Cyclic GMP modulators on vascular adrenergic neurotransmission.

The presence of the endothelium reduced the sensitivity of isolated rabbit carotid artery to endogenous norepinephrine released by electrical stimulation of adrenergic nerves or displaced by tyramine and to exogenously applied norepinephrine, phenylephrine and UK 14304. The maximal contractions induced by the selective alpha 2-agonist UK 14304 were much more profoundly depressed in arteries with endothelium than those induced by the nonselective alpha-adrenoceptor agonist norepinephrine or by the selective alpha 1-agonist. LY 83583, a cyclic-guanosine-monophosphate (GMP)-lowering agent, abolished the endothelium-dependent depression of tone induced by the agonists and converted the sensitivity of arteries with endothelium to that of endothelium-denuded preparations. M & B 22948, a selective cyclic GMP phosphodiesterase inhibitor, significantly inhibited contractions caused by electrical stimulation of adrenergic nerves, tyramine, norepinephrine and UK 14304 in rings with, but not in those without, endothelium. Yohimbine, an alpha 2-adrenoceptor antagonist, increased contractions caused by UK 14304 in rings with endothelium only, but had no significant effect on the contractions caused by exogenously applied norepinephrine or phenylephrine. In the presence of prazosin, an alpha 1-blocker, UK 14304 caused minimal relaxation (about 20%) in rings with endothelium only which were inhibited by yohimbine, suggesting a minor role of direct endothelial cell alpha 2-mediated release of relaxing factors. The over-flow of endogenous norepinephrine caused by electrical stimulation was not affected by treatment with LY 83583 or M & B 22948, suggesting that altering cyclic GMP levels has no major role in prejunctional modulation of norepinephrine release. These findings support the notion that intrinsic levels of cyclic GMP may act as a regulator of adrenergic neurotransmission due primarily to endothelium-derived relaxing factor which is released basally, and to a lesser extent by an activation of endothelial cell alpha 2-adrenoceptors.     

Diagnosing Hypertension by Intradialytic Blood Pressure Recordings

Background and objectives: The diagnosis of hypertension among hemodialysis patients by predialysis or postdialysis blood pressure (BP) recordings is imprecise and biased and has poor test-retest reliability. The use of intradialytic BP measurements to diagnose hypertension is unknown.Design, setting, participants, & measurements: A diagnostic-test study was done with interdialytic ambulatory BP as reference standard. Index BP recordings tested were: predialysis (method 1), postdialysis (method 2), intradialytic (method 3), intradialytic including predialyis and postdialysis (method 4), and the average of predialysis and postdialysis (method 5). Each index BP was recorded over six consecutive dialysis treatments.Results: There were differences among index BP measurements in reproducibility, bias, precision, and accuracy. Method 4 was the most reproducible (intraclass correlation coefficient = 0.70 for systolic and diastolic BP). All 5 measurement methods overestimated 44-h ambulatory systolic BP. Methods 2, 3, or 4 overestimated ambulatory systolic BP by only a small amount. Method 4 was the most precise and accurate. For diagnosis of hypertension, BP cut-point by method 4 of 135/75 mmHg, had a sensitivity of 90.4% and specificity of 75.9% for systolic BP (area under ROC curve 0.90). Median cut-off systolic BP of 140 mmHg from a single dialysis provides approximately 80% sensitivity and 80% specificity in diagnosing systolic hypertension; a median cut-off diastolic BP of 80 mmHg provides approximately 75% sensitivity and 75% specificity in diagnosing diastolic hypertension.Conclusions: Consideration of intradialytic BP measurements together with predialysis and postdialysis BP measurements improves the reproducibility, bias, precision, and accuracy of BP measurement compared with predialysis or postdialysis measurements.The diagnostic and prognostic significance of hypertension among hemodialysis patients continues to be debated (1,2). Whereas many have suggested that blood pressure (BP) recordings are of little value in managing cardiovascular risk (3,4), others have argued that BP control is important (2,5,6). The accurate measurement of arterial pressure is the essential first step in managing this cardiovascular risk factor, yet the diagnosis of hypertension in hemodialysis patients continues to be a vexing problem (7,8).Although home BP monitoring is a superior tool to diagnose hypertension, typically BP measurements obtained just before and after dialysis are used to diagnose and treat hypertension in hemodialysis patients (8,9). However, predialysis and postdialysis BP measurements are generally inaccurate estimates of ambulatory BP measurements (10). In the dialysis unit, BP measurements are obtained every 30 min during dialysis, primarily to ensure the hemodynamic stability of patients during treatment. But the BP measurements so obtained are usually ignored when making a diagnosis of hypertension. The utility of intradialytic BP measurements in diagnosing hypertension among hemodialysis patients therefore remains unknown.The purpose of our study was to evaluate the usefulness of intradialytic BP in diagnosing hypertension among hemodialysis patients. We measured the utility of intradialytic BP by comparing the dialysis-to-dialysis reproducibility and comparing the bias, precision, and accuracy of intradialytic BP measurements to the reference standard of interdialytic ambulatory BP recordings. Finally, we constructed receiver-operating characteristic (ROC) curves to determine clinically useful cut-points and to assess the diagnostic performance of intradialytic BP recordings.     

Local vascular toxicokinetics of stent-based drug delivery

One of the major limitations of balloon angioplasty is early restenosis as a result of elastic recoil leading to vessel occlusion. The constrictive (negative) remodeling of the blood vessel is overcome by implanting a balloon expandible metal stent to dilate the artery and thereby prevent elastic recoil. However, bare metal stent implants cause mechanical injury to the intima and release of inflammatory mediators which then initiates formation of neointimal layer leading to restenosis. In-stent restenosis is histologically distinct from restenosis following balloon angioplasty, in which in-stent restenosis is accompanied by increased smooth muscle proliferation, migration, extracellular matrix and collagen synthesis leading to neointimal hyperplasia. To overcome neointimal hyperplasia, stents have been coated with pharmacological agents that inhibit smooth muscle cell proliferation and migration. The drug and polymer combination coated onto stent device is an efficient form of drug delivery system which can provide high concentrations of drug in the tissues over an extended period of time to achieve antiproliferative therapeutic effect. The permanent stent implants pose the risk of a continuous interaction between the non-biodegradable polymer coating and intimal surface leading to physical irritation, endothelial dysfunction, hypersensitivity reactions, delayed healing and excess risk of late stent thrombosis. This review highlights the relationship between local drug delivery using the stent platform, release kinetics and local vascular toxicity.     

Endothelial injury in the initiation and progression of vascular disorders

Endothelial cell dysfunction is considered to be an early event which subsequently leads to vascular wall disorders. Ultrastructural studies indicate that the endothelial cell changes involve membrane damage, increased permeability, swelling and necrosis. The endothelial cell loss of function could be as a result of changes in hemodynamic forces (shear and/or hoop stress), direct drug-induced cytotoxicity, mechanical device implant-induced injury and/or immune-mediated mechanisms. Drugs may perturb endothelial cell integrity by directly triggering inflammatory signaling cascades, enhancing expression of cellular adhesion molecules, activation of cytotoxic T cells and/or autoantibodies directed against endothelial cell membranes. Local release of inflammatory cytokines and chemokines activate endothelial cells to upregulate soluble adhesion molecules, activate neutrophils and generate reactive oxygen species which serve to amplify the initial inflammation leading to dysregulated apoptosis, secondary necrosis and overt vascular injury lesions. Considering the role of the endothelium in the initiation and propagation of vascular wall injury, there is a need for the discovery of validated biomarkers to serve as a predictor of activation of inflammatory cascades in the development of vascular injury. This article reviews some aspects of the multifaceted mechanisms that lead to the initial endothelial cell disruption and subsequent vascular wall injury.     

Treatment outcome of tuberculosis patients at Gondar University Teaching Hospital, Northwest Ethiopia. A five - year retrospective study

Background  

In Gondar University Teaching Hospital standardized tuberculosis prevention and control programme, incorporating Directly Observed Treatment, Short Course (DOTS) started in 2000. According to the proposal of World Health Organization (WHO), treatment outcome is an important indicator of tuberculosis control programs. This study investigated the outcome of tuberculosis treatment at Gondar University Teaching Hospital in Northwest Ethiopia.     

Magnitude and determinants of nonadherence and nonreadiness to highly active antiretroviral therapy among people living with HIV/AIDS in Northwest Ethiopia: a cross - sectional study

Background  

Adequate antiretroviral drug potency is essential for obtaining therapeutic benefit, however, the behavioral aspects of proper adherence and readiness to medication, often determine therapeutic outcome. Therefore, this study aimed to assess the level and determinants of nonadherence and nonreadiness to highly active antiretroviral therapy (HAART) among people living with HIV/AIDS (PLWHA) at Gondar University Teaching Hospital and Felege Hiwot Hospital in Northwest Ethiopia.