Children with autistic spectrum disorders. I: comparison of placebo and single dose of human synthetic secretin.

AIMS: To examine the effect of a single dose of human synthetic secretin (HSS) on behaviour and communication in children with autism spectrum disorder (ASD) using an objective measure of communication and social reciprocity and standardised rating scales. METHODS: Randomised, crossover, double blind, and placebo controlled trial of a single intravenous dose of human synthetic secretin (HSS) 2 CU/kg. The 62 subjects (3-8 years) were assigned to group 1 (saline placebo/HSS) or group 2 (HSS/saline placebo). Diagnosis was confirmed by ADI-R (Autism Diagnostic Interview-Revised) algorithm. Severity of symptoms was rated using the CARS (Childhood Autism Rating Scale). Outcome measures included Communication and Symbolic Behavior Scale (CSBS), Ritvo Real-life Rating Scale, weekly Global Rating Scale (GBRS) by parents and teachers, and daily log of gastrointestinal symptoms. The communication subscale of the CSBS, specifying communication function, reciprocity, and social-affective signalling was videotaped and scored by a blinded, trained observer. RESULTS: Sixty one children completed the study. After randomisation, there were no significant differences in gender, race, age, and parent and teacher GBRS and Ritvo Scale between the two groups. Compared with placebo, secretin treatment was not associated with significant improvement of CSBS standard scores from baseline to 2 or 4 weeks post-infusion. Five children showed clinical improvement in standard scores: two after HSS and three after placebo. There were no significant changes in gastrointestinal symptoms after HSS or saline placebo. CONCLUSIONS: A single dose of intravenous human secretin is not effective in changing behaviour and communication in children with ASD when compared to placebo.

Children with autistic spectrum disorders. II: parents are unable to distinguish secretin from placebo under double-blind conditions.

BACKGROUND: Standardised measures of behaviour have failed to detect short term improvement in children with autism following treatment with secretin. However, it is possible that standardised measures are insensitive to dimensions of child behaviour that are nonetheless detectable by parents. AIM: To determine the ability of parents of children with autism to guess, under double blind conditions, whether their child had received secretin or placebo. METHODS: 2x2 crossover randomised blinded study, comparing the effect of synthetic human secretin 2 U/kg to placebo (saline). Sixty two children with autism (aged 43-103 months) were randomly allocated to two groups: group 1 received placebo, followed six weeks later by secretin, and group 2 received secretin followed by placebo. At the conclusion of the study, parents were asked to guess their child's group assignment. RESULTS: Twenty seven families guessed their child's group assignment correctly and 27 guessed incorrectly. In 48 instances, parents based their guess on perceived improvement; in six cases, parents based their guess on perceived deterioration. Six families saw no difference after either infusion, and offered no guess. One family dropped out after the first infusion, and one family was lost to follow up after the second infusion. CONCLUSION: In a controlled setting, parents of young children with autism are unable to distinguish the short term behavioural effects of secretin from placebo.

Analysis of polymorphisms affecting immune complex handling in systemic lupus erythematosus.

OBJECTIVES: Systemic lupus erythematosus (SLE) is a polygenic disorder of dysregulated inflammation. Numerous specific candidate genes have been identified and most relate to the handling of immune complexes or antigen presentation. This is consistent with the classic finding of immune complex deposition in affected end organs. We wished to examine combinatorial effects of polymorphic variants of genes involved in immune complex clearance in susceptibility to lupus. METHODS: This study examined the occurrence of polymorphisms in genes which encode proteins known to be involved in immune complex handling and clearance. Each polymorphic variant of a complement protein (C2, mannose binding protein and C4), complement receptor (CR1) or Fc receptor (FcgammaRIIA and FcgammaRIIIA) gene is known to affect function adversely. One hundred and sixty SLE patients and 212 control subjects were genotyped using polymerase chain reaction methods. RESULTS: We found an increasing association of SLE with increasing numbers of gene defects. Combinations of severe defects in FcgammaRIIA and FcgammaRIIIA were particularly deleterious for both African American and Caucasian patients, even though only one defective variant was individually statistically significantly associated with SLE. CONCLUSIONS: The results of the study suggest that genes may interact in ways that either synergize or modify the effect of a single genetic effect and imply that association studies must be interpreted within the genetic background of the populations.

Immunologic features of chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome).

OBJECTIVES: To characterize immunologic function and clinical characteristics in patients with chromosome 22q11.2 deletion syndrome and determine whether there was significant change over time. METHODS: This study characterized the laboratory and clinical features of the immunodeficiency in a cohort of 195 patients with chromosome 22q11.2 deletion syndrome and used cross-sectional and analysis of variance to compare the findings in different age groups with control patients. Changes over time were also characterized by a model effect method in a subset of patients who were studied serially. RESULTS: Diminished T cell counts in the peripheral blood are common in patients with chromosome 22q11.2 deletion syndrome. The pattern of changes seen with aging in normal control patients was also seen in patients with chromosome 22q11.2 deletion syndrome, although the decline in T cells was blunted. Autoimmune disease was seen in most age groups, although the types of disorders varied according to age. Infections were also common in older patients, though they were seldom life threatening. CONCLUSIONS: Slow declines in T cell populations are seen in chromosome 22q11.2 deletion syndrome. Clinical manifestations of immunodeficiency, such as recurrent infection and autoimmune disease, were common in this population but had little relationship to specific immunologic laboratory features.

Cocaine withdrawal symptoms and initial urine toxicology results predict treatment attrition in outpatient cocaine dependence treatment.

This study evaluated the ability of cocaine withdrawal symptoms, measured by the Cocaine Selective Severity Assessment (CSSA) and initial urine toxicology results, to predict treatment attrition among 128 cocaine dependent veterans participating in a 4-week day hospital treatment program. The CSSA was administered and a urine toxicology screen was obtained at intake and at the start of the day hospital (about 1 week later). The combination of a positive urine toxicology screen and a high CSSA score at intake predicted failure to complete treatment. Urine toxicology results at the start of the day hospital, but not at intake, predicted failure to complete treatment. Among participants without other psychiatric illness, high CSSA scores at intake predicted failure to complete treatment. The presence of cocaine withdrawal symptoms and a positive urine toxicology screen are clinically useful predictors of treatment attrition.

Hospital restructuring and its impact on outcomes: nursing staff regulations are premature.

OBJECTIVE: Describe restructuring in the organization and delivery of patient care and the effects of nursing structure and processes on selected patient outcomes. BACKGROUND: Restructuring has been the dominant cost-reduction strategy in acute care hospitals. Changes occurred without a systematic look at how interventions impacted on the processes and outcomes of care. METHODS: Twenty-nine university teaching hospitals participated. Uniform structure, process, and outcome data were collected from each hospital and its study, medical, and surgical units. Outcome data included fall rate, nosocomial pressure ulcer, and urinary tract infection rates and patient satisfaction scores. RESULTS: RNs were fewer in number, with an increase in Unlicensed Assistive Personnel. Outcomes were affected by registered nurse hours worked per patient/day and hours worked per patient day by all staff and their interactions with processes. Increased registered nurse hours worked per patient/day were associated with lower fall rates and higher patient satisfaction levels with pain management. Increased hours worked per patient day by all staff were associated with lower urinary tract infection rates. CONCLUSIONS: Data from this study do not enable specific staffing recommendations. Expanded hospital and unit level data should be collected and reported annually. Nursing staff regulations should be deferred until expanded structure and outcome data from all acute care hospitals are systematically collected, reported, and analyzed.

Palatal length in cleft palate as a predictor of speech outcome.

In an attempt to predict which patients might benefit from primary posterior pharyngeal flaps done at the time of palatal repair, palatal length was assessed before palatal repair and the patient was placed in one of four categories. Patients with longer palates preoperatively had statistically better speech outcomes than patients with shorter palates. Statistical significance was found for most speech parameters. Information on presurgical palatal length can be useful in predicting which patients might profit from primary "pharyngoplasties."

Longitudinal relationship among growth, nutritional status, and pulmonary function in children with cystic fibrosis: analysis of the Cystic Fibrosis Foundation National CF Patient Registry.

OBJECTIVE: To determine prospectively the relationship among growth, nutritional status, and pulmonary function over a 4-year period in a large cohort of children with cystic fibrosis (CF). STUDY DESIGN: CF Foundation National CF Patient Registry data collected from 1991 to 1995 for 968 children (507 male) aged 5 to 8 years with pancreatic insufficiency and forced expiratory volume in 1 second within 60% to 140% of predicted values (FEV(1)%) were analyzed longitudinally. Variables hypothesized to affect FEV(1)% included age, sex, z scores for height, weight, percent of height-appropriate body weight, and annual number of days hospitalized. RESULTS: The significant decline in FEV(1)% was curvilinear and dependent on baseline FEV(1)%; children with initial FEV(1)% > or = 90 declined 2.6 U/y more than those with initial FEV(1)% <90. Boys gained but girls declined in z scores for height. Girls decreased in z scores for weight at a greater rate than boys. The z scores for weight and percent of height-appropriate body weight were significantly associated with longitudinal changes in FEV(1)%, after adjustment was done for hospitalizations. CONCLUSIONS: Growth, nutritional status, and pulmonary function are not stable in prepubertal children with CF and pancreatic insufficiency. Important sex-related differences in growth occur before puberty. Growth and nutritional status are associated with changes in FEV(1)%, suggesting that nutritional intervention may slow the decline in pulmonary function in children with CF.

Cleft palate repair at 3 to 7 months of age.

We report the speech outcome in 90 children with complete unilateral cleft lip and palate who underwent soft palate repair either between 3 and 7 months of age (n = 40) or later than 7 months of age (n = 50). In all patients, palatoplasty was performed by one of two experienced surgeons using a modification of the Furlow technique, and speech evaluations were conducted using the Pittsburgh Weighted Values for Speech Symptoms Associated with Velopharyngeal Incompetence by two speech pathologists with high inter-rater reliability. There were no differences between the groups with respect to resonance, nasal air emission, and articulation. Velopharyngeal function, as measured by the total speech score, was similar between the two groups of patients, as were the rates of secondary pharyngoplasty. These results suggest that very early closure of the soft palate may not offer significant benefit over repair later in infancy with respect to speech outcome.

Azathioprine and 6-mercaptopurine for the treatment of perianal Crohn's disease in children.

Numerous adult studies show a 30-65% response rate to azathioprine (AZA) or 6-mercaptopurine (6-MP) for significant perianal Crohn's disease. The aim of this study was to evaluate whether these drugs healed pediatric perianal Crohn's disease. Records of pediatric Crohn's patients were retrospectively reviewed for significant perianal disease treated with AZA or 6-MP for > or =6 months. The patient's perianal disease was reviewed and evaluated for fistulas, drainage, induration, and tenderness. In addition, the patients were given a score using the Irvine Perianal Disease Activity Index (PDAI). Patients were retrospectively scored upon initiation of treatment and after six months of therapy. Possible scores ranged from 0-20. Twenty patients met the study criteria. Five patients were considered treatment failures. One patient required a colostomy after 1.5 months of therapy, one developed pancreatitis, and three were noncompliant with therapy. Of the remaining 15 patients who were treated for > or =6 months, 67% had an improvement in drainage, 73% in tenderness, 60% in induration, and 40% in fistula closure. The mean Irvine PDAI was 7.67 +/- 2.19 initially and 4.40 +/- 1.72 after six months of therapy. The improvement was statistically significant (p < 0.001). AZA and 6-MP are effective treatments for healing significant perianal Crohn's disease in pediatrics.

Objective evaluation of knee laxity in children.

This study was designed to measure objectively knee laxity in children. Physical examination and the KT 1000 arthrometer were used to test the knee laxity of 150 healthy, uninjured children between 6 and 18 years of age. Data from the knee examinations and the KT 1000 measurements were compared and statistically analyzed to determine the change in knee laxity with age, laxity differences between boys and girls, and the correlation between the KT1000 measurements and subjective tests for laxity described by Carter and Wilkinson. There was no statistical difference in knee laxity between boys and girls of similar ages. We found that knee laxity, determined by measuring the millimeters of tibial translation using the KT 1000 arthrometer, was significantly greater in younger children.

Longitudinal analysis of lymphocyte function and numbers in the first year of life in chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome).

Chromosome 22q11.2 deletion syndrome is a common syndrome typically consisting of variable cardiac defects, hypoparathyroidism, developmental delay, and immunodeficiency. The hemizygous deletion has variable effects on the immune system even within the same kindred, and the extent of the immunodeficiency is difficult to predict. Some patients have shown improvement over time; however, this is the first prospective longitudinal study of the dynamic nature of the immunodeficiency. Nineteen patients were studied prospectively between 1994 and 1997. The results of the newborn immunologic studies in the chromosome 22q11.2 deletion group were significantly different from those of a group of newborns with cardiac disease due to other causes. Peripheral blood T-cell numbers were decreased in the chromosome 22q11.2 deletion group, although T-cell function was largely preserved. The group as a whole demonstrated few changes in the first year of life, but a subset of patients with markedly diminished T-cell numbers did demonstrate improvement. Therefore, improvement in peripheral blood T-cell counts is variable in chromosome 22q11.2 deletion syndrome. The patients with the lowest T-cell counts improved the most in the first year of life.

Risk factors for low bone mineral density in children and young adults with Crohn's disease.

OBJECTIVE: Low bone mineral density (BMD) is a recognized complication of Crohn's disease (CD). The aim of this study was to identify the risk factors for low BMD in pediatric patients with CD. STUDY DESIGN: One hundred nineteen subjects with CD ranging in age from 5 to 25 years were enrolled. BMD of the lumbar spine was measured by dual-energy x-ray absorptiometry. Growth parameters were assessed by examination. Disease-specific variables and use of selected medications were determined by chart review. RESULTS: Powerful risk factors for low BMD z-score included hypoalbuminemia, exposure to nasogastric tube feeds, total parenteral nutrition, 6-mercaptopurine, and corticosteroids. Corticosteroid dosing at a level >7.5 mg/d, 5000 mg lifetime cumulative dose, or >12 months of lifetime exposure were significant risk factors for low BMD z-score. Weaker but significant associations with low BMD z-scores included measures of disease severity such as pediatric Crohn's disease activity index, hospital admissions, and length of hospital stay. Site and duration of disease were not predictive. CONCLUSIONS: The presence of several clinically available factors was predictive of poor bone mineral status in this sample of subjects with CD. Hypoalbuminemia, corticosteroid exposure, nasogastric tube feeds, total parenteral nutrition, and 6-mercaptopurine were the most powerful risk factors for low bone mineral status.

Bone mineral density in children and young adults with Crohn's disease.

Reduced bone mineral density (BMD) has been reported in adults with Crohn's disease (CD). Less is known about abnormal BMD in children and young adults with CD. The aims of this study are to determine the prevalence of low BMD and to evaluate the effect of growth and pubertal development on BMD in children and young adults with CD. One hundred-nineteen patients with CD underwent dual-energy X-ray absorptiometry (DXA) to determine BMD. Anthropometry and pubertal development were measured. Bone age was measured only in patients older than 8 years of age and who had not grown in height during the last year. One hundred-nineteen patients (72 male, 47 female) were evaluated. Seventy percent of patients had BMD z-scores < or = -1.0 and 32% had z-scores < or = -2.0. Weight and height z-scores were significantly associated with BMD z-scores. BMD z-scores based on bone age and on chronological age were highly correlated, except when the chronological age BMD z-score was < or = -2.0. BMD z-score was significantly different between males and females for the group (-1.75 +/- 1.06 vs. -1.08 +/- 1.00), respectively. Children and young adults with CD have a high prevalence of low BMD and routine evaluation by DXA is indicated. In patients with a chronological age-based BMD z-score < or = -2.0, a bone age-based BMD should be considered.

Cleft-palate repair by modified Furlow double-opposing Z-plasty: the Children's Hospital of Philadelphia experience.

Although the optimal technique of cleft-palate repair remains controversial, several small series have suggested that superior speech results may be obtained with the Furlow double-opposing Z-plasty. To examine speech outcome in a large series of Furlow palatoplasties performed at a single center, we retrospectively reviewed the records of 390 cleft-palate patients who underwent Furlow palatoplasty at The Children's Hospital of Philadelphia from 1979 to 1992. Speech outcome at 5 years of age or greater was available for 181 nonsyndromic patients and was scored using the Pittsburgh Weighted Values for Speech Symptoms Associated with Velopharyngeal Incompetence. No or mild hypernasality was noted in 93.4 percent of patients, with 88.4 percent demonstrating no or inaudible nasal escape and 97.2 percent demonstrating no errors in articulation associated with velopharyngeal incompetence. Secondary pharyngeal flap surgery was required in just 7.2 percent of patients. Age at palatoplasty, cleft type, and experience of the operating surgeon had no significant effect on speech results, although there was a trend toward better outcome in those undergoing palatal repair before 6 months of age and toward poorer outcome in those with Veau class I and II clefts. Overall, Furlow palatoplasty yielded outstanding speech results, with rates of velopharyngeal dysfunction that seem to improve upon those reported for other techniques.

Single toxin detection is inadequate to diagnose Clostridium difficile diarrhea in pediatric patients.

BACKGROUND & AIMS: Clostridium difficile is an important cause of symptomatic diarrhea in pediatric patients. The bacterium produces two toxins, although many laboratories assay for only one. We questioned this diagnostic approach when patients had positive results for C. difficile at our institution, but initially had tested negative at outside laboratories. METHODS: We retrospectively analyzed relative frequencies of C. difficile toxin A alone, toxin B alone, and toxins A and B from pediatric patients with diarrhea. Results were stratified according to toxin detection and patient age. RESULTS: Of 1061 specimens, 276 (26.8%) were positive for C. difficile toxin(s). Fifty-one (18.5%) were positive for toxin A alone, 133 (48.2%) for toxin B alone, and 92 (33.3%) for both toxins. Assaying for toxin B identified C. difficile infection more frequently than did assaying for toxin A (P < 0.0001). The frequency of toxin B detection was significantly higher for older children but not for infants. CONCLUSIONS: Testing for C. difficile toxin A or toxin B alone will result in more frequent misdiagnosis than testing for both toxins. This practice may lead to inappropriate further invasive investigations in children, although this finding may not be applicable to adults.

Frequency of 22q11 deletions in patients with conotruncal defects.

OBJECTIVES: This study was designed to determine the frequency of 22q11 deletions in a large, prospectively ascertained sample of patients with conotruncal defects and to evaluate the deletion frequency when additional cardiac findings are also considered. BACKGROUND: Chromosome 22q11 deletions are present in the majority of patients with DiGeorge, velocardiofacial and conotruncal anomaly face syndromes in which conotruncal defects are a cardinal feature. Previous studies suggest that a substantial number of patients with congenital heart disease have a 22q11 deletion. METHODS: Two hundred fifty-one patients with conotruncal defects were prospectively enrolled into the study and screened for the presence of a 22q11 deletion. RESULTS: Deletions were found in 50.0% with interrupted aortic arch (IAA), 34.5% of patients with truncus arteriosus (TA), and 15.9% with tetralogy of Fallot (TOF). Two of 6 patients with a posterior malalignment type ventricular septal defect (PMVSD) and only 1 of 20 patients with double outlet right ventricle were found to have a 22q11 deletion. None of the 45 patients with transposition of the great arteries had a deletion. The frequency of 22q11 deletions was higher in patients with anomalies of the pulmonary arteries, aortic arch or its major branches as compared to patients with a normal left aortic arch regardless of intracardiac anatomy. CONCLUSIONS: A substantial proportion of patients with IAA, TA, TOF and PMVSD have a deletion of chromosome 22q11. Deletions are more common in patients with aortic arch or vessel anomalies. These results begin to define guidelines for deletion screening of patients with conotruncal defects.

Growth of hypercholesterolemic children completing physician-initiated low-fat dietary intervention.

OBJECTIVE: To evaluate the growth of hypercholesterolemic children completing an innovative, physician-initiated, home-based nutrition education program or standard nutrition counseling that aims to lower dietary fat intake. STUDY DESIGN: From suburban pediatric practices, 261 3.9- to 9.9-year-old children with elevated cholesterol levels and 81 children with nonelevated cholesterol levels were identified. The children with hypercholesterolemia were randomly assigned to the home-based education program, standard nutrition counseling, or an at-risk control group. Height, weight, skinfold measures, and dietary intake were evaluated at baseline, 3, 6, and 12 months; changes in anthropometric measures among treatment groups were compared over time. RESULTS: The intervention groups demonstrated significant decreases in fat and saturated fat intake after the interventions; however, weight z-score, height z-weight-for-height-median, and sum of skinfolds did not vary among the treatment groups over the year. At baseline, height z-score, weight z-score, and weight-for-height-median were positively associated with caloric intake, whereas weight z-score, weight-for-height-median, and sum of skinfolds were positively associated with fat intake. When the groups were combined and the children were grouped by average fat intake quintiles, no association between fat intake and changes in weight z-score, height z-score, or weight-for-height-media was observed. Differences over time in sum of skinfolds among fat intake quintile groups (suggesting a negative association between fat intake and body fat) that approached statistical significance (p = 0.06) were observed. CONCLUSIONS: These results support the safety, with respect to growth, of physician-initiated dietary intervention and lower fat diets for children with hypercholesterolemia. In addition, low dietary fat intake was associated with lower body fat.

Age-related changes in cardiovascular disease risk factors of hypercholesterolemic children.

OBJECTIVE: To describe the age-related changes in cardiovascular disease risk factors in young, hypercholesterolemic (HC) children. METHODS: Hypercholesterolemic (n = 227) and nonhypercholesterolemic (NHC) (n = 80) children between the ages of 4 and 10 years were identified. Height, weight, skin-fold and blood pressure measurements, and total cholesterol levels were measured. The HC group also had insulin levels evaluated. The groups were compared by analysis of variance. Simple Spearman correlations evaluated the associations between factors within each group. RESULTS: The HC and NHC groups had similar mean ages, heights, and weights, both contained 51% girls, and all were white subjects. Percent weight-for-height median, and biceps, triceps, suprailiac and subscapular skin-fold measurements were all larger for the HC group. A significant age interaction demonstrated that the HC group's larger suprailiac and sum of skin-fold measures were expressed in the 8.0- to 9.9-year-old children, but not the 4.0- to 5.9-year-olds. For both groups, systolic blood pressure was associated with the measures of adiposity. For the HC group, insulin levels were also associated with adiposity. CONCLUSIONS: These results suggest that: (1) children with HC have greater body fat, (2) the expression of the hypercholesterolemia precedes the expression of increased body fat, (3) body fat increases with age, and (4) altered insulin and blood pressure levels are expressed in association with the increased body fat in children with HC. Confirmation with longitudinal data is necessary.

Lack of correlation between impaired T cell production, immunodeficiency, and other phenotypic features in chromosome 22q11.2 deletion syndromes.

Monosomic deletions of chromosome 22q11.2 are the leading cause of DiGeorge syndrome, velocardiofacial syndrome, and conotruncal anomaly face syndrome. DiGeorge syndrome was originally described as an immunodeficiency disorder secondary to impaired T cell production due to thymic aplasia or hypoplasia; however, the frequency of immunodeficiency in the other clinical syndromes associated with the chromosome 22q11.2 microdeletion has not been previously investigated. This study examines the frequency and severity of impaired T cell production and immunodeficiency in chromosome 22q11.2 deletion syndromes and the relationship of the immunodeficiency to specific phenotypic features. Sixty patients over 6 months of age with the characteristic chromosome 22q11.2 deletion underwent immunologic evaluations. Seventy-seven percent of patients with chromosome 22q11.2 deletions were found to have evidence of immunocompromise. The severity of the immunodeficiency did not correlate with any particular phenotypic feature, nor was it restricted to patients who were categorized as having DiGeorge syndrome. Therefore, impaired T cell production and impaired immunologic function are common in patients with deletions of chromosome 22q11.2. The presence or severity of the immunocompromise cannot be predicted based on other phenotypic features and each child should be individually assessed for immune function.