Expression and functional analysis of EFNB1 mutations in craniofrontonasal syndrome

Magdeburg, Univ., Fak. für Naturwiss., Diss., 2010

Prevalence of Risk for Obstructive Sleep Apnea Syndrome and Association With Risk Factors in Primary Care

Abstract Background: Obstructive sleep apnea syndrome (OSAS) is a chronic, progressive disease with high morbidity and mortality. It is underdiagnosed, especially among women. Objective: To study the prevalence of high risk for OSAS globally and for the Berlin Questionnaire (BQ) categories, and to evaluate the reliability of the BQ use in the population studied. Methods: Observational, cross-sectional study with individuals from the Niterói Family Doctor Program, randomly selected, aged between 45 and 99 years. The visits occurred between August/2011 and December/2012. Variables associated with each BQ category and with high risk for OSAS (global) were included in logistic regression models (p < 0.05). Results: Of the total (616), 403 individuals (65.4%) reported snoring. The prevalence of high risk for OSA was 42.4%, being 49.7% for category I, 10.2% for category II and 77.6% for category III. Conclusion: BQ showed an acceptable reliability after excluding the questions Has anyone noticed that you stop breathing during your sleep? and Have you ever dozed off or fallen asleep while driving?. This should be tested in further studies with samples mostly comprised of women and low educational level individuals. Given the burden of OSAS-related diseases and risks, studies should be conducted to validate new tools and to adapt BQ to better screen OSAS.

Seasonal variation of the effect of high-carbohydrate and high-protein diets on the intermediate metabolism of Parastacus brasiliensis (Crustacea, Decapoda, Parastacidae) maintained in the laboratory

The goal of this study was to evaluate the effect of a high-carbohydrate diet (HC) and a high-protein diet (HP) on the metabolism of the crayfish Parastacus brasiliensis (Von Martens, 1869), collected in different seasons and maintained in the laboratory for 15 days. Crayfish were collected monthly from January 2002 to January 2004 at São Francisco de Paula, Southern Brazil, in Guarapirá stream. In the laboratory, the animals were kept submerged in aquariums under controlled conditions. They were fed ad libitum, for 15 days with either a HC or HP diet. At the end of this period, haemolymph samples were collected, as were hepatopancreas, gills, and abdominal muscle that were removed for determination of glycogen, free glucose, lipids, and triglycerides. The haemolymph samples were used for determination of glucose, proteins, lipids, and triglycerides. Statistical analysis (ANOVA) revealed significant seasonal differences in biochemical composition in crayfish maintained on HC or HP diets. Independent of the diets offered to the animals and the controlled conditions for 15 days, the indications of seasonality were unchanged. The observed changes seemed to be related to the reproductive period. Moreover, the HC diet increased all energy reserves in adult parastacids, which may aid in reproduction.

An atypical 7q11.23 deletion in a normal IQ Williams-Beuren syndrome patient.

Williams-Beuren syndrome (WBS; OMIM no. 194050) is a multisystemic neurodevelopmental disorder caused by a hemizygous deletion of 1.55 Mb on chromosome 7q11.23 spanning 28 genes. Haploinsufficiency of the ELN gene was shown to be responsible for supravalvular aortic stenosis and generalized arteriopathy, whereas LIMK1, CLIP2, GTF2IRD1 and GTF2I genes were suggested to be linked to the specific cognitive profile and craniofacial features. These insights for genotype-phenotype correlations came from the molecular and clinical analysis of patients with atypical deletions and mice models. Here we report a patient showing mild WBS physical phenotype and normal IQ, who carries a shorter 1 Mb atypical deletion. This rearrangement does not include the GTF2IRD1 and GTF2I genes and only partially the BAZ1B gene. Our results are consistent with the hypothesis that hemizygosity of the GTF2IRD1 and GTF2I genes might be involved in the facial dysmorphisms and in the specific motor and cognitive deficits observed in WBS patients.

High fat versus high carbohydrate nutritional supplementation: a one year trial in stunted rural Gambian children.

OBJECTIVE: The study tests the hypothesis that a low daily fat intake may induce a negative fat balance and impair catch-up growth in stunted children between 3 and 9y of age. DESIGN: Randomized case-control study. SETTING: Three rural villages of the West Kiang District, The Gambia. SUBJECTS: Three groups of 30 stunted but not wasted children (height for age z-score < or = -2.0, weight for height z-score > or = -2.0) 3-9 y of age were selected by anthropometric survey. Groups were matched for age, sex, village, degree of stunting and season. INTERVENTION: Two groups were randomly assigned to be supplemented five days a week for one year with either a high fat (n = 29) or a high carbohydrate biscuit (n = 30) each containing approximately 1600 kJ. The third group was a non supplemented control group (n = 29). Growth, nutritional status, dietary intake, resting energy expenditure and morbidity were compared. RESULTS: Neither the high fat nor the high carbohydrate supplement had an effect on weight or height gain. The high fat supplement did slightly increase adipose tissue mass. There was no effect of supplementation on resting energy expenditure or morbidity. In addition, the annual growth rate was not associated with a morbidity score. CONCLUSIONS: Results show that neither a high fat nor a high carbohydrate supplement given during 12 months to stunted Gambian children induced catch-up growth. The authors suggest that an adverse effect of the environment on catch-up growth persists despite the nutritional interventions.

NR2E3 mutations in enhanced S-cone sensitivity syndrome (ESCS), Goldmann-Favre syndrome (GFS), clumped pigmentary retinal degeneration (CPRD), and retinitis pigmentosa (RP).

NR2E3, also called photoreceptor-specific nuclear receptor (PNR), is a transcription factor of the nuclear hormone receptor superfamily whose expression is uniquely restricted to photoreceptors. There, its physiological activity is essential for proper rod and cone photoreceptor development and maintenance. Thirty-two different mutations in NR2E3 have been identified in either homozygous or compound heterozygous state in the recessively inherited enhanced S-cone sensitivity syndrome (ESCS), Goldmann-Favre syndrome (GFS), and clumped pigmentary retinal degeneration (CPRD). The clinical phenotype common to all these patients is night blindness, rudimental or absent rod function, and hyperfunction of the "blue" S-cones. A single p.G56R mutation is inherited in a dominant manner and causes retinitis pigmentosa (RP). We have established a new locus-specific database for NR2E3 (www.LOVD.nl/eye), containing all reported mutations, polymorphisms, and unclassified sequence variants, including novel ones. A high proportion of mutations are located in the evolutionarily-conserved DNA-binding domains (DBDs) and ligand-binding domains (LBDs) of NR2E3. Based on homology modeling of these NR2E3 domains, we propose a structural localization of mutated residues. The high variability of clinical phenotypes observed in patients affected by NR2E3-linked retinal degenerations may be caused by different disease mechanisms, including absence of DNA-binding, altered interactions with transcriptional coregulators, and differential activity of modifier genes.

Phenotypic consequences of copy number variation: insights from Smith-Magenis and Potocki-Lupski syndrome mouse models.

A large fraction of genome variation between individuals is comprised of submicroscopic copy number variation of genomic DNA segments. We assessed the relative contribution of structural changes and gene dosage alterations on phenotypic outcomes with mouse models of Smith-Magenis and Potocki-Lupski syndromes. We phenotyped mice with 1n (Deletion/+), 2n (+/+), 3n (Duplication/+), and balanced 2n compound heterozygous (Deletion/Duplication) copies of the same region. Parallel to the observations made in humans, such variation in gene copy number was sufficient to generate phenotypic consequences: in a number of cases diametrically opposing phenotypes were associated with gain versus loss of gene content. Surprisingly, some neurobehavioral traits were not rescued by restoration of the normal gene copy number. Transcriptome profiling showed that a highly significant propensity of transcriptional changes map to the engineered interval in the five assessed tissues. A statistically significant overrepresentation of the genes mapping to the entire length of the engineered chromosome was also found in the top-ranked differentially expressed genes in the mice containing rearranged chromosomes, regardless of the nature of the rearrangement, an observation robust across different cell lineages of the central nervous system. Our data indicate that a structural change at a given position of the human genome may affect not only locus and adjacent gene expression but also "genome regulation." Furthermore, structural change can cause the same perturbation in particular pathways regardless of gene dosage. Thus, the presence of a genomic structural change, as well as gene dosage imbalance, contributes to the ultimate phenotype.

Neurolysis using a carbohydrate polymer gel for the treatment of postoperative neuropathic pain.

Perineural and intraneural fibrosis is thought to be the main cause of failure of the many surgical treatments of neuropathic pain. We have used Adcon-T/N carbohydrate polymer gel for prevention of perineural fibrosis in several parts of the body. In this retrospective study, 54 patients who presented with postoperative neuropathic pain had microsurgical epineural neurolysis and relocation of a terminal neuroma. In 19 of them, the carbohydrate gel was applied at the same time. The mean follow-up was four years and the nerve distribution varied. Postoperative improvement in pain scores (visual analogue scale (VAS) and neuropathic pain scale inventory (NPSI)), sensitivity, overall improvement and satisfaction were equivalent in the two groups, with pain relief in about 80% of the patients. There was no significant beneficial effect in the carbohydrate gel group. Patients treated with this device had a higher infection rate (21 compared with 0, p = 0.01) and delayed wound healing (31.6 compared with 11.8, p = 0.2). We conclude that good long-term pain relief is obtained postoperatively independently of the addition of carbohydrate gel. There was a slight but not significant trend towards profound pain relief with the gel.

Characterization of protective and non-protective surface membrane carbohydrate epitopes of Schistosoma mansoni

We have produced a number of monoclonal antibodies, protective and non-protective, which recognize a complex of schistosomula antigens, including the 38 kDa antigen. Eight different protective and non-protective monoclonal antibodies, varying in isotypes, were used in the binding assays. Lectin inhibition studies suggested that the monoclonal antibodies probably recognized carbohydrate epitopes on the antigen(s). Immunoprecipitation studies showed that at least two of the monoclonal antibodies recognized different epitopes on the same molecule. Additionally, we tested for monoclonal antibody binding after the antigens were treated with; 1) proteases, 2) periodate, 3) various exo- and endoglycosidases, 4) mild acid hydrolysis. We also tested for binding of the antibodies to keyhole limpet hemocyanin (KLH). Using the 8 monoclonal antibodies as probes, we were able to define at least 4 different carbohydrate epitopes related to the protective monoclonal antibodies, and at least one epitope which is seen by the non-protective antibodies. The epitope seen by the non-protective antibodies was shown to be cross-reactive with epitopes on KLH. These results demonstrate the importance of epitope mapping studies for any defined vaccine.