Salman Mroueh

Mutation in WNT10A Is Associated with an Autosomal Recessive Ectodermal Dysplasia: The Odonto-onycho-dermal Dysplasia

Odonto-onycho-dermal dysplasia is a rare autosomal recessive syndrome in which the presenting phenotype is dry hair, severe hypodontia, smooth tongue with marked reduction of fungiform and filiform papillae, onychodysplasia, keratoderma and hyperhidrosis of palms and soles, and hyperkeratosis of the skin. We studied three consanguineous Lebanese Muslim Shiite families that included six individuals affected with odonto-onycho-dermal dysplasia. Using a homozygosity-mapping strategy, we assigned the disease locus to an ~9-cM region at chromosome 2q35-q36.2, located between markers rs16853834 and D2S353, with a maximum multipoint LOD score of 5.7. Screening of candidate genes in this region led us to identify the same c.697G-->T (p.Glu233X) homozygous nonsense mutation in exon 3 of the WNT10A gene in all patients. At the protein level, the mutation is predicted to result in a premature truncated protein of 232 aa instead of 417 aa. This is the first report to our knowledge of a human phenotype resulting from a mutation in WNT10A, and it is the first demonstration of an ectodermal dysplasia caused by an altered WNT signaling pathway, expanding the list of WNT-related diseases.

Marked benefits in physical activity and well-being, but not in functioning domains, 2 years after successful epilepsy surgery in children.

In this first study comparing epilepsy-specific quality-of-life measures of children after epilepsy surgery (2.4 years after focal resection) with those of a matched comparison group of nonoperated patients, seizure severity, medication side effects, overall quality of life, general health, physical activity, and well-being were better in surgical patients (70.6% seizure free vs 8.3%). Cognitive, social, and behavioral functioning did not differ, suggesting that these may require additional interventions during postsurgical follow-up.

Apoptosis and the activity of ceramide, Bax and Bcl-2 in the lungs of neonatal rats exposed to limited and prolonged hyperoxia

BackgroundThe aim of the study is to examine the effect of limited and prolonged hyperoxia on neonatal rat lung. This is done by examining the morphologic changes of apoptosis, the expression of ceramide, an important mediator of apoptosis, the expression of inflammatory mediators represented by IL-1β and the expression of 2 proto-oncogenes that appear to modulate apoptosis (Bax and Bcl-2).MethodsNewborn rats were placed in chambers containing room air or oxygen above 90% for 7 days. The rats were sacrificed at 3, 7 or 14 days and their lungs removed. Sections were fixed, subjected to TUNEL, Hoechst, and E-Cadherin Staining. Sections were also incubated with anti-Bcl-2 and anti-Bax antisera. Bcl-2 and Bax were quantitated by immunohistochemistry. Lipids were extracted, and ceramide measured through a modified diacylglycerol kinase assay. RT-PCR was utilized to assess IL-1β expression.ResultsTUNEL staining showed significant apoptosis in the hyperoxia-exposed lungs at 3 days only. Co-staining of the apoptotic cells with Hoechst, and E-Cadherin indicated that apoptotic cells were mainly epithelial cells. The expression of Bax and ceramide was significantly higher in the hyperoxia-exposed lungs at 3 and 14 days of age, but not at 7 days. Bcl-2 was significantly elevated in the hyperoxia-exposed lungs at 3 and 14 days. IL-1β expression was significantly increased at 14 days.ConclusionExposure of neonatal rat lung to hyperoxia results in early apoptosis documented by TUNEL assay. The early rise in Bax and ceramide appears to overcome the anti-apoptotic activity of Bcl-2. Further exposure did not result in late apoptotic changes. This suggests that apoptotic response to hyperoxia is time sensitive. Prolonged hyperoxia results in acute lung injury and the shifting balance of ceramide, Bax and Bcl-2 may be related to the evolution of the inflammatory process.

RESPONSE OF INFANTILE SPASMS TO LEVETIRACETAM

Levetiracetam is a suitable drug for investigation in infantile spasms (IS) because it is effective against multiple seizure types, does not have systemic toxicity, has favorable kinetics, and had efficacy against IS in two previous cases.1–3 Here we report our experience in seven cases. ### Methods. Seven patients (six boys) were studied. Inclusion criteria were IS refractory to ≥2 antiepileptic drugs (AEDs) including vigabatrin and ACTH unless either was contraindicated due to the patients medical status and family willing and able to accurately report seizure frequency and side effects. Exclusion criteria were history of other significant serious medical disease, history of poor compliance, and use of an investigational drug within <30 days of levetiracetam. Dose was 20 mg/kg/day then increased in weekly increments to 80 mg/kg/day, then individualized. Follow-up was once/month starting 1 month before levetiracetam and for 3 months after starting it, then once/3 months up to 12 months, unless the patient was dropped out due to the necessity of stopping levetiracetam …

Mutational spectrum of cystic fibrosis in the Lebanese population

BACKGROUND Cystic fibrosis (CF) is the most common autosomal recessive disease in Caucasians; it is however, considered to be rare in the Arab populations. Reports of the cystic fibrosis transmembrane regulator (CFTR) mutations from Arabs, especially from the Lebanese population, are limited. METHODS Twenty-two unrelated Lebanese families, with at least one child with CF, were studied. DNA extracts from blood samples of patients and parents were screened for CFTR gene mutations. RESULTS Eleven different mutations were identified. Of the 44 alleles studied, the most common mutations were: F508del (34%), N1303K (27%), W1282X (7%), and S4X (7%). Five mutations - not previously reported in the Lebanese population - were identified; these are: S549N, G542X, 2043delG, 4016insG, and R117H-7T. CONCLUSIONS The most common CFTR mutations in addition to five mutations not previously described in the Lebanese population were identified. Identification of CFTR mutations in the Lebanese population is important for molecular investigations and genetic counseling.

Endocrine Changes in a Rat Model of Chronic Hypoxia Mimicking Cyanotic Heart Disease

Objective. The endocrine system plays an important role in the adaptation to hypoxia. The aim of this study is to assess the effect of chronic hypoxia on endocrine changes in a neonatal animal model mimicking cyanotic heart disease. Methods. Sprague–Dawley rats were placed in a normobaric hypoxic environment at birth and oxygen levels were maintained at 10% in an airtight Plexiglas chamber. Controls remained in room air. Animals were sacrificed at 4 and 8 weeks of life. Hematocrit, Free T4 (FT4), Thyrotropin (TSH), corticosterone, and Growth hormone (GH) were measured. Results. Significant polycythemia developed in the hypoxic rats. Free T4 levels were significantly lower in the hypoxic (H) group compared to the control (C) group at 4 and 8 weeks with FT4 of 2.44 ± 1.11 ng/dL (H) and 4.35 ± 1.62 (C) at 4 weeks with a p value <0.005 and FT4 of 2.01 ± 0.36 (H) and 3.25 ± 0.54 (C) ng/dL at 8 weeks with p < 0.01. At 8 weeks TSH levels were significantly lower in the hypoxic group (1.84 ± 0.9 ng/mL (H) vs. 3.11 ± 1.1 (C)) with p < 0.05. Corticosterone levels were higher in the hypoxic group with values of 126 ± 14.8 ng/mL (H) and 114.1 ± 12.6 (H) at 4 and 8 weeks respectively, when compared to the control group with values of 82.9 ± 18.1 (C) and 92.7 ± 10.3 (C) and 4 and 8 weeks with p < 0.0005 and <0.05 respectively. Growth hormone levels were significantly lower in the hypoxic group at 4 and 8 weeks with p < 0.05 and p < 0.001, respectively. Conclusion. Chronic hypoxia in our neonatal rat model was associated with a decrease in growth hormone levels and an increase in corticosterone levels. Furthermore, hypoxia resulted in thyroid hormone axis suppression. This effect seems to be centrally mediated.

Treatment of severe status asthmaticus with nitric oxide

The paper reports on a 13‐year‐old girl with chronic asthma who presented in acute respiratory failure following an exacerbation of her disease. Nitric oxide was added to the ventilator circuit at 7 ppm and then 15 ppm after the patient failed to respond to bronchodilators and steroids. This was followed by rapid improvement in respiratory mechanics and blood gases with no adverse effects. Nitric oxide appears to have a direct relaxing effect on the bronchial smooth muscle. Pediatr Pulmonol. 1999; 28:451–453.

Association between low vitamin D levels and the diagnosis of asthma in children: a systematic review of cohort studies

BackgroundThere is conflicting evidence about the association between low vitamin D levels in children and development of asthma in later life. The objective of this study was to systematically review the evidence for an epidemiological association between low serum levels of vitamin D and the diagnosis of asthma in children.MethodsWe used the Cochrane methodology for conducting systematic reviews. The search strategy included an electronic search of MEDLINE and EMBASE in February 2013. Two reviewers completed, in duplicate and independently, study selection, data abstraction, and assessment of risk of bias.ResultsOf 1081 identified citations, three cohort studies met eligibility criteria. Two studies found that low serum vitamin D level is associated with an increased risk of developing asthma late in childhood, while the third study found no association with either vitamin D2 or vitamin D3 levels. All three studies suffer from major methodological shortcomings that limit our confidence in their results.ConclusionsAvailable epidemiological evidence suggests a potential association between low serum levels of vitamin D and the diagnosis of asthma in children. High quality studies are needed to reliably answer the question of interest.

Long-term patterns of weight changes during topiramate therapy: an observational study.

Our aims were to document long-term weight changes during topiramate therapy up to 5 years and to determine predictors of these changes. ### Methods. A cohort of children and adults started on topiramate during 1997 to 2002 was studied. Follow-up was for 1 to 5 years, until the patient discontinued topiramate or until the end of the study on December 31, 2005. Topiramate was started then adjusted according to clinical practice criteria. For most, this was 25 mg/day (1 week), then increased by 25 mg/day each week until 50 mg BID. Further adjustments were individualized. Inclusion criteria were definite diagnosis of epilepsy, failure of at least 2 antiepileptic drugs (AEDs), ability to come for regular follow-up, and topiramate judged to be appropriate. Exclusion criteria were preexisting eating disorder, presence of metabolic abnormalities known to affect weight, and inadequate follow-up. The following were collected at baseline and at each follow-up performed as a rule once every 3 months: age, gender, weight, height, topiramate dose, and concomitant medications (valproate, other AEDs). Baseline body mass index (BMI) (kg/m …

Vitamin D supplementation in children with asthma: a systematic review and meta-analysis

BackgroundEpidemiologic studies suggest an association between vitamin D deficiency and atopic diseases, including asthma. The objective of this study was to systematically review the benefits and harms of vitamin D supplementation in children with asthma.MethodsWe used standard Cochrane systematic review methodology. The search strategy included an electronic search in February 2013 of MEDLINE and EMBASE. Two reviewers completed in duplicate and independently study selection, data abstraction, and assessment of risk of bias. We pooled the results of trials using a random-effects model. We assessed the quality of evidence by outcome using the GRADE methodology.ResultsFour trials with a total of 149 children met eligibility criteria. The trials had major methodological limitations. Given the four studies reporting on asthma symptoms used different instruments to measure that outcome, we opted not to conduct a meta-analysis. Three of those studies reported improvement in asthma symptoms in the vitamin D supplemented group study, while the fourth reported no effect (very low quality evidence). For the lung function outcome, a meta-analysis of two trials assessing post treatment FEV-1 found a mean difference of 0.54 liters per second (95% CI -5.28; 4.19; low quality evidence). For the vitamin D level outcome, a meta-analysis of three trials found a mean difference of 6.56 ng/ml (95% CI -0.64; 13.77; very low quality evidence).ConclusionsThe available very low to low quality evidence does not confirm or rule out beneficial effects of vitamin D supplementation in children with asthma. Large-scale, well-designed and executed randomized controlled trials are needed to better understand the effectiveness and safety of vitamin D in children with asthma.