Missense Mutation R338W in ARHGEF9 in a Family with X-linked Intellectual Disability with Variable Macrocephaly and Macro-Orchidism

Non-syndromal X-linked intellectual disability (NS-XLID) represents a broad group of clinical disorders in which ID is the only clinically consistent manifestation. Although in many cases either chromosomal linkage data or knowledge of the >100 existing XLID genes has assisted mutation discovery, the underlying cause of disease remains unresolved in many families. We report the resolution of a large family (K8010) with NS-XLID, with variable macrocephaly and macro-orchidism. Although a previous linkage study had mapped the locus to Xq12-q21, this region contained too many candidate genes to be analyzed using conventional approaches. However, X-chromosome exome sequencing, bioinformatics analysis and segregation analysis revealed a novel missense mutation (c.1012C>T; p.R338W) in ARHGEF9. This gene encodes collybistin (CB), a neuronal GDP-GTP exchange factor previously implicated in several cases of XLID, as well as clustering of gephyrin and GABAA receptors at inhibitory synapses. Molecular modeling of the CB R338W substitution revealed that this change results in the substitution of a long electropositive side-chain with a large non-charged hydrophobic side-chain. The R338W change is predicted to result in clashes with adjacent amino acids (K363 and N335) and disruption of electrostatic potential and local folding of the PH domain, which is known to bind phosphatidylinositol-3-phosphate (PI3P/PtdIns-3-P). Consistent with this finding, functional assays revealed that recombinant CB CB2SH3- (R338W) was deficient in PI3P binding and was not able to translocate EGFP-gephyrin to submembrane microaggregates in an in vitro clustering assay. Taken together, these results suggest that the R338W mutation in ARHGEF9 is the underlying cause of NS-XLID in this family

Expression of Adhesion Molecules during Tooth Resorption in Feline Teeth: A Model System for Aggressive Osteoclastic Activity

Tooth resorption, a common feline dental problem, is often initiated at the cemento-enamel junction and hence is called cat 'neck' lesion. Studies have demonstrated that osteoclasts/odontoclasts are increased and activated at resorption sites, and that areas of resorption are partly repaired by formation of tissues resembling bone, cementum, and possibly dentin. However, the cellular/molecular mechanisms/factors involved in resorption and repair are unknown. In this study of tissues from cats with 'neck' lesions, we used specific antibodies and immunohistochemical analyses to examine adhesion molecules associated with mineralized tissues, bone sialoprotein (BSP) and osteopontin (OPN), and a cell-surface receptor linked with these molecules, α vβ3, for their localization in these lesions. In addition, to determine general cellular activity during repair, we performed in situ hybridization using a type I collagen riboprobe. Results showed OPN localized to resorption fronts and reversal lines, while BSP was localized to reversal lines. However, some osteoclasts and odontoblasts "sat" on mineralized surfaces not associated with OPN. The cell-surface receptor, αvβ 3, was localized to surfaces of osteoclasts/odontoclasts. Type I collagen mRNA was expressed where osteoblasts attempted to repair mineralized tissue. In contrast, odontoblasts did not express mRNA for type I collagen. This study suggests that osteoclastic resorption is the predominant activity in 'neck' lesions and that this activity was accompanied, at least in part, by increased concentrations of OPN and an associated integrin, α vβ3, at resorption sites. Lack of collagen expression by odontoblasts indicates that odontoblasts do not play an active role in attempts at repair.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66661/2/10.1177_00220345960750090601.pd

Evaluating the efficacy of thoracoscopy and talc poudrage versus pleurodesis using talc slurry (TAPPS trial): protocol of an open-label randomised controlled trial

INTRODUCTION: The management of recurrent malignant pleural effusions (MPE) can be challenging. Various options are available, with the most efficacious and widely used being talc pleurodesis. Talc can either be applied via a chest drain in the form of slurry, or at medical thoracoscopy using poudrage. Current evidence regarding which method is most effective is conflicting and often methodologically flawed. The TAPPS trial is a suitably powered, multicentre, open-label, randomised controlled trial designed to compare the pleurodesis success rate of medical thoracoscopy and talc poudrage with chest drain insertion and talc slurry. METHODS AND ANALYSIS: 330 patients with a confirmed MPE requiring intervention will be recruited from UK hospitals. Patients will be randomised (1:1) to undergo either small bore (<14 Fr) Seldinger chest drain insertion followed by instillation of sterile talc (4 g), or to undergo medical thoracoscopy and simultaneous poudrage (4 g). The allocated procedure will be performed as an inpatient within 3 days of randomisation taking place. Following discharge, patients will be followed up at regular intervals for 6 months. The primary outcome measure is pleurodesis failure rates at 3 months. Pleurodesis failure is defined as the need for further pleural intervention for fluid management on the side of the trial intervention. ETHICS AND DISSEMINATION: The trial has received ethical approval from the National Research Ethics Service Committee North West-Preston (12/NW/0467). There is a trial steering committee which includes independent members and a patient and public representative. The trial results will be published in a peer-reviewed journal and presented at international conferences, as well as being disseminated via local and national charities and patient groups. All participants who wish to know the study results will also be contacted directly on their publication. TRIAL REGISTRATION NUMBER: ISRCTN47845793

Inverse Association between trans Isomeric and Long-Chain Polyunsaturated Fatty Acids in Pregnant Women and Their Newborns: Data from Three European Countries

Background: trans unsaturated fatty acids are thought to interfere with essential fatty acid metabolism. To extend our knowledge of this phenomenon, we investigated the relationship between trans isomeric and long-chain polyunsaturated fatty acids (LCPUFA) in mothers during pregnancy and in their infants at birth. Methods: Fatty acid composition of erythrocyte phosphatidylcholine (PC) and phosphatidylethanolamine (PE) was determined in Spanish (n = 120), German (n = 78) and Hungarian (n = 43) women at the 20th and 30th week of gestation, at delivery and in their newborns. Results: At the 20th week of gestation, the sum of trans fatty acids in PE was significantly (p < 0.01) lower in Hungarian [0.73 (0.51), % wt/wt, median (IQR)] than in Spanish [1.42 (1.36)] and German [1.30 (1.21)] women. Docosahexaenoic acid (DHA) values in PE were significantly (p < 0.01) higher in Hungarian {[}5.65 (2.09)] than in Spanish [4.37 (2.60)] or German [4.39 (3.3.2)] women. The sum of trans fatty acids significantly inversely correlated to DHA in PCs in Spanish (r = -0.37, p < 0.001), German (n = -0.77, p < 0.001) and Hungarian (r = -0.35, p < 0.05) women, and in PEs in Spanish (r = -0.67, p < 0.001) and German (r = -0.71, p < 0.001), but not in Hungarian (r = -0.02) women. Significant inverse correlations were seen between trans fatty acids and DHA in PEs at the 30th week of gestation (n = 241, r = -0.52, p < 0.001), at delivery (n = 241, r = -0.40, p < 0.001) and in cord lipids (n = 218, r = -0.28, p < 0.001). Conclusion: Because humans cannot synthesize trans isomeric fatty acids, the data obtained in the present study support the concept that high maternal trans isomeric fatty acid intake may interfere with the availability of LCPUFA both for the mother and the fetus. Copyright (C) 2011 S. Karger AG, Base

The contribution of diet and genotype to iron status in women:a classical twin study

This is the first published report examining the combined effect of diet and genotype on body iron content using a classical twin study design. The aim of this study was to determine the relative contribution of genetic and environmental factors in determining iron status. The population was comprised of 200 BMI- and age-matched pairs of MZ and DZ healthy twins, characterised for habitual diet and 15 iron-related candidate genetic markers. Variance components analysis demonstrated that the heritability of serum ferritin (SF) and soluble transferrin receptor was 44% and 54% respectively. Measured single nucleotide polymorphisms explained 5% and selected dietary factors 6% of the variance in iron status; there was a negative association between calcium intake and body iron (p = 0.02) and SF (p = 0.04)

Acceptability of novel lifelogging technology to determine context of sedentary behaviour in older adults

<strong>Objective:</strong> Lifelogging, using body worn sensors (activity monitors and time lapse photography) has the potential to shed light on the context of sedentary behaviour. The objectives of this study were to examine the acceptability, to older adults, of using lifelogging technology and indicate its usefulness for understanding behaviour.<strong> </strong><strong>Method:</strong> 6 older adults (4 males, mean age: 68yrs) wore the equipment (ActivPAL^TM and Vicon Revue^TM/SenseCam^TM) for 7 consecutive days during free-living activity. The older adults’ perception of the lifelogging technology was assessed through semi-structured interviews, including a brief questionnaire (Likert scale), and reference to the researcher&#39;s diary. <strong>Results:</strong> Older adults in this study found the equipment acceptable to wear and it did not interfere with privacy, safety or create reactivity, but they reported problems with the actual technical functioning of the camera. <strong>Conclusion:</strong> This combination of sensors has good potential to provide lifelogging information on the context of sedentary behaviour

Effects of UV-B radiation on the structural and physiological diversity of bacterioneuston and bacterioplankton

The effects of UV radiation (UVR) on estuarine bacterioneuston and bacterioplankton were assessed in microcosm experiments. Bacterial abundance and DNA synthesis were more affected in bacterioplankton. Protein synthesis was more inhibited in bacterioneuston. Community analysis indicated that UVR has the potential to select resistant bacteria (e.g., Gammaproteobacteria), particularly abundant in bacterioneuston

Man-made structures in the marine environment: A review of stakeholders’ social and economic values and perceptions

Man-made marine structures (MMS) are commonly used to describe any artificial structure in the marine environment, encompassing oil and gas infrastructure and pipelines, artificial reefs, jetties, piers and shipwrecks. MMS are increasingly proposed to address issues facing marine planners, including augmenting fish stocks through the creation of artificial reefs and the repurposing of redundant offshore oil and gas infrastructure (‘rigs to reefs’). Marine spatial planning is a highly contested process, characterised by multiple stakeholders with often divergent priorities due to competing objectives and values. Understanding stakeholder perspectives in relation to MMS is therefore critical in formulating appropriate policies. This review presents the first systematic and comprehensive integration of information from academic journals and ‘grey’ literature relating to social and economic values and perceptions of MMS. The review identifies that, despite advocacy for research on social and economic values of MMS, there are significant gaps in knowledge, in particular relating to comparative assessments of stakeholder values across different types of MMS. Priority areas for future research are highlighted