Rates of clinically apparent heparin-induced thrombocytopenia for unfractionated heparin vs. low molecular weight heparin in non-surgical patients are low and similar

With the growing use of low-molecular-weight heparins (LMWH) for the treatment and prevention of venous thromboembolism (VTE), it is important to provide an evidence-based comparison with unfractionated heparin (UFH) concerning rates of heparin-induced thrombocytopenia (HIT). Such comparisons are essential in clinical decision-making and cost-modeling. In this paper we review data regarding non-surgical (medical) patients. We conclude that the lack of uniform evaluation and standardized testing for HIT in the current literature precludes making a reliable estimate of the relative risk of HIT in UFH vs. LMWH in either the treatment or prevention of VTE in non-surgical patients. However, current data suggest that the risk of thrombocytopenia and HIT is low and similar for non-surgical patients who receive either LMWH or UFH

The splice site variant rs11078928 may be associated with a genotype-dependent alteration in expression of GSDMB transcripts.

Published onlineJournal ArticleResearch Support, Non-U.S. Gov'tBACKGROUND: Many genetic variants have been associated with susceptibility to complex traits by genome wide association studies (GWAS), but for most, causal genes and mechanisms of action have yet to be elucidated. Using bioinformatics, we identified index and proxy variants associated with autoimmune disease susceptibility, with the potential to affect splicing of candidate genes. PCR and sequence analysis of whole blood RNA samples from population controls was then carried out for the 8 most promising variants to determine the effect of genetic variation on splicing of target genes. RESULTS: We identified 31 splice site SNPs with the potential to affect splicing, and prioritised 8 to determine the effect of genotype on candidate gene splicing. We identified that variants rs11078928 and rs2014886 were associated with altered splicing of the GSDMB and TSFM genes respectively. rs11078928, present in the asthma and autoimmune disease susceptibility locus on chromosome 17q12-21, was associated with the production of a novel Δ exon5-8 transcript of the GSDMB gene, and a separate decrease in the percentage of transcripts with inclusion of exon 6, whereas the multiple sclerosis susceptibility variant rs2014886, was associated with an alternative TFSM transcript encompassing a short cryptic exon within intron 2. CONCLUSIONS: Our findings demonstrate the utility of a bioinformatic approach in identification and prioritisation of genetic variants effecting splicing of their host genes, and suggest that rs11078928 and rs2014886 may affect the splicing of the GSDMB and TSFM genes respectively.Mendip Golf ClubNIHR Exeter Clinical Research Facilit

Adaptive Models for Gene Networks

Biological systems are often treated as time-invariant by computational models that use fixed parameter values. In this study, we demonstrate that the behavior of the p53-MDM2 gene network in individual cells can be tracked using adaptive filtering algorithms and the resulting time-variant models can approximate experimental measurements more accurately than time-invariant models. Adaptive models with time-variant parameters can help reduce modeling complexity and can more realistically represent biological systems

Assessment of Daily Life Physical Activities in Pulmonary Arterial Hypertension

Background: In pulmonary arterial hypertension (PAH), the six-minute walk test (6MWT) is believed to be representative of patient’s daily life physical activities (DLPA). Whether DLPA are decreased in PAH and whether the 6MWT is representative of patient’s DL PA remain unknown. Methods: 15 patients with idiopathic PAH (IPAH) and 10 patients with PAH associated with limited systemic sclerosis (PAH-SSc) were matched with 15 healthy control subjects and 10 patients with limited systemic sclerosis without PAH. Each subject completed a 6MWT. The mean number of daily steps and the mean energy expenditure and duration of physical activities.3 METs were assessed with a physical activity monitor for seven consecutive days and used as markers of DLPA. Results: The mean number of daily steps and the mean daily energy expenditure and duration of physical activities.3 METs were all reduced in PAH patients compared to their controls (all p,0.05). The mean number of daily steps correlated with the 6MWT distance for both IPAH and PAH-SSc patients (r = 0.76, p,0.01 and r = 0.85, p,0.01), respectively. Conclusion: DLPA are decreased in PAH and correlate with the 6MWT distance. Functional exercise capacity may thus be a useful surrogate of DL PA in PAH

Investigating rare pathogenic/likely pathogenic exonic variation in bipolar disorder

Bipolar disorder (BD) is a serious mental illness with substantial common variant heritability. However, the role of rare coding variation in BD is not well established. We examined the protein-coding (exonic) sequences of 3,987 unrelated individuals with BD and 5,322 controls of predominantly European ancestry across four cohorts from the Bipolar Sequencing Consortium (BSC). We assessed the burden of rare, protein-altering, single nucleotide variants classified as pathogenic or likely pathogenic (P-LP) both exome-wide and within several groups of genes with phenotypic or biologic plausibility in BD. While we observed an increased burden of rare coding P-LP variants within 165 genes identified as BD GWAS regions in 3,987 BD cases (meta-analysis OR = 1.9, 95% CI = 1.3-2.8, one-sided p = 6.0 × 10-4), this enrichment did not replicate in an additional 9,929 BD cases and 14,018 controls (OR = 0.9, one-side p = 0.70). Although BD shares common variant heritability with schizophrenia, in the BSC sample we did not observe a significant enrichment of P-LP variants in SCZ GWAS genes, in two classes of neuronal synaptic genes (RBFOX2 and FMRP) associated with SCZ or in loss-of-function intolerant genes. In this study, the largest analysis of exonic variation in BD, individuals with BD do not carry a replicable enrichment of rare P-LP variants across the exome or in any of several groups of genes with biologic plausibility. Moreover, despite a strong shared susceptibility between BD and SCZ through common genetic variation, we do not observe an association between BD risk and rare P-LP coding variants in genes known to modulate risk for SCZ

Toxicity Testing in the 21st Century: Defining New Risk Assessment Approaches Based on Perturbation of Intracellular Toxicity Pathways

The approaches to quantitatively assessing the health risks of chemical exposure have not changed appreciably in the past 50 to 80 years, the focus remaining on high-dose studies that measure adverse outcomes in homogeneous animal populations. This expensive, low-throughput approach relies on conservative extrapolations to relate animal studies to much lower-dose human exposures and is of questionable relevance to predicting risks to humans at their typical low exposures. It makes little use of a mechanistic understanding of the mode of action by which chemicals perturb biological processes in human cells and tissues. An alternative vision, proposed by the U.S. National Research Council (NRC) report Toxicity Testing in the 21st Century: A Vision and a Strategy, called for moving away from traditional high-dose animal studies to an approach based on perturbation of cellular responses using well-designed in vitro assays. Central to this vision are (a) “toxicity pathways” (the innate cellular pathways that may be perturbed by chemicals) and (b) the determination of chemical concentration ranges where those perturbations are likely to be excessive, thereby leading to adverse health effects if present for a prolonged duration in an intact organism. In this paper we briefly review the original NRC report and responses to that report over the past 3 years, and discuss how the change in testing might be achieved in the U.S. and in the European Union (EU). EU initiatives in developing alternatives to animal testing of cosmetic ingredients have run very much in parallel with the NRC report. Moving from current practice to the NRC vision would require using prototype toxicity pathways to develop case studies showing the new vision in action. In this vein, we also discuss how the proposed strategy for toxicity testing might be applied to the toxicity pathways associated with DNA damage and repair

Landscape history, time lags and drivers of change : urban natural grassland remnants in Potchefstroom, South Africa

The history of the landscape directly affects biotic assemblages, resulting in time lags in species response to disturbances. In highly fragmented environments, this phenomenon often causes extinction debts. However, few studies have been carried out in urban settings. To determine if there are time lags in the response of temperate natural grasslands to urbanization. Does it differ for indigenous species and for species indicative of disturbance and between woody and open grasslands? Do these time lags change over time? What are the potential landscape factors driving these changes? What are the corresponding vegetation changes? In 1995 and 2012 vegetation sampling was carried out in 43 urban grassland sites. We calculated six urbanization and landscape measures in a 500 m buffer area surrounding each site for 1938, 1961, 1970, 1994, 1999, 2006, and 2010. We used generalized linear models and model selection to determine which time period best predicted the contemporary species richness patterns. Woody grasslands showed time lags of 20-40 years. Contemporary open grassland communities were, generally, associated with more contemporary landscapes. Altitude and road network density of natural areas were the most frequent predictors of species richness. The importance of the predictors changed between the different models. Species richness, specifically, indigenous herbaceous species, declined from 1995 to 2012. The history of urbanization affects contemporary urban vegetation assemblages. This indicates potential extinction debts, which have important consequences for biodiversity conservation planning and sustainable future scenarios.Peer reviewe

Using C. elegans to decipher the cellular and molecular mechanisms underlying neurodevelopmental disorders

Prova tipográfica (uncorrected proof)Neurodevelopmental disorders such as epilepsy, intellectual disability (ID), and autism spectrum disorders (ASDs) occur in over 2 % of the population, as the result of genetic mutations, environmental factors, or combination of both. In the last years, use of large-scale genomic techniques allowed important advances in the identification of genes/loci associated with these disorders. Nevertheless, following association of novel genes with a given disease, interpretation of findings is often difficult due to lack of information on gene function and effect of a given mutation in the corresponding protein. This brings the need to validate genetic associations from a functional perspective in model systems in a relatively fast but effective manner. In this context, the small nematode, Caenorhabditis elegans, presents a good compromise between the simplicity of cell models and the complexity of rodent nervous systems. In this article, we review the features that make C. elegans a good model for the study of neurodevelopmental diseases. We discuss its nervous system architecture and function as well as the molecular basis of behaviors that seem important in the context of different neurodevelopmental disorders. We review methodologies used to assess memory, learning, and social behavior as well as susceptibility to seizures in this organism. We will also discuss technological progresses applied in C. elegans neurobiology research, such as use of microfluidics and optogenetic tools. Finally, we will present some interesting examples of the functional analysis of genes associated with human neurodevelopmental disorders and how we can move from genes to therapies using this simple model organism.The authors would like to acknowledge Fundação para a Ciência e Tecnologia (FCT) (PTDC/SAU-GMG/112577/2009). AJR and CB are recipients of FCT fellowships: SFRH/BPD/33611/2009 and SFRH/BPD/74452/2010, respectively

Recent developments in immunotherapy of acute myeloid leukemia

The advent of new immunotherapeutic agents in clinical practice has revolutionized cancer treatment in the past decade, both in oncology and hematology. The transfer of the immunotherapeutic concepts to the treatment of acute myeloid leukemia (AML) is hampered by various characteristics of the disease, including non-leukemia-restricted target antigen expression profile, low endogenous immune responses, and intrinsic resistance mechanisms of the leukemic blasts against immune responses. However, considerable progress has been made in this field in the past few years. Within this manuscript, we review the recent developments and the current status of the five currently most prominent immunotherapeutic concepts: (1) antibody-drug conjugates, (2) T cell-recruiting antibody constructs, (3) chimeric antigen receptor (CAR) T cells, (4) checkpoint inhibitors, and (5) dendritic cell vaccination. We focus on the clinical data that has been published so far, both for newly diagnosed and refractory/relapsed AML, but omitting immunotherapeutic concepts in conjunction with hematopoietic stem cell transplantation. Besides, we have included important clinical trials that are currently running or have recently been completed but are still lacking full publication of their results. While each of the concepts has its particular merits and inherent problems, the field of immunotherapy of AML seems to have taken some significant steps forward. Results of currently running trials will reveal the direction of further development including approaches combining two or more of these concepts