Mach's Principle and the Origin of Inertia

The current status of Mach's principle is discussed within the context of general relativity. The inertial properties of a particle are determined by its mass and spin, since these characterize the irreducible unitary representations of the inhomogeneous Lorentz group. The origin of the inertia of mass and intrinsic spin are discussed and the inertia of intrinsic spin is studied via the coupling of intrinsic spin with rotation. The implications of spin-rotation coupling and the possibility of history dependence and nonlocality in relativistic physics are briefly mentioned.Comment: 14 pages. Dedicated to Carl Brans in honor of his 80th birthday. To appear in the Brans Festschrift; v2: typo corrected, published in: At the Frontier of Spacetime, edited by T. Asselmeyer-Maluga (Springer, 2016), Chapter 10, pp. 177-18

Identification of Estrogen Receptor Dimer Selective Ligands Reveals Growth-Inhibitory Effects on Cells That Co-Express ERα and ERβ

Estrogens play essential roles in the progression of mammary and prostatic diseases. The transcriptional effects of estrogens are transduced by two estrogen receptors, ERα and ERβ, which elicit opposing roles in regulating proliferation: ERα is proliferative while ERβ is anti-proliferative. Exogenous expression of ERβ in ERα-positive cancer cell lines inhibits cell proliferation in response to estrogen and reduces xenografted tumor growth in vivo, suggesting that ERβ might oppose ERα's proliferative effects via formation of ERα/β heterodimers. Despite biochemical and cellular evidence of ERα/β heterodimer formation in cells co-expressing both receptors, the biological roles of the ERα/β heterodimer remain to be elucidated. Here we report the identification of two phytoestrogens that selectively activate ERα/β heterodimers at specific concentrations using a cell-based, two-step high throughput small molecule screen for ER transcriptional activity and ER dimer selectivity. Using ERα/β heterodimer-selective ligands at defined concentrations, we demonstrate that ERα/β heterodimers are growth inhibitory in breast and prostate cells which co-express the two ER isoforms. Furthermore, using Automated Quantitative Analysis (AQUA) to examine nuclear expression of ERα and ERβ in human breast tissue microarrays, we demonstrate that ERα and ERβ are co-expressed in the same cells in breast tumors. The co-expression of ERα and ERβ in the same cells supports the possibility of ERα/β heterodimer formation at physio- and pathological conditions, further suggesting that targeting ERα/β heterodimers might be a novel therapeutic approach to the treatment of cancers which co-express ERα and ERβ

The role of sports clubs in helping older people to stay active and prevent frailty: a longitudinal mediation analysis

Background Frailty is a common syndrome in older adults characterised by increased vulnerability to adverse health outcomes as a result of decline in functional and physiological measures. Frailty predicts a range of poor health and social outcomes and is associated with increased risk of hospital admission. The health benefits of sport and physical activity and the health risks of inactivity are well known. However, less is known about the role of sports clubs and physical activity in preventing and managing frailty in older adults. The objective of this study is to examine the role of membership of sports clubs in promoting physical activity and reducing levels of frailty in older adults. Methods We used data from waves 1 to 7 of the English Longitudinal Study of Ageing (ELSA). Survey items on physical activity were combined to produce a measure of moderate or vigorous physical activity for each wave. Frailty was measured using an index of accumulated deficits. A total of sixty deficits, including symptoms, disabilities and diseases were recorded through self-report and tests. Direct and indirect relationships between sports club membership, levels of physical activity and frailty were examined using a cross-lagged panel model. Results We found evidence for an indirect relationship between sports club membership and frailty, mediated by physical activity. This finding was observed when examining time-specific indirect pathways and the total of all indirect pathways across seven waves of survey data (Est = −0.097 [95% CI = −0.124,-0.070], p = <0.001). Conclusions These analyses provide evidence to suggest that sports clubs may be useful in preventing and managing frailty in older adults, both directly and indirectly through increased physical activity levels. Sports clubs accessible to older people may improve health in this demographic by increasing activity levels and reducing frailty and associated comorbidities. There is a need for investment in these organisations to provide opportunities for older people to achieve the levels of physical activity necessary to prevent health problems associated with inactivity

Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes.

Abstract BACKGROUND: The cardiovascular effects of adding once-weekly treatment with exenatide to usual care in patients with type 2 diabetes are unknown. METHODS: We randomly assigned patients with type 2 diabetes, with or without previous cardiovascular disease, to receive subcutaneous injections of extended-release exenatide at a dose of 2 mg or matching placebo once weekly. The primary composite outcome was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The coprimary hypotheses were that exenatide, administered once weekly, would be noninferior to placebo with respect to safety and superior to placebo with respect to efficacy. RESULTS: In all, 14,752 patients (of whom 10,782 [73.1%] had previous cardiovascular disease) were followed for a median of 3.2 years (interquartile range, 2.2 to 4.4). A primary composite outcome event occurred in 839 of 7356 patients (11.4%; 3.7 events per 100 person-years) in the exenatide group and in 905 of 7396 patients (12.2%; 4.0 events per 100 person-years) in the placebo group (hazard ratio, 0.91; 95% confidence interval [CI], 0.83 to 1.00), with the intention-to-treat analysis indicating that exenatide, administered once weekly, was noninferior to placebo with respect to safety (P<0.001 for noninferiority) but was not superior to placebo with respect to efficacy (P=0.06 for superiority). The rates of death from cardiovascular causes, fatal or nonfatal myocardial infarction, fatal or nonfatal stroke, hospitalization for heart failure, and hospitalization for acute coronary syndrome, and the incidence of acute pancreatitis, pancreatic cancer, medullary thyroid carcinoma, and serious adverse events did not differ significantly between the two groups. CONCLUSIONS: Among patients with type 2 diabetes with or without previous cardiovascular disease, the incidence of major adverse cardiovascular events did not differ significantly between patients who received exenatide and those who received placebo. (Funded by Amylin Pharmaceuticals; EXSCEL ClinicalTrials.gov number, NCT01144338 .)

Evidence of trimonoecy in Phyllanthaceae: Phyllanthus acidus

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Pollen from staminate flowers and pistillate flowers with "staminodes" of Phyllanthus acidus Skeels were analyzed under scanning electron microscopy, and tests of pollen viability and in vitro germination were carried out to verify possible similarities between the three types of flowers. The results show that pistillate flowers with "staminodes" are bisexual, indicating the occurrence of trimonoecy in this species.29641732283286Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)FAPESP [05/59543-7

Lifetime cost-effectiveness simulation of once-weekly exenatide in type 2 diabetes: a cost-utility analysis based on the EXSCEL trial

Aims The Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial assessed once-weekly exenatide (EQW) vs. placebo, added to usual care in 14,752 patients with type 2 diabetes mellitus (Clinicaltrials.gov: NCT01144338). We assessed the lifetime cost-effectiveness of adding EQW vs. usual care alone from a healthcare perspective. Methods Medical resource use and EQ-5D utilities were collected throughout the study. Within-trial results were extrapolated to a lifetime horizon using the UK Prospective Diabetes Study Outcomes Model version 2 (UKPDS-OM2), predicting predict cardiovascular and microvascular events. Cost-effectiveness was evaluated separately for US and UK settings, with outcomes measured in quality-adjusted life-years (QALYs). Results EQW plus usual care gained 0.162 QALYs at an additional cost of 41,545 dollars/patient, compared with usual care in a US setting. The incremental cost-effectiveness ratio (ICER) was 259,223 dollars/QALY. In a UK setting, the QALY gain was 0.151 at an additional cost of £6357: an ICER of £42,589/QALY. Sensitivity analyses ranged between 34,369-269,571 dollars and £3,430-£46,560 per QALY gained. Conclusions In a lifetime extrapolation, adding EQW to usual care increased QALYs and costs compared with usual care alone. The base-case ICERs exceeded the commonly-cited cost-effectiveness thresholds of 100,000 dollars/QALY and £20,000/QALY. However, ICERs were considerably lower in some subgroups, and in sensitivity analyses