No abstract available.
Meningitis, Aseptic*

BACKGROUND: Until recently, genome-wide association study (GWAS)-based findings have provided a substantial genetic contribution to type 2 diabetes mellitus (T2DM) or related glycemic traits. However, identification of allelic heterogeneity and population-specific genetic variants under consideration of potential confounding factors will be very valuable for clinical applicability. To identify novel susceptibility loci for T2DM and glycemic traits, we performed a two-stage genetic association study in a Korean population. METHODS: We performed a logistic analysis for T2DM, and the first discovery GWAS was analyzed for 1,042 cases and 2,943 controls recruited from a population-based cohort (KARE, n=8,842). The second stage, de novo replication analysis, was performed in 1,216 cases and 1,352 controls selected from an independent population-based cohort (Health 2, n=8,500). A multiple linear regression analysis for glycemic traits was further performed in a total of 14,232 nondiabetic individuals consisting of 7,696 GWAS and 6,536 replication study participants. A meta-analysis was performed on the combined results using effect size and standard errors estimated for stage 1 and 2, respectively. RESULTS: A combined meta-analysis for T2DM identified two new (rs11065756 and rs2074356) loci reaching genome-wide significance in CCDC63 and C12orf51 on the 12q24 region. In addition, these variants were significantly associated with fasting plasma glucose and homeostasis model assessment of beta-cell function. Interestingly, two independent single nucleotide polymorphisms were associated with sex-specific stratification in this study. CONCLUSION: Our study showed a strong association between T2DM and glycemic traits. We further observed that two novel loci with multiple diverse effects were highly specific to males. Taken together, these findings may provide additional insights into the clinical assessment or subclassification of disease risk in a Korean population.
Blood Glucose ; Cohort Studies ; Diabetes Mellitus, Type 2* ; Fasting ; Genetic Association Studies ; Genome-Wide Association Study* ; Homeostasis ; Humans ; Linear Models ; Male ; Polymorphism, Single Nucleotide ; Population Characteristics

Intraportal islet transplantation (IPIT) may potentially cure Type 1 diabetes mellitus; however, graft failure in the early post-transplantation period presents a major obstacle. In this study, we tested the ability of nicotinamide to prevent early islet destruction in a syngeneic mouse model. Mice (C57BL/6) with chemically-induced diabetes received intraportal transplants of syngeneic islet tissue in various doses. Islets were cultured for 24 h in medium with or without 10 mM nicotinamide supplementation. Following IPIT, islet function was confirmed by an intraperitoneal glucose tolerance test (IPGTT) and hepatectomy. The effects of nicotinamide were evaluated by blood glucose concentration, serum monocyte chemoattractant protein-1 (MCP-1) concentration, and immunohistology at 3 h and 24 h after IPIT. Among the various islet doses, an infusion of 300 syngeneic islets treated with nicotinamide exhibited the greatest differences in glucose tolerance between recipients of treated and untreated (i.e., control) islets. One day after 300 islet equivalent (IEQ) transplantation, islets treated with nicotinamide were better granulated than the untreated islets (P = 0.01), and the recipients displayed a slight decrease in serum MCP-1 concentration, as compared to controls. After 15 days, recipients of nicotinamide-pretreated islets showed higher levels of graft function (as measured by IPGTT) than controls. The pretreatment also prolonged graft survival (> 100 days) and function; these were confirmed by partial hepatectomy, which led to the recurrence of diabetes. Pretreatment of islet grafts with nicotinamide may prevent their deterioration on the early period following IPIT in a syngeneic mouse model.
Animals ; Blood Glucose/metabolism ; Chemokine CCL2/blood ; Diabetes Mellitus, Experimental/blood/*therapy ; Diabetes Mellitus, Type 1/blood/*therapy ; Glucose Tolerance Test ; Graft Rejection ; Graft Survival/drug effects ; Insulin-Secreting Cells/metabolism ; *Islets of Langerhans Transplantation ; Mice ; Niacinamide/adverse effects/*pharmacology ; Time Factors ; Transplantation, Homologous ; Vitamin B Complex/adverse effects/*pharmacology

Endocardial fibroelastosis (EFE) is characterized by deposition of collagen and elastin leading to ventricular hypertrophy and diffuse endocardial thickening. Here we report (for the first time in Korea) the case of a EFE presenting with heart failure. The patient was a 57-year-old woman who had complained of dyspnea on exertion {New York Heart Association (NYHA) functional class 3} and abdominal distension at the time of hospital admission. Echocardiography showed severe diastolic dysfunction with normal systolic function. On MRI, the contrast-enhanced delayed myocardial image demonstrated hyperenhancement in the endocardium. Owing to progressive heart failure, the patient was transplanted. Histological examination of the explanted heart showed irregularly thickened endocardium with fibrosis and elastosis in the both ventricles, compatible with the diagnosis of EFE.
Cardiomyopathy, Restrictive ; Collagen ; Dyspnea ; Echocardiography ; Elastin ; Endocardial Fibroelastosis ; Endocardium ; Female ; Fibrosis ; Heart ; Heart Failure ; Heart Transplantation ; Humans ; Hypertrophy ; Middle Aged ; Transplants

PURPOSE: Pigs are promising donor species for xenotransplantation. This study was performed to examine acute cyclosporine (CsA) nephrotoxicity in a pig model. METHODS: Adult pigs were treated daily for 1 week with vehicle (VH), or 7.5 mg/kg (CsA7.5), 15 mg/kg (CsA15), and 30 mg/kg (CsA30) CsA. The renal function, electrolyte levels, whole- blood CsA levels, and histopathological results (vacuolization and tubulointerstitial fibrosis) were compared among the different treatment groups. RESULTS: After 1 week of treatment, it was found that CsA induced characteristic lesions that were remarkably similar to those of chronic CsA nephropathy in humans. Compared with the results obtained for the VH group, CsA reduced renal function and yielded poor histopathological results. With an increase in the CsA concentration, the renal function and histological parameters worsened in a dose-dependent manner. CONCLUSION: The study showed that CsA dose-dependently induced renal injury in a pig model. These results provide basic data to estimate or prevent the adverse renal effects of immunosuppressants during porcine xenotransplantation in the future.
Adult ; Cyclosporine* ; Humans ; Immunosuppressive Agents ; Swine ; Tissue Donors ; Transplantation, Heterologous

Polyomavirus BK viral allograft nephritis is a great challenge in posttransplant management and graft survival because of difficulty in diagnosing and treatment. Initial treatment usually involves reducing immunosuppressive medications. However if concomitant acute rejection exist, it is more challenging in managing these patients, because acute rejection requires increase in immunosuppression. We present a case of a 35-year-old man who developed BK viral allograft nephritis and concomitant acute rejection 3 months after transplantation. BK viral allograft nephritis was missed in diagnosis and only pulse steroids for anti-rejection therapy was done. Initially, renal function was improved, but 4 months later, he presented with deterioration in renal function. Second renal biopsy showed BK allograft nephritis without rejection. BK viral DNA in plasma by PCR and urinary decoy cell were also positive. Reduction in immunosuppression by discontinuing mycophenolate mofetil stabilized the deterioration in renal function, however it failed to clear viremia.
Adult ; Allografts* ; Biopsy ; BK Virus* ; Diagnosis ; DNA, Viral ; Graft Survival ; Humans ; Immunosuppression ; Kidney Transplantation ; Nephritis ; Nephritis, Interstitial* ; Plasma ; Polymerase Chain Reaction ; Polyomavirus ; Steroids ; Viremia

PURPOSE: The combination of intravenous cyclophosphamide (CYC) and prednisolone is effective for the treatment of severe lupus nephritis but has serious adverse effects. Mycophenolate mofetil (MMF) Is a new immunosuppressive agent that selectively inhibits activated lymphocytes. This study reports on the clinical experiences at our clinic with MMF and intravenous CYC for the initial induction treatment in patients with lupus nephritis. METHODS: 50 patients with lupus nephritis received induction therapy consisting of MMF and prednisolone (n=22) or intravenous CYC and prednisolone (n=28), and followed up for six months. Complete remission was defined as a value for urinary protein: urinary creatinine ratio (U(p/Cr)) that was less than 0.3, with normal urinary sediment, a normal serum albumin concentration and values for serum creatinine that were no more than 15 percent above the base-line values. Partial remission was defined as a value for U(p/Cr) that was between 0.3 and 2.9, with a serum albumin concentration of at least 3.0 g/dL. RESULTS: 22 patients treated with MMF and 28 patients with intravenous CYC resulted in complete remission (31.8% vs 39.3%), partial remission (45.5% vs 39.3%) and treatment failure (22.7% vs 21.4 %). Fewer severe infections occurred among patients treated with MMF and prednisolone. CONCLUSION: As for the induction therapy of lupus nephritis, the combination of MMF and prednisolone may be an effective regimen. However, further randomized, prospective studies are needed to prove the effectiveness of MMF therapy in lupus nephritis.
Creatinine ; Cyclophosphamide* ; Humans ; Lupus Nephritis* ; Lymphocytes ; Prednisolone ; Serum Albumin ; Treatment Failure

Pancreatic islet transplantation can correct the abnormal glucose metabolism of Type 1 diabetes. Although immunosuppressants greatly reduce the acute rejection rate in transplant patients, the long-term side effects can be debilitating. Therefore, researchers are seeking to develop new immunosuppressive regimens that induce maximal levels of immunosuppression with minor side effects. Rosmarinic acid (Ros A) is a secondary metabolite of certain herbs and has multiple biological activities, including anti-inflammatory effects. Here, we have investigated whether treatment of mice with a combination of Ros A and anti-CD154 monoclonal antibody (MR1) improves islet allograft survival in a murine model. After transplantation, the mice were treated with either Ros A, MR1, or both (the "double" treatment). Allograft survival was prolonged in the double-treated animals compared to animals that received only Ros A or MR1. As is the case with the single-treated animals at 15 days after transplantation, the double-treated recipients did not display a significant decrease in the expression of cytokines or the population of activated T cells. Infiltrating CD3+ T cells were reduced in the MR1- or double therapy relative to control or RosA group. However, at the same time point, double-treated graft showed fewer apoptotic cells and increased expression of insulin and glucagons, compared to the single-treatment groups. Furthermore, long-term (>150 days) allografts that were received with double therapy exhibited larger islet clusters and contained more insulin- and glucagon-positive cells, relative to the MR1-treated grafts. In conclusion, treatment with both Ros A and MR1 has a synergistic effect in murine islet allotransplantation.
Animals ; Antibodies, Monoclonal/*pharmacology ; Apoptosis/drug effects ; CD40 Ligand/*immunology ; Cinnamates/*pharmacology ; Cytokines/biosynthesis ; Depsides/*pharmacology ; Diabetes Mellitus, Experimental ; Flow Cytometry ; Glucose/metabolism ; Glucose Tolerance Test ; Graft Survival/*drug effects ; In Situ Nick-End Labeling ; Injections, Intraperitoneal ; Islets of Langerhans/drug effects/pathology ; *Islets of Langerhans Transplantation ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Time Factors ; Transplantation, Homologous

PURPOSE: Local activation of the complement system plays a role in target organ damage. The aim of our study was to investigate the influence of cyclosporine (CsA)- induced renal injury on the complement system in the kidney. MATERIALS AND METHODS: Mice fed a low salt (0.01%) diet were treated with vehicle (VH, olive oil, 1mL/kg/day) or CsA (30mg/kg/day) for one or four weeks. Induction of chronic CsA nephrotoxicity was evaluated with renal function and histomorphology. Activation of the complement system was assessed through analysis of the expression of C3, C4d, and membrane attack complex (MAC), and the regulatory proteins, CD46 and CD55. CsA treatment induced renal dysfunction and typical morphology (tubulointerstitial inflammation and fibrosis) at four weeks. RESULTS: CsA-induced renal injury was associated with increased the expression of C3, C4d, and MAC (C9 and upregulation of complement regulatory proteins (CD 46 and CD55). Immunohistochemistry revealed that the activated complement components were mainly confined to the injured tubulointerstitium. CONCLUSION: CsA-induced renal injury is associated with activation of the intrarenal complement system.
Animals ; Antigens, CD45/analysis ; Antigens, CD46/analysis ; Antigens, CD55/analysis ; Complement C3/analysis ; Complement C4b/analysis ; Complement Membrane Attack Complex/analysis ; Complement System Proteins/*analysis ; Cyclosporine/*toxicity ; Disease Models, Animal ; Immunity, Innate/drug effects ; Immunoblotting ; Immunohistochemistry ; Immunosuppressive Agents/toxicity ; Kidney/*drug effects/immunology/pathology ; Kidney Diseases/*chemically induced/immunology ; Mice ; Microscopy, Confocal ; Peptide Fragments/analysis

The concentration of adenosine in the normal kidney increases markedly during renal hypoxia, ischemia, and inflammation. A recent study reported that an A3 adenosine receptor (A3AR) antagonist attenuated the progression of renal fibrosis. The adriamycin (ADX)-induced nephropathy model induces podocyte injury, which results in severe proteinuria and progressive glomerulosclerosis. In this study, we investigated the preventive effect of a highly selective A3AR antagonist (LJ1888) in ADX-induced nephropathy. Three groups of six-week-old Balb/c mice were treated with ADX (11 mg/kg) for four weeks and LJ1888 (10 mg/kg) for two weeks as following: 1) control; 2) ADX; and 3) ADX + LJ1888. ADX treatment decreased body weight without a change in water and food intake, but this was ameliorated by LJ1888 treatment. Interestingly, LJ1888 lowered plasma creatinine level, proteinuria, and albuminuria, which had increased during ADX treatment. Furthermore, LJ1888 inhibited urinary nephrin excretion as a podocyte injury marker, and urine 8-isoprostane and kidney lipid peroxide concentration, which are markers of oxidative stress, increased after injection of ADX. ADX also induced the activation of proinflammatory and profibrotic molecules such as TGF-β1, MCP-1, PAI-1, type IV collagen, NF-κB, NOX4, TLR4, TNFα, IL-1β, and IFN-γ, but they were remarkably suppressed after LJ1888 treatment. In conclusion, our results suggest that LJ1888 has a renoprotective effect in ADX-induced nephropathy, which might be associated with podocyte injury through oxidative stress. Therefore, LJ1888, a selective A3AR antagonist, could be considered as a potential therapeutic agent in renal glomerular diseases which include podocyte injury and proteinuria.
Adenosine* ; Albuminuria ; Animals ; Anoxia ; Body Weight ; Collagen Type IV ; Creatinine ; Doxorubicin ; Eating ; Fibrosis ; Inflammation ; Ischemia ; Kidney ; Mice* ; Oxidative Stress ; Plasma ; Plasminogen Activator Inhibitor 1 ; Podocytes ; Proteinuria ; Receptors, Purinergic P1* ; Water