Cardiomyopathy in congenital complete lipodystrophy

Molecular genetic studies have pointed to a relationship between congenital lipodystrophy syndromes and some cardiac disorders. For instance, mutations in LMNA cause either lipodystrophy or cardiomyopathy, indicating that different mutations in the same gene can produce these clinical syndromes. The present authors describe a 10-year-old female with Berardinelli-Seip congenital complete lipodystrophy (MIM 606158) caused by homozygosity for a frameshift mutation in BSCL2. In addition to the typical attributes of complete lipodystrophy, this subject had hypertrophic cardiomyopathy diagnosed in the first year of her life; its progress has been followed with non-invasive imaging. The mechanism underlying the hypertrophic cardiomyopathy in complete lipodystrophy is unclear. It may result from a direct effect of the mutant gene or it might be secondary to the effects of hyperinsulinemia on cardiac development. The variability of the associated cardiomyopathy in patients with complete generalized lipodystrophy may be caused by differential effects of mutations in the same gene or of mutations in different genes which underlie the lipodystrophy phenotype.     

Decreases in plasma TNF-alpha level and IFN-gamma mRNA level in peripheral blood mononuclear cells (PBMC) and an increase in IL-2 mRNA level in PBMC are associated with effective highly active antiretroviral therapy in HIV-infected patients

In this study, we investigated the cytokine profiles of 14 treatment-naive HIV-infected patients on the initiation of highly active antiretroviral therapy (HAART). At baseline, plasma levels of TNF-alpha and its mRNA in peripheral blood mononuclear cells (PBMC) were highest in the most severely immunocompromised patients (<200 CD4+ cells/mm3). After 12 months of HAART, the virus was undetectable in the plasma of all patients (<200 copies/ml), and median CD4 T cell counts had increased (+164 cells/mm3). We also observed a gradual decrease in the number of proviral DNA copies in PBMC and in immune activation, with lower levels of IFN-gamma mRNA in PBMC associated with weaker activation of CD8+ T cells and lower levels of plasma TNF-alpha. IL-2 mRNA levels in PBMC were found to increase in parallel. The decrease in TNF-alpha and IFN-gamma levels and the increase in IL-2 production appear to be correlated with the efficacy of HAART in naive immunocompromised HIV-infected individuals.     

Plasma adiponectin and insulin resistance in Korean type 2 diabetes mellitus

Insulin resistance, which implies impairment of insulin signaling in the target tissues, is a common cause of type 2 diabetes. Adipose tissue plays an important role in insulin resistance through the dysregulated production and secretion of adipose-derived proteins, including tumor necrosis factor-alpha, plasminogen activator inhibitor-1, leptin, resistin, angiotensinogen, and adiponectin. Adiponectin was estimated to be a protective adipocytokine against atherosclerosis, and also to have an anti-inflammatory effect. In this study, the relationship between fasting plasma adiponectin concentration and adiposity, body composition, insulin sensitivity (ITT, HOMAIR, QUICK), lipid profile, fasting insulin concentration were examined in Korean type 2 diabetes. The difference in the adiponectin concentrations was also examined in diabetic and non-diabetic subjects, with adjustment for gender, age and body mass index. 102 type 2 diabetics and 50 controls were examined. After a 12-h overnight fast, all subjects underwent a 75 gram oral glucose tolerance test. Baseline blood samples were drawn for the determinations of fasting plasma glucose, insulin, adiponectin, total cholesterol, triglyceride, LDL-cholesterol, and HDL-cholesterol. The body composition was estimated using a bioelectric impedance analyzer (Inbody 2.0). The insulin sensitivity was estimated using the insulin tolerance test (ITT), HOMAIR and QUICK methods. In the diabetic group, the fasting adiponectin concentrations were significantly lower in men than in women. They were negatively correlated with BMI (r=-0.453), hip circumference (r=-0.341), fasting glucose concentrations (r=-0.277) and HOMAIR (r= -0.233). In addition, they were positively correlated with systolic blood pressure (r=0.321) and HDL-cholesterol (r= 0.291). The systolic blood pressure and HDL-cholesterol were found to be independent variables, from a multiple logistic regression analysis, which influenced the adiponectin concentration. Compared with the non-diabetic group, the adiponectin concentrations were significantly lower in the diabetic group, with the exception of obese males. In conclusion, the plasma adiponectin concentrations were closely related to the insulin resistance parameters in Korean type 2 diabetic patients.     

Low interleukin-10 production is associated with diabetes in HIV-infected patients undergoing antiviral therapy

Reduced interleukin-10 (IL-10) production is associated with type 2 diabetes in elderly individuals. Antiviral therapy (ARV)-induced immune modulation results in diminished IL-10 production, and diabetes can be observed in ARV-treated human immunodeficiency virus (HIV)-infected individuals. We analyzed, in a cross-sectional pilot study, HIV-antigen-stimulated IL-10 and tumor necrosis factor alpha (TNFα) production, and intracellular concentration (ICC), as well as B7-H1 expression, a marker preferentially presented by IL-10-producing cells, in 20 ARV-treated individuals in whom diabetes did (n=10; diabetes mellitus, DM) or did not (n=10; controls) develop. Pre-ARV glucose, cholesterol, and triglycerides levels, duration of HIV infection and of therapy, exposure to protease inhibitors (PI), HIV plasma viremia, CD4 counts, and nadir were similar in DM and control patients. Results showed that: (1) IL-10 production was lower; (2) IL-10 ICC was reduced; (3) B7-H1-expressing CD19+ cells were diminished; and (4) TNFα production and ICC by CD4+ T cells was augmented in DM patients. Development of diabetes in HIV infected, ARV-treated individuals could be a response to therapy. Similar to what is observed in elderly individuals, low IL-10 production is associated with diabetes in antiviral-treated HIV infection. Further studies will be necessary to clarify whether low IL-10 is a risk factor for, or a consequence of, diabetes.     

A Randomized,Double-Blind,Placebo-Controlled Study of Benfluorex in HIV-Infected Patients with Insulin Resistance or Impaired Glucose Tolerance

Abstract

Purpose: We previously reported a beneficial effect of benfluorex (BFL) on oral glucose tolerance test (OGTT) and visceral fat mass in an open-label study conducted in 60 HIV-infected patients. The objective of this study was to assess whether administration of BFL compared to placebo (PBO) improves insulin resistance (IR) in HIV+ patients with HAART- induced lipodystrophy. Method: 22 HIV-infected patients with IR or impaired glucose tolerance were double-blind randomly assigned to receive BFL 3 tablets/day or PBO for 24 weeks. Efficacy assessments included OGTT, abdominal computed tomography, and the measurement of fasting lipids. Results: Change of median insulin AUC was –53.0 μIU/mL (IQR, –126.0 to –12.7) in the BFL group vs. +33.6 μIU/mL (IQR, 7.0 to 115.6) (p = .01) in PBO group. Weight decreased significantly in the BFL group (–2 kg ± 2.6; IQR, –6.8 to 2.0) compared to the PBO group (0.8 kg ± 1.7; IQR, –2.0 to 0.5) (p = .02). No significant changes in visceral or subcutaneous fat mass and plasma lipid level were observed between the two groups. Conclusion: Added to antiretroviral therapy, a 6-month therapy with BFL improved insulin sensitivity but is not sufficient to reduce significantly visceral fat mass.     

Increased homocysteine plasma level is associated with shortened prothrombin time in HIV-infected patients

Objective: To find factors associated with increased homocysteine plasma level in HIV-infected patients.

Methods: Cross-sectional study, carried out as a supplementary task to the standard care of HIV-infected patients. The possible association of increased homocysteine plasma level with blood analyses results was assessed with a multiple linear regression analysis, using the automatic linear modeling available in SPSS version 22.

Results: A total of 145 patients were included. Creatinine was higher than normal in 7 patients (5%), prothrombin time was shortened in 36 patients (25%), and a monoclonal gammopathy was detected in 2 patients (1%). In the regression analysis, an association was found between high homocysteine plasma level and the following variables: low prothrombin time (β coefficient ?0.286, confidence interval ?1.1854 to ?0.754, p < 0.001), high creatinine (coefficient 9.926, confidence interval 6.351–15.246, p < 0.001), low folic acid (coefficient ?0.331, confidence interval ?0–483 to ?0.187, p < 0.001), and low vitamin B₁₂ (coefficient ?0.007, confidence interval ?0.01 to ?0.001, p = 0.005).

Conclusion: An association was found between increased homocysteine plasma level and shortened prothrombin time.     

High plasma level of interleukin-18 in HIV-infected subjects with lipodystrophy

The level of interleukin-18 (IL-18) is elevated in patients with HIV infection as well as in people with insulin resistance (IR). As HIV-associated lipodystrophy (LD) shares metabolic characteristics with the metabolic syndrome, it was hypothesized that IL-18 would be elevated in patients with LD. Two groups of HIV-infected men with LD, one with fat accumulation (mixed group) (n = 12) and one without fat accumulation (lipoatrophic group) (n = 15) were included. Controls were HIV-positive men without LD (n = 15) and HIV-negative, age-matched men (n = 12). The levels of plasma IL-18 were elevated in all 3 HIV groups compared with HIV-negative controls (P <0.01). In the HIV groups the lipoatrophic group had the highest IL-18, followed by the mixed group and the HIV-positive controls. Only the differences between the lipoatrophic group and the HIV-positive controls were significant (P <0.01). Plasma IL-18 correlated with tumor necrosis factor-alpha (P <0.05), but not IL-6, adiponectin, or HOMA-IR (homeostasis model of insulin resistance). In contrast to the HIV-negative controls, IL-18 did not correlate with total or low-density cholesterol in either of the HIV groups. An inverse correlation was observed between IL-18 and limb fat (P <0.05). In conclusion, the level of IL-18 is elevated in patients with LD and closely linked to limb atrophy, whereas it is not associated with cholesterol or IR.     

Efficacy and safety of stavudine plus didanosine in asymptomatic HIV-infected children with plasma HIV RNA below 50,000 copies per milliliter

Abstract

BACKGROUND: Simple antiretroviral drug combinations might provide a comparable benefit to standard triple regimens in patients with mild HIV disease, because poor adherence and toxicities often compromise the sustained benefit of the latest triple regimens, especially when protease inhibitors are used. Bad adherence is the main cause of virological failure in HIV-positive children. The activity and safety of a double combination of nucleosides with high genetic barrier for resistance (stavudine plus didanosine) was assessed in children with nonadvanced HIV disease. METHOD: From February 1998 to March 1999, 16 children were enrolled in six Spanish hospitals in a trial in which didanosine (180 mg/m²/day) and stavudine (2 mg/Kg/day) were administered for 48 weeks to asymptomatic naive children with plasma HIV RNA below 50,000 copies/mL and CD4 counts above 15%. Genotypic resistance to nucleoside analogues was examined at baseline and at the end of the study. RESULTS: At baseline, median age was 6.5 years (range, 2-14). The absolute and percentage mean CD4 counts were 864 and 32%, respectively (z score: -0.48 and -1.1). Mean plasma viral load was 4.05 log. No clinical events occurred during the 1-year study period. Minor side effects were recorded in two thirds of children, although none led to drug discontinuation. Lipoatrophy was not recognized in any of the participants. Plasma HIV RNA below 400 copies/mL was reached by 43% and 44% of patients at 24 and 48 weeks, respectively. The z score for absolute and percentage CD4 count increased significantly at 48 weeks (+0.63 and +0.97, respectively) in respect to baseline (p < .05). Resistance mutations linked to didanosine (L74V or M184V) or stavudine (V75T) were not recognized and neither were multinucleoside resistant genotypes (151 complex or 69 inserts). However, four children developed AZT-like mutations T215Y and/or M41L. CONCLUSION: Treatment with a dual combination of didanosine plus stavudine in naive children with nonadvanced HIV disease is safe and provides a satisfactory virological outcome at 1 year. Toxicity and drug resistance seem to occur rarely when this combination is used, which allows good adherence and spares other future treatment options.     

Insulin resistance in patients with polycystic ovary syndrome is associated with elevated plasma homocysteine

BACKGROUND: Elevated levels of plasma homocysteine have recently been implicated as a significant risk factor for cardiovascular disease, pre-eclampsia, and recurrent pregnancy loss, and have been found to be associated with insulin resistance in a number of clinical situations. We examined the relationship between plasma homocysteine and insulin resistance in patients with polycystic ovary syndrome (PCOS). METHODS: A total of 155 infertile patients with PCOS as defined by clinical, biochemical and ultrasound criteria were screened for insulin resistance utilizing single-sample fasting insulin and glucose measurement, calculated by glucose:insulin ratio or homeostasis model assessment (HOMA) index. Total plasma homocysteine was measured by fluorescence polarization immunoassay. One hundred normo-ovulatory women with normal ovaries being treated for other infertility diagnoses served as a control group. RESULTS: Insulin resistance was found in the majority of PCOS patients: -53.5% (83/155), 60.6% (94/155) and 65.8% (102/155), when defined by fasting insulin, glucose:insulin ratio, or logHOMA respectively. Mean plasma homocysteine in the PCOS group was significantly higher than in the normal ovary group (11.5 +/- 7.4 versus 7.4 +/- 2.1 micromol/l, P < 0.001). Insulin-resistant PCOS patients had significantly higher plasma homocysteine (12.4 +/- 8.4 micromol/l) than non-insulin-resistant PCOS patients (9.6 +/- 4.4 micromol/l) regardless of body mass index (P = 0.003 by groups, P = 0.005 by correlation of single samples). Thirty-four per cent (53/155) of the PCO patients had homocysteine values >95th percentile of the controls (11.0 micromol/l, P < 0.0001). Statistically significant correlations were found between all insulin resistance indices and homocysteine levels. Multiple logistic regression defined insulin resistance as the major factor examined that influenced homocysteine levels. CONCLUSIONS: Insulin resistance and hyperinsulinaemia in patients with PCOS is associated with elevated plasma homocysteine, regardless of body weight. This finding may have important implications in the short term regarding reproductive performance, and in the long term regarding cardiovascular complications associated with insulin-resistant PCOS.     

Highly active anti-retroviral therapy (HAART) is associated with a lower level of CD4+ T cell apoptosis in HIV-infected patients

HAART may increase CD4+ T cell counts despite a persistently detectable HIV load. The impact of HAART on apoptosis, which may play a role in the disease process in HIV-infected patients, has not been extensively studied. We performed a study to compare the level of spontaneous T cell apoptosis and anti-retroviral treatments in a cohort of HIV-1-infected patients. Data were obtained from a computerized medical record. Quantification of apoptotic cells was by cytofluorometric technique. From November 1995 to December 1997 we studied T cell apoptosis in 112 HIV-infected patients. Forty patients were classified A, 36 B and 36 C. Thirty patients were naive and 82 received an anti-retroviral treatment, 49 including a protease inhibitor (PI). The median plasma viraemia determined in 63 patients was 3.6 (range 1.3-5.6) log10. The median apoptotic cell count was 22% (range 2-73%) and 12% (range 2-60%) for CD4+ and CD8+ T cells, respectively. We did not observe any correlation between the HIV viraemia and the level of apoptosis of T cell subsets. Patients with HAART showed a lower percentage of apoptotic CD4+ T cells only: 16% (range 2-61%) versus 25% (range 5-73%) for patients receiving two nucleoside analogues (P = 0.02). This effect was significant in stage A patients and remained observable during the whole course of HIV disease. In conclusion, HAART, without any relation to plasma viraemia, is able to reduce apoptosis of CD4+ T cells.     

Associations of single nucleotide polymorphisms in the adiponectin gene with adiponectin levels and cardio-metabolic risk factors in patients with cancer

Objectives: The aims of this study are to (1) study the influence of polymorphisms in adiponectin gene on adiponectin levels and potential associations with breast, prostate and colon cancer; (2) investigate the associations of adiponectin levels with other adipokines and breast, prostate and colon cancers. Subjects: We measured fasting adiponectin, leptin, insulin, Sex steroids in 132 (66 females, 66 males) cancer patients and 68 age and sex matched apparently healthy subjects. Body Mass Index (BMI) and waist circumference were used as indices of obesity. Insulin Resistance was assessed using Homeostasis Model Assessment (HOMA). Three single nucleotide polymorphisms (SNP rs182052 (G-10066-A), SNP rs1501299 (276G > T), SNP rs224176 (45T > G) in adiponectin gene were studied using Real Time Polymerase Chain Reaction. Results: GG genotype of SNP rs1501299 was significantly associated with higher levels of adiponectin (OR=1.2, 95%CI(1.03–1.3), p = 0.02); breast (OR=8.6, 95%CI(1.03–71), p = 0.04), colon cancers (OR= 12, 95%CI(1.2–115), p = 0.03). GT genotype was also associated significantly with colon cancer (OR=2.6, 95%CI (1.1–6), p = 0.03). However SNP rs224176 was associated with only breast cancer. Conclusion: Our results demonstrate that adiponectin gene SNP rs1501299 and SNP rs224176 may be the predisposing factors in some cancers but our results differ from what has been reported in other populations suggesting a complex relationship between genetic variations and phenotypic adiponectin levels.     

Increased lipodystrophy is associated with increased exposure to highly active antiretroviral therapy in HIV-infected children

OBJECTIVE: To assess body composition changes in HIV-infected children receiving highly active antiretroviral therapy (HAART). METHODS: Thirty-seven HIV-positive children were enrolled. Dual-energy X-ray absorptiometry (DXA) scans were performed in all HIV-infected children at baseline and after an additional 12 months of HAART and in 54 matched (for sex, age, body mass index [BMI], and pubertal stage) healthy controls. Abdominal MRI was performed in 14 of 37 HIV-positive children at baseline and in 28 of 37 HIV-positive children after additional 12 months of HAART. RESULTS: During the study period, mean HAART exposure increased from 39.3 to 50.9 months and the number of HIV-infected children with clinical lipodystrophy (LD) increased from 6 to 8, whereas mean BMI, CD4 percentage, and percentage of HIV-infected children with HIV RNA <50 copies/mL did not change. DXA scans showed an increase in lean mass, peripheral fat loss, and central fat accumulation in all HIV-infected children. As compared with controls, 70% and 84% of HIV-infected children showed DXA-detectable LD at baseline and at 12 months of follow-up, respectively. Mixed LD and central fat accumulation were the most common LD phenotype. At baseline and at 12 months of follow-up, intra-abdominal adipose tissue (IAT) was greater than in controls in 33% and 35% of HIV-infected children, and it was greater in those with LD than in those without. Peripheral fat loss and IAT content were associated with duration of HAART and were independent of immunologic stage of disease and immunologic response. CONCLUSIONS: Changes in body composition related to LD in HAART-treated children are frequent, precocious, and progressive. Duration of HAART negatively influences visceral adiposity and peripheral fat loss.     

脂联素、核因子-kB在胰岛素抵抗大鼠表达

目的 观察炎症相关因子脂联素、核因子-kB（NF—kB）在胰岛素抵抗大鼠的表达。方法 20只Wistar大鼠随机分为空白对照组与胰岛素抵抗组，分别给予基础饮食和高糖高脂饮食8周，应用高血浆胰岛素-正常血糖钳夹技术证明胰岛素抵抗的存在。用全自动生化分析仪测定各组血脂、脂联素等，并应用免疫组化技术测定NF-kB在血管内皮细胞的表达。结果 ①应用钳夹技术证明，胰岛素抵抗组存在胰岛素抵抗，而空白对照组未出现胰岛素抵抗；②胰岛素抵抗组甘油三酯、胆固醇、低密度脂蛋白、高密度脂蛋白较空白对照组明显升高（P〈0．05），而保护性因子脂联素浓度则明显降低（P〈0．05）；③免疫组化显示，胰岛素抵抗组大鼠血管内皮细胞NF-kB阳性细胞百分率明显多于空白对照组（P〈0．05）；④脂联素浓度与NF—kB的表达呈明显负相关（r=-0．854，P〈0．05）；结论 胰岛素抵抗时，脂联素浓度降低，NF—kB过表达，二者呈明显负相关。     

Low resistin level is associated with poor hospitalization-free survival in hemodialysis patients

Malnutrition and inflammation are related to high rates of morbidity and mortality in hemodialysis patients. Resistin is associated with nutrition and inflammation. We attempted to determine whether resistin levels may predict clinical outcomes in hemodialysis patients. We conducted a prospective evaluation of 100 outpatients on hemodialysis in a single dialysis center (male, 46%; mean age, 53.7 ± 16.4 yr). We stratified the patients into 4 groups according to quartiles of serum resistin levels. During the 18-month observational period, patients with the lowest quartile of serum resistin levels had poor hospitalization-free survival (log rank test, P = 0.016). After adjustment of all co-variables, patients with the lowest quartile of serum resistin levels had poor hospitalization-free survival, compared with reference resistin levels. Higher levels of interleukin-6 were an independent predictor of poor hospitalization-free survival. In contrast, serum resistin levels were not correlated with interleukin-6 levels. The current data showed that low resistin levels may independently predict poor hospitalization free survival in hemodialysis patients.     

Analysis of apoptosis and a Th1/Th2 phenotype in HIV-infected patients

Lymphocytes from HIV patients, unlike those from normal HIV-negative subjects, underwent apoptosis upon in vitro culture. We found that the percentage of lymphocytes undergoing apoptosis was significantly higher (P = 0.005) in patients with low CD4 cell counts (< 200 CD4 cells/μl) (60%) than in patients at earlier stage (> 500 CD4 cells/μl) (35%). Serum IgE levels increased in two of six patients at last stage and in two of five patients at earlier stage. Spontaneous production of both IL-2 and IL-10, by peripheral blood mononuclear cells (PBMC) after 48 h in culture, was greater in HIV-infected subjects and increased with disease progression. IFN-γ production was greater in HIV-infected subjects but there was no evident change with disease progression. IL-4 production was barely detectable or not detected in both HIV-infected and HIV-negative individuals. These results indicate that spontaneous apoptosis is associated with advanced disease. However, there was no evidence of in vivo switch from the Th1 to Th2 phenotype in HIV-infected patients.     

脂联素与非酒精性脂肪肝肝纤维化及胰岛素抵抗的关系

目的：研究脂联素水平与非酒精性脂肪肝（NAFLD）患者肝纤维化指标及胰岛素抵抗指数（IRI）的关系。方法：采用ELISA法检测NAFLD患者和正常对照组的脂联素水平及Ⅲ型前胶原（PCⅢ）、透明质酸（HA）、Ⅳ型胶原（CⅣ）、层黏蛋白（LN）水平,采用稳态模式胰岛素抵抗指数（HOMA IRI）评估胰岛素抵抗。结果：NAFLD组脂联素水平显著低于对照组,胰岛素抵抗指数与肝纤维化指标显著高于对照组（P〈0.05）,IRI与PCⅢ、PCⅣ、HA和LN呈显著正相关（P〈0.05）,脂联素水平与WHR、BMI、FBG、Tg、FINS、HOMA-IRI、PCⅢ、PCⅣ、HA和LN呈显著负相关（P〈0.01或〈0.05）。结论：NAFLD患者血清脂联素水平降低,脂联素的表达在NAFLD患者肝纤维化与胰岛素抵抗进程中可能起重要作用。     

Severity of the toxicity associated with combinations that include didanosine plus stavudine in HIV-infected experienced patients

BACKGROUND: The combination of didanosine (ddI) and stavudine (d4T) is no longer recommended as a first-line treatment because of toxicity, but it may be useful in experienced patients. METHODS: Retrospective chart review of experienced patients on ddI plus d4T was conducted at a single institution, recording the development of adverse events as well as their severity and action taken. The risk of developing severe toxicities was estimated by Kaplan-Meier analysis. RESULTS: A total of 616 patients were on ddI plus d4T for a median time of 12 months (interquartile range: 5.0-24.7 months). Among them, 213 (34.6%) had AIDS, 161 (27.4%) had CD4 counts <200 cells/mm, and 503 (81.2%) had >2 previous treatment failures. Adverse events related to ddI plus d4T were recorded in 136 patients (22.1%), which were mild to moderate in 118 (19.1%) patients and severe in 18 (2.9%) patients. The mean times to development of severe and nonsevere adverse events were 72 (95% confidence interval [CI]: 70 to 75) weeks and 52 (95% CI: 48 to 55) weeks, respectively. The probability of developing severe adverse events was related to the nadir CD4 count, with higher risk in patients with <200 cells/mm (log rank test, P = 0.045). CONCLUSIONS: Multiexperienced patients treated with combinations, including ddI plus d4T, frequently develop drug-related toxicity, but these events are rarely severe. Thus, these drugs can still be considered a valid option for salvage regimens.