Endothelial Insulin Receptor Restoration Rescues Vascular Function in Male Insulin Receptor Haploinsufficient Mice

Reduced systemic insulin signaling promotes endothelial dysfunction and diminished endogenous vascular repair. We investigated whether restoration of endothelial insulin receptor expression could rescue this phenotype. Insulin receptor knockout (IRKO) mice were crossed with mice expressing a human insulin receptor endothelial cell–specific overexpression (hIRECO) to produce IRKO-hIRECO progeny. No metabolic differences were noted between IRKO and IRKO-hIRECO mice in glucose and insulin tolerance tests. In contrast with control IRKO littermates, IRKO-hIRECO mice exhibited normal blood pressure and aortic vasodilatation in response to acetylcholine, comparable to parameters noted in wild type littermates. These phenotypic changes were associated with increased basal- and insulin-stimulated nitric oxide production. IRKO-hIRECO mice also demonstrated normalized endothelial repair after denuding arterial injury, which was associated with rescued endothelial cell migration in vitro but not with changes in circulating progenitor populations or culture-derived myeloid angiogenic cells. These data show that restoration of endothelial insulin receptor expression alone is sufficient to prevent the vascular dysfunction caused by systemically reduced insulin signaling

Piezo1 integration of vascular architecture with physiological force

The mechanisms by which physical forces regulate endothelial cells to determine the complexities of vascular structure and function are enigmatic¹⁻⁵. Studies of sensory neurons have suggested Piezo proteins as subunits of Ca²⁺-permeable non-selective cationic channels for detection of noxious mechanical impact⁶⁻⁸. Here we show Piezo1 (Fam38a) channels as sensors of frictional force (shear stress) and determinants of vascular structure in both development and adult physiology. Global or endothelial-specific disruption of mouse Piezo1 profoundly disturbed the developing vasculature and was embryonic lethal within days of the heart beating. Haploinsufficiency was not lethal but endothelial abnormality was detected in mature vessels. The importance of Piezo1 channels as sensors of blood flow was shown by Piezo1 dependence of shear-stress-evoked ionic current and calcium influx in endothelial cells and the ability of exogenous Piezo1 to confer sensitivity to shear stress on otherwise resistant cells. Downstream of this calcium influx there was protease activation and spatial reorganization of endothelial cells to the polarity of the applied force. The data suggest that Piezo1 channels function as pivotal integrators in vascular biology

Human immunodeficiency virus risk: is it possible to dissuade people from having unsafe sex?

The cumulative number of human immunodeficiency virus (HIV) infections worldwide has reached 60 million in little over 30 years. HIV continues to spread despite a detailed understanding of the manner in which it spreads and measures which can prevent spread. Some governments have been highly successful in containing the spread of HIV through blood products and from mother to child and among injecting drug users. Lack of political will, lack of resources or challenges to widely accepted scientific evidence have held back similar interventions in other countries. It has proved much more difficult to reduce the sexual transmission of HIV in both high and low income countries. A wide range of strategies has been identified but it remains unclear which strategies deserve priority and what methods of promoting them have the greatest effect. There is ample evidence that awareness of HIV and changes in sexual behaviour have occurred widely but the penetration of information remains poor in some vulnerable groups especially adolescents and women in poorer countries. Further obstacles face those who have information about the risk. The subordinate position of women and a desire for large families are important obstacles to condom negotiation and use. Urbanization, poverty, conflict and declining public services all exacerbate unsafe sexual behaviour. We argue that so-called 'structural' interventions directed at these wider contexts of unsafe behaviour merit greater attention. Such approaches have the added benefit of being less susceptible to 'risk compensation' which has the potential to undermine strategies directed at reducing the transmission efficiency of HIV. Copyright 2003 Royal Statistical Society.

Parents' relationship with their surrogate in cross-border and domestic surrogacy arrangements: comparisons by sexual orientation and location.

OBJECTIVE: To study heterosexual and gay couples' relationship with their surrogate and their disclosure decisions when the surrogacy arrangement was completed domestically compared with internationally. DESIGN: Cross-sectional study. SETTING: Not applicable. PATIENT(S): Participants were 40 gay couples and 76 heterosexual couples who had domestic surrogacy in the United Kingdom (UK) (n = 38) or international surrogacy in the United States (n = 58) or Asia (20). Most (75%) of the children were aged <4 years. INTERVENTION(S): Online surveys containing open-ended and multiple-choice questions. MAIN OUTCOME MEASURE(S): Experiences of finding a surrogate, relationship with the surrogate, and disclosure to the child were examined among UK parents who had undergone surrogacy in the UK, United States, or India/Thailand. RESULT(S): Parents who had surrogacy in the UK and United States felt very involved in the pregnancy compared with those who had surrogacy in Asia. Couples whose surrogacy was completed in Asia were less likely to want contact with their surrogate after the birth and were also less likely to have any current contact with the surrogate. Parents who had surrogacy in the UK and United States described positive relationships with their surrogate. Gay couples intended to tell their child about surrogacy more than heterosexual couples. CONCLUSION(S): The specific country where couples conducted their surrogacy arrangement (i.e. United States, UK, or Thailand/India) was associated with how involved they were in the pregnancy and their contact with the surrogate over time. Limitations of the study include use of survey methodology and that the representativeness of the sample is not known.Wellcome Trus

Factors associated with HIV seroconversion in gay men in England at the start of the 21st century

Objectives: To detect and quantify current risk factors for HIV seroconversion among gay men seeking repeat tests at sexual health clinics.Design: Unmatched case control study conducted in London, Brighton and Manchester, UK.Methods: 75 cases (recent HIV positive test following a negative test within the past 2 years) and 157 controls (recent HIV negative test following a previous negative test within the past 2 years) completed a computer assisted self interview focused on sexual behaviour and lifestyle between HIV tests.Results: Cases and controls were similar in sociodemographics, years since commencing sex with men, lifetime number of HIV tests, reasons for seeking their previous HIV tests and the interval between last HIV tests (mean=10.5 months). Risk factors between tests included unprotected receptive anal intercourse (URAI) with partners not believed to be HIV negative (adjusted odds ratio (AOR) and 95% confidence interval 4.1, 1.8 to 9.3), where increased risk was associated with concomitant use of nitrite inhalants, receiving ejaculate and increasing numbers of partners. Independent risk was also detected for unprotected insertive anal intercourse (UIAI) with more than one man (AOR 2.7, 1.3 to 5.5) and use of nitrite inhalants (AOR 2.4, 1.1 to 5.2).Conclusions: HIV serodiscordant unprotected anal intercourse remains the primary context for HIV transmission among gay men, with increased risk associated with being the receptive partner, receiving ejaculate and use of nitrite inhalants. Although the HIV transmission risk of URAI is widely acknowledged, this study highlights the risk of UIAI and that nitrite inhalants may be an important facilitator of transmission when HIV exposure occurs