Abbas F. Jawad

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.

Cognitive and behavior profile of preschool children with chromosome 22q11.2 deletion

A microscopic deletion of chromosome 22q11.2 has been identified in most patients with the DiGeorge, velocardiofacial syndrome, conotruncal anomaly face syndrome, and in some patients with isolated conotruncal cardiac anomalies. This study presents the neurodevelopmental outcome, including cognitive development, language development, speech, neuromuscular development, and behavioral characteristics of 40 preschool children (ages 13 to 63 months) who have been diagnosed with the 22q11.2 deletion. The impact of cardiac disease, cardiac surgery, and the palatal anomalies on this population was also studied. In the preschool years, children with a 22q11.2 deletion are most commonly found to be developmentally delayed, have mild hypotonia, and language and speech delays. The more significantly delayed children are at high risk to be subsequently diagnosed with mild or moderate mental retardation. The global delays and the variations in intelligence found are directly associated with the 22q11.2 deletion and are not explained by physical anomalies such as palatal defects or cardiac defects, or therapeutic interventions such as cardiac surgery. Our findings demonstrate that there is a pattern of significant speech disorders within this population. All of the children had late onset of verbal speech. Behavioral outcomes included both inhibition and attention disorders. Early intervention services are strongly recommended beginning in infancy to address the delays in gross motor skills, speech and language, and global developmental delays.

Computer-Assisted Segmentation of White Matter Lesions in 3D MR images, Using Support Vector Machine

RATIONALE AND OBJECTIVES Brain lesions, especially white matter lesions (WMLs), are associated with cardiac and vascular disease, but also with normal aging. Quantitative analysis of WML in large clinical trials is becoming more and more important. MATERIALS AND METHODS In this article, we present a computer-assisted WML segmentation method, based on local features extracted from multiparametric magnetic resonance imaging (MRI) sequences (ie, T1-weighted, T2-weighted, proton density-weighted, and fluid attenuation inversion recovery MRI scans). A support vector machine classifier is first trained on expert-defined WMLs, and is then used to classify new scans. RESULTS Postprocessing analysis further reduces false positives by using anatomic knowledge and measures of distance from the training set. CONCLUSIONS Cross-validation on a population of 35 patients from three different imaging sites with WMLs of varying sizes, shapes, and locations tests the robustness and accuracy of the proposed segmentation method, compared with the manual segmentation results from two experienced neuroradiologists.

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 Crohns 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 Crohns 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.

Enteric defensin expression in necrotizing enterocolitis

Immaturity of local innate defenses has been suggested as a factor involved in the pathophysiology of necrotizing enterocolitis (NEC). The mRNA of enteric human defensins 5 (HD5) and 6 (HD6), antibiotic peptides expressed in Paneth cells of the small intestine, have significantly lower levels of expression in fetal life compared with the term newborn and adult. In the current study, intracellular HD5 was demonstrated by immunohistochemistry at 24 wk of gestation, but at low levels, consistent with findings at the mRNA level. These data suggest that the low level enteric defensin expression, characteristic of normal intestinal development, may contribute to the immaturity of local defense, which predisposes the premature infant to NEC. To test if levels of defensin expression are altered in NEC, specimens from six cases of patients with NEC and five control subjects (four patients with atresia and one with meconium ileus) were analyzed to determine HD5 and HD6 mRNA levels by in situ hybridization. Compared with the control group, the level of enteric defensin expression per Paneth cell assessed by image analysis was increased 3-fold in cases of NEC (p = 0.02, analysis of variance and covariance). In addition, the number of Paneth cells was increased 2-fold in the small intestinal crypts of NEC specimens compared with those of control subjects (p < 0.01, covariance analysis). In healthy tissue, peptide levels within Paneth cells paralleled mRNA levels through development. In tissue from infants with NEC, the steady state level of intracellular peptide was not increased in conjunction with the observed rise in defensin mRNA. A straightforward interpretation of this finding is that HD5 is actively secreted in this setting and the Paneth cells maintain a constant steady state level of intracellular peptide, but the possibility of translational regulation of peptide expression is also consistent with these data. The associations between NEC and enteric defensin expression reported here offer support for future studies to address the role of these endogenous host defense factors in the pathophysiology of this disease.

Lifetime Prevalence of Major Depression and Its Effect on Treatment Outcome in Obese Type II Diabetic Patients

Objective — To assess the lifetime prevalence of major depression (MD) and its relation to glycemic control among a group of non-insulin-dependent (type II) diabetic subjects seeking obesity treatment and to determine whether a history of MD affected response to treatment. Research Design and Methods — Sixty-six obese subjects with type II diabetes (22 men, 44 women) completed the Inventory to Diagnose Depression-Lifetime Version before a 52-wk behavioral weight-control program. Weight, glycosylated hemoglobin, fasting blood glucose, and mood were assessed at pre-and posttreatment. Results — Thirty-two percent of the subjects reported a history of MD. Neither a history of MD nor current depressive symptoms were associated with pretreatment glycemic control. However, a history of MD was related to treatment attrition (52.4 vs. 22.2%, P = 0.03). Subjects with and without a history of MD showed comparable improvements in weight, glycemic control, and mood. Conclusions — A history of MD among type II diabetic patients seeking obesity treatment was not related to pretreatment glycemic control but was associated with higher rates of attrition from treatment. Individuals with a history of MD who completed the program did not differ from those with no history of MD in response to treatment.

A Family-School Intervention for Children with ADHD: Results of a Randomized Clinical Trial.

OBJECTIVE Accumulating evidence highlights the importance of using psychosocial approaches to intervention for children with attention-deficit/hyperactivity disorder (ADHD) that target the family and school, as well as the intersection of family and school. This study evaluated the effectiveness of a family-school intervention, Family-School Success (FSS), designed to improve the family and educational functioning of students in Grades 2-6 who meet criteria for ADHD combined and inattentive types. Key components of FSS were conjoint behavioral consultation, daily report cards, and behavioral homework interventions. METHOD FSS was provided over 12 weekly sessions, which included 6 group sessions, 4 individualized family sessions, and 2 school-based consultations. Participating families were given the choice of placing their children on medication; 43% of children were on medication at the time of random assignment. Children (n = 199) were randomly assigned to FSS or a comparison group controlling for non-specific treatment effects (Coping With ADHD Through Relationships and Education [CARE]). Outcomes were assessed at post-intervention and 3-month follow-up. The analyses controlled for child medication status. RESULTS FSS had a significant effect on the quality of the family-school relationship, homework performance, and parenting behavior. CONCLUSIONS The superiority of FSS was demonstrated even though about 40% of the participants in FSS and CARE were on an optimal dose of medication and there were significant time effects on each measure. This relatively brief intervention produced effect sizes comparable to those of the more intensive Multimodal Treatment Study of Children With ADHD (MTA) behavioral intervention.

Effects of limb exercise after spinal cord injury on motor neuron dendrite structure.

An integration center subserving locomotor leg movements resides in the upper lumbar spinal cord. If this neuronal network is preserved after a spinal cord injury, it is possible to stimulate this circuitry to initiate and promote walking. The several effective approaches (electrical stimulation, pharmacologic agents, physical therapy training programs) may all share a common modus operandi of altering synaptic activity within segmental spinal cord. To understand the neural substrate for the use‐dependent behavioral improvement, we studied the dendritic architecture of spinal motor neurons. In the first experiment, we compared three groups of animals: animals with an intact spinal cord, animals that had a complete spinal cord transection (SCT) and animals with SCT who engaged in a daily exercise program of actively moving paralyzed hindlimbs through the motions of walking. When compared with animals with an intact spinal cord, the motor neurons from animals with SCT displayed marked atrophy, with loss of dendritic membrane and elimination of branching throughout the visible tree within transverse tissue slices. None of these regressive changes were found in the motor neurons from SCT animals that underwent exercise. In a second experiment, we inquired whether exercise of animals with an intact spinal cord influenced dendrite structure. Increased exercise had very modest effects on dendrite morphology, indicating an upper limit of use‐dependent dendrite growth. Our findings suggest that the dendritic tree of motor neurons deprived of descending influences is rapidly pruned, and this finding is not observed in motor neurons after SCT if hindlimbs are exercised. The functional benefits of exercise after SCT injury may be subserved, in part, by stabilizing or remodeling the dendritic tree of motor neurons below the injury site. J. Comp. Neurol. 476:130–145, 2004.

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 Childrens 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.

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

Reduced bone mineral density (BMD) has been reported in adults with Crohns 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.