Hydrochlorothiazide Increases Efferent Glomerular Arteriolar Resistance in Spontaneously Hypertensive Rats

BACKGROUND: Micropuncture studies were performed to determine the intrarenal hemodynamic effects of two conventional antihypertensive agents, hydrochlorothiazide (HCTZ) and hydralazine (HYDR) alone and in combination. METHODS AND RESULTS: Male spontaneously hypertensive and normotensive Wistar Kyoto rats (19 weeks old) were treated for 3 weeks with vehicle (control), HCTZ (80 mg/kg/d), HYDR (5 mg/kg/d), or combined therapy (HCTZ 30 mg/kg/d and HYDR 2 mg/kg/d). Each treatment significantly reduced arterial pressure while effective renal plasma flow, glomerular filtration rate and single nephron glomerular filtration rate were unaffected by any treatment in either strain. In spontaneously hypertensive rats HCTZ decreased single nephron plasma flow (111 +/- 8 to 84 +/- 4 nL/min; P <.05) but, despite this reduction, glomerular pressure remained unchanged (51.4 +/- 0.7 to 52.1 +/- 0.8 mmHg) attributable to increased efferent glomerular resistance (1.58 +/- 0.14 to 2.11 +/- 0.12 10 U; P <.05). By contrast, HYDR increased single nephron plasma flow (to 147 +/- 8 nL/min; P <.01) and decreased efferent glomerular resistance (to 1.09 +/- 0.09 U; P <.05). Combined treatment produced responses similar to HCTZ when used alone, thereby nullifying the beneficial efferent glomerular resistance effects: single nephron plasma flow +/- fell (to 89 +/- 7 nL/min; P <.05) and efferent glomerular resistance increased (to 2.05 +/- 0.17 U; P <.05). In Wistar Kyoto rats, HCTZ and combined treatment had no effect. HCTZ alone induced glomerular ischemia that was associated with efferent glomerular arteriolar constriction in these spontaneously hypertensive rats. CONCLUSIONS: These findings provide a possible explanation for the lack of improved renal target-organ damage in controlled multicenter trials employing thiazide diuretics.     

Can measurement of serum apolipoprotein B replace the lipid profile monitoring of patients with lipoprotein disorders?

BACKGROUND: Current clinical guidelines require that five indices (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, and the total/HDL cholesterol ratio) be measured or calculated to assess the lipid-related risk of vascular disease. All five are also targets of therapy and therefore all must be measured initially and at follow-up. Considerable evidence indicates that apolipoprotein B (apo B) is a better index of reaching or not reaching treatment targets than total or LDL cholesterol. METHODS: The objective of this study was to examine whether measurement of a single marker (apo B) led to the same categorization of risk as the traditional five indices (lipid profile). If both apo B and lipid profile indicated that the patient was either within or outside their respective treatment targets, the indices were considered concordant. If not, the indices were considered discordant. Concordance/discordance was examined in 215 patients at their first and last clinic visit. RESULTS: Concordance was high in both higher (88% at the first and 92% at the last clinic visit) and lower (76% at the first and 78% at the last clinic visit) risk groups at both the initial and final visits. Discordance was virtually restricted to the group with hypertriglyceridemia with normal concentrations of apo B, a group in which little independent evidence points to any substantially increased risk of vascular disease. CONCLUSIONS: These data raise the possibility that at least for high risk patients treated with statins, follow-up could be simplified and expenses reduced if only apo B were measured. They also raise the possibility that outcome might be improved if the therapeutic algorithm were simplified.     

Cholesteryl ester transfer activity in plasma of patients with familial high-density lipoprotein deficiency

We determined cholesteryl ester transfer activity in whole plasma and in lipoprotein-depleted plasma of normolipidemic subjects and of patients with severe high-density lipoprotein (HDL) deficiency: Tangier disease, lecithin:cholesterol acyltransferase (LCAT) deficiency, and "fish-eye" disease. Transfer rates in plasma were positively correlated (r = 0.950) with rates measured in the absence of the endogenous lipoproteins. This suggests that lipoprotein composition and content may not affect total cholesteryl ester transfer activity in normolipidemic and the HDL-deficient subjects. Cholesteryl ester transfer from solid-phase-bound HDL to plasma lipoproteins was decreased by 39% in fish-eye disease and 33% in LCAT deficiency but increased by 57% in Tangier disease, as compared with normal values. Changes were similar for lipoprotein-depleted plasma from the same individuals. Transfer to plasma HDL was significantly decreased in all HDL-deficient patients, whereas transfer to very-low- and low-density lipoproteins was increased only in Tangier disease. Differences in transfer rates between the patients studied appeared to reflect the LCAT activity and the need to transport cholesteryl ester rather than the HDL cholesterol concentration. Thus, the concentration of HDL in plasma does not directly affect total cholesteryl ester transfer activity in HDL deficiency.     

Anaphylaxis after treatment with recombinant factor VIII

BACKGROUND: Treatment of hemophilia patients with recombinant factor VIII concentrates has not previously been associated with anaphylaxis. STUDY DESIGN AND METHODS: A 5-week-old boy with severe hemophilia A developed dyspnea, cyanosis, hypotension, and a diffuse urticarial rash following treatment with a recombinant factor VIII (Recombinate). To identify the cause of anaphylaxis in this patient, the vial lot was examined for the presence of endotoxin, and a checkerboard immunoblotting technique was used to test serum and/or plasma samples from the patient and mother for the presence of antibodies (IgA, IgG, IgE, and IgM) to Recombinate-related antigens (recombinant factor VIII, von Willebrand factor, human serum albumin, Chinese hamster ovary proteins, bovine serum albumin, mouse monoclonal anti-human factor VIII, polyethylene glycol 3350), and to ethylene oxide, the agent used to sterilize the infusion equipment. RESULTS: No immune response directed against the Recombinate-related antigens or ethylene oxide that could be associated with the anaphylactic reaction was identified. Endotoxin was not present upon rabbit pyrogen testing of the therapeutic product. CONCLUSION: These studies failed to show any association between Recombinate and the onset of the allergic reaction. This seems to be the first reported case of anaphylaxis following the infusion of a recombinant form of factor VIII concentrate.     

The role of apoproteins in disorders of lipoprotein metabolism

Apolipoproteins are essential components of plasma lipoproteins. They facilitate the absorption and secretion of fat from the intestine, serve as activators of enzymes of lipoprotein metabolism and act as ligands for lipoprotein receptors on cell surfaces. Changes in the apoprotein quantity or composition affect plasma lipid concentrations. Specific examples of apolipoprotein alterations are known for apo A-I, apo B, and for C and E apolipoproteins. With the availability of both apolipoprotein protein and gene analytical techniques both quantitative and qualitative assays of apolipoproteins are becoming more important in the diagnosis of lipoprotein disorders. Assays of apo A-I, apo B and, less frequently, apo C-II and E apolipoproteins are useful diagnostic tools, if performed properly. Major problems with the standardization and quality control of these assays remain to be solved.     

2型糖尿病患者勃起功能障碍患病率及西地那非的疗效和安全性评价

目的调查内分泌门诊中糖尿病患者阴茎勃起功能障碍(ED)患病率,并评价西地那非(万艾可)在糖尿病合并ED患者中的疗效和安全性。方法多中心收集2型糖尿病男性患者6193例,入选6178例,患者签署知情同意书后,根据国际勃起功能指数表(IIEF5)患者进行自我评分。对3个月内服用3剂万艾可的患者除要求填写治疗前的IIEF5表评分外,还要求填写治疗后的总体疗效问题回答表,以评价万艾可治疗的疗效,并记录患者服药后的不良事件以评价其安全性。结果国内42家医院内分泌门诊2型糖尿病患者中ED的患病率为75.2%,其中重度、中度和轻度ED分别为9.1%、17.2%、48.9%。该受检人群中ED的知晓率为85.0%,但治疗率仅为9.4%。多因素回归分析显示患者年龄、糖尿病病程、血糖控制不佳(HbA1C>6.5%)与糖尿病患者ED的发生独立相关。共有389例患者服用万艾可治疗,治疗后患者IIEF5总评分和各问题的评分均显著高于治疗前(P<0.01);根据IIEF5评分,治疗后重、中度ED患者例数明显少于治疗前(P<0.01)。根据总体疗效评估问题的回答,给予万艾可治疗后勃起功能改善率达86.4%。对安全性评价显示服用万艾可后出现的与药物有关的不良事件主要是颜面潮红、头痛、心悸和口干等,大多为轻度。结论在2型糖尿病患者中ED是常见的合并症,万艾可治疗糖尿病合并ED疗效确切,并有良好的安全性。     

Screening for ‘window‐period’ acute HIV infection among pregnant women in rural South Africa

Objectives

The aim of this study was to evaluate the HIV‐1 RNA pooled nucleic acid amplification testing (NAAT) strategy to screen pregnant women in the ‘window period’ of acute HIV infection (AHI) in rural South Africa.

Methods

In 2007 and 2008, 750 consecutive pregnant women on their first antenatal care visit to a primary health care clinic were tested anonymously for HIV infection. HIV‐1 RNA pooled NAAT was performed on HIV antibody‐negative samples. All positive pools were tested individually and positive samples were classified as incident cases to calculate HIV incidence.

Results

The overall HIV prevalence was 37.3% [95% confidence interval (CI) 34.3–41.3]. Of the 467 HIV antibody‐negative samples, four (0.9%) were HIV‐1 RNA‐positive. The mean viral load in the four samples was 386 260 HIV‐1 RNA copies/mL (range 64 200–1 228 130). The HIV incidence was 11.2% per year (95% CI 0.3–22.1) and all women with AHI were ≤21 years of age.

Conclusions

Identifying AHI in pregnancy is important for health interventions to reduce perinatal and heterosexual transmission of HIV, and to estimate HIV incidence for epidemiological surveillance.     

The phospholipase A2 inhibitor methyl indoxam suppresses diet-induced obesity and glucose intolerance in mice

Background and purpose:

Previous results have shown that mice lacking in the group 1B phospholipase A₂ (Pla2g1b) are resistant to obesity and diabetes induced by feeding a diabetogenic high-fat/high-carbohydrate diet. This study examined the potential of using the Pla2g1b inhibitor methyl indoxam as therapy to suppress diet-induced obesity and diabetes.

Experimental approach:

Male C57BL/6 mice were fed the diabetogenic diet with or without methyl indoxam supplementation. Body weight gain, fasting plasma glucose levels, glucose tolerance and postprandial lysophospholipid absorption were compared.

Key results:

Wild-type C57BL/6 mice fed the diabetogenic diet without Pla2g1b inhibitor showed 31 and 69% body weight gain after 4 and 10 weeks respectively. These animals also showed elevated plasma glucose levels and were glucose intolerant. In contrast, C57BL/6 mice fed the diabetogenic diet with 90 mg·kg⁻¹ of methyl indoxam gained only 5% body weight after 10 weeks. These animals were also euglycaemic and displayed normal glucose excursion rates in glucose tolerance test. Methyl indoxam suppression of diet-induced body weight gain and glucose intolerance was correlated with the inhibition of Pla2g1b-mediated postprandial lysophospholipid absorption.

Conclusions and implications:

These results show that oral supplementation of a diabetogenic diet with the Pla2g1b inhibitor methyl indoxam effectively suppresses diet-induced obesity and diabetes in mice. This suggests that Pla2g1b inhibition may be a potentially effective oral therapeutic option for treatment of obesity and diabetes.