Somatic PIK3R1 Variation as a Cause of Vascular Malformations and Overgrowth

PurposeSomatic activating variants in the PI3K-AKT pathway cause vascular malformations with and without overgrowth. We previously reported an individual with capillary and lymphatic malformation harboring a pathogenic somatic variant in PIK3R1, which encodes three PI3K complex regulatory subunits. Here, we investigate PIK3R1 in a large cohort with vascular anomalies and identify an additional 16 individuals with somatic mosaic variants in PIK3R1.MethodsAffected tissue from individuals with vascular lesions and overgrowth recruited from a multisite collaborative network was studied. Next-generation sequencing targeting coding regions of cell-signaling and cancer-associated genes was performed followed by assessment of variant pathogenicity.ResultsThe phenotypic and variant spectrum associated with somatic variation in PIK3R1 is reported herein. Variants occurred in the inter-SH2 or N-terminal SH2 domains of all three PIK3R1 protein products. Phenotypic features overlapped those of the PIK3CA-related overgrowth spectrum (PROS). These overlapping features included mixed vascular malformations, sandal toe gap deformity with macrodactyly, lymphatic malformations, venous ectasias, and overgrowth of soft tissue or bone.ConclusionSomatic PIK3R1 variants sharing attributes with cancer-associated variants cause complex vascular malformations and overgrowth. The PIK3R1-associated phenotypic spectrum overlaps with PROS. These data extend understanding of the diverse phenotypic spectrum attributable to genetic variation in the PI3K-AKT pathway

Measurement of the top quark mass using the matrix element technique in dilepton final states

We present a measurement of the top quark mass in pp¯ collisions at a center-of-mass energy of 1.96 TeV at the Fermilab Tevatron collider. The data were collected by the D0 experiment corresponding to an integrated luminosity of 9.7  fb−1. The matrix element technique is applied to tt¯ events in the final state containing leptons (electrons or muons) with high transverse momenta and at least two jets. The calibration of the jet energy scale determined in the lepton+jets final state of tt¯ decays is applied to jet energies. This correction provides a substantial reduction in systematic uncertainties. We obtain a top quark mass of mt=173.93±1.84  GeV

Cluster Lenses

Clusters of galaxies are the most recently assembled, massive, bound structures in the Universe. As predicted by General Relativity, given their masses, clusters strongly deform space-time in their vicinity. Clusters act as some of the most powerful gravitational lenses in the Universe. Light rays traversing through clusters from distant sources are hence deflected, and the resulting images of these distant objects therefore appear distorted and magnified. Lensing by clusters occurs in two regimes, each with unique observational signatures. The strong lensing regime is characterized by effects readily seen by eye, namely, the production of giant arcs, multiple-images, and arclets. The weak lensing regime is characterized by small deformations in the shapes of background galaxies only detectable statistically. Cluster lenses have been exploited successfully to address several important current questions in cosmology: (i) the study of the lens(es) - understanding cluster mass distributions and issues pertaining to cluster formation and evolution, as well as constraining the nature of dark matter; (ii) the study of the lensed objects - probing the properties of the background lensed galaxy population - which is statistically at higher redshifts and of lower intrinsic luminosity thus enabling the probing of galaxy formation at the earliest times right up to the Dark Ages; and (iii) the study of the geometry of the Universe - as the strength of lensing depends on the ratios of angular diameter distances between the lens, source and observer, lens deflections are sensitive to the value of cosmological parameters and offer a powerful geometric tool to probe Dark Energy. In this review, we present the basics of cluster lensing and provide a current status report of the field.Comment: About 120 pages - Published in Open Access at: http://www.springerlink.com/content/j183018170485723/ . arXiv admin note: text overlap with arXiv:astro-ph/0504478 and arXiv:1003.3674 by other author

Identification of the Photoreceptor Transcriptional Co-Repressor SAMD11 as Novel Cause of Autosomal Recessive Retinitis Pigmentosa

Retinitis pigmentosa (RP), the most frequent form of inherited retinal dystrophy is characterized by progressive photoreceptor degeneration. Many genes have been implicated in RP development, but several others remain to be identified. Using a combination of homozygosity mapping, whole-exome and targeted next-generation sequencing, we found a novel homozygous nonsense mutation in SAMD11 in five individuals diagnosed with adult-onset RP from two unrelated consanguineous Spanish families. SAMD11 is ortholog to the mouse major retinal SAM domain (mr-s) protein that is implicated in CRX-mediated transcriptional regulation in the retina. Accordingly, protein-protein network analysis revealed a significant interaction of SAMD11 with CRX. Immunoblotting analysis confirmed strong expression of SAMD11 in human retina. Immunolocalization studies revealed SAMD11 was detected in the three nuclear layers of the human retina and interestingly differential expression between cone and rod photoreceptors was observed. Our study strongly implicates SAMD11 as novel cause of RP playing an important role in the pathogenesis of human degeneration of photoreceptors.This work was supported by several grants from the Spanish Centre for Biomedical Network Research on Rare Diseases (CIBERER)(06/07/0036), Instituto de Salud Carlos III (ISCIII, Spanish Ministry of Health)/FEDER, including FIS (PI013/00226) and RETICS (RD09/0076/00101 and RD12/0034/0010), Ministry of Economy and Competitiveness (MINECO), including FEDER (BFU2012-36845), and BIO2011-27069, Conselleria de Educació of the Valencia Community (PROMETEOII/2014/025), Spanish National Organization of the Blind (ONCE) and the Spanish Fighting Blindness Foundation (FUNDALUCE). M.C. was sponsored by the Miguel Servet Program for Researchers in the Spanish National Health Service (CP12/03256) and RSA by Sara Borrel Postdoctoral Program (CD12/00676), both from the ISCIII/FEDER. A.A-F. was sponsored by CIBERER, RPC is supported by Fundación Conchita Rábago (FCR), L.C is sponsored by RETICS (RD12/0034/0010) from ISCIII and L.d.S. was supported by CAPES Foundation, Ministry of Education of Brazil

Association between single nucleotide polymorphisms in the mu opioid receptor gene (OPRM1) and self-reported responses to alcohol in American Indians

Abstract Background Variation in response to the hedonic and adverse effects of a substance is in part an inherited factor that may influence its use, abuse and dependence. The mu opioid receptor is the primary site of action for opiates and individuals with polymorphisms in this receptor appear to have variation in the CNS effects of opiates. Several studies have suggested that this receptor may also mediate some of the effects of non-opioid drugs, such as alcohol. The purpose of this study was to investigate associations between 13 single nucleotide polymorphisms in the mu opioid receptor gene (OPRM1) with self-reported responses to alcohol, an endophenotype associated with the development of alcohol dependence, in American Indians living on eight contiguous reservations. Methods Each participant gave a blood sample and completed a structured diagnostic interview. Additionally, response to alcohol was indexed using the expectation version of the subjective high assessment scale (SHAS-E). SNPs were genotyped in 251 participants and data analyses were conducted using SOLAR. Results The estimated heritability (h2) for the SHAS-E phenotypes ranged from 0.01 to 0.28. Endorsing the expectation of a more intense response on one or more of the following items from the SHAS-E: buzzed, clumsy, dizzy, drunk, effects, high, nausea, sleepy, talkative, terrible, and/or uncomfortable after imbibing 2–3 drinks was significantly associated with having at least one minor allele for at least one of 7 SNPs (p < 0.01) in the OPRM1 receptor gene. Conclusion These studies provide data to suggest that the minor allele, for most of the polymorphisms in the OPRM1 receptor gene investigated, was found to be associated with a more intense, and/or more adverse, response to alcohol, traits that are significantly correlated with lowered quantity of alcohol consumption and less susceptibility to dependence in this Indian population. These data further suggest that making conclusions on the role of the mu opiod receptor gene in the development of alcohol dependence may be limited if only one polymorphism in the gene is evaluated in isolation

Consequences of a large-scale fragmentation experiment for Neotropical bats : disentangling the relative importance of local and landscape-scale effects

Context Habitat loss, fragmentation and degradation are widespread drivers of biodiversity decline. Understanding how habitat quality interacts with landscape context, and how they jointly affect species in human-modified landscapes, is of great importance for informing conservation and management. Objectives We used a whole-ecosystem manipulation experiment in the Brazilian Amazon to investigate the relative roles of local and landscape attributes in affecting bat assemblages at an interior-edge-matrix disturbance gradient. Methods We surveyed bats in 39 sites, comprising continuous forest (CF), fragments, forest edges and intervening secondary regrowth. For each site, we assessed vegetation structure (local-scale variable) and, for five focal scales, quantified habitat amount and four landscape configuration metrics. Results Smaller fragments, edges and regrowth sites had fewer species and higher levels of dominance than CF. Regardless of the landscape scale analysed, species richness and evenness were mostly related to the amount of forest cover. Vegetation structure and configurational metrics were important predictors of abundance, whereby the magnitude and direction of response to configurational metrics were scale-dependent. Responses were ensemble-specific with local-scale vegetation structure being more important for frugivorous than for gleaning animalivorous bats. Conclusions Our study indicates that scale-sensitive measures of landscape structure are needed for a more comprehensive understanding of the effects of fragmentation on tropical biota. Although forest fragments and regrowth habitats can be of conservation significance for tropical bats our results further emphasize that primary forest is of irreplaceable value, underlining that their conservation can only be achieved by the preservation of large expanses of pristine habitat

HFE Gene Variants Modify the Association between Maternal Lead Burden and Infant Birthweight: A Prospective Birth Cohort Study in Mexico City, Mexico

<p>Abstract</p> <p>Background</p> <p>Neonatal growth is a complex process involving genetic and environmental factors. Polymorphisms in the hemochromatosis (<it>HFE</it>) iron regulatory genes have been shown to modify transport and toxicity of lead which is known to affect birth weight.</p> <p>Methods</p> <p>We investigated the role of <it>HFE C282Y</it>, <it>HFE H63 D</it>, and transferrin <it>(TF) P570 S </it>gene variants in modifying the association of lead and infant birthweight in a cohort of Mexican mother-infant pairs. Subjects were initially recruited between 1994-1995 from three maternity hospitals in Mexico City and 411 infants/565 mothers had archived blood available for genotyping. Multiple linear regression models, stratified by either maternal/infant <it>HFE </it>or <it>TF </it>genotype and then combined with interaction terms, were constructed examining the association of lead and birthweight after controlling for covariates.</p> <p>Results</p> <p>3.1%, 16.8% and 17.5% of infants (N = 390) and 1.9%, 14.5% and 18.9% of mothers (N = 533) carried the <it>HFE C282Y</it>, <it>HFE H63D</it>, and <it>TF P570 S </it>variants, respectively. The presence of infant <it>HFE H63 D </it>variants predicted 110.3 g (95% CI -216.1, -4.6) decreases in birthweight while maternal <it>HFE H63 D </it>variants predicted reductions of 52.0 g (95% CI -147.3 to 43.2). Interaction models suggest that both maternal and infant <it>HFE H63 D </it>genotype may modify tibia lead's effect on infant birthweight in opposing ways. In our interaction models, maternal <it>HFE H63 D </it>variant carriers had a negative association between tibia lead and birthweight.</p> <p>Conclusions</p> <p>These results suggest that the <it>HFE H63 D </it>genotype modifies lead's effects on infant birthweight in a complex fashion that may reflect maternal-fetal interactions with respect to the metabolism and transport of metals.</p

Macular hole formation, progression, and surgical repair: case series of serial optical coherence tomography and time lapse morphing video study

<p>Abstract</p> <p>Background</p> <p>To use a new medium to dynamically visualize serial optical coherence tomography (OCT) scans in order to illustrate and elucidate the pathogenesis of idiopathic macular hole formation, progression, and surgical closure.</p> <p>Case Presentations</p> <p>Two patients at the onset of symptoms with early stage macular holes and one patient following repair were followed with serial OCTs. Images centered at the fovea and at the same orientation were digitally exported and morphed into an Audiovisual Interleaving (avi) movie format. Morphing videos from serial OCTs allowed the OCTs to be viewed dynamically. The videos supported anterior-posterior vitreofoveal traction as the initial event in macular hole formation. Progression of the macular hole occurred with increased cystic thickening of the fovea without evidence of further vitreofoveal traction. During cyst formation, the macular hole enlarged as the edges of the hole became elevated from the retinal pigment epithelium (RPE) with an increase in subretinal fluid. Surgical repair of a macular hole revealed initial closure of the macular hole with subsequent reabsorption of the sub-retinal fluid and restoration of the foveal contour.</p> <p>Conclusions</p> <p>Morphing videos from serial OCTs are a useful tool and helped illustrate and support anterior-posterior vitreofoveal traction with subsequent retinal hydration as the pathogenesis of idiopathic macular holes.</p

Could giardiasis be a risk factor for low zinc status in schoolchildren from northwestern Mexico? A cross-sectional study with longitudinal follow-up

<p>Abstract</p> <p>Background</p> <p>Both giardiasis and zinc deficiency are serious health problems worldwide. In Mexico, the prevalence of <it>G. intestinalis </it>was estimated at 32% in 1994. It remains a health problem in northwestern Mexico. Recent surveys (1987, 1995, and 1999) reported zinc deficiency in the Mexican population. The association of giardiasis and malabsorption of micronutrients has been well documented, although the association with zinc remains controversial. This study investigated the association between giardiasis and zinc deficiency in schoolchildren from northwestern Mexico.</p> <p>Methods</p> <p>We combined a cross-sectional design with a longitudinal follow-up six months after parasite treatment. The baseline sample consisted of 114 schoolchildren (mean age 8.8 yr) from seven suburban public schools, grouped as <it>Giardia</it>-free (<it>n </it>= 65, 57%) and <it>Giardia</it>-infected (<it>n </it>= 49, 43%). Three stool analyses per child were done using Faust's method. Children with giardiasis received secnidazole. Serum zinc was determined by atomic absorption spectrophotometry. Height and weight were measured. Socioeconomic information was obtained in an oral questionnaire, and daily zinc intake was assessed using 24 hour-recalls. Pearson's correlation and ANCOVA and paired t-test analyses were used to determine the association between giardiasis and zinc status.</p> <p>Results</p> <p>Longitudinal analysis demonstrated a significant increase of the mean serum zinc levels in the <it>Giardia</it>-infected group six months after treatment (13.78 vs. 19.24 μmol/L μmol/L; p = 0.001), although no difference was found between the <it>Giardia</it>-free and the <it>Giardia</it>-infected groups (p = 0.86) in the baseline analysis. Z scores for W/A and H/A were lower in the <it>Giardia</it>-infected than in the <it>Giardia</it>-free group (p < 0.05). No difference was observed in the socioeconomic characteristics and mean daily intakes of zinc between the groups (p > 0.05).</p> <p>Conclusions</p> <p>Giardiasis may be a risk factor for zinc deficiency in schoolchildren from northwestern Mexico.</p

National Prevalence and Trends of HIV Transmitted Drug Resistance in Mexico

BACKGROUND: Transmitted drug resistance (TDR) remains an important concern for the management of HIV infection, especially in countries that have recently scaled-up antiretroviral treatment (ART) access. METHODOLOGY/PRINCIPAL FINDINGS: We designed a study to assess HIV diversity and transmitted drug resistance (TDR) prevalence and trends in Mexico. 1655 ART-naïve patients from 12 Mexican states were enrolled from 2005 to 2010. TDR was assessed from plasma HIV pol sequences using Stanford scores and the WHO TDR surveillance mutation list. TDR prevalence fluctuations over back-projected dates of infection were tested. HIV subtype B was highly prevalent in Mexico (99.9%). TDR prevalence (Stanford score>15) in the country for the study period was 7.4% (95% CI, 6.2∶8.8) and 6.8% (95% CI, 5.7∶8.2) based on the WHO TDR surveillance mutation list. NRTI TDR was the highest (4.2%), followed by NNRTI (2.5%) and PI (1.7%) TDR. Increasing trends for NNRTI (p = 0.0456) and PI (p = 0.0061) major TDR mutations were observed at the national level. Clustering of viruses containing minor TDR mutations was observed with some apparent transmission pairs and geographical effects. CONCLUSIONS: TDR prevalence in Mexico remains at the intermediate level and is slightly lower than that observed in industrialized countries. Whether regional variations in TDR trends are associated with differences in antiretroviral drug usage/ART efficacy or with local features of viral evolution remains to be further addressed