Risk prediction of developing venous thrombosis in combined oral contraceptive users.

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.

The novel hydroxylamine derivative NG-094 suppresses polyglutamine protein toxicity in Caenorhabditis elegans.

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.

The heat shock response in moss plants is regulated by specific calcium-permeable channels in the plasma membrane.

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.