group II (1.47± 0.15, 38.3± 2.11, 28.4± 2.01 and 10.3± 1.12) respectively; p>0.05. Average daily caloric intake in Group I (137.6± 19.2 cal/kg) was not different than Group II (132.3± 29.4); p=0.12. At the end of the trial period, Group I infants were significantly longer than Group II (42.3± 2.22 vs. 39.9± 2.28); p<0.001. However, there was no difference between groups in head circumference or in forearm length: Group I (30.5± 2.87 and 11.6± 0.93) and Group II (28.4± 2.01 and 11.0± 1.11) respectively; p=>0.05. Mean hospital stay was significantly shorter for Group I (12.1± 2.25 days) than Group II (20.1± 4.65 days); p<0.01.
CONCLUSION: Daily physical exercise can enhance the growth of the premature infant.

Tuesday, May 7
8:00am – 10:00am, Ballroom IV
7062    Late Breaker Platform Session    

LB11       Presentation Time 8:00am
PKHD1, the Polycystic Kidney and Hepatic Disease 1 Gene Encodes a Novel Large Protein Containing Multiple IPT Domains and PbH1 Repeats
Luiz F. Onuchic, Laszlo Furu, Yasuyuki Nagasawa, Xiaoying Hou, Thomas Eggermann, Zhiyong Ren, Carsten Bergmann, Jan Senderek, Ernie Esquivel, Raoul Zeltner, Sabine Rudnik-Schöneborn, Michael Mrug, William Sweeney, Ellis D. Avner, Klaus Zerres, Lisa M. Guay-Woodford, Stefan Somlo, Gregory G. Germino. Depts Med. and Genet., Johns Hopkins Univ., Baltimore MD; Dept Med., Univ. Sao Paulo, Sao Paulo, Brazil; Dept Med. and Genet., Yale University School of Medicine, New Haven CT; Dept of Med. and Pediatr., UAB, Birmingham, AL; Instit. Human Genet., Technical Univ. Aachen, Germany; Dept. Pediatr., Case Western Reserve Univ., Cleveland OH.
Autosomal recessive polycystic kidney disease (ARPKD) is a severe form of polycystic kidney disease with an estimated incidence of 1:20,000. The typical onset occurs in neonates and infants and is characterized by cystic dilatation of the renal collecting ducts and congenital hepatic fibrosis. Although disease expression is variable, all phenotypes have been linked to a single locus, PKHD1, on chromosome 6p21.1-p12. Using a positional cloning strategy, we have identified the PKHD1 gene. The genomic sequence extends over 469 kb and includes at least 86 exons that are variably assembled into a number of alternatively spliced transcripts. The gene is primarily expressed in fetal and adult kidney. The longest continuous open reading frame encodes a 4074 amino acid protein, polyductin, that is predicted to have a single transmembrane spanning domain (TM) near its carboxyl terminus and IPT (Ig-like, Plexin, Transcription factor) domains and PbH1 (parallel beta-helix) repeats in its amino terminus. Several transcripts encode truncated products that lack the TM and may be secreted if translated. The PKHD1 gene products are members of a novel protein class that share structural features with hepatocyte growth factor receptor and plexins and belong to a superfamily of proteins involved in regulation of cellular adhesion and repulsion and of cell proliferation.

LB12      Presentation Time 8:15am
Correction of Krabbe Disease with Neonatal Hematopoietic Stem Cell Transplantation
Joanne Kurtzberg, Karen Richards, David Wenger, James Provenzale, Maria L. Escolar, Donna Wall, Martin A. Champagne, William Krivit. Duke University Medical Center, Durham, NC; San Antonio Military Pediatric Center, San Antonio, TX; Jefferson Medical College, Philadelphia, PA; Texas Transplant Institute, San Antonio, TX; Universite de Montreal by Hopital Sainte-Justine, Montreal, ON, Canada; University of Minnesota, Minneapolis, MN.
Globoid cell leukodystrophy is caused by a deficiency of galactocerebrosidase resulting in accumulation of psychosine which is toxic to the brain. When this occurs in the infantile form (Krabbe disease, KD), loss of central nervous system function is rapid and death occurs before 2 years of age. We now report outcomes of 7 infants with KD transplanted (6 with unrelated umbilical cord blood [UCB] and 1 with matched sibling bone marrow) after preparation with high dose chemotherapy in the neonatal period. All patients had a previous sibling who had died from KD leading to early diagnosis and treatment. In the 6 patients lacking a related donor, unrelated UCB donors were selected.
All babies survived the transplant and engrafted neutrophils within 4 weeks and platelets within 8 weeks of transplant. All achieved 100% donor chimerism before 100 days post transplant. The 6/7 recipients of unrelated UCB remain full donor chimeras from 2 months – 4.5 years post transplant. The 1 patient who received HLA-matched sibling bone marrow is a mixed chimera (75% donor, 25% host) 5 years post transplant. With a median follow-up of >3 years, all patients have survived well beyond their affected siblings and all have experienced remarkably positive clinical courses, gaining normal milestones, development and growth post transplant. In all cases, MRI demonstrated increased myelination and nerve conduction velocities improved over time.
We conclude that neonatal transplantation for KD produces excellent results. The use of UCB donors for patients lacking related donors facilitates transplantation therapy shortly after birth. In contrast, the use of stem cell transplantation in patients without a family history who were symptomatic at >3 months after birth, fails to produce positive results. Planning is now underway for identifying non-familial cases by neonatal screening as well as for selection of UCB donors with high levels of endogenous enzyme.

LB13       Presentation Time 8:30am
Mutations in the IRF6 Gene Cause Van der Woude and Popliteal Pterygium Syndromes
Brian C. Schutte, Shinji Kondo, Bryan C. Bjork, Yoriko Watanabe, Michael J. Dixon, Jeffrey C. Murray. Department of Pediatrics and Genetics PhD Program, The University of Iowa, Iowa City, IA; School of Biological Sciences, The University of Manchester, UK
BACKGROUND AND OBJECTIVE: Non-syndromic orofacial clefts are a common birth defect with complex etiology, involving multiple genetic and environmental factors. In order to identify genetic factors that cause clefts, we study disorders that exhibit Mendelian inheritance.
DESIGN: We used a positional cloning approach to identify the gene responsible for Van der Woude syndrome (VWS). VWS is an autosomal dominant clefting disorder. It is significant because it is fairly common, accounting for 2% of all clefts; and it has a remarkably similar phenotype to non-syndromic clefts, distinguished only by pits in the lower lip.
RESULTS: We mapped the VWS locus to a 350 kb region at chromosome 1q32-q41 that contains at least 11 genes, including the IRF6 gene. We screened these genes for mutations by direct DNA sequence analysis and identified a stop codon in the IRF6 gene in the affected sib of a monozygotic twin pair discordant for VWS. The unaffected sib and parents did not carry this mutation. DNA sequence analysis of 121 unrelated individuals with VWS identified 30 additional mutations in this gene. The IRF6 gene belongs to a family of nine transcription factor genes that are best known for regulating interferon expression following viral infection. We discovered nonsense and frameshift mutations throughout the coding region and found missense mutations clustered in the DNA binding domain and the protein binding domain. We also identified a distinct set of mutations in 11 individuals affected with Poplyteal Pterygium syndrome, a similar orofacial clefting disorder that includes webbing of the lower limbs.
CONCLUSIONS: We conclude that the IRF6 gene is essential for craniofacial development and is involved in limb development. The distribution of nonsense and frameshift mutations in the VWS population confirms that is caused by haploinsufficiency, and the cluster of missense mutations predicts the protein domains important for function. The distinctive mutations and more extensive phenotype in the PPS population suggest a dominant negative effect by mutations that cause PPS.

LB14       Presentation Time 8:45am
Possible Innate Variation in Biological Susceptibility to Inhalational Anthrax
Anne W. Rimoin, Derek A. Cummings, Donald S. Burke, Mark C. Steinhoff. Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
BACKGROUND: Inhalational anthrax (IA) is a rare disease, but exceptionally unusual in children.
OBJECTIVE: To evaluate the hypothesis that children have reduced innate biological susceptibility to IA, compared to older subjects using existing data.
DESIGN/METHODS: Retrospective analysis of age distribution and latency period in outbreaks of IA in Sverdlovsk, USSR, 1979 and United States, 2001.
RESULTS: In Sverdlovsk, USSR, approximately 7000 people were exposed in an accidental aerosol release of anthrax. All 77 reported cases were adults (24 – 72 years). Assuming no differential reporting of disease or deaths between adults and children, it appears that no children within the estimated aerosol spore isopleths became ill, hence may have been less susceptible to an exposure in which at least 2% (10/450) of exposed adults became ill. Among the reported adults with IA, there is an inverse association between age and length of the latent period (range: 2 – 43 days). (R² = -.435, p=.001). The mean latent period for those less than the median age of 44 years was 23 vs. 15 days for cases > 45 years (Wilcoxon rank-sum, p=.015). In the USA outbreak of 2001, 22 cases of anthrax have been reported; 11 confirmed as IA, and 11 (7 confirmed, 4 suspected) cutaneous. Median ages for cutaneous and inhalational groups are 35 (range: 7 months – 51 years) vs. 56 years (range 47 – 94 years). (Wilcoxon rank-sum, p= .000). The oldest reported case of IA in the US outbreak at 94 years was probably exposed to a very low dose by cross-contamination of mail. This suggests that a much lower dose will cause IA in older subjects, a reflection of possible increased susceptibility.
CONCLUSION: The relative lack of clinical reports of IA in children and infants compared to adults may be due to 1) absence of occupational aerosol exposure of younger children, 2) lack of recognition of the disease in children, or 3) decreased susceptibility after exposure of children. In Sverdlovsk, assumption of approximately equal exposure by age group suggests that there may be an age-associated susceptibility to IA. In the USA outbreak there is a significant difference in age distribution of anthrax clinical syndromes. These data suggest that there may be a difference in the biology of IA in younger vs. older populations, similar to other infectious diseases.

LB15       Presentation Time 9:00am
Reported Fatal and Serious Adverse Events Associated with Palivizumab
Thomas J. Moore, Sheila R. Weiss, Carol J. Blaisdell. Center for Health Services Research and Policy, George Washington Univ., Washington, DC; Schools of Pharmacy and Medicine, and Pediatric Pulmonology, Univ. of Maryland, Baltimore, MD.
BACKGROUND: Monthly injections of palivizumab, a humanized monoclonal antibody, reduced hospitalizations for RSV in a randomized clinical trial prior to approval. Adverse events reported to the FDA provide safety data from a much larger and more diverse patient population.
OBJECTIVE: To compare reported fatal and serious adverse events associated with palivizumab during its first 2 full years of marketing with other medications used in children under 2 years age.
DESIGN/METHODS: From data abstracts of all adverse event reports received by the FDA in 1999-2000, we extracted reports for infants and children under 2 years age. The study included only adverse events resulting in death or hospitalization, or events that were life threatening or required intervention to prevent permanent harm. Only drugs identified as a principal suspect were considered.
RESULTS: Among 341 different drugs named as suspect in 2239 reports, palivizumab accounted for 36% of all fatal and serious adverse event reports, more than the combined total of the 40 next most frequently implicated medications. In the 2-year period, palivizumab was associated with 117 deaths, and 623 other serious adverse events in infants and children under 2 years. In reports with a death outcome, 53% had adverse event terms referring to the respiratory organ system, 27% to infections, 26% to cardiac functions and 67% referred to 1 or more of the preceding.
CONCLUSIONS: These data provide a warning signal that palivizumab may be associated with serious or fatal adverse events that are not revealed in the literature, on the product label, or in the FDA evaluation prior to approval. The data abstracts from the reports in this study were not detailed enough to permit a medically specific characterization of the adverse events. The reporting rate for serious and fatal adverse events in infants is unknown, with estimates that among all individuals about 10% are reported, with some studies showing 1% or less. The volume of voluntary reports can be influenced by company contacts with consumers, the severity of underlying illness, the number of infants exposed, and other factors unrelated to the safety of palivizumab.
Dr. Blaisdell has been a consultant to the manufacturer, MedImmune

LB16       Presentation Time 9:15am
Early vs Delayed Tube Placement for Persistent Middle-Ear Effusion in the First 3 Years of Life: Effects on Intelligence, Receptive Language, and Auditory Processing at Age 6 Years
H. M. Feldman, J. L. Paradise, C. A. Dollaghan, T. F. Campbell, D.K. Colborn, D. L. Pitcairn, H.E. Rockette, J. E. Janosky, M. Kurs-Lasky, D. L. Sabo, B. S. Bernard, C. G. Smith. Departments of Pediatrics, Children’s Hosp. of Pittsburgh and U. of Pittsburgh School of Medicine, Pittsburgh, PA
BACKGROUND: Tympanostomy-tube placement (TTP) is often undertaken out of concern about adverse developmental effects of persistent middle-ear effusion (MEE). We randomly assigned children with persistent MEE in the first 3 years of life to undergo TTP either promptly or after an extended period if MEE persisted. Thereafter the early-TTP group had substantially less MEE than the delayed-TTP group. Nonetheless we found no differences between the two groups in measures of speech, language, cognition, and psychosocial development at age 3 yr (NEJM 2001;344:1179-87).
OBJECTIVE: To determine whether differences are present at age 6 yr between the early-TTP group and the delayed-TTP group in measures of intelligence, receptive language, and auditory processing.
DESIGN/METHODS: We enrolled 6350 healthy infants aged < 2 mo and monitored them closely for MEE. 429 who reached specified thresholds for persistent MEE during the first 3 years of life were randomly assigned to undergo TTP either promptly or 6 months later if bilateral MEE persisted or 9 months later if unilateral MEE persisted. At ages 3, 4, and 6 yr we administered a battery of tests to the children; 395 (92%) were tested at age 6. We administered the Weschler Intelligence Scale for Children-III (full-scale IQ[FS IQ], verbal IQ [VIQ], and performance IQ [PIQ]), the Peabody Picture Vocabulary Test-Revised (PPVT-R), and the SCAN, a test of auditory processing abilities.
RESULTS: Mean (SD) values were as follows. None of the differences were statistically significant.

CONCLUSIONS: Results suggest that early TTP for persistent MEE in the first three years of life does not benefit intelligence, receptive vocabulary, or auditory processing abilities at age 6 years.
Funded by NICHD, AHRQ, GlaxoSmithKline, and Pfizer.

LB17       Presentation Time 9:45am
A Comparison of the Efficacy and Safety of Atorvastatin Versus Placebo in the Treatment of Children and Adolescents with Familial or Severe Hypercholesterolemia
Brian W. McCrindle, Leiv Ose, and David Marais. Hospital for Sick Children, Toronto, Canada; Rikshospitalet, Oslo, Norway; University of Cape Town Medical School, Cape Town, South Africa.
BACKGROUND: Drug treatment of elevated lipid levels in children ≥ 10 years old is recommended if their plasma low-density lipoprotein cholesterol (LDL-C) level is ≥ 190 mg/dL (4.91 mmol/L), or if LDL-C is ≥ 160 mg/dL (4.14 mmol/L) and there is either a positive family history of premature cardiovascular disease (CVD), or the presence of at least 2 risk factors for CVD.
OBJECTIVES: To evaluate the efficacy and safety of lipid-lowering therapy with atorvastatin, versus placebo, in decreasing elevated lipid levels in pediatric subjects, aged 10-17 years, who have familial hypercholesterolemia (FH) or severe hypercholesterolemia (SH).
DESIGN/METHOD: This was a 1-year, randomized, double-blind, placebo-controlled, multicenter study. After a 4-week placebo run-in period, subjects were randomized to receive either placebo (n=47), or atorvastatin 10 mg/day (titrated to 20 mg/day at Week 4 if LDL-C > 130 mg/dL)(n=140), for 6 months. The double-blind phase was followed by a 6-month atorvastatin 10 mg/day open-label extension. The primary efficacy parameter was the percent change in LDL-C from baseline to Week 26. Secondary parameters included the percent change in total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and apo B, from baseline to Week 26.
RESULTS: Atorvastatin treatment resulted in a significant reduction in LDL-C from baseline to Week 26, compared with placebo (-40% vs. -0.4%; P < 0.001). By Week 26, 60% of subjects in the atorvastatin group, compared with 0% in the placebo group, achieved the LDL-C target of < 130 mg/dL. Mean % changes, from baseline to Week 26, were also significantly in favor of atorvastatin for TC (-32.3% vs. -2.0%; P < 0.001), TG (-12.0% vs. +1.0%; P =0.029), HDL-C (-2.4% vs. -8.0%; P =0.022), and apo B (-32.8% vs. +2.2%; P < 0.001). The incidence of treatment-related adverse events was low, and similar for the atorvastatin and placebo treatment groups (7.1% vs. 4.3%).
CONCLUSION: Lipid-lowering therapy with atorvastatin 10 or 20 mg/day for 6 months is effective and safe for pediatric subjects with known FH or SH. Administration of atorvastatin 10 mg/day for a further 6 months was also shown to be effective and safe.
The study was funded by Pfizer Inc.