Disease activity-dependent expression of nerve growth factor TRKA and P75 receptors on elevated dendritic cells and peripheral leucocytes in patients with systemic lupus erythematosus.

INTRODUCTION: The nervous system modulates rheumatic diseases in neurogenic inflammation (NI). Nerve growth factor (NGF) plays a pivotal role in NI and chronic nociceptive pain. However, the role of NGF in autoimmune inflammatory diseases is not well understood. The aim of this study was to analyse NGF high- (TrkA) and low-affinity (p75) receptors on all major leucocyte subsets of patients with systemic lupus erythematosus (SLE) as a potential indicator of NI. METHODS: A total of 13 patients were analysed by fluorescence-activated cell sorting and compared to 13 healthy control (HC) subjects. Patients were also stratified for high or low disease activity (CRP, ESR, SLEDAI, ANA, anti-dsDNA and C3/C4). Statistics included the Kruskal-Wallis test and Mann-Whitney U-test. RESULTS: When comparing patients and HC, TrkA was not differentially expressed. In contrast, p75 was increased on CD16+ and CD56+ leucocytes in patients. CD11c+ dendritic cells (DC) were in total increased in SLE. DCs were also significantly elevated in active patients. Furthermore, we found an intermediate CD11b+ population strongly expressing TrkA in patients and HC. CONCLUSION: We demonstrate for the first time differential NGF receptor expression in SLE. The increased CD11c+ DCs might indicate additional activation in SLE.

Different in the dark: The effect of habitat characteristics on community composition and beta diversity in bromeliad microfauna.

The mechanisms which structure communities have been the focus of a large body of research. Here, we address the question if habitat characteristics describing habitat quality may drive changes in community composition and beta diversity of bromeliad-inhabiting microfauna. In our system, changes in canopy cover along an environmental gradient may affect resource availability, disturbance in form of daily water temperature fluctuations and predation, and thus may lead to changes in community structure of bromeliad microfauna through differences in habitat quality along this gradient. Indeed, we observed distinct changes in microfauna community composition along the environmental gradient explained by changes in the extent of daily water temperature fluctuations. We found beta diversity to be higher under low habitat quality (low canopy cover) than under high habitat quality (high canopy cover), which could potentially be explained by a higher relative importance of stochastic processes under low habitat quality. We also partitioned beta diversity into turnover and nestedness components and we found a nested pattern of beta diversity along the environmental gradient, with communities from the lower-quality habitat being nested subsets of communities from the higher-quality habitat. However, this pattern resulted from an increase in microfauna alpha diversity with an increase in habitat quality. By providing insights into microfauna-environment relationships our results contribute to the mechanistic understanding of community dynamics in small freshwater bodies. Here, we highlight the importance of habitat characteristics representing habitat quality in structuring communities, and suggest that this information may help to improve conservation practices of small freshwater ecosystems.

Population Pharmacokinetics and Target Attainment of Meropenem in Plasma and Tissue of Morbidly Obese Patients after Laparoscopic Intraperitoneal Surgery.

Meropenem serves as a clinically important, broad-spectrum antibiotic. While meropenem is commonly used in obese patients, its pharmacokinetics in this patient group is not well known. Our aim was to characterize the population pharmacokinetics and target attainment in plasma, subcutaneous tissue, and peritoneal fluid for meropenem in morbidly obese patients. Four doses of 1g meropenem were given as 15-min infusions every 8 h to five morbidly obese patients (body mass index [BMI], 47.6 to 62.3 kg/m(2)). After the fourth dose, serial meropenem concentrations were determined in plasma and, via microdialysis, in subcutaneous tissue and peritoneal fluid. All concentrations were analyzed simultaneously via population modeling, and target attainment probabilities predicted via Monte Carlo simulations using the target of unbound meropenem concentrations above the MIC for at least 40% of the dosing interval. For patients with 53 kg fat-free mass, total clearance was 18.7 liters/h and volume of distribution at steady state was 27.6 liters. The concentrations in subcutaneous tissue and peritoneal fluid largely paralleled those in plasma (equilibration half-life, <30 min). The area under the curve (AUC) in subcutaneous tissue divided by the plasma AUC had a mean of 0.721. For peritoneal fluid, this AUC ratio had a mean of 0.943. Target attainment probabilities were >90% after 1 g meropenem every 8 h as a 15-min infusion for MICs of up to 2 mg/liter in plasma and peritoneal fluid and 0.5 mg/liter in subcutaneous tissue. Meropenem pharmacokinetics in plasma and peritoneal fluid of obese patients was predictable, but subcutaneous tissue penetration varied greatly. (This study has been registered at ClinicalTrials.gov under registration no. NCT01407965.).

Brain insulin lowers circulating BCAA levels by inducing hepatic BCAA catabolism.

Circulating branched-chain amino acid (BCAA) levels are elevated in obesity/diabetes and are a sensitive predictor for type 2 diabetes. Here we show in rats that insulin dose-dependently lowers plasma BCAA levels through induction of hepatic protein expression and activity of branched-chain α-keto acid dehydrogenase (BCKDH), the rate-limiting enzyme in the BCAA degradation pathway. Selective induction of hypothalamic insulin signaling in rats and genetic modulation of brain insulin receptors in mice demonstrate that brain insulin signaling is a major regulator of BCAA metabolism by inducing hepatic BCKDH. Short-term overfeeding impairs the ability of brain insulin to lower BCAAs in rats. High-fat feeding in nonhuman primates and obesity and/or diabetes in humans is associated with reduced BCKDH protein in liver. These findings support the concept that decreased hepatic BCKDH is a major cause of increased plasma BCAAs and that hypothalamic insulin resistance may account for impaired BCAA metabolism in obesity and diabetes.

Fibrates ameliorate the course of bacterial sepsis by promoting neutrophil recruitment via CXCR2.

Bacterial sepsis results in high mortality rates, and new therapeutics to control infection are urgently needed. Here, we investigate the therapeutic potential of fibrates in the treatment of bacterial sepsis and examine their effects on innate immunity. Fibrates significantly improved the survival from sepsis in mice infected with Salmonella typhimurium, which was paralleled by markedly increased neutrophil influx to the site of infection resulting in rapid clearance of invading bacteria. As a consequence of fibrate-mediated early control of infection, the systemic inflammatory response was repressed in fibrate-treated mice. Mechanistically, we found that fibrates preserve chemotaxis of murine neutrophils by blocking LPS-induced phosphorylation of ERK. This results in a decrease of G protein-coupled receptor kinase-2 expression, thereby inhibiting the LPS-mediated downregulation of CXCR2, a chemokine receptor critical for neutrophil recruitment. Accordingly, application of a synthetic CXCR2 inhibitor completely abrogated the protective effects of fibrates in septicemia in vivo. Our results unravel a novel function of fibrates in innate immunity and host response to infection and suggest fibrates as a promising adjunct therapy in bacterial sepsis.

Obesity-induced overexpression of miR-802 impairs glucose metabolism through silencing of Hnf1b.

Insulin resistance represents a hallmark during the development of type 2 diabetes mellitus and in the pathogenesis of obesity-associated disturbances of glucose and lipid metabolism. MicroRNA (miRNA)-dependent post-transcriptional gene silencing has been recognized recently to control gene expression in disease development and progression, including that of insulin-resistant type 2 diabetes. The deregulation of miRNAs miR-143 (ref. 4), miR-181 (ref. 5), and miR-103 and miR-107 (ref. 6) alters hepatic insulin sensitivity. Here we report that the expression of miR-802 is increased in the liver of two obese mouse models and obese human subjects. Inducible transgenic overexpression of miR-802 in mice causes impaired glucose tolerance and attenuates insulin sensitivity, whereas reduction of miR-802 expression improves glucose tolerance and insulin action. We identify Hnf1b (also known as Tcf2) as a target of miR-802-dependent silencing, and show that short hairpin RNA (shRNA)-mediated reduction of Hnf1b in liver causes glucose intolerance, impairs insulin signalling and promotes hepatic gluconeogenesis. In turn, hepatic overexpression of Hnf1b improves insulin sensitivity in Lepr(db/db) mice. Thus, this study defines a critical role for deregulated expression of miR-802 in the development of obesity-associated impairment of glucose metabolism through targeting of Hnf1b, and assigns Hnf1b an unexpected role in the control of hepatic insulin sensitivity.

De novo lipogenesis in human fat and liver is linked to ChREBP-ß and metabolic health.

Clinical interest in de novo lipogenesis has been sparked by recent studies in rodents demonstrating that de novo lipogenesis specifically in white adipose tissue produces the insulin-sensitizing fatty acid palmitoleate. By contrast, hepatic lipogenesis is thought to contribute to metabolic disease. How de novo lipogenesis in white adipose tissue versus liver is altered in human obesity and insulin resistance is poorly understood. Here we show that lipogenic enzymes and the glucose transporter-4 are markedly decreased in white adipose tissue of insulin-resistant obese individuals compared with non-obese controls. By contrast, lipogenic enzymes are substantially upregulated in the liver of obese subjects. Bariatric weight loss restored de novo lipogenesis and glucose transporter-4 gene expression in white adipose tissue. Notably, lipogenic gene expression in both white adipose tissue and liver was strongly linked to the expression of carbohydrate-responsive element-binding protein-ß and to metabolic risk markers. Thus, de novo lipogenesis predicts metabolic health in humans in a tissue-specific manner and is likely regulated by glucose-dependent carbohydrate-responsive element-binding protein activation.

Panniculus, giant hernias and surgical problems in patients with morbid obesity.

Prevalence of morbid obesity is rising. Along with it, the adipose associated co-morbidities increase - included panniculus morbidus, the end stage of obesity of the abdominal wall. In the course of time panniculus often develop a herniation of bowel. An incarcerated hernia and acute exacerbation of a chronic inflammation of the panniculus must be treated immediately and presents a surgical challenge. The resection of such massive abdominal panniculus presents several technical problems to the surgeon. Preparation of long standing or fixed hernias may require demanding adhesiolysis. The wound created is huge and difficult to manage, and accompanied by considerable complications at the outset. We provide a comprehensive overview of a possible approach for panniculectomy and hernia repair and overlook of the existing literature.

Potential role of regulatory T cells in reversing obesity-linked insulin resistance and diabetic nephropathy.

OBJECTIVE: To assess the potential role of FoxP3-expressing regulatory T cells (Tregs) in reversing obesity-linked insulin resistance and diabetic nephropathy in rodent models and humans. RESEARCH DESIGN AND METHODS: To characterize the role of Tregs in insulin resistance, human visceral adipose tissue was first evaluated for Treg infiltration and second, the db/db mouse model was evaluated. RESULTS: Obese patients with insulin resistance displayed significantly decreased natural Tregs but an increase in adaptive Tregs in their visceral adipose tissue as compared with lean control subjects. To further evaluate the pathogenic role of Tregs in insulin resistance, the db/db mouse model was used. Treg depletion using an anti-CD25 monoclonal antibody enhanced insulin resistance as shown by increased fasting blood glucose levels as well as an impaired insulin sensitivity. Moreover, Treg-depleted db/db mice developed increased signs of diabetic nephropathy, such as albuminuria and glomerular hyperfiltration. This was paralleled by a proinflammatory milieu in both murine visceral adipose tissue and the kidney. Conversely, adoptive transfer of CD4(+)FoxP3(+) Tregs significantly improved insulin sensitivity and diabetic nephropathy. Accordingly, there was increased mRNA expression of FoxP3 as well as less abundant proinflammatory CD8(+)CD69(+) T cells in visceral adipose tissue and kidneys of Treg-treated animals. CONCLUSIONS: Data suggest a potential therapeutic value of Tregs to improve insulin resistance and end organ damage in type 2 diabetes by limiting the proinflammatory milieu.

A murine model of phosphate nephropathy.

We established a murine model of phosphate nephropathy with secondary hyperparathyroidism. db/db mice, which develop obesity and type 2 diabetes mellitus, were uninephrectomized at the age of 6 weeks and were fed either standard chow or a phosphorus-rich diet during the next 8 weeks. Thereafter, renal cryosections showed abundant tubular casts with a strong histochemical von Kossa reaction in all db/db mice on the phosphorus-rich diet but none in the controls. X-ray diffraction and Raman spectroscopy proved that these tubular casts consist mostly of hydroxyapatite Ca5(PO4)3(OH). These intraluminal precipitations were located in distal tubuli and collecting ducts and were associated with degenerative tubular changes and peritubular infiltration of T cells and macrophages. In line, kidneys of db/db mice on the phosphorus-rich diet displayed significantly increased mRNA expression of the T(H)1 cytokines interferon γ, IL-6, and tumor necrosis factor α. In addition, mice developed signs of secondary hyperparathyroidism as shown by elevated serum phosphate, decreased serum calcium, and increased parathyroid hormone, osteopontin, and fibroblast growth factor 23 levels. db/db mice on the phosphorus-rich diet also presented with significantly lower body weight, lower homeostasis model assessment of insulin resistance index, and hypertrophic cardiomyopathy. Thus, we provide a murine model of phosphate nephropathy and secondary hyperparathyroidism, which can be used for future pharmacologic and pathophysiologic studies to analyze the effect of hyperphosphatemia on renal, metabolic, and cardiovascular phenotypes.

Association of adiponectin levels and insulin demand in critically ill patients.

PURPOSE: Intensive care unit patients usually have a deregulated glucose homeostasis and present with hyperglycemia and hyperinsulinemia, suggesting overall insulin resistance. Adiponectin has significant anti-inflammatory and insulin-sensitizing effects and is diminished in morbidly obese and in critically ill patients. Reduced adiponectin could contribute to insulin resistance in these patients. We examined how far insulin demand in critically ill patients is correlated with patient adiponectin levels. PATIENTS AND METHODS: Adiponectin, resistin, leptin, insulin demand, minimal and maximal blood sugar levels, epinephrine, and hydrocortisone demand were measured 1 day after diagnosis of severe sepsis or septic shock in 25 patients (8 female, 17 male; median age 65 years; range: 31 to 87 years). RESULTS: INSULIN DEMAND (RANGE: 0-8 IU/h; median 3.5 IU) was positively correlated with serum adiponectin levels (median: 10.1 µg/mL; range: 2.9-47.6 µg/mL; r = +0.56, P < 0.01). There was no significant correlation between insulin demand and leptin serum levels (median: 18.1 ng/mL; range: 0.3-80.7 ng/mL; r = +0.29, P = 0.08) or resistin serum levels (median: 103.9 ng/mL; range: 14.7-352.3 ng/mL; r = +0.13, P = 0.27). Epinephrine demand (median: 0.08 µg/kg*min; range: 0.02-0.63 µg/kg*min) was negatively correlated with male adiponectin levels (r = -0.58; P < 0.01; females: r = -0.36; P = 0.19) and positively correlated with resistin levels (r = 0.43; P = 0.02). Patient body mass index (median 26 kg/m(2); range: 18-37) was positively correlated with serum leptin (r = 0.60; P < 0.01) but was not correlated with insulin demand (r = 0.19; P = 0.19), or adiponectin (females: r = -0.37, P = 0.18; males: r = -0.16, P = 0.27), or resistin levels (r = +0.17; P = 0.21). CONCLUSION: Adiponectin levels and insulin demand were positively correlated during sepsis. Adiponectin levels were negatively correlated with epinephrine demand in male patients and epinephrine demand was positively correlated with resistin levels, which might have increased insulin resistance. The relationship between adiponectin and insulin action in humans is more complex than often suggested.

IL-9 production by regulatory T cells recruits mast cells that are essential for regulatory T cell-induced immune suppression.

Both mast cells (MCs) and regulatory T cells (Tregs) have gained attention as immunosuppressive cell populations. To investigate a possible interaction, we used the Th1- and Th17-dependent model of nephrotoxic serum nephritis (NTS), in which both MCs and Tregs have been shown to play a protective role. Transfer of wild-type (wt) Tregs into wt recipients almost completely prevents development of NTS and leads to a profound increase of MCs in the renal draining lymph nodes (LNs). By contrast, transfer of wt Tregs into animals deficient in MCs, which are characterized by an exaggerated susceptibility to NTS, no longer exhibited protective effects. Blocking the pleiotropic cytokine IL-9, known to be involved in MC recruitment and proliferation, by means of a mAb in mice receiving Tregs abrogated protection from NTS. Moreover, transfer of IL-9-deficient Tregs also failed to protect from NTS. In the absence of Treg-derived IL-9, MCs fail to accumulate in the LNs, despite the fact that IL-9 deficiency does not alter the general suppressive activity of Tregs. In summary, to our knowledge, we provide the first direct in vivo evidence that the nephroprotective, anti-inflammatory effects of Tregs critically depend on IL-9-mediated attraction of MCs into kidney-draining LNs.

Sepsis induced changes of adipokines and cytokines - septic patients compared to morbidly obese patients.

BACKGROUND: Hyperglycemia and insulin resistance frequently occur in critically ill and in morbidly obese (MO) patients. Both conditions are associated with altered serum levels of cytokines and adipokines. In addition, obesity related alterations in adipokine expression contribute to insulin resistance in metabolic syndrome. In this study we examined the serum adipocytokine profile in critically ill patients, MO patients, and healthy blood donors. METHODS: 33 patients who fulfilled the clinical criteria for severe sepsis or septic shock (SP) were prospectively enrolled in this study. A multiplex analysis was performed to evaluate plasma levels of adiponectin, resistin, leptin, active PAI-1, MCP-1, IL-1 alpha, IL-6, IL-8, IL-10, and TNF-alpha in 33 critically ill patients, 37 MO patients and 60 healthy blood donors (BD). RESULTS: In SP, adiponectin was significantly lowered and resistin, active PAI-1, MCP-1, IL-1 alpha, IL-6, IL-8, IL-10, and TNF-alpha were significantly elevated compared to BD. Leptin levels were unchanged. In MO, adiponectin and IL-8 were significantly lowered, leptin, active PAI-1, MCP-1, IL-1 alpha, IL-6, and IL-10 significantly elevated, whereas resistin was unaltered. In SP, adiponectin correlated negatively with BMI, SAPS II and SOFA scores, while resistin correlated positively with SAPS II and SOFA scores and leptin correlated positively with the BMI. Adiponectin was approximately equally diminished in SP and MO compared to BD. With the exception of active PAI-1, cytokine levels in SP were clearly higher compared to MO. CONCLUSION: A comparable adipocytokine profile was determined in critically ill and MO patients. As in MO, SP showed reduced adiponectin levels and elevated MCP-1, active PAI-1, IL-1 alpha, IL-6, and IL-10 levels. Leptin is only elevated in MO, while resistin, IL-8, and TNF-alpha is only elevated in SP. As in MO patients, increased levels of proinflammatory cytokines and altered levels of adipokines may contribute to the development of insulin resistance in critically ill patients.

Tim3 is upregulated and protective in nephrotoxic serum nephritis.

T cell immunoglobulin and mucin protein-3 (Tim3) is mainly expressed on the cell surface of T-helper lymphocytes (T(H)) that negatively regulates T(H)-type 1 (T(H)-1) responses. Because blockade of Tim3 aggravates disease activity in T(H)-1-dependent diseases, we investigated whether Tim3 is involved in the pathogenesis of the T(H)-1-dependent nephrotoxic nephritis (NTS). We first evaluated Tim3 expression in mice after induction of nephrotoxic serum nephritis (NTS) and then studied the effects of anti-Tim3 treatment toward the course of NTS for up to seven days. Whereas Tim3 expression was undetectable in control mice, we found significantly increased Tim3 expression in kidneys, but not in draining lymph nodes, at one, four, and eight weeks after induction of NTS. Tim3-expressing cells that infiltrated kidneys of mice subjected to NTS turned out to be CD4(+) T cells rather than CD8(+) cytotoxic T cells and dendritic cells. Administration of a blocking anti-Tim3 antibody aggravated nephritis as shown by significantly increased albuminuria, respective histological changes, and increased expression of the kidney injury molecule lipocalin-2. In parallel, an increase of infiltrating T cells, macrophages, and macrophage pro-inflammatory cytokine formation as well as increased proliferation and apoptosis in kidneys of anti-Tim3-treated mice was detected. Together, we provide the first evidence that Tim3 is up-regulated in kidneys in NTS and that Tim3 exerts protective roles in the course of disease.

CCR7 deficiency exacerbates injury in acute nephritis due to aberrant localization of regulatory T cells.

The homing of dendritic cells and T cells to secondary lymphoid organs requires chemokine receptor 7 (CCR7) expression on these cells. T cells mediate the pathogenesis of experimental accelerated nephrotoxic serum nephritis (NTS), including its suppression by regulatory T cells (Tregs), but the contribution of CCR7 to this disease is unknown. Here, we compared the development of NTS in CCR7-knockout (KO) and wild-type (WT) mice. Compared with WT mice, CCR7KO mice developed more severe disease with significantly more inflammatory cells infiltrating the kidney. These cells included FoxP3(+) Tregs, which were virtually absent from WT kidneys. The adoptive transfer of WT Tregs into CCR7KO mice at the time of immunization protected the recipients from disease; these cells homed to secondary lymphoid organs but not to kidneys. Conversely, adoptive transfer of CCR7KO Tregs into WT mice did not inhibit development of NTS. These data suggest that NTS can develop without CCR7 expression, but Treg-mediated disease suppression, which seems to occur in secondary lymphoid organs, requires CCR7.

Atorvastatin attenuates murine anti-glomerular basement membrane glomerulonephritis.

Statins mediate many of their protective effects by lowering lipids as well as by modulating inflammation. Here, we studied their potential immunomodulatory role in renal inflammation using an autoimmune mouse model of anti-glomerular basement membrane glomerulonephritis. Oral treatment with Atorvastatin dramatically reduced albuminuria and histological changes in the kidneys as compared to vehicle-treated control animals. There was a significant decrease in the Th1 and Th17 response in the regional lymph nodes draining the kidneys. This systemic effect was accompanied by decreased infiltration of the kidneys with inflammatory CD4(+) T and Th17 cells, macrophages, and neutrophils in statin-treated mice. Regulatory T cells were not altered in their number, FoxP3 expression, or suppressive capacity, but their interleukin-10 production was significantly increased by statin treatment. Hence, Atorvastatin systemically and locally decreased the Th1 and Th17 response, thereby protecting the mice against anti-glomerular basement membrane glomerulonephritis. Whether statins can be used to treat human autoimmune renal diseases will require more direct studies.

Intratumoral interferon regulatory factor (IRF)-1 but not IRF-2 is of relevance in predicting patient outcome in ovarian cancer.

IRF-1 and IRF-2 expression was determined by real-time PCR in 138 ovarian cancer samples and 30 healthy ovarian biopsies and was correlated with the expression of other relevant immunologic parameters and common clinicopathologic variables. Regulation of IRF-1 and IRF-2 was evaluated by cytokine treatment of various ovarian cancer cell lines, human peritoneal mesothelial cells and ovarian surface epithelium. IRF-1 but not IRF-2 was constitutively over-expressed in 5 of 7 ovarian cancer cell lines. Both IRFs were inducible with IFN-gamma and to a lesser extent with IL-1 or TNF-alpha, but not with IL-6. Epidermal growth factor (EGF) treatment down-regulated both IRFs. In ovarian cancer samples only IRF-1, but not IRF-2 mRNA, was up-regulated when compared with healthy ovarian tissue. IRF-1 but not IRF-2 expression was significantly associated with interferon (IFN)-gamma and forkhead box P3 (FoxP3). In univariate survival analysis, strong expression of IRF-1 and IRF-2 predicted improved disease-free survival (DFS) and overall survival (OS). In Cox regression analyses, IRF-1 retained independent prognostic significance for DFS and OS and IFN-gamma for OS. In contrast to other solid tumors, IRF-2 expression cannot be regarded as a classic oncoprotein associated with poor prognosis in ovarian cancer. Of the immunologic parameters investigated, intratumoral IRF-1 expression is the most powerful independent predictor of a favorable clinical outcome.

Differential effects of rapamycin in anti-GBM glomerulonephritis.

The immunosuppressive mammalian target of rapamycin inhibitor rapamycin is widely used in solid-organ transplantation, but the effect of rapamycin on kidney disease is controversial. This study evaluated the effect of rapamycin in the autologous phase of anti-glomerular basement membrane (anti-GBM) glomerulonephritis. Disease was induced by preimmunizing the animals with rabbit IgG 5 d before administration of rabbit anti-mouse GBM antiserum. When rapamycin was started on the day of immunization (group 1), mice were protected from glomerulonephritis, suggested by a dramatic decrease in albuminuria, influx of inflammatory cells, and Th1-cytokine expression in the kidneys. Activation of T cells and production of autologous mouse anti-rabbit IgG were also significantly reduced in rapamycin-treated animals. In contrast, when rapamycin was started 14 d after immunization (group 2), mice had a significant increase in albuminuria and renal infiltration of inflammatory cells compared with vehicle-treated animals, and there were no differences in T and B cell responses. A significant decrease in vascular endothelial growth factor-A and an increase in IL-6 were detected in kidneys of these rapamycin-treated mice. In conclusion, rapamycin has the potential to significantly reduce the B and T cell responses and thereby protect from glomerulonephritis when administered early in disease. Once disease is established, however, rapamycin seems to worsen glomerulonephritis by disturbing the endothelial cell/vascular endothelial growth factor system in the kidney.

Comparison of metabolic risk factors between severely and very severely obese patients.

OBJECTIVE: A prospective clinical intervention study was performed to estimate the metabolic risk factors in patients with very severe obesity (VSO) vs. severe obesity (SO). RESEARCH METHODS AND PROCEDURES: Two hundred twenty-eight VSO (BMI > or = 50 kg/m(2)) and 221 SO patients (BMI = 40 to 49.9 kg/m(2)) participated in the study (367 women and 82 men). Metabolic measurements included plasma lipids, glucose and insulin, hemoglobin A(1c), leptin, and sex hormones, as well as hepatic steatosis in a subgroup of patients. Subgroups of patients with non-insulin-dependent diabetes and hyperlipidemia (HLP) were examined. RESULTS: The most unexpected result of our study was that VSO men showed significantly better lipid profiles than SO men. Furthermore, 18% of VSO men had no metabolic aberrations, whereas all SO men did. The advantageous metabolic status of VSO men was associated with sex hormone changes that favor gynoid fat distribution. The beneficial metabolic situation with VSO seems to be sex specific for men. DISCUSSION: This study shows that the metabolic situation in VSO is not more severe than in the less obese cohort. These findings distinctly differ from the positive associations that have previously been reported between BMI, lipids, and other metabolic indices among individuals whose BMI is <40 kg/m(2).