Bmc Med
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Short-course, rifamycin-based regimens could facilitate scale-up of tuberculosis preventive therapy (TPT), but it is unclear how stringently tuberculosis (TB) disease should be ruled out before TPT use. ⋯ All modeled TPT strategies prevent TB relative to no intervention, and differences between TPT regimens or between screening approaches are small relative to uncertainty in the outcomes of any given strategy. If most TPT-eligible individuals can be screened for subclinical TB, then pairing such screening with rifamycin-based TPT maximizes active TB prevention and does not increase rifampicin resistance. Where subclinical TB cannot be routinely excluded without substantially reducing TPT access, the choice of TPT regimen requires weighing 4R's efficacy advantages (as well as its greater safety and shorter duration that we did not directly model) against the consequences of rifampicin resistance in a small fraction of recipients.
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Recent genome-wide association studies (GWASs) have revealed the polygenic nature of psychiatric disorders and discovered a few of single-nucleotide polymorphisms (SNPs) associated with multiple psychiatric disorders. However, the extent and pattern of pleiotropy among distinct psychiatric disorders remain not completely clear. ⋯ Our study is among the first large-scale effort to characterize gene-level pleiotropy among a greatly expanded set of psychiatric disorders and provides important insight into shared genetic etiology underlying these disorders. The findings would inform psychiatric nosology, identify potential neurobiological mechanisms predisposing to specific clinical presentations, and pave the way to effective drug targets for clinical treatment.
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Metabolomics is a promising molecular tool for identifying novel etiological pathways leading to cancer. In an earlier prospective study among pre- and postmenopausal women not using exogenous hormones, we observed a higher risk of breast cancer associated with higher blood concentrations of one metabolite (acetylcarnitine) and a lower risk associated with higher blood concentrations of seven others (arginine, asparagine, phosphatidylcholines (PCs) aa C36:3, ae C34:2, ae C36:2, ae C36:3, and ae C38:2). ⋯ These associations may indicate possible mechanisms underlying associations between lifestyle and anthropometric factors, and risk of breast cancer. Further research is needed to identify potential non-lifestyle correlates of the metabolites investigated.
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During starvation, fasting, or a diet containing little digestible carbohydrates, the circulating insulin levels are decreased. This promotes lipolysis, and the breakdown of fat becomes the major source of energy. The hepatic energy metabolism is regulated so that under these circumstances, ketone bodies are generated from β-oxidation of fatty acids and secreted as ancillary fuel, in addition to gluconeogenesis. ⋯ Sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors may also exert their cardioprotective action via increasing ketone body levels and ketolysis. We conclude that the increased synthesis and use of ketone bodies as ancillary fuel during periods of deficient food supply and low insulin levels causes oxidative stress in the mitochondria and that the latter initiates a protective (hormetic) response which allows cells to cope with increased oxidative stress and lower energy availability. KEYWORDS: Ketogenic diet, Ketone bodies, Beta hydroxybutyrate, Insulin, Obesity, Type 2 diabetes, Inflammation, Oxidative stress, Cardiovascular disease, SGLT2, Hormesis.
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Prenatal adverse environments can cause fetal intrauterine growth retardation (IUGR) and higher susceptibility to multiple diseases after birth, related to multi-organ development programming changes mediated by intrauterine overexposure to maternal glucocorticoids. As a glucocorticoid barrier, P-glycoprotein (P-gp) is highly expressed in placental syncytiotrophoblasts; however, the effect of P-gp on the occurrence of IUGR remains unclear. ⋯ This study, for the first time, clarified the critical role and epigenetic regulation mechanism of P-gp in mediating the opening mechanism of the placental glucocorticoid barrier, providing a novel idea for exploring the early warning, prevention, and treatment strategies of IUGR.