Generation and comparative analysis of approximately 3.3 Mb of mouse genomic sequence orthologous to the region of human chromosome 7q11.23 implicated in Williams syndrome.

Williams syndrome is a complex developmental disorder that results from the heterozygous deletion of a approximately 1.6-Mb segment of human chromosome 7q11.23. These deletions are mediated by large (approximately 300 kb) duplicated blocks of DNA of near-identical sequence. Previously, we showed that the orthologous region of the mouse genome is devoid of such duplicated segments. Here, we extend our studies to include the generation of approximately 3.3 Mb of genomic sequence from the mouse Williams syndrome region, of which just over 1.4 Mb is finished to high accuracy. Comparative analyses of the mouse and human sequences within and immediately flanking the interval commonly deleted in Williams syndrome have facilitated the identification of nine previously unreported genes, provided detailed sequence-based information regarding 30 genes residing in the region, and revealed a number of potentially interesting conserved noncoding sequences. Finally, to facilitate comparative sequence analysis, we implemented several enhancements to the program, including the addition of links from annotated features within a generated percent-identity plot to specific records in public databases. Taken together, the results reported here provide an important comparative sequence resource that should catalyze additional studies of Williams syndrome, including those that aim to characterize genes within the commonly deleted interval and to develop mouse models of the disorder.     

Costello syndrome: Clinical phenotype,genotype, and management guidelines

Costello syndrome (CS) is a RASopathy caused by activating germline mutations in HRAS. Due to ubiquitous HRAS gene expression, CS affects multiple organ systems and individuals are predisposed to cancer. Individuals with CS may have distinctive craniofacial features, cardiac anomalies, growth and developmental delays, as well as dermatological, orthopedic, ocular, and neurological issues; however, considerable overlap with other RASopathies exists. Medical evaluation requires an understanding of the multifaceted phenotype. Subspecialists may have limited experience in caring for these individuals because of the rarity of CS. Furthermore, the phenotypic presentation may vary with the underlying genotype. These guidelines were developed by an interdisciplinary team of experts in order to encourage timely health care practices and provide medical management guidelines for the primary and specialty care provider, as well as for the families and affected individuals across their lifespan. These guidelines are based on expert opinion and do not represent evidence‐based guidelines due to the lack of data for this rare condition.     

Violence exposure,catecholamine excretion,and blood pressure nondipping status in African American male versus female adolescents

OBJECTIVE: Nondipping status (<10% decrease in blood pressure [BP] from awake to asleep) has been associated with end-organ disease (stroke and left ventricular hypertrophy) in adults. Nondipping status has also been observed in 30% of healthy African American adolescents, but little is known about the correlates of nondipping status in adolescents. This study examined the relationship between violence exposure, catecholamine excretion, and BP nondipping status in 56 healthy African American adolescents (27 boys, 29 girls; ages 11-18 years). METHODS: Participants completed the Survey of Exposure to Community Violence, wore an ambulatory BP monitor and provided one timed day and night urine collection for determination of epinephrine and norepinephrine excretion. RESULTS: Boys had higher daytime epinephrine (5.1 +/- 3.3 vs. 2.6 +/- 2.3 ng/min, p < .001) and norepinephrine excretion (29.2 +/- 25.1 vs. 16.5 +/- 14.9 ng/min, p < .05) and showed a greater prevalence of mean BP nondipping status than girls (37% vs. 10%, p < .03). Mean BP nondipping status was positively associated with victimization (r = 0.42, p < .0001). Regression analyses indicated a significant interaction between hearing about violence and sex for predicting daytime epinephrine (p < .02), with male nondippers showing a stronger positive association (partial correlation = 0.59, p < .05) than females (partial correlation = 0.03, p = NS). Logistic regressions also demonstrated a significant interaction between hearing about violence and sex for predicting mean BP dipping status, with male nondippers reporting the greatest exposure. CONCLUSIONS: Mean BP nondipping was associated with victimization in both boys and girls. Boys who reported higher levels of hearing about violence showed greater daytime epinephrine excretion and were more likely to be classified as nondippers.     

Anti-idiotypic antibodies specific for HLA in heart and kidney allograft recipients

Chronic rejection is the major threat to both heart and renal allograft survival. We have explored the possibility that some patients with anti-donor HLA antibodies (Ab1) develop specific anti-idiotypic antibodies (Ab2) which suppress the production of Ab1, and subsequently, the progression of chronic rejection. analysis of Ab2 in sera obtained from Ab1 producers showed that 22% of heart and 18% of kidney recipients produced Ab2. The 4- and 5-year actuarial graft survivals in Ab2 producers were 100% and 83%, respectively, compared to 57% in patients who formed Ab1 but not Ab2 (p<0.004). Patients carrying the DR2 alleles, DRB1*1501,*1502 or*1601 were at a lower risk of producing anti-donor HLA antibodies.     

Clustering patterns of LOD scores for asthma-related phenotypes revealed by a genome-wide screen in 295 French EGEA families

A genome-wide scan for asthma phenotypes was conducted in the whole sample of 295 EGEA families selected through at least one asthmatic subject. In addition to asthma, seven phenotypes involved in the main asthma physiopathological pathways were considered: SPT (positive skin prick test response to at least one of 11 allergens), SPTQ score being the number of positive skin test responses to 11 allergens, Phadiatop (positive specific IgE response to a mixture of allergens), total IgE levels, eosinophils, bronchial responsiveness (BR) to methacholine challenge and %predicted FEV(1). Four regions showed evidence for linkage (P相似文献   

Left temporal impairment of auditory information processing in prematurely born 9-year-old children: an electrophysiological study.

Children born preterm more than average display cognitive difficulties that are significant enough to prevent normal schooling. The aim of our study was to provide better understanding of the long-term neuropathological processes associated with preterm injury, through the hypothesis that mild cognitive disorders might be related to slight deficits in primary functions such as attention and perception. Assessment of auditory pre-attentive processes was performed by recording the obligatory sensory response (N250) and the change-detection response (Mismatch Negativity, MMN). Topographic study of these responses was performed in fifteen 9-year-old children born preterm (27-33 weeks gestational age) matched to fifteen control children born at term. The auditory stimulus sequence consisted of 1000 Hz standard and 1100 Hz deviant tones (15%) delivered binaurally with an interstimulus interval of 700 ms. The results showed that MMN was similar in both groups. Analysis of the responses to standard repetitive tones demonstrated significantly smaller N250 wave amplitude in children born preterm. Scalp current density maps showed that this reduction in amplitude was associated with lower activity of both frontal and left supratemporal generators. Although the functional significance of the N250 wave in children remains to be clarified, our results indicate a disorder of auditory processes related to prematurity that might have consequences on the development of higher-level processes.     

Epitope specificity is critical for high and moderate avidity cytotoxic T lymphocytes associated with control of viral load and clinical disease in horses with equine infectious anemia virus

Equine infectious anemia virus (EIAV) is a lentivirus that causes persistent infections in horses. We hypothesized that high-avidity CTL specific for nonvariable epitopes might be associated with low viral load and minimal disease in EIAV-infected horses. To test this hypothesis, memory CTL (CTLm) responses were analyzed in two infected horses with high plasma viral loads and recurrent disease (progressors), and in two infected horses with low-to-undetectable viral loads and mild disease (nonprogressors). High-avidity CTLm in one progressor recognized an envelope gp90 epitope, and the data documented for the first time in EIAV that viral variation led to CTL escape. Each of the nonprogressors had high-to-moderate avidity CTLm directed against epitopes within Rev, including the nuclear export and nuclear localization domains. These results suggested that the epitope specificity of high- and moderate-avidity CTLm was an important determinant for disease outcome in the EIAV-infected horses examined.