Decreased plasma adiponectin concentrations in women with low-grade C-reactive protein elevation

OBJECTIVE: Inflammation has been suggested as a risk factor for the development of atherosclerosis, while some components of metabolic syndrome X have been related to inflammatory markers. We hypothesized that adipocyte secreting protein, adiponectin and leptin, for which have been demonstrated an association with metabolic syndrome X and coronary artery disease, may be associated with inflammatory markers in nondiabetic humans. DESIGN AND METHODS: We measured high-sensitivity C-reactive protein (hs-CRP), as an inflammatory marker, and adiponectin and leptin concentrations in 384 nondiabetic Japanese women (mean+/-s.e.m. age 53.6+/-0.8 Years, body mass index (BMI) 23.0+/-0.2 kg/m(2)) undergoing measurement of markers of metabolic syndrome X. RESULTS: The women who had a low-grade hs-CRP elevation (>2.0 mg/l) were significantly older and had higher BMI, body fat mass (BFM), total cholesterol (TC), triglyceride (TG), atherogenic index (AI=(TC-HDLC)/HDLC), where HDLC is high-density lipoproten-cholesterol), fasting blood glucose and leptin concentrations before and after adjustment for BMI or BFM, while lower HDLC and adiponectin concentrations before and after adjustment compared with women with normal CRP levels (<0.5 mg/l). BMI, BFM, TG, AI and leptin before and after adjustment were found to be correlated with hs-CRP levels, while HDLC and adiponectin before and after adjustment were inversely correlated (all P<0.0001). hs-CRP was independently associated with white blood cell count, blood urea nitrogen and AI and inversely with adiponectin/BFM in the stepwise regression analysis model. CONCLUSIONS: These data demonstrate a significant decrease in plasma adiponectin in low-grade chronic inflammation, and suggest that there is an important linkage between inflammation/adipose tIssue/atherosclerosis.     

Molecular mimicry of mitochondrial and nuclear autoantigens in primary biliary cirrhosis

BACKGROUND & AIMS: The mechanism for development of primary biliary cirrhosis (PBC) remains enigmatic, but molecular mimicry has been implicated because of well-known cross-reactivity of human mitochondrial autoantigens and equivalent bacterial antigens. Virtually all patients with PBC have antimitochondrial autoantibodies (AMA), but, interestingly, approximately 50% also manifest antinuclear antibodies (ANA). METHODS: To determine whether generation of ANA are due to molecular mimicry of mitochondrial peptides, we established 6 T-cell clones selected by a peptide corresponding to the E2 subunit of mitochondrial pyruvate dehydrogenase complex and analyzed for reactivity to mimicry peptides derived from mitochondrial and nuclear autoantigens, including control sequences. RESULTS: For mitochondrial autoantigens, 1 peptide from the E2 subunit of the pyruvate dehydrogenase complex, 1 peptide from the E2 subunit of the oxo-glutarate dehydrogenase complex, 1 peptide from the E2 subunit of the branched-chain 2-oxoacid dehydrogenase complex, and 1 peptide from the E3-binding protein cross-reacted with these T-cell clones. For the nuclear autoantigens, 5 peptides from gp210 and 1 from Sp100 cross-reacted with these clones. Furthermore, 1 of 3 T-cell clones selected by recombinant gp210 protein reacted with a mimicry peptide corresponding to amino acids 188-201 of gp210, indicating that this part of the protein is a naturally processed immunodominant T-cell epitope. CONCLUSIONS: These results demonstrate molecular mimicry between mitochondrial and nuclear autoantigens in PBC and that a mimicry peptide may become an immunodominant T-cell epitope. These data have significance not only for PBC but also for the production of ANA in other disease processes.     

A case of Mycobacterium intracellulare pulmonary infection with vertebral osteomyelitis

A 78-year-old woman seen in June 2005 for chest abnormal shadows after 3 months of steroid therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies was found in chest computed tomography (CT) revealed bronchiectasis and small nodules in the right middle lobe and left lingula. Sputum cultures were positive for Mycobacterium intracellulare. Based on a diagnosis of pulmonary nontuberculous mycobacteriosis, the woman underwent antimycobacterial therapy with clarithromycin, rifampicin, and ethambutol hydrochloride for 10 months. She was then admitted in June 2009 with right chest pain. Chest CT showed consolidation shadows with bronchiectasis in the right middle lobe and the left lingula and left pleural effusion. Magnetic resonance imaging (MRI) showed that Th7-Th8 vertebral bodies had collapsed. A vertebral body specimen obtained by CT-guided biopsy was positive for M. intracellulare. Based on a diagnosis of vertebral osteomyelitis due to M. intracellulare, she underwent antimycobacterial therapy with clarithromycin (800 mg), rifampicin (450 mg), ethambutol hydrochloride (750 mg), and streptomycin (750 mg). After 4 weeks of antimycobacterial therapy, she underwent radical debridement and decompression surgery with anterior and posterior spinal fusion. Four weeks postoperatively, streptomycin was discontinued. We continued clarithromycin, rifampicin, and ethambutol hydrochloride for 18 months, and no recurrence was detected. Although vertebral osteomyelitis due to nontuberculous mycobacteria is rare, clinicians should consider the combination of nontuberculous mycobacteriosis and vertebral osteomyelitis in cases such at these.     

Detection of Borna Disease Virus-Reactive Antibodies from Patients with Psychiatric Disorders and from Horses by Electrochemiluminescence Immunoassay

The prevalence of Borna disease virus (BDV)-specific antibodies among patients with psychiatric disorders and healthy individuals has varied in several reports using several different serological assay methods. A reliable and specific method for anti-BDV antibodies needs to be developed to clarify the pathological significance of BDV infections in humans. We developed a new electrochemiluminescence immunoassay (ECLIA) for the antibody to BDV that uses two recombinant proteins of BDV, p40 and p24 (full length). Using this ECLIA, we examined 3,476 serum samples from humans with various diseases and 917 sera from blood donors in Japan for the presence of anti-BDV antibodies. By ECLIA, 26 (3.08%) of 845 schizophrenia patients and 9 (3.59%) of 251 patients with mood disorders were seropositive for BDV. Among 323 patients with other psychiatric diseases, 114 with neurological diseases, 75 with chronic fatigue syndrome, 85 human immunodeficiency virus-infected patients, 50 with autoimmune diseases including rheumatoid arthritis and systemic lupus erythematosis and 17 with leprosy, there was no positive case except one case each with alcohol addiction, AIDS, and dementia. Although 19 (1.36%) of 1,393 patients with various ocular diseases, 10 (1.09%) of 917 blood donors, and 3 (4.55%) of 66 multitransfused patients were seropositive for BDV-specific antigen, high levels of seroprevalence in schizophrenia patients and young patients (16 to 59 years old) with mood disorders were statistically significant. The immunoreactivity of seropositive sera could be verified for specificity by blocking with soluble p40 and/or p24 recombinant protein. Anti-p24 antibody was more frequent than p40 antibody in most cases, and in some psychotic patients antibody profiles showed only p40 antibody. Although serum positive for both p40 and p24 antibodies was not found in this study, the p40 ECLIA count in schizophrenia patients was higher than that of blood donors. Furthermore, we examined 90 sera from Japanese feral horses. Antibody profiles of control human samples are similar to that of naturally BDV-infected feral horses. We concluded that BDV infection was associated in some way with psychiatric disorders.     

Knockdown of macrophage migration inhibitory factor disrupts adipogenesis in 3T3-L1 cells

Obesity is a condition in which adipose tissue mass is expanded. Increases in both adipocyte size and number contribute to enlargement of adipose tissue. The increase in cell number is thought to be caused by proliferation and differentiation of preadipocytes. Macrophage migration inhibitory factor (MIF) is expressed in adipocytes, and intracellular MIF content is increased during adipogenesis. Therefore, we hypothesized that MIF is associated with adipocyte biology during adipogenesis and focused on the influence of MIF on adipogenesis. To examine the effects of MIF on adipocytes, MIF expression in 3T3-L1 preadipocytes was inhibited by RNA interference, and cell differentiation was induced by standard procedures. The triglyceride content of MIF small interfering RNA (siRNA)-transfected 3T3-L1 cells was smaller than that of nonspecific siRNA-transfected cells. In addition, MIF knockdown apparently abrogated increases in adiponectin mRNA levels during differentiation. Gene expression of peroxisome proliferator-activated receptor (PPAR)gamma, CCAAT/enhancer binding protein (C/EBP)alpha, and C/EBPdelta decreased with MIF siRNA transfection, but C/EBPbeta expression increased. Cell number and incorporation of 5-bromo-2-deoxyuridine into cells decreased from 1-3 d and from 14-20 h, respectively, after induction of differentiation in MIF siRNA-transfected cells, thus suggesting that MIF siRNA inhibits mitotic clonal expansion. Taken together, these results indicated that MIF regulates differentiation of 3T3-L1 preadipocytes, at least partially, through inhibition of mitotic clonal expansion and/or C/EBPdelta expression.     

Influence of mild-to-moderate alcohol consumption on cardiovascular diseases in men from the general population

Background and methodsThere is controversy about the association between mild-to-moderate alcohol consumption and a reduced risk of cardiovascular diseases. The relationships between daily alcohol consumption and the incidence of acute myocardial infarction (MI) or ischemic stroke (IS) were examined in men in a community-based, prospective cohort study (n = 8014, age 40–80 years, mean age = 64.1 years). Alcohol consumption was categorized into 3 groups (A1, none or occasional; A2, ≤25 g/day; A3, >25 g/day as ethanol) at baseline.ResultsDuring the mean follow-up of 5.5 years, 53 MIs and 186 ISs occurred. On Cox regression analysis adjusted for age, hypertension, diabetes, dyslipidemia, smoking index, and body mass index (BMI), the hazard ratio (HR) for incident MI was significantly lower in the A2 group than in the A1 group (HR = 0.49, p = 0.043). The HR for incident MI in the A3 group tended to be lower than in the A1 group (HR = 0.53, p = 0.10). In obese subjects, while a significantly lower HR for incident MI in the A2 group was retained (HR = 0.29, p = 0.049), no significant difference in the HR of the A3 group compared with the A1 group was found. No significant differences were found in the IS-free curve among the 3 groups of alcohol consumption.ConclusionsAlcohol consumption may have a protective effect on the onset of MI but not on IS in the general population. A U-shaped relation between alcohol consumption and incident MI was found in obese subjects. An appropriate limit for daily alcohol consumption, depending on the risk of ischemic heart disease, may need to be established.     

Efficacy and safety of micafungin as an empirical therapy for invasive fungal infections in patients with hematologic disorders: a multicenter, prospective study

This study was conducted as a prospective, multicenter trial to evaluate the efficacy and safety of micafungin as an empirical therapy for suspected invasive fungal infections (IFIs), including febrile neutropenia (FN), and to evaluate the usefulness of β-D: -glucan (BG) and Aspergillus galactomannan (GM) antigen in patients with hematologic diseases. A total of 121 patients were enrolled and assessed for safety, and 119 were examined for clinical efficacy. The main underlying diseases were acute myeloid leukemia (38.0%), acute lymphoblastic leukemia (18.2%), and malignant lymphoma (18.2%). The median initial daily dose and duration of micafungin treatment were 150?mg/day and 13?days, respectively. The overall response rate for suspected IFIs (n?=?119), based on four composite endpoints, including baseline IFI, breakthrough IFIs (proven and probable), survival, and premature discontinuation, was 79.0%. In addition, the response rate for FN (n?=?81), based on these four endpoints as well as defervescence during neutropenia, was 39.5%. Breakthrough IFIs (proven, probable, and possible) occurred in five patients during micafungin treatment. All of these patients were positive for either BG or GM before the breakthrough IFIs. The incidence of adverse events (AEs) associated with micafungin was 10.7% and most were mild. The majority of AEs were liver dysfunction. These results indicate the effectiveness and safety of micafungin as an empirical therapy for suspected IFIs, including FN, and the usefulness of monitoring both BG and GM to detect breakthrough IFIs.