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Background: Venous thromboembolism (VTE) is a complex multifactorial disease influenced by genetic and environmental risk factors. An example for the latter is the regular use of combined oral contraceptives (CC), which increases the risk to develop VTE by 3 to 7 fold, depending on estrogen dosage and the type of progestin present in the pill. One out of 1'000 women using CC develops thrombosis, often with life-long consequences; a risk assessment is therefore necessary prior to such treatment. Currently known clinical risk factors associated with VTE development in general are routinely checked by medical doctors, however they are far from being sufficient for risk prediction, even when combined with genetic tests for Factor V Leiden and Factor II G20210A variants. Thus, clinical and notably genetic risk factors specific to the development of thrombosis associated with the use of CC in particular should be identified., Methods and Findings: Step-wise (logistic) model selection was applied to a population of 1622 women using CC, half of whom (794) had developed a thromboembolic event while using contraceptives. 46 polymorphisms and clinical parameters were tested in the model selection and a specific combination of 4 clinical risk factors and 9 polymorphisms were identified. Among the 9 polymorphisms, there are two novel genetic polymorphisms (rs1799853 and rs4379368) that had not been previously associated with the development of thromboembolic event. This new prediction model outperforms (AUC 0.71, 95% CI 0.69-0.74) previously published models for general thromboembolic events in a cross-validation setting. Further validation in independent populations should be envisaged., Conclusion: We identified two new genetic variants associated to VTE development, as well as a robust prediction model to assess the risk of thrombosis for women using combined oral contraceptives. This model outperforms current medical practice as well as previously published models and is the first model specific to CC use.

Background and Objectives: Transfusion-related acute lung injury (TRALI) prevention strategies in platelet (PLT) apheresis donors focus on identifying antileucocyte antibody-positive donors. The use of microbead based assays for screening purposes is hampered by the lack of a consensus cut-off for TRALI prevention and the undefined role of anti-leucocyte antibodies in never-alloexposed donors. This study evaluated anti-leucocyte antibody assays in PLT apheresis donors with and without prior immunizing events with special focus on microbead assay cut-offs, antibody specificities and their potential significance in never-alloexposed donors., Material and Methods: Blood samples of male and female PLT apheresis donors with and without history of prior immunization were tested for anti-leucocyte antibodies., Results: Of 262 female and 118 male PLT apheresis donors, 37·4% had prior immunizing events. Fifty-eight of 238 (24·4%) donors without prior immunizing event had anti-HLA antibodies confirmed in microbead single antigen assay (mean fluorescence intensity (MFI) >500). Even with a cut-off MFI >3000, anti-HLA antibodies were detected in 10·6% of female and 4·3% of male donors without history of immunization. Of the antibody specificities found, 6 of 17 (35·3%) anti-HLA-A, 4 of 8 (50·0%) anti-HLA-B and 4 of 6 (66·6%) anti-HLA class II antibodies have been detected in donors associated with TRALI cases in the literature., Conclusion: Platelet apheresis donors without history of immunization have anti-leucocyte antibodies that potentially can cause TRALI. In our opinion, this cohort should be included in screening strategies for TRALI prevention. As references and consensus cut-offs have not yet been established, it is premature to use microbead assays as standard for donor screening., (© 2013 The Author(s) Vox Sanguinis © 2013 International Society of Blood Transfusion.)

Aggregation-prone polyglutamine (polyQ) expansion proteins cause several neurodegenerative disorders, including Huntington disease. The pharmacological activation of cellular stress responses could be a new strategy to combat protein conformational diseases. Hydroxylamine derivatives act as co-inducers of heat-shock proteins (HSPs) and can enhance HSP expression in diseased cells, without significant adverse effects. Here, we used Caenorhabditis elegans expressing polyQ expansions with 35 glutamines fused to the yellow fluorescent protein (Q35-YFP) in body wall muscle cells as a model system to investigate the effects of treatment with a novel hydroxylamine derivative, NG-094, on the progression of polyQ diseases. NG-094 significantly ameliorated polyQ-mediated animal paralysis, reduced the number of Q35-YFP aggregates and delayed polyQ-dependent acceleration of aging. Micromolar concentrations of NG-094 in animal tissues with only marginal effects on the nematode fitness sufficed to confer protection against polyQ proteotoxicity, even when the drug was administered after disease onset. NG-094 did not reduce insulin/insulin-like growth factor 1-like signaling, but conferred cytoprotection by a mechanism involving the heat-shock transcription factor HSF-1 that potentiated the expression of stress-inducible HSPs. NG-094 is thus a promising candidate for tests on mammalian models of polyQ and other protein conformational diseases.

Land plants are prone to strong thermal variations and must therefore sense early moderate temperature increments to induce appropriate cellular defenses, such as molecular chaperones, in anticipation of upcoming noxious temperatures. To investigate how plants perceive mild changes in ambient temperature, we monitored in recombinant lines of the moss Physcomitrella patens the activation of a heat-inducible promoter, the integrity of a thermolabile enzyme, and the fluctuations of cytoplasmic calcium. Mild temperature increments, or isothermal treatments with membrane fluidizers or Hsp90 inhibitors, induced a heat shock response (HSR) that critically depended on a preceding Ca(2+) transient through the plasma membrane. Electrophysiological experiments revealed the presence of a Ca(2+)-permeable channel in the plasma membrane that is transiently activated by mild temperature increments or chemical perturbations of membrane fluidity. The amplitude of the Ca(2+) influx during the first minutes of a temperature stress modulated the intensity of the HSR, and Ca(2+) channel blockers prevented HSR and the onset of thermotolerance. Our data suggest that early sensing of mild temperature increments occurs at the plasma membrane of plant cells independently from cytosolic protein unfolding. The heat signal is translated into an effective HSR by way of a specific membrane-regulated Ca(2+) influx, leading to thermotolerance.