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Query: UMLS:C0028754 (obesity)
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Focal and segmental glomerulosclerosis (FSGS) is a common, non-specific renal lesion. Although it is often secondary to other disorders, including HIV infection, obesity, hypertension and diabetes, FSGS also appears as an isolated, idiopathic condition. FSGS is characterized by increased urinary protein excretion and decreasing kidney function. Often, renal insufficiency in affected patients progresses to end-stage renal failure, a highly morbid state requiring either dialysis therapy or kidney transplantation. Here we present evidence implicating mutations in the gene encoding alpha-actinin-4 (ACTN4; ref. 2), an actin-filament crosslinking protein, as the cause of disease in three families with an autosomal dominant form of FSGS. In vitro, mutant alpha-actinin-4 binds filamentous actin (F-actin) more strongly than does wild-type alpha-actinin-4. Regulation of the actin cytoskeleton of glomerular podocytes may be altered in this group of patients. Our results have implications for understanding the role of the cytoskeleton in the pathophysiology of kidney disease and may lead to a better understanding of the genetic basis of susceptibility to kidney damage.
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PMID:Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal segmental glomerulosclerosis. 1070 Jan 77

Despite widespread nutrient deficiencies, a substantial proportion of the MIDAS cohort exhibits obesity, which has been linked to immune dysregulation in other clinical settings. Herein, the effects of obesity on immune function, disease progression, and mortality were evaluated longitudinally in 125 HIV-1-seropositive drug users, with comparison measures in 148 HIV-1-seronegative controls. Data were collected at a community clinic from 1992 to 1996, before administration of highly active antiretroviral therapy. Results indicated that overweight/obesity, defined as body mass index (BMI; kg/m2) > or =27, was evident in 18% of the HIV-1-seropositive patients and 29% of the seronegative patients. At baseline, no significant immunologic differences were observed among lean, nonobese, and obese groups. Over an 18-month period, 60.5% of the nonobese HIV-1-seropositive patients exhibited a 25% decline in CD4 cell count, compared with 18% of the obese patients (p<.004). During the follow-up period, 38% of the lean and 13% of the nonobese study subjects died of HIV-1-related causes. Measurements of BMI were inversely associated with progression to death, independent of CD4 count <200 cells/mm3 (p<.02). These data suggest that mild-to-moderate obesity in HIV-1-infected chronic drug users does not impair immune function and is associated with better HIV-1-related survival.
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PMID:When obesity is desirable: a longitudinal study of the Miami HIV-1-infected drug abusers (MIDAS) cohort. 1070 60

HIV infection induces an early decrease of cholesterol and a late increase of triglycerides (TG) with a reduction of HDL. These changes are proportional with the lowering of CD4, which reflects the infection's severity. Both the increase of TG synthesis and the decrease of TG catabolism, in relation with a reduction of lipoprotein lipase activity, are responsible of these changes. Moreover, LDL catabolism is enhanced by macrophage scavenger receptors, due to a high proportion of small, dense LDL which are more easily oxidized. Many cytokines (interferon alpha, interleukins, TNF) play probably a pathogenic role in the dyslipidemia. Some HIV patients who received antiproteases may develop lipodystrophy with central obesity, insulino-resistance, glucose intolerance and sometimes diabetes (like in syndrome X). Other patients present a cushingoid, buffalo hump. This complication may be observed also with antiretroviral treatment other than antiproteases. The physiopathology of these findings could be in relation with structural homologies between antiproteases and some important proteins, involved in lipid and adipocyte metabolism. Cardiovascular risk linked to these perturbations is evident. The treatment is not different from the treatment for seronegative, hyperlipidemic patients: struggle against risk factors, diet advices, fibrates or statins. The antiproteases bring huge contribution to the prognosis of AIDS patients but the risk of cardiovascular complications could impair this therapeutic progress. So, it is essential to understand the pathogeny of these complications in order to discover new antiproteases, without these adverse side effects.
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PMID:[Lipids and AIDS]. 1074 83

Many of the diseases that cause premature illness and death--including some cancers, heart disease, and AIDS--could be prevented if persons made behavior changes to reduce their risk for developing the illnesses. Over the past two decades, there have been great advances in our scientific understanding of how to promote health risk behavior change. This paper briefly reviews elements and examples of effective behavior change interventions, including programs that can be offered in service settings as well as community-level interventions. The prevention of diseases through behavioral public health interventions requires the investment of funds but can reduce burdens on health care systems, reduce the human toll caused by premature deaths, and be highly cost-effective. A remarkable number of diseases could be prevented if individuals were effectively assisted in changing the risk behaviors responsible for those illnesses. The causal association between cigarette smoking and lung cancer, other pulmonary diseases, and cardiovascular disease is well-known, and millions of premature deaths could be prevented if people stopped smoking cigarettes. Deaths due to cardiovascular disease could be dramatically reduced if persons made behavioral and lifestyle changes to improve their fitness through exercise, obesity reduction, and maintenance of low blood cholesterol levels. The World Health Organization estimates that over 45 million persons worldwide have already contracted HIV infection, and nearly 1 million of these cases are in the United States. Over 40,000 Americans continue to contract HIV infection each year. Virtually every new case of HIV infection is preventable if individuals at risk made changes in their sexual or drug use practices. While lung cancer, cardiovascular disease, and AIDS are three of the clearest examples, persons' behavior plays a direct or a contributing role in the development of many other diseases that cause premature death or that worsen health and life quality. Recognition of the link between behavior and preventable illness--and recognition that enormous health, economic, and quality of life benefits could be realized through healthier behavior patterns--is not new. We have known all of this for a long time. We have also known for a very long time that helping people to successfully change risky behavior habits is often very difficult. Over the past 20 years, a field of scientific study and applied practice has developed with the purpose of better understanding why persons engage in health risk behavior patterns and developing approaches to help people change these patterns. Under the rubric of "behavioral medicine", this field makes use of behavioral science theory and behavior change techniques applied to health and disease prevention.
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PMID:Behavior changes & disease prevention: MCW research shows effectiveness of HIV/AIDS risk reduction interventions. Medical College of Wisconsin. 1075 83

The nutritional condition of children with human immunodeficiency virus (HIV) infection continues to be a problem both in developed and developing countries. HIV-infected children grow below normal standards in both height and weight when compared with HIV-exposed non-infected children. These patterns persist over time. It is possible that acute infectious episodes and increased HIV viral burden contribute to decrements in all growth variables. Potential aetiologies for abnormal growth include inadequate dietary intake, gastrointestinal malabsorption, increased energy utilization and psycho-social problems. It is likely that all these factors contribute to the growth problems of these children to some extent. With the development of protease inhibitor anti-retroviral therapy and highly-active anti-retroviral treatment regimens, children with HIV infection in developed countries are living longer with a chronic illness. New nutritional problems have arisen with the development of the fat redistribution syndrome or lipodystrophy. Emerging problems are now being recognized, with the development of insulin resistance and truncal obesity which may potentially lead to premature cardiovascular disease.
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PMID:Nutrition in paediatric human immunodeficiency virus infection. 1082 85

Objective: To compare single-dose antibiotic prophylaxis (cefotetan 1 g vs cefoxitin 2 g) in various subpopulations based upon risk factors for postsurgical infection following cesarean section.Methods: Patients undergoing cesarean section from April 1993 through March 1994 were included in a retrospective analysis if either of the above antibiotics were administered, surgery was non-emergent, gestational age was less than 32 weeks, absence of fever or prior antibiotics therapy within 72 hours, and no history of organ transplantation or HIV. Cases classified as high risk for infection: IDDM, obesity, autoimmune disease, sickle cell disease, or corticosteroid use. Cases classified as high risk for endometritis (any 2 factors): labor >12 hours, >4 vaginal examinations, ruptured membranes >9 hours, and internal fetal monitor. Cases were separated into 4 groups: elective vs non-elective, low vs high surgical risk. A chi(2) analysis was used to test for differences in infection rates between groups (P <.05).Results: Of 1383 cesarean sections, 385 met criteria for inclusion. Non-elective cases accounted for 77% of cases. Postsurgical infection rate was greater in non-elective cases, 7.4%, vs elective cases, 3.0% (P =.056) as was the rate of endometritis (3.2% vs 1.2%, P =.185). No differences were noted based on antibiotic regimen. Postsurgical infection rate was greater for 28 cases at high risk for both surgical infection and endometritis (17.9%) when compared to all 357 other cases (4.5%), P =.003. No difference was noted for endometritis. Of the 28 cases 28.6% of patients treated with cefoxitin and 7.1% of cases treated with cefotetan developed postsurgical infection (P =.13).Conclusion: Overall cefoxitin and cefotetan provided equivalent clinical outcome. A small subset of patients with multiple risk factors for infection may benefit from cefotetan.
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PMID:Single-dose antibiotic prophylaxis during cesarean section. 1083 70

Malnutrition is common in HIV infection. Early studies demonstrated a disproportionate depletion of body cell mass compared to body weight, plus relative expansion of extracellular water volume. Neutron activation studies showed that both potassium and nitrogen were depleted in the HIV+ subjects, whereas cross-sectional imaging documented depletion of skeletal muscle mass. The etiology of malnutrition affects the composition of lost weight. Malnutrition is associated with adverse outcomes, whereas clinical stability is associated with nutritional stability. Increasingly, body composition studies are being incorporated into clinical trials. Hypercaloric feeding promotes gains in weight and body fat, but not in lean mass. Adjunctive therapies include anabolic agents, both steroids and recombinant human growth hormone (rhGH), cytokine inhibitors, and resistance training exercise. In addition to increasing fat-free mass, these therapies also have benefits in quality of life, notably functional performance, as well as physical function. Current research on alterations in body composition in HIV have noted a redistribution of fat, with visceral obesity in patients receiving highly active antiretroviral therapies.
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PMID:Body composition studies in HIV-infected individuals. 1086 3

The introduction of HAART has changed the nutritional status of HIV patients. In the pre-protease inhibitor (PI) era, more than 60% of HIV-positive persons presented with protein energy malnutrition (PEM) and vitamin and mineral deficit. This caused progressive physical-metabolic wasting (wasting syndrome/cachexia) and increased susceptibility to opportunistic infections and drug toxicity. PEM was a concurrent cause in 80% of deaths attributed to AIDS. Since 1996, the year in which PIs were introduced, the number of patients dying as a result of AIDS has decreased by two thirds, and cachexia is no longer the AIDS terminal phase in developed countries. But different patterns of nutritional status changes have appeared in association with the use of newer anti-HIV therapies and with longer survival of HIV-infected patients. A new clinical and laboratory syndrome--lipodystrophy syndrome--now affects patients receiving PI-based therapy. This syndrome consists of changes in body shape that are caused by an abnormal redistribution of fat. Fat accumulates in the abdominal area (truncal and visceral obesity), in the axillary pads (bilateral symmetric lipomatosis), and in the dorsocervical pads ("buffalo hump," "bull neck") but decreases in the legs, arms, and nasolabial and cheek pads (peripheral lipodystrophy). Hyperlipidemia and insulin resistance are also frequently present (metabolic syndrome X). Pathogenic mechanisms of lipid and fat tissue disturbances are discussed in this article, and the clinical approach to patient management and therapeutic options for lipodystrophy and lipid dysmetabolism is evaluated.
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PMID:Reversal of cachexia in patients treated with potent antiretroviral therapy. 1088 68

HIV-lipodystrophy (HIV-LD) is characterized by the loss of body fat from the limbs and face, an increase in truncal fat, insulin resistance, and hyperlipidemia, factors placing affected patients at increased risk for vascular disease. This study evaluated insulin sensitivity and inflammatory status associated with HIV-LD and provides suggestions about its etiology. Insulin sensitivity and immune activation markers were assessed in 12 control subjects and 2 HIV-positive groups, 14 without and 15 with LD syndrome. Peripheral insulin sensitivity (mostly skeletal muscle) was determined with the hyperinsulinemic-euglycemic clamp. Circulating insulin-like growth factor (IGF) binding protein-1 (IGFBP-1) and free fatty acid (FFA) levels, and their response to insulin infusion were indicative of insulin responsiveness of liver and adipose tissue, respectively. Serum levels of soluble type 2 tumor necrosis factor-alpha (TNF-alpha) receptor (sTNFR2) were used as an indicator of immune activation. HIV-LD study subjects had significantly reduced (twofold) peripheral insulin sensitivity, but normal levels of FFA and reduced levels of IGFBP-1, relative to the nonlipodystrophy groups, indicating that the loss of insulin sensitivity was more pronounced in skeletal muscle than in liver or fat. The significant loss of peripheral fat in the HIV-LD group (34%; p <.05) closely correlated with the reduced peripheral insulin sensitivity (p =. 0001). Levels of sTNFR2 were elevated in all HIV-infected study subjects, but they were significantly higher in those with lipodystrophy than without, and sTNFR2 levels strongly correlated with the reduction in insulin sensitivity (p =.0001). Loss of peripheral fat, normal levels of FFA, and reduced levels of IGFBP-1 indicate that insulin resistance in HIV-LD is distinct from type 2 diabetes and obesity. The relationship between the degree of insulin resistance and sTNFR2 levels suggests an inflammatory stimulus is contributing to the development of HIV-associated lipodystrophy.
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PMID:Association of severe insulin resistance with both loss of limb fat and elevated serum tumor necrosis factor receptor levels in HIV lipodystrophy. 1151 29

Patients with glucocorticoid excess develop central obesity, yet in simple obesity, circulating glucocorticoid levels are normal. We have suggested that the increased activity and expression of the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) generating active cortisol from cortisone within adipose tissue may be crucial in the pathogenesis of obesity. In this study primary cultures of human hepatocytes and adipose stromal cells (ASC) were used as in vitro models to investigate the tissue-specific regulation of 11betaHSD1 expression and activity. Treatment with tumor necrosis factor-alpha (TNFalpha) caused a dose-dependent increase in 11betaHSD1 activity in primary cultures of both sc [1743.1 +/- 1015.4% (TNFalpha, 10 ng/ml); P < 0.05 vs. control (100%)] and omental [375.8 +/- 57.0% (TNFalpha, 10 ng/ml); P < 0.01 vs. control (100%)] ASC, but had no effect on activity in human hepatocytes [90.2 +/- 2.8% (TNFalpha, 10 ng/ml); P = NS vs. control (100%)]. Insulin-like growth factor I (IGF-I) caused a dose-dependent inhibition of 11betaHSD1 activity in sc [49.7 +/- 15.0% (IGF-I, 100 ng/ml]; P < 0.05 vs. control (100%)] and omental [71.6 +/- 7.5 (IGF-I, 100 ng/ml); P < 0.01 vs. control (100%)] stromal cells, but not in human hepatocytes [101.8 +/- 15.7% (IGF-I, 100 ng/ml); P = NS vs. control (100%)]. Leptin treatment did not alter 11betaHSD1 activity in human hepatocytes, but increased activity in omental ASC [135.8 +/- 14.1% (leptin, 100 ng/ml); P = 0.08 vs. control (100%)]. Treatment with interleukin-1beta induced 11betaHSD1 activity and expression in sc and omental ASC in a time- and dose-dependent manner. 15-Deoxy-12,14-PGJ2, the putative endogenous ligand of the orphan nuclear receptor peroxisome proliferator-gamma, significantly increased 11betaHSD1 activity in omental cells [179.7 +/- 29.6% (1 microM); P < 0.05 vs. control (100%)] and sc [185.3 +/- 12.6% (1 microM); P < 0.01 vs. control (100%)] ASC, and it is possible that expression of this ligand may ensure continued cortisol generation to permit adipocyte differentiation. Protease inhibitors used in the treatment of human immunodeficiency virus infection are known to cause a lipodystrophic syndrome and central obesity, but saquinavir, indinavir, and neflinavir caused a dose-dependent inhibition of 11betaHSD1 activity in primary cultures of human omental ASC. 11betaHSD1 expression is increased in human adipose tissue by TNFalpha, interleukin-1beta, leptin, and orphan nuclear receptor peroxisome proliferator-gamma agonists, but is inhibited by IGF-I. This autocrine and/or paracrine regulation is tissue specific and explains recent clinical data and animal studies evaluating cortisol metabolism in obesity. Tissue-specific 11betaHSD1 regulation offers the potential for selective enzyme inhibition within adipose tissue as a novel therapy for visceral obesity.
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PMID:Regulation of expression of 11beta-hydroxysteroid dehydrogenase type 1 in adipose tissue: tissue-specific induction by cytokines. 1131 64


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