Mutational and phenotypic characterisation of hereditary hemorrhagic telangiectasia

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular dysplasia. Care delivery for HHT patients is impeded by the need for laborious, repeated phenotyping and gaps in knowledge regarding the relationships between causal DNA variants in ENG, ACVRL1, SMAD4 and GDF2, and clinical manifestations. To address this, we analyzed DNA samples from 183 previously uncharacterized, unrelated HHT and suspected HHT cases using the ThromboGenomics high-throughput sequencing platform. We identified 127 rare variants across 168 heterozygous genotypes. Applying modified American College of Medical Genetics and Genomics Guidelines, 106 variants were classified as pathogenic/likely pathogenic and 21 as nonpathogenic (variant of uncertain significance/benign). Unlike the protein products of ACVRL1 and SMAD4, the extracellular ENG amino acids are not strongly conserved. Our inferences of the functional consequences of causal variants in ENG were therefore informed by the crystal structure of endoglin. We then compared the accuracy of predictions of the causal gene blinded to the genetic data using 2 approaches: subjective clinical predictions and statistical predictions based on 8 Human Phenotype Ontology terms. Both approaches had some predictive power, but they were insufficiently accurate to be used clinically, without genetic testing. The distributions of red cell indices differed by causal gene but not sufficiently for clinical use in isolation from genetic data. We conclude that parallel sequencing of the 4 known HHT genes, multidisciplinary team review of variant calls in the context of detailed clinical information, and statistical and structural modeling improve the prognostication and treatment of HHT

Complex exon-intron marking by histone modifications is not determined solely by nucleosome distribution

It has recently been shown that nucleosome distribution, histone modifications and RNA polymerase II (Pol II) occupancy show preferential association with exons (“exon-intron marking”), linking chromatin structure and function to co-transcriptional splicing in a variety of eukaryotes. Previous ChIP-sequencing studies suggested that these marking patterns reflect the nucleosomal landscape. By analyzing ChIP-chip datasets across the human genome in three cell types, we have found that this marking system is far more complex than previously observed. We show here that a range of histone modifications and Pol II are preferentially associated with exons. However, there is noticeable cell-type specificity in the degree of exon marking by histone modifications and, surprisingly, this is also reflected in some histone modifications patterns showing biases towards introns. Exon-intron marking is laid down in the absence of transcription on silent genes, with some marking biases changing or becoming reversed for genes expressed at different levels. Furthermore, the relationship of this marking system with splicing is not simple, with only some histone modifications reflecting exon usage/inclusion, while others mirror patterns of exon exclusion. By examining nucleosomal distributions in all three cell types, we demonstrate that these histone modification patterns cannot solely be accounted for by differences in nucleosome levels between exons and introns. In addition, because of inherent differences between ChIP-chip array and ChIP-sequencing approaches, these platforms report different nucleosome distribution patterns across the human genome. Our findings confound existing views and point to active cellular mechanisms which dynamically regulate histone modification levels and account for exon-intron marking. We believe that these histone modification patterns provide links between chromatin accessibility, Pol II movement and co-transcriptional splicing

The role of a probiotics mixture in the treatment of childhood constipation: a pilot study

<p>Abstract</p> <p>Background</p> <p>Inconsistent data exist about the efficacy of probiotics in the treatment of constipation. Several studies in adults with constipation showed positive effects of probiotics on constipation. Inconsistent data exist regarding the effect of a single probiotic strain in constipated children. The aim of this pilot study was to determine the effect of a mixture of probiotics containing bifidobacteria and lactobacilli in the treatment of childhood constipation.</p> <p>Methods</p> <p>Children aged 4–16 years with constipation as defined by the Rome III criteria were eligible for the study. During a 4 week period, children received a daily mix of 4 × 10⁹colony forming units of a probiotic mixture (<it>Ecologic</it>^®<it>Relief</it>) containing Bifidobacteria (B.) bifidum, B. infantis, B. longum, Lactobacilli (L.) casei, L. plantarum and L. rhamnosus. Primary outcome measures were frequency of bowel movements (BMs) per week and stool consistency. Secondary outcome measures were number of faecal incontinence episodes per week, abdominal pain and side effects.</p> <p>Results</p> <p>Twenty children, 50% male, median age 8 (range 4–16) were included.</p> <p>The frequency of BMs per week increased from 2.0 (1.0–5.0) to 4.2 (0.0–16.0) in week 2 (p = 0.10) and 3.8 (2.1–7.0) in week 4 (p = 0.13). In 12 children presenting with <3 BMs/week, BMs per week increased significantly from 1.0 (0.0–2.0) to 3.0 (0.0–7.0) in week 2 (p = 0.01) and 3.0 (0.0–10.0) in week 4 (p = 0.01). The stool consistency was reported as hard in 7 children at baseline, in 4 children at week 2 (p = 0.23) and in 6 children after 4 weeks of treatment (p = 1.00). A significant decrease in number of faecal incontinence episodes per week was found in the entire group: 4.0 (0.0–35.0) to 1.5 (0.0–14.0) in week 2 (p = 0.01) and 0.3 (0.0–7.0) in week 4 (p = 0.001). The presence of abdominal pain decreased significantly from 45% to 25% in week 2 (p = 0.04) and 20% at week 4 (p = 0.006). No side effects were reported.</p> <p>Conclusion</p> <p>This pilot study shows that a mixture of probiotics, has positive effects on symptoms of constipation. To confirm these findings, a large randomised placebo controlled trial is required.</p

Goal Priming in Dieters: Recent Insights and Applications

What are the psychological mechanisms that make dieting so challenging in our food-rich living environment? Social psychological research on goal priming provides a useful framework for answering this question, as well as implications for how to enhance dieting success. This review presents and discusses recent research which shows that attractive food cues prime the hedonic eating goal in dieters, and thus facilitate overeating. However, external cues priming the goal of weight control can be used to offset these effects and thus to facilitate dieting success, as is demonstrated in both field and laboratory experiments. In addition, recent strategies to prevent hedonic effects of attractive food, such as mindful attention, can facilitate self-regulation. These recent advances in our understanding of dieting behavior have theoretical and practical implications for how successful dieting can be facilitated, both by means of individual strategies, as well as by environmental changes

Treatment of COVID-19 with remdesivir in the absence of humoral immunity: a case report

The response to the coronavirus disease 2019 (COVID-19) pandemic has been hampered by lack of an effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antiviral therapy. Here we report the use of remdesivir in a patient with COVID-19 and the prototypic genetic antibody deficiency X-linked agammaglobulinaemia (XLA). Despite evidence of complement activation and a robust T cell response, the patient developed persistent SARS-CoV-2 pneumonitis, without progressing to multi-organ involvement. This unusual clinical course is consistent with a contribution of antibodies to both viral clearance and progression to severe disease. In the absence of these confounders, we take an experimental medicine approach to examine the in vivo utility of remdesivir. Over two independent courses of treatment, we observe a temporally correlated clinical and virological response, leading to clinical resolution and viral clearance, with no evidence of acquired drug resistance. We therefore provide evidence for the antiviral efficacy of remdesivir in vivo, and its potential benefit in selected patients

Exome sequencing identifies NBEAL2 as the causative gene for gray platelet syndrome.

Gray platelet syndrome (GPS) is a predominantly recessive platelet disorder that is characterized by mild thrombocytopenia with large platelets and a paucity of α-granules; these abnormalities cause mostly moderate but in rare cases severe bleeding. We sequenced the exomes of four unrelated individuals and identified NBEAL2 as the causative gene; it has no previously known function but is a member of a gene family that is involved in granule development. Silencing of nbeal2 in zebrafish abrogated thrombocyte formation