Association between the HOXA1 A218G polymorphism and increased head circumference in patients with autism.

BACKGROUND: The HOXA1 gene plays a major role in brainstem and cranial morphogenesis. The G allele of the HOXA1 A218G polymorphism has been previously found associated with autism. METHODS: We performed case-control and family-based association analyses, contrasting 127 autistic patients with 174 ethnically matched controls, and assessing for allelic transmission disequilibrium in 189 complete trios. RESULTS: A, and not G, alleles were associated with autism using both case-control (chi(2) = 8.96 and 5.71, 1 df, p <.005 and <.025 for genotypes and alleles, respectively), and family-based (transmission/disequilibrium test chi(2) = 8.80, 1 df, p <.005) association analyses. The head circumference of 31 patients carrying one or two copies of the G allele displayed significantly larger median values (95.0th vs. 82.5th percentile, p <.05) and dramatically reduced interindividual variability (p <.0001), compared with 166 patients carrying the A/A genotype. CONCLUSIONS: The HOXA1 A218G polymorphism explains approximately 5% of the variance in the head circumference of autistic patients and represents to our knowledge the first known gene variant providing sizable contributions to cranial morphology. The disease specificity of this finding is currently being investigated. Nonreplications in genetic linkage/association studies could partly stem from the dyshomogeneous distribution of an endophenotype morphologically defined by cranial circumference.     

Loss of breast cancer metastasis suppressor 1 protein expression predicts reduced disease-free survival in subsets of breast cancer patients.

PURPOSE: This study aims to determine the effect of loss of breast cancer metastasis suppressor 1 (BRMS1) protein expression on disease-free survival in breast cancer patients stratified by estrogen receptor (ER), progesterone receptor (PR), or HER2 status, and to determine whether loss of BRMS1 protein expression correlated with genomic copy number changes. EXPERIMENTAL DESIGN: A tissue microarray immunohistochemical analysis was done on tumors of 238 newly diagnosed breast cancer patients who underwent surgery at the Cleveland Clinic between January 1, 1995 and December 31, 1996, and a comparison was made with 5-year clinical follow-up data. Genomic copy number changes were determined by array-based comparative genomic hybridization in 47 breast cancer cases from this population and compared with BRMS1 staining. RESULTS: BRMS1 protein expression was lost in nearly 25% of cases. Patients with tumors that were PR negative (P=0.006) or HER2 positive (P=0.039) and <50 years old at diagnosis (P=0.02) were more likely to be BRMS1 negative. No overall correlation between BRMS1 staining and disease-free survival was observed. A significant correlation, however, was seen between loss of BRMS1 protein expression and reduced disease-free survival when stratified by either loss of ER (P=0.008) or PR (P=0.029) or HER2 overexpression (P=0.026). Overall, there was poor correlation between BRMS1 protein staining and copy number status. CONCLUSIONS: These data suggest a mechanistic relationship between BRMS1 expression, hormone receptor status, and HER2 growth factor. BRMS1 staining could potentially be used in patient stratification in conjunction with other prognostic markers. Further, mechanisms other than genomic deletion account for loss of BRMS1 gene expression in breast tumors.     

Triplet morbidity and mortality in a large case series.

OBJECTIVE: A significant increase in the triplet birth rate has occurred recently. This rise is of concern, as these infants are historically reported to be at risk of adverse outcome. Thus, we examined the outcome of triplet births in a large contemporary case series. STUDY DESIGN: Since 1993, detailed clinical data have been collected on all patients admitted to our Neonatal Intensive Care Unit. We retrospectively analyzed this database to examine triplet outcome. RESULTS: A total of 51 consecutive sets of triplets were born over a 9-year period. The mean birth weight for triplets was 1789+/-505 g, mean gestational age was 32.6+/-2.7 weeks, with discordancy present in 17.6% of neonates. Complications of prematurity were infrequent. Triplet survival to discharge was 96%. CONCLUSIONS: This large contemporary case series of triplets demonstrates excellent survival with low associated morbidity. These data suggest that there may no longer be medical justification for offering selective fetal reduction to parents with triplet pregnancies.     

NOS1 polymorphism is associated with atopy but not exhaled nitric oxide levels in healthy children

Exhaled nitric oxide (FE_NO) is raised in atopy. The mechanism for this is unclear. The aim of this study was to investigate whether the number of AAT repeats in intron 20 of the NOS1 gene, recently associated with variations in FE_NO in adults with asthma and cystic fibrosis, was associated with the raised FE_NO in healthy atopic children. Eighty-seven healthy children (44 girls, 42 atopic, age range 6–18 years) underwent measurements of FE_NO, spirometry, airway responsiveness and skin prick testing. Genotyping was carried out to determine the number of AAT repeats. There was no association between the number of AAT repeats and FE_NO in either the whole sample of healthy children (n = 87) or in the subsample of healthy atopics (n = 42). However, a greater number of atopic children had two high repeat alleles compared with non-atopic children (33.3% vs. 13.6%, respectively, p = 0.03). This suggests that variations in the NOS1 gene may contribute to atopy without this relationship being reflected by FE_NO.     

Longitudinal,population-based study of racial/ethnic differences in colorectal cancer survival: impact of neighborhood socioeconomic status,treatment and comorbidity

Background  

Colorectal cancer, if detected early, has greater than 90% 5-year survival. However, survival has been shown to vary across racial/ethnic groups in the United States, despite the availability of early detection methods.     

Disposition of 14C-dapoxetine in rats: Complementary experiments with whole-body autoradiographic and tissue dissection techniques

Tissue distribution studies, utilizing whole-body autoradiography and organ dissection techniques, were conducted in male Fischer 344 rats following the oral administration of ¹⁴C-dapoxetine HCl, a potent serotonin reuptake inhibitor. The preliminary study using whole-body autoradiography proved invaluable in locating radioactivity in an organ not usually harvested in a tissue distribution study, namely the preputial gland. Selected organs, based on whole-body autoradiography findings, were dissected from rats and analyzed for radiocarbon content by liquid scintillation counting and for parent drug and N-dealkylated metabolites by extraction and HPLC analysis. Highest concentrations of radiocarbon were observed in the organs of absorption and elimination (ileum, cecum, stomach, duodenum, liver, colon, and kidney) but notable quantities were observed in the lung and preputial and Harderian glands. Most tissues had returned to background radioactive levels 72 h after dosing but persistent concentrations of radiocarbon were present in the preputial gland and liver one week after the single dose of ¹⁴C-dapoxetine. Analysis by HPLC demonstrated the presence of parent drug and N-desmethyl metabolite (nor-dapoxetine) in those organs examined; however, the majority of the radioactivity remained unidentified.