Plos One
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Etomidate and propofol are potent general anesthetics that act via GABAA receptor allosteric co-agonist sites located at transmembrane β+/α- inter-subunit interfaces. Early experiments in heteromeric receptors identified βN265 (M2-15') on β2 and β3 subunits as an important determinant of sensitivity to these drugs. Mechanistic analyses suggest that substitution with serine, the β1 residue at this position, primarily reduces etomidate efficacy, while mutation to methionine eliminates etomidate sensitivity and might prevent drug binding. ⋯ Using α1M236C as a modifiable and anesthetic-protectable site occupancy reporter in β+/α- interfaces, we found that βN265M reduced apparent anesthetic affinity for receptors in both resting and GABA-activated states. βN265M also impaired the transduction of gating effects associated with α1M236W, a mutation that mimics β+/α- anesthetic site occupancy. Our results show that βN265M mutations dramatically reduce the efficacy/transduction of anesthetics bound in β+/α- sites, and also significantly reduce anesthetic affinity for resting state receptors. These findings are consistent with a role for βN265 in anesthetic binding within the β+/α- transmembrane sites.
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Accurate determination of left ventricular filling pressure is essential for differentiation of pre-capillary pulmonary hypertension (PH) from pulmonary venous hypertension (PVH). Previous data suggest only a poor correlation between left ventricular end-diastolic pressure (LVEDP) and its commonly used surrogate, the pulmonary capillary wedge pressure (PCWP). However, no data exist on the diagnostic accuracy of PCWP in veterans. Furthermore, the effects of age and comorbidities on the PCWP-LVEDP relationship remain unknown. ⋯ Reliance on PCWP rather than LVEDP results in misclassification of veterans as having pre-capillary PH rather than PVH in almost 50% of cases. This is clinically relevant, as misclassification may lead to inappropriate therapies and adverse events.
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The dysregulated expressions of circulating miRNAs have been detected in various cardiovascular diseases. In our previous experiments, the altered expressions of circulating miRNA-21-5p, miRNA-361-5p and miRNA-519e-5p were confirmed in patients with coronary atherosclerosis by miRNA microarrays. However, the expression levels of these circulating miRNAs in the early phase of acute myocardial infarction (AMI) are still unknown. In the present study, our aims were to examine the expressions of circulating miR-21-5p, miR-361-5p and miR-519e-5p in AMI patients, and assess their clinical applications for diagnosing and monitoring AMI. ⋯ Circulating miRNAs may be novel and powerful biomarkers for AMI and they could be potential diagnostic tool for AMI.
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Mild cognitive impairment (MCI) is an intermediate stage between normal cognitive function and dementia among aging individuals. This study was designed to estimate the prevalence of MCI and explore the possible risk factors including gender disparities among community-dwelling older individuals. The study was conducted in Xi'an, China. ⋯ For women, the risk factors were lower level of educational and lack of religious attendance. Results suggested that the factors capable of influencing MCI differed profoundly between older men and older women. For this reason, different preventative measures should be adopted to delay or reverse cognitive impairment among community-dwelling older men and women.
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Urine albumin creatinine ratio, UACR, is positively associated with all-cause mortality, cardiovascular disease and diabetes in observational studies. Whether a high UACR is also associated with other causes of death is unclear. We investigated the association between UACR and cause-specific mortality. ⋯ We found statistically significant positive associations between baseline UACR and death from all-cause mortality, endocrine nutritional and metabolic diseases, and diseases of the circulatory system and possibly mental and behavioural disorders, and diseases of the respiratory and digestive system.