Background-Endothelial dysfunction may contribute to the risk of premature atherosclerosis in patients with diabetes.Endothelin (ET-1) may be involved in this process by activating smooth muscle cell mitogenesis and leukocyte adhesion. We sought to assess the activity of endogenous ET-1 in a group of patients with type II diabetes mellitus with the use of antagonists of ET-1 receptors. Methods and Results-Forearm blood flow (FBF) responses (strain gauge plethysmography) to intraarterial infusion of a selective blocker of ET A receptors (BQ-123) and, on a different occasion, to ET-1, were measured in 15 patients with diabetes and 12 healthy controls. In addition, 5 patients with diabetes received coinfusion of BQ-123 and BQ-788 (a selective blocker of ET B receptors). In normal subjects, BQ-123 did not significantly modify FBF from baseline (Pϭ0.16). In contrast, BQ-123 administration resulted in a significant vasodilator response in patients with diabetes (PϽ0.001). Infusion of exogenous ET-1 resulted in lower vasoconstrictor responses in patients with diabetes than in controls (Pϭ0.001), whereas the vasoconstrictor response to norepinephrine was similar in the 2 groups (Pϭ0.78). In patients with diabetes, the vasodilator response to selective ET A blockade was not significantly modified by nonselective blockade of ET-1 receptors obtained by coinfusion of BQ-123 and BQ-788. Conclusions-The activity of endogenous ET-1 on ET A receptors is enhanced in the resistance vessels of patients with diabetes, whereas their sensitivity to exogenous ET-1 is blunted. This abnormality may participate in the pathophysiology of vascular complications associated with diabetes.

Background-It has been proposed that flow-mediated shear stress regulates vascular tone; however, whether this operates in the human microcirculation is unknown. This study was designed to investigate the effect of shear stress on human microvascular tone, to assess the contribution of nitric oxide (NO), and to determine whether this mechanism is defective in hypertension and in hypercholesterolemia. Methods and Results-In 9 normal controls (NC), 11 hypertensive patients (HT), and 12 hypercholesterolemic patients (HChol), arteries (internal diameter 201Ϯ26 m) isolated from gluteal fat biopsies were cannulated and perfused in chambers. Shear stress was induced by increasing the flow rate from 1 to 50 L/min after preconstriction with norepinephrine (NE). Arterial internal diameter was expressed as percent of NE-induced constriction. In NC, shear stress induced flow-dependent vasodilation from 23Ϯ9% at 1 L/min to 53Ϯ14% at 50 L/min (PϽ0.0001), which was abolished by endothelial removal. The NO synthase inhibitor N-nitro-L-arginine (L-NNA) significantly blunted this response (mean vasodilation decreased from 27Ϯ6% to 6Ϯ9%; Pϭ0.04). HT had significant impairment of flow-mediated dilation (mean vasodilation 5Ϯ6%; Pϭ0.01 versus NC), which was not affected by L-NNA. HChol had preserved flow-mediated vasodilation (mean vasodilation 24Ϯ7%; Pϭ0.56 versus NC), but this was not significantly modified by L-NNA. Conclusions-In the human microvasculature, shear stress induces endothelium-dependent, NO-mediated vasodilation.This phenomenon is blunted in HT patients because of reduced activity of NO. In contrast, the HChol microvasculature has preserved shear stress-induced dilation despite diminished NO activity.

African Americans show reduced responsiveness of conductance vessels to both endogenous and exogenous NO compared with Caucasian Americans. These findings expand our understanding of racial differences in vascular function and suggest a mechanistic explanation for the increased incidence and severity of cardiovascular disease observed in African Americans.

Background and Purpose-Fabry disease is an X-linked lysosomal storage disease secondary to deficiency of ␣-galactosidase A with resulting glycolipid accumulation, particularly globotriaosylceramide in arterial smooth muscle and endothelial cells. A systemic vasculopathy, including early-onset stroke, is prevalent without a clear pathogenesis. Methods-Seventeen normotensive and normocholesterolemic hemizygous Fabry patients (aged 21 to 49 years) and 13 control subjects (aged 21 to 48 years) were investigated by venous plethysmography, allowing assessment of forearm blood flow. Plethysmographic measurements were obtained at baseline and during intra-arterial infusion of acetylcholine and sodium nitroprusside both with and without N

BACKGROUNDThe current study evaluated factors influencing survival in patients diagnosed with human immunodeficiency virus (HIV)‐related primary central nervous system lymphoma (PCNSL), with a focus on the effects of therapeutic radiotherapy (RT) and highly active antiretroviral therapy (HAART).METHODSA retrospective chart review of patients with a diagnosis of HIV‐related PCNSL at one of five university hospitals between 1987 and 1998 was performed. Clinical details including antiretroviral agent use, brain imaging scan results, RT use, and survival outcomes were recorded.RESULTSOne hundred eleven patients with HIV‐related PCNSL were identified. The annual incidence decreased significantly between 1992 and 1995 and between 1996 and 1998 (P = 0.04). The median survival period was 50 days (mean, 109 days; range, 4–991 days), with improved survival for patients diagnosed after 1993. Patients treated with two or more antiretroviral agents had improved survival (P = 0.01), as did patients who received RT (P < 0.0001). For patients who received RT, completion of the prescribed course and treatment to ≥ 30 Gray (Gy) independently predicted a more favorable outcome. RT used in conjunction with antiretroviral therapy involving two or more agents had an additive positive effect on survival. For patients who did not receive RT, poor performance status and encephalopathy predicted a shorter survival duration.CONCLUSIONSThe results of the current study suggest that HAART and treatment with RT to ≥ 30 Gy improve survival for patients with HIV‐related PCNSL. This combination of therapies may provide a standard of care as the basis for further trials of chemotherapy, novel adjunctive treatment, and quality of life assessment. Cancer 2004. © 2004 American Cancer Society.

Harmonisation of disease management practices across global space and the devolution of responsibility to a broader range of actors are two increasingly important approaches for ordering biosecurity governance. While these forms of ordering have been examined individually, the social science biosecurity literature provides limited insights into how they interact and interfere with one another, and the consequences for biosecurity implementation. This paper draws upon an institutional logics approach to examine the different and competing logics through which government agencies, industry bodies and farming enterprises engage in biosecurity. It focuses specifically on the ways in which these logics pose challenges for harmonisation of biosecurity as well as create alternative spaces of negotiation for making life safe. Through the analysis of policy documents and semi-structured interviews with government and industry stakeholders, as well as with beef producers, we identify three institutional logics being the neoliberal, productivist and agrarian logics. We argue that the existence of multiple logics poses significant challenges for efforts to achieve improved harmonisation of biosecurity in an environment of devolved responsibility to industry, farming bodies and producers. In this context, greater emphasis by stakeholders on the productivist logic holds the most potential for improving biosecurity implementation in that it works with existing agricultural circulations and flows, and with producers' herd health practices.

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International efforts to prevent the spread of biological threats to agro-food production are increasingly being devolved from national governments to farming industries and farmers. Previous research has highlighted the farm-level and institutional challenges in engaging farmers in biosecurity. However, little is known sociologically about what farmers already know and do to manage disease risk, and specifically how they practice biosecurity. This article addresses this issue through the application of theoretical work on the choreography of care. Drawing from a qualitative study of biosecurity in the Australian beef industry, we argue that farmers' localised practices of caring for their herd health and farm are crucial in making biosecurity workable. These practices take two key forms: skilled craftwork, through which farmers construct and hold together different objects and elements of care; and fluid engineering, which involves efforts to construct barriers for separating on-farm practices of care from perceived off-farm disease risks. In engaging in these care practices, farmers make an important contribution to national livestock biosecurity principles and practices. We argue that greater recognition of localised practices of biosecure care may provide the basis for engaging farmers more effectively in a devolved form of biosecurity governance.