Antiretroviral therapy is associated with sexual dysfunction and with increased serum oestradiol levels in men

Our objective was to determine the relationship between highly active antiretroviral therapy (HAART), serum total oestradiol and sexual dysfunction in HIV-infected men. Sexual difficulties were recorded prospectively in a cohort of HIV-negative (or unknown status) gay/bisexual men (MSM) and a cohort of HIV-infected men. The HIV-infected men were divided into those on and not on HAART and by sexuality. Serum total oestradiol and testosterone levels were evaluated where possible. One hundred HIV-negative MSM and 73 HIV-infected men (88% MSM) were analysed. Low libido and erectile dysfunction (ED) were reported in the control group in 2% and 10% respectively. This compared to a prevalence of 26% for both problems in HIV-infected MSM not taking HAART. In those MSM on HAART reduced libido was noted in 48% and ED in 25%. In the group of men taking HAART the mean oestradiol level was 228 pmol/L and was significantly above normal limits. Low libido and ED are more commonly reported in HIV-infected men compared to gay men of negative or unknown status. HAART is associated with a higher prevalence of lack of sexual desire and raised serum oestradiol levels.     

The apolipoprotein CI content of triglyceride-rich lipoproteins independently predicts early atherosclerosis in healthy middle-aged men

OBJECTIVES: In this study, we examined the apolipoprotein (apo) CI content of triglyceride-rich lipoproteins (TRLs) in relation to established coronary heart disease (CHD) risk factors and early atherosclerosis. BACKGROUND: In Western society, the postprandial state constitutes a nearly constant stress on the vasculature and the metabolism of lipoproteins. Delayed clearance of postprandial TRL remnants has repeatedly been associated with premature CHD and may include the enrichment of these remnants with apoCI. METHODS: We examined 72 healthy 50-year-old men with an apoE3/E3 genotype who had undergone an oral fat load test and B-mode ultrasound examination of the intima-media thickness (IMT) of the common carotid artery. RESULTS: In the fasting state, plasma, very-low-density lipoprotein (VLDL), and low-density lipoprotein cholesterol, proinsulin, and apoB100-containing intermediate density lipoprotein levels were related to IMT (p < 0.05). In the postprandial state, IMT was related to triglycerides at 2 h (p < 0.01), large VLDL concentration at 3 h (p < 0.05), the apoCI plasma and TRL concentrations at 6 h (p < 0.05, p < 0.05), and the apoCI content of TRLs at 6 h (p < 0.002). Multivariate analysis revealed that the apoCI content of TRLs at 6 h (p < 0.0001), plasma triglyceride concentrations at 2 h (p < 0.006), and fasting plasma cholesterol concentration (p < 0.05) independently predicted IMT. In addition, the apoCI content of postprandial TRLs correlated strongly with the cholesterol content (r = 0.64, p < 0.0001). CONCLUSIONS: Our results indicate that the apoCI content of postprandial TRLs is a novel independent risk factor for early atherosclerosis in normolipidemic healthy middle-aged men with possible implication for the enrichment of TRL remnant lipoproteins with cholesterol.     

Large triglyceride-rich lipoproteins from fasting patients with type 2 diabetes activate platelets

AimsType 2 diabetes (T2D) patients present with risk factors for atherothrombosis such as fasting hypertriglyceridaemia and platelet hyperactivity. Our study objective was to determine the effect of large triglyceride-rich lipoproteins (TGRL) from fasting T2D patients on platelet aggregation and, if any, to identify the signaling pathway involved.MethodsLarge TGRL were isolated from the plasma of 25 T2D patients by ultracentrifugation (density < 1.000 g/mL). Platelets were isolated from healthy blood donors (HBD) and suspended in buffer, then preincubated in the presence or absence of TGRL and stimulated with either collagen or thrombin. Platelet aggregation and the arachidonic acid (AA) signaling pathway were studied.ResultsFasting T2D large TGRL were mostly of hepatic origin (apoB100/apoB48 ratio: 42 ± 7) and rich in triglycerides (TG/total apoB ratio: 4.2 ± 0.5), and able to potentiate agonist-stimulated platelet aggregation (collagen: +68%, P < 0.05; thrombin: +771%, P < 0.05). It should also be mentioned that TGRL from the plasma of HBD (n = 7) had no effect on platelet aggregation. In addition, T2D large TGRL increased thromboxane B₂ (TxB₂) concentration in platelets stimulated with either collagen (+34%, P < 0.05) or thrombin (+37%, P < 0.05) compared with platelets stimulated with either of these agonists without TGRL. Phosphorylation of p38 MAPK and cytosolic phospholipase A₂ (cPLA₂) was enhanced after incubation of platelets with T2D TGRL and thrombin (+87% and +32%, respectively, P < 0.05) compared with platelets incubated with thrombin only.ConclusionLarge TGRL from fasting T2D patients may play a role in the development of atherothrombosis by increasing platelet aggregation and activating the platelet AA signaling pathway.     

Insulin and non-esterified fatty acid relations to alimentary lipaemia and plasma concentrations of postprandial triglyceride-rich lipoproteins in healthy middle-aged men

Aims/hypothesis. Enhanced and prolonged postprandial lipaemia is related to cardiovascular disease but how postprandial lipaemia is regulated is poorly known. We therefore determined the relations of fasting insulin concentrations to fasting and postprandial lipids, lipoproteins and non-esterified fatty acids in middle-aged men.¶Methods. The subjects, 99 healthy 50-year-old men with an apolipoprotein E3/3 genotype, ate a mixed meal. The apolipoprotein B-48 and B-100 contents were determined in triglyceride-rich lipoproteins as a measure of chylomicron remnant and very low density lipoprotein particle concentrations.¶Results. Fasting plasma insulin was associated with the triglyceride response to the test meal, independently of body mass index, waist-to-hip circumference ratio, blood glucose and the insulin effect on fasting plasma triglycerides. Exaggerated and prolonged postprandial lipaemia in subjects in the upper quartile of the plasma insulin distribution was largely accounted for by large (Svedberg flotation rate > 60) very low density lipoproteins and chylomicron remnants. Insulin relations to large postprandial triglyceride-rich lipoproteins exclusively reflected the association between plasma insulin and the fasting plasma concentrations of these lipoprotein species, whereas plasma insulin and late postprandial plasma concentrations of small (Svedberg flotation rate 20–60) chylomicron remnants were related, independently of insulin influences on fasting concentrations. Strong positive relations were found between the late increases in large triglyceride-rich lipoproteins and plasma non-esterified fatty acid concentrations after 6 h.¶Conclusion/interpretation. The degree of insulin sensitivity is a major determinant of postprandial lipaemia in healthy middle-aged men and could add to the regulation of the basal production of large triglyceride-rich lipoproteins. [Diabetologia (2000) 43: 185–193]     

Antiretroviral therapy maintenance among HIV-positive women in Ghana: the influence of poverty

ABSTRACT

This study examines the role of poverty in the acquisition of and the adherence to antiretroviral therapy (ART) and prescribed clinical follow-up regimens among HIV-positive women. We conducted in-depth interviews with 40 women living with HIV (WLHIV) in Ghana and 15 stakeholders with a history of work in HIV-focused programs. Our findings indicate that financial difficulty contributed to limited ability to maintain treatment, the recommended nutrient-rich diet, and clinical follow-up schedules. However, enacted stigma and concurrent illness of family members also influenced the ability of the WLHIV to generate income; therefore, HIV infection itself contributed to poverty. To further examine the relation between finances, ART adherence, and the maintenance of recommended clinical follow-up, we present the perspectives of several HIV-positive peer counselor volunteers in Ghana’s Models of Hope program. We recommend that programs to combat stigma continue to be implemented, as decreased stigma may reduce the financial difficulties of HIV-positive individuals. We also recommend enhancing current support programs to better assist peer counselor volunteers, as their role directly supports Ghana’s national strategic HIV/AIDS plan. Finally, additional investment in poverty-reduction across Ghana, such as broadening meal assistance beyond the currently limited food programs, would lighten the load of those struggling to combat HIV and meet basic needs.     

Metabolism of plasma low density lipoproteins in familial combined hyperlipidaemia: effect of acipimox therapy.

Ten male patients with familial combined hyperlipidaemia (FCHL) were studied with regard to LDL metabolism and composition. The FCHL patients had higher LDL levels than healthy controls (5.4 +/- 1.4 vs. 3.7 +/- 0.7 mmol l-1; P < 0.005) and a higher rate of production of the lipoprotein (15.8 +/- 3.1 mg kg-1 d-1 in FCHL vs. 13.1 +/- 1.8 mg kg-1 d-1 in the normals; P < 0.005). The fractional catabolic rate of LDL was low-normal in the FCHL patients, with a high level of interindividual variation. The actual individual LDL cholesterol level within the FCHL patient group appeared to be more closely associated with the LDL apoB FCR value than the rate of production of the particle. Analysis of the LDL particles from FCHL patients revealed a relative enrichment in triglycerides, while the cholesterol content of the lipoprotein was normal. Institution of acipimox therapy in 8 patients reversed the high rate of synthesis of LDL (15.2 +/- 3.5 mg kg-1 d-1) to a more normal level (13.9 +/- 4.0 mg kg-1 d-1; P = 0.08), while the FCR did not change significantly. In conclusion, patients with FCHL show an apparent overproduction of LDL apoB, while the actual degree of LDL elevation appears to be dependent on the clearance capacity of the lipoprotein, measured as LDL apoB FCR. The overproduction defect of LDL apoB can, at least in part, be managed by treatment with the nicotinic acid analogue acipimox.     

Plasma fatty acids and lipoproteins in type 2 diabetic patients

BACKGROUND: The dyslipidemia of type 2 diabetic patients is characterized by high VLDL, abnormal LDL composition and low HDL cholesterol concentrations. The aim of this study was to establish whether the type of dietary fats affects LDL size and density and HDL cholesterol concentrations in these patients. METHODS: Plasma phospholipid fatty acid composition, which reflects the type of dietary fatty acids, was quantified by gas chromatography. LDL relative flotation (LDL-Rf), a measure of LDL particle size and density, was determined by single vertical spin density gradient ultracentrifugation in 97 type 2 diabetic patients. RESULTS: By linear regression analysis of the data, plasma fatty acids were associated neither with LDL-cholesterol levels nor with LDL-Rf. The HDL cholesterol concentrations were negatively related with saturated fatty acids (r = -0.23; p = 0.02) but positively related with monounsaturated fatty acids (r = +0.20; p = 0.00). Furthermore, higher HDL concentrations were associated with large and buoyant LDL particles (HDL cholesterol vs LDL-Rf: r = +0.47; p = 0.00). In the multiple regression analysis, the LDL-Rf was significantly related both to triglycerides (beta coefficient = -0.55, p = 0.000) and HDL cholesterol (beta coefficient = 0.19, p = 0.034) concentrations. In a stepwise regression analysis including both triglycerides and HDL cholesterol, triglycerides alone explained the 43.0% of the LDL-Rf variability. CONCLUSIONS: A reduction of the dietary saturated fats and an increment of monounsaturated fats might increase HDL cholesterol concentrations in type 2 diabetic patients. Modifications of LDL composition might be expected from interventions aimed to reduce plasma triglycerides.     

Antiretroviral therapy with tenofovir is associated with mild renal dysfunction

A cross-sectional study was conducted to compare patients treated with tenofovir with patients never treated with tenofovir. Patients on tenofovir showed a lower mean glomerular filtration rate estimated by creatinine clearance or cystatin C clearance compared with control patients. In total, 24 patients on tenofovir versus five control patients had proteinuria greater than 130 mg/day. In the majority of patients on tenofovir proteinuria was of tubular origin.     

The Q/E27 polymorphism in the beta2-adrenoceptor gene is associated with increased body weight and dyslipoproteinaemia involving triglyceride-rich lipoproteins

OBJECTIVES: To investigate whether a substitution of glutamine by glutamic acid at amino acid position 27 (Q/E27) and an arginine to glycine transition at amino acid 16 (R/G16) in the beta2-adrenoceptor gene are associated with lipid and lipoprotein disturbances and/or increased body weight in men. DESIGN: Population-based study. SETTING: Department of medicine at a university hospital. SUBJECTS: A total of 180 healthy men, aged 30-45 years, were recruited at random from a register containing all permanent residents in Stockholm County (response rate of 70%). MAIN OUTCOME MEASURES: Frequency of beta2-adrenoceptor genotypes and alleles in relation to plasma lipid and lipoprotein levels and body mass index. RESULTS: Individuals carrying the E27 allele and/or the G16 allele had significantly higher body mass index (BMI). Furthermore, carriers of the E27 allele had significantly higher plasma concentrations of cholesterol, triglycerides, VLDL cholesterol and VLDL triglycerides than did subjects homozygous for the Q allele. CONCLUSION: The E27 allele of the beta2-adrenoceptor gene is associated with slightly to moderately elevated BMI and dyslipoproteinaemia involving triglyceride-rich lipoproteins in healthy younger and middle-aged men.     

Increased bleeding associated with protease inhibitor therapy in HIV-positive patients with bleeding disorders

The use of protease inhibitor (PI) drugs in treatment regimens for HIV-infected patients with hereditary bleeding disorders has been associated with an increased bleeding tendency. To characterize the nature of this bleeding tendency, a retrospective case record analysis was performed on 67 HIV-positive patients with hereditary bleeding disorders who had been treated with PI therapy. 34 patients (51%) developed an increased bleeding tendency on PI therapy, usually within the first few weeks of treatment. As well as an increase in usual joint bleeds, patients developed spontaneous atypical small joint, soft tissue and muscle bleeds. Haematuria was also common. Bleeding episodes tended to respond suboptimally to factor concentrate replacement. Ritonavir was most likely to be associated with bleeding. Nine patients switched first-line PI therapy as a direct consequence of bleeding and seven had no further bleeding problem on their second PI. Factor concentrate usage was significantly increased during the first 6 months of PI therapy compared to the 6 months preceeding treatment. PI therapy is frequently associated with increased bleeding in patients with hereditary bleeding disorders. The mechanism of the bleeding tendency remains to be elucidated.     

Effect of pravastatin on intermediate-density and low-density lipoproteins containing apolipoprotein CIII in patients with diabetes mellitus

The apolipoprotein (apo) B lipoproteins, intermediate-density lipoproteins (IDL) and low-density lipoproteins (LDL) that contain apo-CIII are associated with coronary heart disease in patients with diabetes mellitus. Apo-CIII is prominent in diabetic dyslipidemia. We studied whether these apo-B lipoprotein types containing apo-CIII in diabetics are reduced by 1 year of pravastatin treatment. We randomly selected 45 age- and gender-matched placebo/pravastatin pairs from diabetic patients in the Cholesterol and Recurrent Events trial, a randomized, double-blinded trial of pravastatin 40 mg monotherapy. Very-low-density lipoproteins (VLDL) and IDL + LDL particles were subdivided based on the presence of apo-E and apo-CIII to yield 3 particle types: E+CIII+, E-CIII+, and E-CIII-. Compared with placebo, pravastatin reduced IDL + LDL apo-B concentrations for E+CIII+, E-CIII+, and E-CIII- by 42% (p = 0.02), 17% (p = 0.7), and 29% (p = 0.002), respectively, commensurate with IDL + LDL cholesterol concentration reductions in the particle types of 29% (p = 0.002), 25% (p = 0.2), and 36% (p <0.0001), respectively. These IDL + LDL CIII+ particles are rich in triglycerides and cholesterol and are likely to be remnant particles of VLDL. Thus, pravastatin reduced potentially atherogenic remnant particles, a prominent component of diabetic dyslipidemia associated with coronary events; these results may contribute to its demonstrated effectiveness in reducing coronary heart disease in diabetics.     

Hypertriglyceridemia but not diabetes status is associated with VLDL containing apolipoprotein CIII in patients with coronary heart disease

High apoCIII concentration in apoB lipoproteins is a prominent component of atherogenic dyslipidemia, and explains the risk of coronary heart disease (CHD) associated with high triglyceride (TG). We hypothesized that diabetic people have atherogenic dyslipidemia with apoCIII in excess of that accounted for by their high TG levels. We selected 30 diabetic and 30 nondiabetic persons, 15 of each with fasting TG<160 mg/dl and 15 with TG>/=200 mg/dl. Using immunoaffinity chromatography and ultracentrifugation, we prepared large and small VLDL, IDL and LDL with or without apoCIII or apoE. The groups with TG>/=200 mg/dl, regardless of diabetes status, had higher concentrations of large and small VLDL particles with apoCIII and higher apoCIII concentrations than the groups with fasting TG<160 mg/dl. The diabetes groups did not have higher concentrations of these lipoproteins than the nondiabetes groups within the same fasting TG criteria. In conclusion, high concentrations of apoCIII-containing VLDL are associated with hypertriglyceridemia, which may play a critical role in identifying the high risk of CHD in hypertriglyceridemic patients whether diabetic or nondiabetic. Diabetes status per se does not appear to be associated with high concentrations of apoCIII-containing TG-rich lipoprotein particles, if the plasma TG levels are similar.     

Abnormal preponderance of sialylated apolipoprotein CIII in triglyceride rich lipoproteins in type V hyperlipoproteinemia

Triglyceride rich lipoproteins contain apolipoproteins (apo) CII and CIII. Apo CII and CIII activate and inhibit tissue lipoprotein lipase, respectively. Apo CIII is a glycoprotein containing 0, 1 or 2 moles of sialic acid (designated apo CIII₀, CIII₁ and CIII₂, respectively). This study was designed to determine whether an abnormal distribution of these biologically active apoproteins occurred in triglyceride rich lipoproteins isolated from hypertriglyceridemic individuals. Triglyceride rich lipoproteins were isolated by preparative ultracentrifugation from 10 patients with primary type V hyperlipoproteinemia, eight patients with primary type IV hyperlipoproteinemia, and 11 normal healthy normolipidemic matched control subjects. After delipidation with tetramethyl urea, apo CII and CIII subspecies were separated by analytical isoelectric focussing with a pl range between 3.5 and 5.0. This technique allows a clear separation of apo CIII₀ from its sialylated subspecies and also from apo CII. The ratios of the individual apo CIII subspecies to each other and to apo CII were calculated from densitometric scanning of the stained gels. Desialylated apo CIII₀ comprised 3.3 ± 1.9% (M ± SD.) of total apo CIII in patients with type V hyperlipoproteinemia and was significantly lower (p = 0.0001) than the proportion found in normal subjects (14.3 ± 5.9%) and patients with primary type IV hyperlipoproteinemia (16.7 ± 6.2%). Apo CIII₁ comprised 62.4 ± 5.9% of total apo CIII in type V patients being significantly higher than that in normal subjects (52.6 ± 6.9%; p = 0.003) and patients with primary type IV hyperlipoproteinemia (47.1 ± 3.7%; p = 0.0001). Apo CIII₂ as percent of total apo CIII was similar in the three groups. The distribution of the apo CIII subspecies in patients with primary type IV hyperlipoproteinemia was similar to control subjects. In patients with type V hyperlipoproteinemia, the ratio of apo CIII₀; CII (0.11 ± 0.05) was significantly lower than normal (0.47 ± 0.26; p = 0.002), and also lower than the mean ratio observed in patients with primary type IV hyperlipoproteinemia (0.60 ± 0.25; p = 0.0001). Apo CIII₁;CII ratio in type V hyperlipoproteinemia (2.24 ± 0.58) was significantly higher than normal (1.64 ± 0.41; p = 0.02) and type IV hyperlipoproteinemia (1.67 ± 0.32; p = 0.047). Apo CIII₂:CII ratio was similar in the three groups. Total apo CIII:CII ratio in types IV and V (3.5 ± 0.86 and 3.55 ± 0.66, respectively) was higher than normal (3.15 ± 0.83), but the differences were not statistically significant. These data indicate that type V hyperlipoproteinemia is associated with an abnormal preponderance of sialylated to the desialylated apo CIII in triglyceride rich lipoproteins. Further work is needed to define the precise mechanism(s) responsible for this abnormality.     

Relevance of different apolipoprotein content in binding of homocysteine to plasma lipoproteins

BACKGROUND AND AIMS: In plasma the atherogenic thiol homocysteine (Hcy) circulates either free or bound to proteins (Pb-Hcy). The present study sets out to evaluate the lipoprotein-Hcy (LP-Hcy) binding in vivo and the possible influence of different apolipoprotein content in this binding, being lipoprotein oxidation a possible mechanism of Hcy-induced damage. METHODS AND RESULTS: In 34 healthy subjects we assayed fasting plasma lipoprotein and correspondent apolipoprotein (apo A-I, apo A-II, apo C-II, apo C-III, apo B, apo(a) and apo E content, and Hcy bound to different plasma protein fractions; moreover ten subjects underwent an oral methionine load in order to evaluate possible "dynamic" modifications of Pb-Hcy and LP-Hcy after induction of hyperhomocysteinemia. Pb-Hcy (mean values 9.22 +/- 1.7 mumol/L) represented about 78% of total plasma Hcy (mean values 11.8 +/- 1.8 mumol/L). Pb-Hcy distribution between the different fractions was as follows (mumol/L): VLDL = 0.25 +/- 0.08 (2.7%); LDL = 0.88 +/- 0.22 (9.5%); HDL = 1.40 +/- 0.36 (15.2%); fractions with density greater than 1.21 g/mL (Lipoprotein-Free Protein Fraction, LPDS) = 6.7 +/- 1.2 (72.6%). Hcy/protein ratios (nmol/mg of protein) in each protein fraction were: VLDL = 0.32 +/- 0.19, LDL = 0.43 +/- 0.37, HDL = 0.26 +/- 0.18, LPDS < 0.1, thus suggesting a higher binding capacity for Hcy by VLDL and LDL. These data were confirmed by the higher increase in Hcy content in LDL and VLDL (76 and 90%, respectively vs 36% and 3.1% for HDL and LPDS fractions) after hyperhomocysteinemia. Lp-Hcy binding significantly correlated with the apo B content of VLDL and LDL and Apo A-I content of HDL. CONCLUSIONS: An important fraction of plasma Hcy circulates bound to LP (about 27% of Pb-Hcy); VLDL and LDL show the highest binding capacity for Hcy, probably due to their content in Apo B, a possible high capacity binding site for Hcy.     

Hemolytic-uremic syndrome associated with pancreatitis in an HIV-positive patient

Summary Hemolytic-uremic syndrome (HUS) is a newly recognized hematologic manifestation of HIV infection that may be triggered by local or systemic infections as well as by immunological disorders. We report the case of a 36-year-old HIV-positive man, an intravenous drug abuser who developed HUS during an episode of acute pancreatitis. Hematologic and clinical improvement occurred following 2 weeks of nonaggressive therapy including vitamin E and fresh-frozen plasma.