PBT-6, a Novel PI3KC2γ Inhibitor in Rheumatoid Arthritis

Phosphoinositide 3-kinase (PI3K) is considered as a promising therapeutic target for rheumatoid arthritis (RA) because of its involvement in inflammatory processes. However, limited studies have reported the involvement of PI3KC2γ in RA, and the underlying mechanism remains largely unknown. Therefore, we investigated the role of PI3KC2γ as a novel therapeutic target for RA and the effect of its selective inhibitor, PBT-6. In this study, we observed that PI3KC2γ was markedly increased in the synovial fluid and tissue as well as the PBMCs of patients with RA. PBT-6, a novel PI3KC2γ inhibitor, decreased the cell growth of TNF-mediated synovial fibroblasts and LPS-mediated macrophages. Furthermore, PBT-6 inhibited the PI3KC2γ expression and PI3K/AKT signaling pathway in both synovial fibroblasts and macrophages. In addition, PBT-6 suppressed macrophage migration via CCL2 and osteoclastogenesis. In CIA mice, it significantly inhibited the progression and development of RA by decreasing arthritis scores and paw swelling. Three-dimensional micro-computed tomography confirmed that PBT-6 enhanced the joint structures in CIA mice. Taken together, our findings suggest that PI3KC2γ is a therapeutic target for RA, and PBT-6 could be developed as a novel PI3KC2γ inhibitor to target inflammatory diseases including RA.

Factors Associated with the Presence and Severity of Diabetic Ketoacidosis at Diagnosis of Type 1 Diabetes in Korean Children and Adolescents

The aim of this study was to identify the risk factors for presence and severity of diabetic ketoacidosis (DKA) at the onset of type 1 diabetes mellitus (T1DM) in Korean children and adolescents. A retrospective chart review of children and adolescents newly diagnosed with T1DM was conducted in seven secondary and tertiary centers in Korea. Eligible subjects were < 20 years of age and had records on the presence or absence of DKA at the time of T1DM diagnosis. DKA severity was categorized as mild, moderate, or severe. Data were collected on age, height, body weight, pubertal status, family history of diabetes, delayed diagnosis, preceding infections, health insurance status, and parental education level. A total of 361 patients (male 46.3%) with T1DM were included. Overall, 177 (49.0%) patients presented with DKA at T1DM diagnosis. Risk factors predicting DKA at T1DM diagnosis were age ≥ 12 years, lower serum C-peptide levels, presence of a preceding infection, and delayed diagnosis. Low parental education level and preceding infection increased the severity of DKA. These results suggest that alertness of the physician and public awareness of diabetes symptoms are needed to decrease the incidence and severity of DKA at T1DM diagnosis.

The Short-term Result of NexGen CR-Flex(R) Total Knee Arthroplasty

PURPOSE: The purpose of this study is to evaluate the result of primary total knee arthroplasty(TKA) with using NexGen CR-Flex(R) (Zimmer, Warsaw, IN, USA) after a follow-up of at least 2 years. MATERIALS AND METHODS: A total of 63 patients (98 knees) were included in this study. The same surgeon performed all the TKAs between August 2005 and May 2006 with using NexGen CR-Flex(R). The patients' age ranged from 52 to 81 years, and the mean follow-up period was 28 months. The patients were assessed clinically and radiographically with using the HSS score, the possibility that they could squat or kneel, the tibiofemoral angle, the radiolucency and the posterior condylar offset. RESULTS: The mean HSS score was 58.3 points preoperatively, and it was 91.1 points at the last follow-up. The mean range of motion improved from 123.2degrees preoperatively to 137.1degrees postoperatively. Forty-nine patients (78%) were able to squat and 24 patients (38%) could kneel down at the last follow-up. The mean tibiofemoral angle was 6degrees of varus preoperatively, and 7degrees of valgus postoperatively. And there was no radiolucency in any case. The mean posterior condylar offset was 26.1mm preoperatively and 27.2 mm postoperatively. CONCLUSION: TKA with using NexGen CR-Flex(R) showed favorable results at a mean follow-up of 28 months. Adequate patient selection, restoration of the posterior condylar offset and thorough clearing of posterior condylar osteophytes are thought to be the key elements to achieve a satisfactory range of motion after TKAs.

Clinical significance of acanthosis nigricans in children and adolescents with obesity induced metabolic complications / 소아과

PURPOSE: This study investigated the clinical significance of AN in children and adolescents with obesity induced metabolic complications. METHODS: Forty-nine patients who had obesity induced metabolic complications were participated in this cross-sectional study. Obesity induced metabolic complications are as follows: hypertension, dyslipidemia, impaired fasting glucose (IFG), impaired glucose tolerance (IGT), nonalcoholic steatohepatitis (NASH), homeostasis model assessment of insulin resistance (HOMA-IR)>3.16. Clinical characteristics, such as, age, percentage-weight-for-height (PWH), pubertal status, blood pressure (BP), fasting plasma insulin level, fasting and post-oral glucose tolerance test 2-hour glucose levels, liver function test, lipid profile, HOMA-IR were compared according to the presence of AN. RESULTS: Sixty-five percent of patients had AN, 57.1% NASH, 57.1% dyslipidemia, 55.1% hypertension, 46.9% IFG, 24.5% HOMA-IR>3.16 and 16.2% IGT. The patients who were moderately to severely obese with AN had higher incidence of IGT and HOMA-IR>3.16. The patients with AN had significantly higher diastolic BP (79.4+/-6.9 vs 75.4+/-5.6 mmHg), fasting levels of plasma insulin (10.6+/-6.0 vs 6.2+/-5.4 microIU/mL), HOMA-IR index (2.6+/-1.4 vs 1.4+/-1.3) and PWH (42.4+/-13.0 vs 34.3+/-1.8%). The increasing tendency for the presence of AN was significantly related to the cumulative number of obesity induced metabolic complications. Binary logistic regression analysis revealed that the presence of AN was significantly associated with fasting plasma insulin level, PWH and IFG. CONCLUSION: AN could be useful as a clinical surrogate of obesity induced metabolic complications.