A definition of normovolaemia and consequences for cardiovascular control during orthostatic and environmental stress

The Frank–Starling mechanism describes the relationship between stroke volume and preload to the heart, or the volume of blood that is available to the heart—the central blood volume. Understanding the role of the central blood volume for cardiovascular control has been complicated by the fact that a given central blood volume may be associated with markedly different central vascular pressures. The central blood volume varies with posture and, consequently, stroke volume and cardiac output (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\dot{Q}$$\end{document}) are affected, but with the increased central blood volume during head-down tilt, stroke volume and \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\dot{Q}$$\end{document} do not increase further indicating that in the supine resting position the heart operates on the plateau of the Frank–Starling curve which, therefore, may be taken as a functional definition of normovolaemia. Since the capacity of the vascular system surpasses the blood volume, orthostatic and environmental stress including bed rest/microgravity, exercise and training, thermal loading, illness, and trauma/haemorrhage is likely to restrict venous return and \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\dot{Q}$$\end{document}. Consequently the cardiovascular responses are determined primarily by their effect on the central blood volume. Thus during environmental stress, flow redistribution becomes dependent on sympathetic activation affecting not only skin and splanchnic blood flow, but also flow to skeletal muscles and the brain. This review addresses the hypothesis that deviations from normovolaemia significantly influence these cardiovascular responses

Sexual conflict over remating interval is modulated by the sex peptide pathway

Sexual conflict, in which the evolutionary interests of males and females diverge, shapes the evolution of reproductive systems across diverse taxa. Here we used the fruit fly to study sexual conflict in natural, three-way interactions comprising a female, her current and previous mates. We manipulated the potential for sexual conflict by using sex peptide receptor (SPR) null females and by varying remating from 3 to 48h, a period during which natural rematings frequently occur. SPR-lacking females do not respond to sex peptide transferred during mating and maintain virgin levels of high receptivity and low fecundity. In the absence of SPR there was a convergence of fitness interests, with all individuals gaining highest productivity at 5h remating. This suggests that the expression of sexual conflict was reduced. We observed an unexpected second male-specific advantage to early remating, resulting from an increase in the efficiency of second male sperm use. This early window of opportunity for exploitation by second males depended on the presence of SPR. The results suggest that the sex peptide pathway can modulate the expression of sexual conflict in this system, and show how variation in the selective forces that shape conflict and co-operation can be maintained

Bitopic binding mode of an M1 muscarinic acetylcholine receptor agonist associated with adverse clinical trial outcomes

The realisation of the therapeutic potential of targeting the M1 muscarinic acetylcholine receptor (M1 mAChR) for the treatment of cognitive decline in Alzheimer's disease has prompted the discovery of M1 mAChR ligands showing efficacy in alleviating cognitive dysfunction in both rodents and humans. Among these is GSK1034702, described previously as a potent M1 receptor allosteric agonist, which showed pro-cognitive effects in rodents and improved immediate memory in a clinical nicotine withdrawal test but induced significant side-effects. Here we provide evidence using ligand binding, chemical biology and functional assays to establish that rather than the allosteric mechanism claimed, GSK1034702 interacts in a bitopic manner at the M1 mAChR such that it can concomitantly span both the orthosteric and an allosteric binding site. The bitopic nature of GSK1034702 together with the intrinsic agonist activity and a lack of muscarinic receptor subtype selectivity reported here, all likely contribute to the adverse effects of this molecule in clinical trials. We conclude that these properties, whilst imparting beneficial effects on learning and memory, are undesirable in a clinical candidate due to the likelihood of adverse side effects. Rather, our data supports the notion that "pure" positive allosteric modulators showing selectivity for the M1 mAChR with low levels of intrinsic activity would be preferable to provide clinical efficacy with low adverse responses

Molecular structure and genetic mapping of the mouse gastrin gene

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/117035/1/feb20014579396004309.pd

Risk of post-pregnancy hypertension in women with a history of hypertensive disorders of pregnancy: nationwide cohort study.

Objectives To determine how soon after delivery the risk of post-pregnancy hypertension increases in women with hypertensive disorders of pregnancy and how the risk evolves over time.Design Nationwide register based cohort study.Setting Denmark.Populations 482 972 primiparous women with a first live birth or stillbirth between 1995 and 2012 (cumulative incidence analyses), and 1 025 118 women with at least one live birth or stillbirth between 1978 and 2012 (Cox regression analyses).Main outcome measures 10 year cumulative incidences of post-pregnancy hypertension requiring treatment with prescription drugs, and hazard ratios estimated using Cox regression.Results Of women with a hypertensive disorder of pregnancy in a first pregnancy in their 20s, 14% developed hypertension in the first decade post partum, compared with 4% of women with normotensive first pregnancies in their 20s. The corresponding percentages for women with a first pregnancy in their 40s were 32% and 11%, respectively. In the year after delivery, women with a hypertensive disorder of pregnancy had 12-fold to 25-fold higher rates of hypertension than did women with a normotensive pregnancy. Rates in women with a hypertensive disorder of pregnancy were threefold to 10-fold higher 1-10 years post partum and remained twice as high even 20 or more years later.Conclusions The risk of hypertension associated with hypertensive disorders of pregnancy is high immediately after an affected pregnancy and persists for more than 20 years. Up to one third of women with a hypertensive disorder of pregnancy may develop hypertension within a decade of an affected pregnancy, indicating that cardiovascular disease prevention in these women should include blood pressure monitoring initiated soon after pregnancy

The evolution of multiple mating: Costs and benefits of polyandry to females and of polygyny to males

Polyandry is a paradox: why do females mate multiple times when a single ejaculate often provides enough sperm for lifetime egg production? Gowaty et al. addressed explanations for polyandry in Drosophila pseudoobscura from the perspective of hypotheses based on sex differences in costs of reproduction (CoR). Contrary to CoR, Gowaty et al. showed that (1) a single ejaculate was inadequate for lifetime egg production; (2) polyandry provided fitness benefits to females beyond provision of adequate sperm and (3) fitness benefits of polyandry were not offset by costs. Here, I discuss predictions of the ad hoc hypotheses of CoR and three alternative hypotheses to CoR to facilitate a discussion and further development of a strong inference approach to experiments on the adaptive significance of polyandry for females. Each of the hypotheses makes testable predictions; simultaneous tests of the predictions will provide a strong inference approach to understanding the adaptive significance of multiple mating. I describe a sex-symmetric experiment meant to evaluate variation in fitness among lifelong virgins (V); monogamous females and males with one copulation (MOC); monogamous females and males with multiple copulations (MMC); PAND, polyandrous females; and PGYN, polygynous males. Last, I recommend the study of many different species, while taking care in choice of study species and attention to the assumptions of specific hypotheses. I particularly urge the study of many more Drosophila species both in laboratory and the wild to understand the “nature of flies in nature,” where opportunities and constraints mold evolutionary responses

Adjunctive dabigatran therapy improves outcome of experimental left-sided <i>Staphylococcus aureus</i> endocarditis

<div><p>Background</p><p><i>Staphylococcus aureus</i> is the most frequent and fatal cause of left-sided infective endocarditis (IE). New treatment strategies are needed to improve the outcome. <i>S</i>. <i>aureus</i> coagulase promotes clot and fibrin formation. We hypothesized that dabigatran, could reduce valve vegetations and inflammation in <i>S</i>. <i>aureus</i> IE.</p><p>Methods</p><p>We used a rat model of severe aortic valve <i>S</i>. <i>aureus</i> IE. All infected animals were randomized to receive adjunctive dabigatran (10 mg/kg b.i.d., <i>n</i> = 12) or saline (controls, <i>n</i> = 11) in combination with gentamicin. Valve vegetation size, bacterial load, cytokine, cell integrins expression and peripheral platelets and neutrophils were assessed 3 days post-infection.</p><p>Results</p><p>Adjunctive dabigatran treatment significantly reduced valve vegetation size compared to controls (p< 0.0001). A significant reduction of the bacterial load in aortic valves was seen in dabigatran group compared to controls (p = 0.02), as well as expression of key pro-inflammatory markers keratinocyte-derived chemokine, IL-6, ICAM-1, TIMP-1, L-selectin (p< 0.04). Moreover, the dabigatran group had a 2.5-fold increase of circulating platelets compared to controls and a higher expression of functional and activated platelets (CD62p⁺) unbound to neutrophils.</p><p>Conclusion</p><p>Adjunctive dabigatran reduced the vegetation size, bacterial load, and inflammation in experimental <i>S</i>. <i>aureus</i> IE.</p></div