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We investigated signal transducer and activator of transcription-5 (STAT5) activation status in renal cell carcinoma (RCC) and the role of transforming growth factor-β (TGF-β) in the process. Twenty normal and RCC tissues were obtained from radical nephrectomy specimens for the assessment of expressions of phosphorylated STAT5 (p-STAT5) and TGF-β1 (Western blot) and for localization and assessment of their relationship (immunohistochemical and immunofluorescence stains). By using four RCC cell lines and four primary cultured cells, the effect of TGF-β1 and/or interleukin-2 (IL-2) on the expressions of p-STAT5 were analyzed. In RCC samples, expression of p-STAT5 was significantly reduced while expression of TGF-β was enhanced compared with normal kidney tissues ( P < 0.001 and P = 0.003, respectively). P-STAT5 was observed almost exclusively in the nuclei of normal kidney tissues while TGF-β was identified in the cytoplasm of cells of both tissues reflecting the Western results. In both RCC cell lines and cells from primary cultures, treatment with TGF-β or antibody did not significantly alter STAT5 activation. However, TGF-β significantly suppressed IL-2-induced STAT5 activation, whereas anti-TGF-β antibodies enhanced IL-2-induced STAT5 further. STAT5 activation is suppressed in RCC compared with normal renal parenchyma. It may be attributed to the RCC-derived TGF-β which also interferes with IL-2-induced STAT5 pathway activation. [ABSTRACT FROM AUTHOR]

BACKGROUND:To identify factors for starting biosimilar TNF inhibitors (TNFI) in patients with rheumatic diseases. METHODS AND FINDING:Using a national claims database, we identified patients with rheumatoid arthritis (RA) or ankylosing spondylitis (AS) who had used TNFIs since they were approved in Korea in 2004. We assessed changes in the proportion of each form of TNFI used between 2004 and 2017. We then selected patients starting on TNFIs between 2013 and 2017 to identify factors for starting biosimilars. In RA (n = 4,216), biosimilars were more likely to be initiated in clinics [odds ratio (OR) 2.54] and in the metropolitan area (OR, 2.02), but were less likely to be initiated in general hospitals (OR 0.40) or orthopedics (OR 0.44). In AS (n = 2,338), biosimilars were common at the hospital level (OR 2.20) and tended to increase over the years (OR 1.16), but were initiated less in orthopedics (OR 0.07). In addition, RA patients were more likely to initiate biosimilars in combination with methotrexate (OR 1.37), but biosimilars were not initiated frequently by patients with higher comorbidity scores (OR 0.97) or receiving glucocorticoids (OR 0.67). The patient factors favoring biosimilar in AS use were not clear. CONCLUSIONS:In Korea, the proportion of biosimilar TNFIs has increased. Type of institution and physician specialty are more important than patient factors in affecting biosimilar use. In RA, biosimilar TNFIs tend to be initiated in combination with MTX, and are less likely to be initiated in patients taking glucocorticoids or in those with high comorbidities.

Objectives Clinical practice guidelines for the management of pain and sedation in critically ill patients have been developed and applied; however, there is limited data on medication use among elderly patients. This study identifies current practice patterns for analgo-sedative use in mechanically ventilated elderly patients in Korea using a national claims database.Design Cross-sectional study.Setting and participants Ventilated elderly patients aged 65 years or older in intensive care units (ICUs) from an aged patients’ national claims database in KoreaPrimary outcome measures Use of sedatives including benzodiazepines, opioids and non-opioid analgesics, neuromuscular blocking agents (NMBAs) and antipsychotic drugs were analysed by the duration of mechanical ventilation (MV), age and time.Results From 2012 to 2016, 22 677 elderly patients underwent MV in 267 general or tertiary ICUs. Mean age was 77.2 (±6.9) years and the median duration of MV was 4.1 days; 77.2% of patients received sedatives, 65.0% analgesics, 29.1% NMBAs and 19.6% antipsychotics. Midazolam (62.0%) was the most commonly prescribed medication. The proportions of sedatives, analgesics and NMBAs increased, whereas the percentages of person-days decreased with longer MV duration (p

It is important to detect signals of abrupt changes in adverse event reporting in order to notice public safety concerns and take prompt action, especially for vaccines under national immunization programs. In this study, we assessed the applicability of change point analysis (CPA) for signal detection in vaccine safety surveillance. The performances of three CPA methods, namely Bayesian change point analysis, Taylor’s change point analysis (Taylor-CPA), and environmental time series change point detection (EnvCpt), were assessed via simulated data with assumptions for the baseline number of events and degrees of change. The analysis was validated using the Korea Adverse Event Reporting System (KAERS) database. In the simulation study, the Taylor-CPA method exhibited better results for the detection of a change point (accuracy of 96% to 100%, sensitivity of 7% to 100%, specificity of 98% to 100%, positive predictive value of 25% to 85%, negative predictive value of 96% to 100%, and balanced accuracy of 53% to 100%) than the other two CPA methods. When the CPA methods were applied to reports of syncope or dizziness following human papillomavirus (HPV) immunization in the KAERS database, Taylor-CPA and EnvCpt detected a change point (Q2/2013), which was consistent with actual public safety concerns. CPA can be applied as an efficient tool for the early detection of vaccine safety signals.

We aimed to analyze the incidence of Guillain-Barré syndrome (GBS) and its association with influenza vaccination (IV) in the elderly population. This study included 2470 patients hospitalized with GBS (G61.0) between 2014 and 2016 based on the Korean National Health Insurance Service (NHIS) claims data. We reviewed every medical claim in the 42 days preceding GBS diagnosis looking for precedent causes of GBS. To assess the relationship between IV and the development of GBS, data from the NHIS and the National Vaccination Registry were combined and analyzed. Using a self-controlled case series (SCCS) approach, we calculated the incidence rate ratio by setting the risk period as 42 days following vaccination. The annual background incidence of GBS was estimated at 4.15 per 100,000 persons. More than half of the patients with newly developed GBS had a previous infection or surgery. The incidence of GBS within 42 days of IV was estimated at 0.32 per 100,000 vaccinated persons. SCCS analysis showed that the risk of GBS was not significantly higher. While GBS can potentially develop from various infections, no association was found between GBS and IV. These results will contribute to developing an evidence-based vaccine policy that includes a clear causality assessment of adverse events.

South Korea operates a National Vaccine Injury Compensation Program (VICP) for people who experience adverse events following immunization (AEFI). To run this program rationally, it is a prerequisite to confirm whether adverse events were caused by immunization. Guillain−Barré syndrome (GBS), a severe neurological disease with limb pain and muscle weakness as cardinal symptoms, is attracting attention as an AEFI. However, algorithm or guidelines for assessing the causality between vaccination and the incidence of GBS are lacking. We aimed to develop guidelines for causality assessment of GBS as an AEFI and suggest using these guidelines in alignment with the VICP. We systematically searched for other previously published algorithms or guidelines and found a WHO-AEFI guideline used worldwide; however, it only provides general instructions and is not tailored to specific adverse events. We translated and locally adapted the structure of this guideline and then added contents related to GBS. The GBS-specific guideline consists of four steps: case ascertainment of GBS, checklist (including (1) order of incidence, (2) temporal proximity, (3) evidence for other causes and (4) published evidence), an algorithm, and final classification. We listed key information on confirming GBS and whether any other causes of GBS were present. For real world application of the guideline along with the VICP, we collaborated with a panel of neurologists, epidemiologic investigators, and committee members from the VICP. To ensure transparency and a scientific approach, regular updates and collaboration with neurologists are essential. We expect that this guideline will contribute to logical causality assessment and compensation decisions for GBS and will provide the basic structure for causality assessment of other AEFIs.

Purpose Maternal lipopolysaccharide (LPS) injection induces neurodevelopmental disorders, such as cerebral palsy. Exercise activates phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt) signaling pathway that enhances neurogenesis. Wnt ligands are also implicated in the hippocampal neurogenesis and synaptic plasticity. Glycogen synthase kinase-3β (GSK-3β) is a downstream molecule of Akt, and GSK-3β is known to modulate hippocampal neurogenesis negatively. Methods Cerebral palsy was made by maternal LPS-injection. On the 5 weeks after birth, treadmill running was applied to the rat pups of the exercise groups, for 30 minutes, 5 times a week during 6 weeks. Results Treadmill running alleviated short-term memory impairments of the cerebral palsy rat pups. Hippocampal cell proliferation was increased and hippocampal apoptosis was suppressed by treadmill running in the cerebral palsy rat pups. Hippocampal phosphorylated-PI3K/PI3K ratio, phosphorylated-Akt/Akt ratio, and Wnt expression were enhanced by treadmill running in the cerebral palsy rat pups. In contrast, hippocampal phosphorylated-GSK-3β/GSK-3β ratio and β-catenin expression were suppressed by treadmill running in the cerebral palsy rat pups. Conclusions The results of this study showed that short-term memory improvement due to treadmill running in cerebral palsy occurs via activation of the PI3K-Akt-Wnt pathway.

Objectives: An outbreak of joint and cutaneous infections among patients who had been injected at a single clinic in South Korea was investigated. Methods: In this retrospective case–control study, 61 cases were diagnosed based on symptoms and signs of septic arthritis or cutaneous infection that developed after injections at the clinic between April and September 2012; 64 controls were investigated by administering questionnaires on risk factors and analyzing the clinic medical records. An environmental investigation was performed, and clinical specimens of the cases were analyzed by pulsed-field gel electrophoresis. Results: All cases were injected with triamcinolone. A greater number of triamcinolone injections (adjusted odds ratio 4.3, 95% confidence interval 1.5–12.1 for six or more visits, compared with one or two visits) was associated with the development of an infection. In the clinic, only the triamcinolone injection was prepared by mixing with lidocaine and normal saline, and an alcohol swab was prepared using boiled tap water by members of the clinic staff. Although injected medications and environmental cultures were not found to be responsible, a single strain of Mycobacterium massiliense was isolated from the affected sites of 16 cases. Conclusions: Repeated injection of triamcinolone contaminated with NTM from the clinic environment may have caused this post-injection outbreak.

BACKGROUND:Bisphosphonate can irritate the gastrointestinal mucosa and increase the risk of esophageal or gastric cancer. The relatively high prevalence of upper gastrointestinal cancers and the widespread use of bisphosphonate in Korea call for further investigation. We conducted a case-control study to evaluate the risk of esophageal or gastric cancer after exposure to oral bisphosphonates in Korean patients with osteoporosis. METHODS:We used the National Health Insurance Service-National Sample Cohort database of Korea from 2002 to 2013. Among osteoporotic patients (>40 years), cases were defined as incident diagnosis of esophageal or gastric cancer between 2006 and 2013. For each case, four controls were matched for age, sex, and income level by type of insurance. We categorized bisphosphonate use as non-user, recent user, past user, and past and recent user, depending on prescription in two periods (1 to 2 years and 2 to 4 years prior to the index date). We also assessed the duration of bisphosphonate use by measuring cumulative duration of exposure (CDE). To examine the association between oral bisphosphonates and esophageal or gastric cancer, we estimated adjusted odds ratios (aORs) and 95% confidence intervals (CIs) using conditional logistic regression analysis, adjusting for concomitant diseases. RESULTS:A total of 1,708 cases and 6,832 controls were identified. The aORs (95% CIs) of recent, past, and continuous bisphosphonate use compared to non-users were 1.18 (0.93-1.51), 1.04 (0.83-1.29), and 1.25 (0.95-1.58)), respectively. In addition, no significant association was observed by CDE, even when different outcome definitions were applied. CONCLUSIONS:This study did not prove an increased risk of esophageal or gastric cancer risk associated with bisphosphonate use, with respect to both risk windows and duration of exposure, in an Asian population-based, real-world setting.

OBJECTIVE: To evaluate the risk of severe cutaneous adverse drug reactions (SCAR) after exposure to multi-indication antiepileptic drugs for in Korean elderly patients. METHODS: We used a nationwide database from the Korean Health Insurance Review and Assessment Service claims constructed for the monitoring of drug utilization among the entire Korean elderly population from January 2005 to June 2006. We identified cases of SCARs among inpatients aged ≥ 65 years and those newly diagnosed with erythema multiforme according to the International Classification of Diseases, 10th revision code (L51). Each case was matched to four controls for gender, age, and the first hospitalization date as the index date. The use of carbamazepine, gabapentin, lamotrigine, topiramate, phenobarbital, phenytoin, and valproate during a 60-day period before the index date was compared. A conditional logistic regression analysis was performed to calculate the odds ratios (OR) and 95% confidence intervals (CI) of SCARs for antiepileptic drug. RESULTS: We identified 286 cases of SCAR and 1,144 matched controls. Among the 25 patients who were prescribed antiepileptic drugs within 60 days of the index date. There were 11 cases (3.8%) of severe ocular manifestations, and most elderly patients were first-time or short-term users of antiepileptic drugs. Among the 10 cases of carbamazepine use, only 2 cases were prescribed carbamazepine for seizure. All antiepileptic drugs were associated with an increased SCAR risk (adjusted OR = 3.42, 95% CI: 1.75-6.63). The SCAR risk was highest in patients treated with carbamazepine (adjusted OR = 10.39, 95% CI: 2.64-40.86, for multi-indication; adjusted OR = 6.84, 95% CI: 1.55-30.10, for neuropathic pain). CONCLUSION: Carbamazepine use was associated with a nearly 10-fold increase in severe cutaneous drug reactions in Korean elderly patients. This association was consistently high with SCAR patients who received carbamazepine for neuropathic pain.

AIM: Glucagon is an essential regulator of hepatic glucose production (HGP), which provides an alternative therapeutic target for managing type 2 diabetes with glucagon antagonists. We studied the effect of a novel human monoclonal antibody against glucagon receptor (GCGR), NPB112, on glucose homeostasis in diet-induced obese (DIO) mice. METHODS: The glucose-lowering efficacy and safety of NPB112 were investigated in DIO mice with human GCGR for 11 weeks, and a hyperinsulinemic-euglycemic clamp study was conducted to measure HGP. RESULTS: Single intraperitoneal injection of NPB112 with 5 mg/kg effectively decreased blood glucose levels in DIO mice for 5 days. A significant reduction in blood glucose was observed in DIO mice treated with NPB112 at a dose ≥5 mg/kg for 6 weeks, and its glucose-lowering effect was dose-dependent. Long-term administration of NPB112 also caused a mild 29% elevation in glucagon level, which was returned to the normal range after discontinuation of treatment. The clamp study showed that DIO mice injected with NPB112 at 5 mg/kg were more insulin sensitive than control mice, indicating amelioration of insulin resistance by treatment with NPB112. DIO mice treated with NPB112 showed a significant improvement in the ability of insulin to suppress HGP, showing a 33% suppression (from 8.3 mg/kg/min to 5.6 mg/kg/min) compared to the 2% suppression (from 9.8 mg/kg/min to 9.6 mg/kg/min) in control mice. In addition, no hypoglycemia or adverse effect was observed during the treatment. CONCLUSIONS: A novel human monoclonal GCGR antibody, NPB112, effectively lowered the glucose level in diabetic animal models with mild and reversible hyperglucagonemia. Suppression of excess HGP with NPB112 may be a promising therapeutic modality for the treatment of type 2 diabetes.

Presents the case of a 20-year-old Korean man diagnosed with diffuse large B-cell lymphoma with Homer-Wright-type Rosette formation. Medical history of the patient; Results of examination by light microscopy; Immunohistochemistry technique for tumor diagnosis; Considerations in the diagnosis of soft tissue tumors.

Ewing sarcoma/primitive neuroectodermal tumor (ES/ PNET) most commonly occurs in the soft tissues of the extremities and the paravertebral areas. To our knowledge, no case of PNET has been reported in the gallbladder to date. We report a case of PNET of the gallbladder occur- ring in a 53-year-old woman. Microscopically, the monotonous small round cells with a formation of Homer-Wright rosettes showed intense membranous positive immunoreactivity for MIC2/CD99, as well as for neuron-specific enolase and synaptophysin. Other small round cell tumors, such as lymphoma, rhabdomyosarcoma, or melanoma, were excluded in light of negative immunoreactivity for leukocyte common antigen, desmin, and S100. The diagnosis of PNET was rendered based on the characteristic morphology and immunohistochemical findings, despite an absence of chromosomal translocations, such as t(11; 22)(q24;q12) and t(21 ;22)(q22;q12). [ABSTRACT FROM AUTHOR]