Increased interleukin-17 production via a phosphoinositide 3-kinase/Akt and nuclear factor κB-dependent pathway in patients with rheumatoid arthritis

Inflammatory mediators have been recognized as being important in the pathogenesis of rheumatoid arthritis (RA). Interleukin (IL)-17 is an important regulator of immune and inflammatory responses, including the induction of proinflammatory cytokines and osteoclastic bone resorption. Evidence for the expression and proinflammatory activity of IL-17 has been demonstrated in RA synovium and in animal models of RA. Although some cytokines (IL-15 and IL-23) have been reported to regulate IL-17 production, the intracellular signaling pathways that regulate IL-17 production remain unknown. In the present study, we investigated the role of the phosphoinositide 3-kinase (PI3K)/Akt pathway in the regulation of IL-17 production in RA. Peripheral blood mononuclear cells (PBMC) from patients with RA (n = 24) were separated, then stimulated with various agents including anti-CD3, anti-CD28, phytohemagglutinin (PHA) and several inflammatory cytokines and chemokines. IL-17 levels were determined by sandwich enzyme-linked immunosorbent assay and reverse transcription–polymerase chain reaction. The production of IL-17 was significantly increased in cells treated with anti-CD3 antibody with or without anti-CD28 and PHA (P < 0.05). Among tested cytokines and chemokines, IL-15, monocyte chemoattractant protein-1 and IL-6 upregulated IL-17 production (P < 0.05), whereas tumor necrosis factor-α, IL-1β, IL-18 or transforming growth factor-β did not. IL-17 was also detected in the PBMC of patients with osteoarthritis, but their expression levels were much lower than those of RA PBMC. Anti-CD3 antibody activated the PI3K/Akt pathway; activation of this pathway resulted in a pronounced augmentation of nuclear factor κB (NF-κB) DNA-binding activity. IL-17 production by activated RA PBMC is completely or partly blocked in the presence of the NF-κB inhibitor pyrrolidine dithiocarbamate and the PI3K/Akt inhibitor wortmannin and LY294002, respectively. However, inhibition of activator protein-1 and extracellular signal-regulated kinase 1/2 did not affect IL-17 production. These results suggest that signal transduction pathways dependent on PI3K/Akt and NF-κB are involved in the overproduction of the key inflammatory cytokine IL-17 in RA

Deterioration in Global Organization of Structural Brain Networks in Schizophrenia: A Diffusion MRI Tractography Study

Schizophrenia is a heterogenous neuropsychiatric disorder with varying degrees of altered connectivity in a wide range of brain areas. Network analysis using graph theory allows researchers to integrate and quantify relationships between widespread changes in a network system. This study examined the organization of brain structural networks by applying diffusion MRI, probabilistic tractography, and network analysis to 48 schizophrenia patients and 24 healthy controls. T1-weighted MR images obtained from all participants were parcellated into 87 regions of interests (ROIs) according to a prior anatomical template and registered to diffusion-weighted images (DWI) of the same subjects. Probabilistic tractography was performed to obtain sets of white matter tracts between any two ROIs and determine the connection probabilities between them. Connectivity matrices were constructed using these estimated connectivity probabilities, and several network properties related to network effectiveness were calculated. Global efficiency, local efficiency, clustering coefficient, and mean connectivity strength were significantly lower in schizophrenia patients (p = 0.042, p = 0.011, p = 0.013, p = 0.046). Mean betweenness centrality was significantly higher in schizophrenia (p = 0.041). Comparisons of node wise properties showed trends toward differences in several brain regions. Nodal local efficiency was consistently lower in the basal ganglia, frontal, temporal, cingulate, diencephalon, and precuneus regions in the schizophrenia group. Inter-group differences in nodal degree and nodal betweenness centrality varied by region and showed inconsistent results. Robustness was not significantly different between the study groups. Significant positive correlations were found between t-score of color trails test part-1 and local efficiency and mean connectivity strength in the patient group. The findings of this study suggest that schizophrenia results in deterioration of the global network organization of the brain and reduced ability for information processing

A case of malignant hyperthermia during anesthesia induction with sevoflurane -A case report-

We experienced a case of malignant hyperthermia (MH) in 6-year-old boy during anesthesia induction for strabismus surgery. It has been generally reported that sevoflurane can induce the delayed onset of MH in the absence of succinylcholine. Our case of MH was elicited after about 2-3 min of sevoflurane administration with N2O, O2 and rocuronium. However, we successfully treated the patient by early recognition of his condition and administering symptomatic treatment and dantrolene

A Protective Role for Heme Oxygenase-1 in INS-1 Cells and Rat Islets that are Exposed to High Glucose Conditions

Heme oxygenase-1 (HO-1) has been described as an inducible protein that is capable of cytoprotection via radical scavenging and the prevention of apoptosis. Chronic exposure to hyperglycemia can lead to cellular dysfunction that may become irreversible over time, and this process has been termed glucose toxicity. Yet little is known about the relation between glucose toxicity and HO-1 in the islets. The purposes of the present study were to determine whether prolonged exposure of pancreatic islets to a supraphysiologic glucose concentration disrupts the intracellular balance between reactive oxygen species (ROS) and HO-1, and so this causes defective insulin secretion; we also wanted to evaluate a protective role for HO-1 in pancreatic islets against high glucose levels. The intracellular peroxide levels of the pancreatic islets (INS-1 cell, rat islet) were increased in the high glucose media (30 mM glucose or 50 mM ribose). The HO-1 expression was induced in the INS-1 cells by the high glucose levels. Both the HO-1 expression and glucose stimulated insulin secretion (GSIS) was decreased simultaneously in the islets by treatment of the HO-1 antisense. The HO-1 was upregulated in the INS-1 cells by hemin, an inducer of HO-1. And, HO-1 upregulation induced by hemin reversed the GSIS in the islets at a high glucose condition. These results suggest HO-1 seems to mediate the protective response of pancreatic islets against the oxidative stress that is due to high glucose conditions

Korean Shock Society septic shock registry: a preliminary report

Objective To evaluate the clinical characteristics, therapeutic interventions, and outcomes of patients with septic shock admitted to the emergency department (ED). Methods This study was a preliminary, descriptive analysis of a prospective, multi-center, observational registry of the EDs of 10 hospitals participating in the Korean Shock Society. Patients aged 19 years or older who had a suspected or confirmed infection and evidence of refractory hypotension or hypoperfusion were included. Results A total of 468 patients were enrolled (median age, 71.3 years; male, 55.1%; refractory hypotension, 82.9%; hyperlactatemia without hypotension, 17.1%). Respiratory infection was the most common source of infection (31.0%). The median Sepsis-related Organ Failure Assessment score was 7.5. The sepsis bundle compliance was 91.2% for lactate measurement, 70.3% for blood culture, 68.4% for antibiotic administration, 80.3% for fluid resuscitation, 97.8% for vasopressor application, 68.0% for central venous pressure measurement, 22.0% for central venous oxygen saturation measurement, and 59.2% for repeated lactate measurement. Among patients who underwent interventions for source control (n=117, 25.1%), 43 (36.8%) received interventions within 12 hours of ED arrival. The in-hospital, 28-day, and 90-day mortality rates were 22.9%, 21.8%, and 27.1%, respectively. The median ED and hospital lengths of stay were 6.8 hours and 12 days, respectively. Conclusion This preliminary report revealed a mortality of over 20% in patients with septic shock, which suggests that there are areas for improvement in terms of the quality of initial resuscitation and outcomes of septic shock patients in the ED

Tcap gene mutations in hypertrophic cardiomyopathy and dilated cardiomyopathy

ObjectivesWe sought to explore the relationship between a Tcap gene (TCAP)abnormality and cardiomyopathy.BackgroundHypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) cause severe heart failure and sudden death. Recent genetic investigations have revealed that mutations of genes encoding Z-disc components, including titin and muscle LIM protein (MLP), are the primary cause of both HCM and DCM. The Z-disc plays a role in establishing the mechanical coupling of sarcomeric contraction and stretching, with the titin/Tcap/MLP complex serving as a mechanical stretch sensor. Tcap interacts with the calsarcin, which tethers the calcineurin to the Z-disc.MethodsThe TCAPwas analyzed in 346 patients with HCM (236 familial and 110 sporadic cases) and 136 patients with DCM (34 familial and 102 sporadic cases). Two different in vitro qualitative assays—yeast two-hybrid and glutathion S-transferase pull-down competition—were performed in order to investigate functional changes in Tcap's interaction with MLP, titin, and calsarcin-1 caused by the identified mutations and a reported DCM-associated mutation, R87Q.ResultsTwo TCAPmutations, T137I and R153H, were found in patients with HCM, and another TCAPmutation, E132Q, was identified in a patient with DCM. It was demonstrated by the qualitative assays that the HCM-associated mutations augment the ability of Tcap to interact with titin and calsarcin-1, whereas the DCM-associated mutations impair the interaction of Tcap with MLP, titin, and calsarcin-1.ConclusionsThese observations suggest that the difference in clinical phenotype (HCM or DCM) may be correlated with the property of altered binding among the Z-disc components

Successful Retrieval of a Fractured and Entrapped 0.035-Inch Terumo Wire in the Femoral Artery Using Biopsy Forceps

A 0.035-inch guide wire fracture and entrapment in a peripheral artery is a very rare complication, but when it does occur it may lead to life-threatening complications, such as perforation, thrombus formation, embolization, and subsequent limb ischemia. We describe our experience of successfully retrieving a fractured 0.035-inch Terumo guide wire in the external iliac artery using a biopsy forcep

Impact of the Metabolic Syndrome on the Clinical Outcome of Patients with Acute ST-Elevation Myocardial Infarction

We sought to determine the prevalence of metabolic syndrome (MS) in patients with acute myocardial infarction and its effect on clinical outcomes. Employing data from the Korea Acute Myocardial Infarction Registry, a total of 1,990 patients suffered from acute ST-elevation myocardial infarction (STEMI) between November 2005 and December 2006 were categorized according to the National Cholesterol Education Program-Adult Treatment Panel III criteria of MS. Primary study outcomes included major adverse cardiac events (MACE) during one-year follow-up. Patients were grouped based on existence of MS: group I: MS (n=1,182, 777 men, 62.8±12.3 yr); group II: Non-MS (n=808, 675 men, 64.2±13.1 yr). Group I showed lower left ventricular ejection fraction (LVEF) (P=0.005). There were no differences between two groups in the coronary angiographic findings except for multivessel involvement (P=0.01). The incidence of in-hospital death was higher in group I than in group II (P=0.047), but the rates of composite MACE during one-year clinical follow-up showed no significant differences. Multivariate analysis showed that low LVEF, old age, MS, low high density lipoprotein cholesterol and multivessel involvement were associated with high in-hospital death rate. In conclusion, MS is an important predictor for in-hospital death in patients with STEMI