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Yoona Choi,1,2,* Bo Kyung Kim,3,4,* Jung-Hyun Won,2,5 Jae Won Yoo,6 Wona Choi,7 Surin Jung,7 Jae Yoon Kim,7,8 In Young Choi,7 Nack-Gyun Chung,6 Jae Wook Lee,6 Jung Yoon Choi,3,4 Hyoung Jin Kang,3,4,9 Howard Lee1,2,5,10,11 1Department of Applied Bioengineering, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea; 2Center for Convergence Approaches in Drug Development, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea; 3Department of Pediatrics, Seoul National University Hospital, Seoul, Republic of Korea; 4Seoul National University Cancer Research Institute, Seoul, Republic of Korea; 5Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea; 6Department of Pediatrics, Seoul St. Mary’s Hospital, College of Medicine, the Catholic University of Korea, Seoul, Republic of Korea; 7Department of Medical Informatics, College of Medicine, the Catholic University of Korea, Seoul, Republic of Korea; 8Department of Biomedicine & Health Sciences, the Catholic University of Korea, Seoul, Republic of Korea; 9Department of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of Korea; 10Advanced Institutes of Convergence Technology, Suwon, Republic of Korea; 11Department of Clinical Pharmacology and Therapeutics, Seoul National University Hospital, Seoul, Republic of Korea*These authors contributed equally to this workCorrespondence: Howard Lee, Department of Clinical Pharmacology and Therapeutics, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea, Email howardlee@snu.ac.kr Hyoung Jin Kang, Department of Pediatrics, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea, Email kanghj@snu.ac.krBackground: Rapid reduction of leukemic cells in the bone marrow during remission induction chemotherapy (RIC) can lead to significant complications such as tumor lysis syndrome (TLS). We investigated whether prephase steroid treatment before RIC could decrease TLS incidence and improve overall survival in pediatric patients with acute lymphoblastic leukemia (ALL).Methods: Data were extracted from the Common Data Model databases in two tertiary-care hospitals in Seoul, South Korea. Patients were classified into the treated or untreated group if they had received RIC with prephase steroid treatment ≥ 7 days before RIC in 2012– 2021 or not, respectively. Stabilized Inverse Probability of Treatment Weighting (sIPTW) was applied to ensure compatibility between the treated and untreated groups. The incidence of TLS within 14 days of starting RIC, overall survival (OS), and the incidence of adverse events of special interest were the primary endpoints. Multiple sensitivity analyses were performed.Results: Baseline characteristics were effectively balanced between the treated (n=308.4) and untreated (n=246.6) groups after sIPTW. Prephase steroid treatment was associated with a significant 88% reduction in the risk of TLS (OR 0.12, 95% CI: 0.03– 0.41). OS was numerically greater in the treated group than in the untreated group although the difference was not statistically significant (HR 0.64, 95% CI 0.25– 1.64). The treated group experienced significantly elevated risks for hyperbilirubinemia and hyperglycemia. The reduction in TLS risk by prephase steroid treatment was maintained in all of the sensitivity analyses.Conclusion: Prephase steroid treatment for ≥ 7 days before RIC in pediatric patients with ALL reduces the risk of TLS, while careful monitoring for toxicities is necessary. If adequately analyzed, real-world data can provide crucial effectiveness and safety information for proper management of pediatric patients with ALL, for whom prospective randomized studies may be difficult to perform for ethical and practical reasons.Keywords: pediatric acute lymphoblastic leukemia, tumor lysis syndrome, remission induction chemotherapy, prephase steroid treatment, common data model

Ji Yeong Kim,1,&ast; Yookyung Jang,2,&ast; Eun Jang Yoon,1 Wootaek Lee,1 Jaewoo Kim,2 Jae Chul Koh2 1Department of Anesthesiology and Pain Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea; 2Department of Anesthesiology and Pain Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea&ast;These authors contributed equally to this workCorrespondence: Jae Chul Koh, Department of Anesthesiology and Pain Medicine, Korea University Anam Hospital, Korea University College of Medicine, 73, Goryeodae-ro, Seongbuk-gu, Seoul, 02841, Republic of Korea, Tel +82-2-920-5632, Fax +82-2-928-2275, Email jaykoh@korea.ac.krPurpose: The aim of this prospective study was to develop a virtual reality simulator (VRS) for spinal cord stimulation (SCS) trials and establish its effectiveness.Methods: We developed a VRS for SCS training by integrating patient imaging data analytics, creating artificial X-ray images, and using spatial alignment techniques and virtual reality technologies. The simulator was created by a physician with considerable experience in performing SCS, and can simulate the feeling of the procedure in a virtual environment. The efficacy of the simulator for SCS trials was assessed using a cohort of 20 novice trainees. The primary outcomes were duration of the procedure, checklist score, number of C-arm images captured, and overall trainee satisfaction.Results: The cohort that utilized the VRS had better Zwisch scale scores (P < 0.001), completed the procedure in a shorter time (P < 0.001), took fewer C-arm images (P < 0.001), and reported better overall satisfaction (P = 0.011) than the cohort that did not.Conclusion: We developed a realistic and efficient VRS for educating novice trainees on SCS trials, thereby eliminating the risk of radiation exposure associated with cadaver training. The results of this study indicate that our VRS has potential as an instrumental resource that can be integrated into the educational framework for SCS trials.Keywords: surgical procedure, simulation training, spinal cord stimulator, virtual reality, virtual reality simulator

Jong Yeup Kim,1 Dong Won Yang,1 Sangjae Kim,2 Jong Gwon Choi3 1Department of Biomedical Informatics, College of Medicine, Konyang University, Daejeon, Republic of Korea; 2Department of Research and Development, Teloid Inc., Los Angeles, CA, 90010, USA; 3Department of Oncology-Hematology, Konyang University Hospital, Daejeon, Republic of KoreaCorrespondence: Jong Gwon Choi, Oncology-Hematology, Konyang University Hospital, 158 Gwanjeodong-Ro, Seo-Gu, Daejeon, Republic of Korea, Email jabuss@naver.comPurpose: Telomerase activation, a critical step in cancer progression, occurs in approximately 95% of breast cancer cases. Telomerase is an attractive therapeutic target for breast cancer owing to its unique expression pattern. GV1001, a telomerase-derived peptide, is loaded onto human leukocyte antigen (HLA) class II antigen-presenting cells and binds to CD4+ T cell activating immune responses. This study aimed to evaluate the effectiveness and safety of co-administration of GV1001 and cytotoxic chemotherapy in patients with heavily-treated metastatic breast cancer.Patients and methods: We analyzed 63 patients with breast cancer who received both GV1001 and cytotoxic chemotherapy. The GV 1001 administration methods involves 0.56 mg intradermal injection three times during the first week, one time at weeks 2, 3, 4, and 6, and then once every 28 days. The primary endpoint of this study was quality of life according to EORTC QLO-C30 and EQ-5D, while the secondary endpoint was the antitumor response according to RECIST 1.1, progression-free survival, overall survival, and toxicity profile.Results: In 34 patients with HR+ breast cancer evaluable for tumor response, the disease control rate (DCR) and overall response rate (ORR) were 58.8% and 26.4%, respectively. The DCR and ORR were 66.6% and 28.5% in 21 patients with HER-2+ and 50% and 25% in patients with triple-negative breast cancer (TNBC), respectively. The median progression free survival was 10.4, 8.7, and 5.6 months in HR+, HER-2+, TNBC, respectively. The overall survival was 19.7, 13.2, and 9.4 months for patients with HR+, HER-2+, and TNBC, respectively. Most patients had an improved quality of life with statistically significant differences in some variables. The patients in this study experienced no additional toxicities other than the cytotoxic chemotherapy-associated side effects.Conclusion: GV1001 is a relatively safe anticancer vaccine for patients with heavily-treated breast cancer and can to improve the quality of life.Keywords: telomerase, GV1001, quality of life, safety, breast cancer

Hee Kyung Kim,1,&ast; Hyun-Jo Kim,2,&ast; Jae Yun Kim,3 Myung Jin Ban,4 Jiwon Son,5 Yongsung Hwang,5,6 Sung Bin Cho7 1Department of Pathology, Soonchunhyang University Bucheon Hospital, Bucheon, Korea; 2CNP Skin Clinic, Cheonan, Korea; 3Department of Dermatology, Soonchunhyang University Hospital, Cheonan, Korea; 4Department of Otorhinolaryngology-Head and Neck Surgery, Soonchunhyang University Hospital, Cheonan, Korea; 5Soonchunhyang Institute of Medi-Bio Science (SIMS), Soonchunhyang University, Cheonan, Korea; 6Department of Integrated Biomedical Science, Soonchunhyang University, Cheonan, Korea; 7Yonsei Seran Dermatology and Laser Clinic, Seoul, Korea&ast;These authors contributed equally to this workCorrespondence: Sung Bin Cho, Yonsei Seran Dermatology and Laser Clinic, Geumcheon REMAIN CITY 6F, 224 Siheung-daero, Geumcheon-gu, Seoul, 08628, Korea, Tel +82 2-2135-1375, Fax +82 70-8250-1375, Email drsbcho@gmail.comBackground: Single to multiple pulse packs of bipolar, alternating current radiofrequency (RF) oscillations have been used for various medical purposes using invasive microneedle electrodes. This study was designed to evaluate the effects of pulse widths and cycles of RF pulse packs on immediate and delayed thermal tissue reactions in in vivo rat skin.Methods: RF energy at the frequency of 1 MHz and power of 70 W was delivered at each experimental setting into in vivo rat skin at 1.5-mm microneedle penetration, and then, tissue samples were obtained after 1 h and 3, 7, 14, and 21 days and histologically analyzed.Results: A single-pulse-pack RF treatment generated coagulative necrosis zones in the dermal peri-electrode area and zones of non-necrotic thermal reactions in the dermal inter-electrode area. Multiple pulse-pack, RF-treated rat skin specimens revealed that the number and size of peri-electrode coagulative necrosis were markedly decreased by increasing the number of pulse packs and accordingly decreasing the conduction time of each pulse pack. The microscopic changes in RF-induced non-necrotic thermal reaction in the inter-electrode area were more remarkable in specimens treated with RF of 7 or 10 pulse packs than in specimens treated with RF of 1– 4 pulse packs.Conclusion: The gated delivery of multiple RF pulse packs using a bipolar, alternating current, 1-MHz RF system using insulated microneedle electrodes efficiently generates non-necrotic thermal tissue reactions over the upper, mid, and deep dermis and subcutaneous fat in the inter-electrode areas.Keywords: radiofrequency, bipolar, alternating current, gated pulse, tissue reaction, rat

Yun-Jeong Jeong,1,&ast; Kyoung-Hee Lee,2,&ast; Jisu Woo,2 Ji Yeon Kim,2 Chang-Hoon Lee,2,3 Chul-Gyu Yoo2,3 1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Dongguk University Ilsan Hospital, Ilsan Dong-gu, Goyang-si, Gyeonggi-do, Korea; 2Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea; 3Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea&ast;These authors contributed equally to this workCorrespondence: Chul-Gyu Yoo, 101 Daehakno, Jongno-gu, Seoul, 03080, Korea, Tel +82-2-2072-3760, Fax +82-2-762-9662, Email cgyoo@snu.ac.krBackground: Macroautophagy plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD), but the role of chaperone-mediated autophagy (CMA) has not been investigated. We investigated if and how CMA is involved in the pathogenesis of COPD.Methods: We measured the level of lysosome-associated membrane protein-2A (LAMP-2A), which is a critical component of CMA that functions as a receptor for cytosolic substrate proteins, in total lung tissues and primary human bronchial epithelial cells (HBECs) from healthy never smokers, smokers, and COPD patients. We assessed the effects of LAMP-2A knock-down on cigarette smoke extract (CSE)-induced aging, cell cycle arrest, and apoptosis in BEAS-2B cells and the expression levels of apoptosis hallmarks in primary HBECs and lung tissue sections.Results: We found that the protein levels of LAMP-2A in lung homogenates and primary HBECs from smokers and COPD patients were lower than those from never smokers. In addition, its level in primary HBECs was negatively correlated with years of smoking. CSE caused degradation of LAMP-2A protein via the lysosomal pathway by activating macroautophagy. Knock-down of LAMP-2A markedly enhanced CSE-induced expression of senescence markers such as p16, p21, p27, and p53. G2/M cell cycle arrest, up-regulation of cyclin B1, and apoptosis in BEAS-2B cells. Apoptosis was increased in CSE-treated primary HBECs and in lung tissues from smokers and COPD patients.Conclusion: Cigarette smoke-induced down-regulation of LAMP-2A is involved in acceleration of aging and apoptosis of lung epithelial cells, which might at least partially contribute to COPD pathogenesis.Keywords: COPD, LAMP-2A, lung epithelial cells, aging, apoptosis

Jae Hyun Kang,1 Il Tae Son,2 Byung Chun Kim,3 Jun Ho Park,4 Jeong Yeon Kim,1 Jong Wan Kim1 1Department of Surgery, Dongtan Sacred Heart Hospital, Hallym University College of Medicine, Hwaseong-si, Gyeonggi, 445-170, Republic of Korea; 2Department of Surgery, Hallym Sacred Heart Hospital, Hallym University College of Medicine, Anyang, 445-907, Republic of Korea; 3Department of Surgery, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, 150-950, Republic of Korea; 4Department of Surgery, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, 134-701, Republic of KoreaCorrespondence: Jong Wan Kim, Department of Surgery, Dongtan Sacred Heart Hospital, Hallym University College of Medicine, 40, Sukwoo-Dong, Hwaseong-Si, Gyeonggi-Do, 445-170, Republic of Korea, Tel +82 31-8086-2430, Fax +82 31-8086-2709, Email kjw0153@hanmail.netBackground: T4 tumor, lymphovascular invasion (LVI) and perineural invasion (PNI) are regarded as one of risk factors and associated with poor outcomes in colorectal cancer. The relationship between these three combined risk factors and the prognosis for colon cancer is not yet clear. The purpose of this study was to evaluate the prognostic value of combining the risk factors T4 tumor, LVI, and PNI in stage II–III colon cancer.Methods: Between January 2011 and December 2019, we retrospectively reviewed the medical records of patients who underwent curative resection for stage II–III colon cancer at four Hallym University-affiliated hospitals. These patients are categorized into three groups based on T4, LVI and PNI: no-risk group (no risk factors), low-risk group (one risk factor), and high-risk group (two or more risk factors).Results: Of 1684 patients, the incidence of no-, low-, and high-risk group were 49.3%, 32.6%, 18.0%, respectively. The median follow-up period was 48.9 months, and the 5-year recurrence-free survival (RFS) rate decreased from 78.5% to 58.7% as the number of risk factors increased (P < 0.001). Cox’s proportional hazard regression models showed that T4 (P < 0.001), LVI (P = 0.043), and PNI (P = 0.018) were independent prognostic factors for poor RFS. In subgroup analysis in stage II colon cancer, patients with one or more risk factors showed the better 5-year RFS rate when they received adjuvant chemotherapy than in those who did not (P < 0.001). Poor/mucinous differentiation, obstruction, and lymph-node positivity were independent predictors in the high risk group.Conclusion: The present study showed the histological combination of LVI, PNI, and T4 indicates a poor prognosis for RFS in patients with stage II–III colon cancer. Therefore, patients with one of these risk factors should be considered for chemotherapy and have close follow-up.Keywords: colon cancer, T4 tumor, lymphovascular invasion, perineural invasion

Jae-Kwang Lim,1 Byunggeon Park,1 Jongmin Park,1 Keum-Ju Choi,2 Chi-Young Jung,2 Young Hwan Kim,3 Jin Young Kim,4 Sungjun Moon,5 Yong Hoon Lee,6 Jaehee Lee6 1Department of Radiology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea; 2Department of Internal Medicine, Daegu Catholic University School of Medicine, Daegu, Republic of Korea; 3Department of Radiology, Daegu Catholic University School of Medicine, Daegu, Republic of Korea; 4Department of Radiology, Dongsan Hospital, Keimyung University School of Medicine, Daegu, Republic of Korea; 5Department of Radiology, College of Medicine, Yeungnam University, Daegu, Republic of Korea; 6Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of KoreaCorrespondence: Jaehee LeeDepartment of Internal Medicine, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, 41944, Daegu, Republic of KoreaTel +82-53-420-5536Fax +82-53-426-2046Email jaelee@knu.ac.krBackground: Chronic obstructive pulmonary disease (COPD) is considered a risk factor for poor outcomes in patients with coronavirus disease 2019 (COVID-19). However, data on the prognostic impact of radiological emphysema extent on patients with COVID-19 are limited. Thus, this study aimed to examine whether computed tomography (CT)-quantified emphysema score is associated with a worse clinical outcome in patients with COVID-19.Methods: Volumetric quantitative analyses of CT images were performed to obtain emphysema scores in COVID-19 patients admitted to four tertiary referral hospitals in Daegu, South Korea, between February 18 and March 25, 2020. Patients were divided into three groups according to emphysema score (emphysema score ≤ 1%, 1%< emphysema score ≤ 5%, and emphysema score > 5%).Results: A total of 146 patients with confirmed SARS-CoV-2 infection were included. The median emphysema score was 1.0% (interquartile range, 0.5– 1.8%). Eight patients (6%) had a previous COPD diagnosis. Eighty (55%), 55 (38%), and 11 (8%) patients had emphysema scores ≤ 1%, between 1% and 5%, and > 5%, respectively. The number of patients who received oxygen therapy two weeks after admission was significantly higher in the group with emphysema scores > 5% than in other groups (p=0.025). The frequency of deaths was three (27%) in the group with emphysema scores > 5% and tended to be higher than that in other groups. Multivariate analysis revealed that age, COPD, and serum lactate dehydrogenase levels were associated with a greater risk of in-hospital mortality in patients with COVID-19.Conclusion: The current study demonstrated that patients with CT-quantified emphysema scores > 5% tended to progress to severe disease over time; however, they did not exhibit an increased risk of mortality in our COVID-19 cohort. Further studies with consideration of both emphysema extent and airflow limitation degree are warranted.Keywords: COVID-19, emphysema, computed tomography, COPD, mortality

Yeon-Cheol Park,1,* Bon-Hyuk Goo,2,* Kyeong-Ju Park,3 Jun-Yeon Kim,3 Yong-Hyeon Baek1 1Department of Acupuncture & Moxibustion, College of Korean Medicine, Kyung Hee University, Seoul, 02447, South Korea; 2Department of Acupuncture & Moxibustion, Kyung Hee University Hospital at Gangdong, Seoul, 05278, South Korea; 3Department of Clinical Korean Medicine, Graduate School, Kyung Hee University, Seoul, 02447, South Korea*These authors contributed equally to this workCorrespondence: Yong-Hyeon BaekDepartment of Acupuncture & Moxibustion, College of Korean Medicine, Kyung Hee University, 26, Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, South KoreaTel +82 02 440 8642Fax +82 02 440 7770Email byhacu@khu.ac.krBackground: Knee osteoarthritis (OA) is a degenerative disease of the joint cartilage with no definite treatment in the early stage. Several previous review studies have shown that alternative medical treatments, including acupuncture, moxibustion, and herbal medicines, are effective in improving the symptoms of the disease and the patient’s quality of life. However, no systematic review study has shown the effectiveness of the combination of conventional and alternative therapies. Therefore, the aim of our study is to determine the most effective combination therapies and to provide evidence for the effectiveness and safety of integrated therapies. This article describes the protocol for the methods that will be applied in our systematic review.Methods: We will conduct an electronic search of nine databases: PubMed, Embase, Cochrane, Google Scholar (first 100 articles), four Korean databases (KoreaMed, Korean Studies Information Service System, Research Information Service System, and Oriental Medicine Advanced Searching Integrated System), and one Chinese database (China National Knowledge Infrastructure). Only randomized controlled studies that reported on both conventional treatment (drugs and hyaluronic acid) and traditional Korean medicine (acupuncture, moxibustion, and herbal medicines) will be selected. The primary outcomes will be pain and function of the joint. The secondary outcomes will include pain relief duration, total effective rate, incidence of adverse events, and quality of life. We will assess the methodological quality of the included studies using the Cochrane risk of bias tool. For the meta-analysis, standardized mean differences and risk ratios with 95% confidence intervals will be applied for continuous and dichotomous data, respectively.Results: This review will evaluate the effectiveness and safety of several Korean medicine treatments combined with conventional treatments for knee OA.Conclusion: Our review will provide a good foundation for the integrative treatment of knee OA.Keywords: acupuncture, herbal medicine, hyaluronic acid injection, knee osteoarthritis, moxibustion, NSAIDs

Jae Ik Kim,1,* Chang-Hyun Han,2,3,* Ju Hyun Jeon,1 Jin Youp Kim,4 Ojin Kwon,2 So-Young Jung,2 Jun-Hwan Lee,2,3 Changsop Yang,2 Eunseok Kim,1 Young Il Kim1 1Department of Acupuncture & Moxibustion Medicine, College of Korean Medicine, Daejeon University, Daejeon, Republic of Korea; 2Clinical Medicine Division, Korea Institute of Oriental Medicine, Daejeon, Republic of Korea; 3Korean Medicine Life Science, University of Science & Technology (UST), Campus of Korea Institute of Oriental Medicine, Daejeon, Republic of Korea; 4Department of Clinical Korean Medicine, Graduate School, Kyung Hee University, Seoul, Republic of Korea*These authors contributed equally to this workCorrespondence: Young Il KimDepartment of Acupuncture & Moxibustion Medicine, Daejeon University Daejeon Korean Medicine Hospital, 75, Daedeok-daero 176, Seo-gu, Daejeon, Republic of KoreaTel +82-42-470-9137Fax +82-42-477-9005Email omdkim01@dju.krEunseok KimDepartment of Acupuncture & Moxibustion Medicine, Daejeon University Seoul Korean Medicine Hospital, 32, Beobwon-ro 11, Songpa-gu, Seoul, Republic of KoreaTel +82-2-2222-8103Fax +82-2-2222-8111Email mybestcando@naver.comBackground: Thread embedding acupuncture (TEA) has recently been used as a conservative treatment method for non-specific chronic neck pain (CNP). The objective of this study was to evaluate the effectiveness and safety of TEA compared to physical therapy (PT) for treating patients with CNP.Methods: A total of 128 patients diagnosed with CNP were randomly assigned to a TEA group and a PT group at a 1:1 ratio. The TEA group received four sessions of TEA, while the PT group received eight sessions of PT over 4 weeks. Outcomes were assessed using Neck Pain and Disability Scale (NPDS), clinically important difference (CID), cervical spinal angle, Beck Depression Inventory II (BDI-II), Beck Anxiety Inventory (BAI), Patient Global Impression of Change (PGIC), and EuroQol Five-Dimension (EQ-5D) at baseline and 5, 9, and 13 weeks.Results: The TEA group showed significant improvement in NPDS compared to the PT group at 5, 9, and 13 weeks. Proportions of patients with decreased NPDS scores of more than 11.5 points (minimal CID) were significantly higher in the TEA group at 5, 9, and 13 weeks. There were significant differences between the two groups at 5, 9, and 13 weeks for BDI-II, and at 5 and 9 weeks for BAI. For EQ-5D, the TEA group showed significant improvement at 5, 9, and 13 weeks. There was no significant difference in cervical spinal angle between the two groups. For PGIC, better improvement was observed at 9 and 13 weeks in the TEA group. Adverse events associated with interventions were mostly temporary and mild.Conclusion: For patients with CNP, TEA treatment was found to be more effective than PT treatment for improving their pain and dysfunction, quality of life, and psychological distress. Despite some post-treatment discomfort, TEA treatment can be considered as a useful treatment method for patients with CNP.Trial Registration: This trial has been registered 5 April 2019 in Clinical Research Information Service of South Korea (CRIS- KCT0003720).Keywords: thread embedding acupuncture, physical therapy, non-specific chronic neck pain, randomized controlled trial

Priya Desai, Lorin Donovan, Elizabeth Janowitz, Joon Young Kim Department of Exercise Science, Syracuse University, Syracuse, NY, USACorrespondence: Joon Young KimDepartment of Exercise Science, Syracuse University, Women’s Building 204E, 820 Comstock Ave, Syracuse, NY 13244, USATel +1 315-443-1411Fax +1 315-443-9375Email jkim291@syr.eduAbstract: Type 2 diabetes is traditionally diagnosed by the use of an oral glucose tolerance test and/or HbA1c, both of which require serum collection. Various biomarkers, which are measurable biological substances that provide clinical insight on disease state, have also been effective in the early identification and risk prediction of inflammatory diseases. Measuring biomarker concentrations has traditionally been obtained through serum collection as well. However, numerous biomarkers are detectable in saliva. Salivary analysis has more recently been introduced into research as a potential non-invasive, cost-effective diagnostic for the early identification of type 2 diabetes risk in adults and youth. Therefore, the purpose of this review was to compare 6 established inflammatory biomarkers of type 2 diabetes, in serum and saliva, and determine if similar diagnostic effectiveness is seen in saliva. A lack of standardized salivary analysis, processing, and collection accounts for errors and inconsistencies in conclusive data amongst studies. Proposing a national standardization in salivary analysis, coupled with increased data and research on the utility of saliva as a diagnostic, poses the potential for salivary analysis to be used in diagnostic settings.Keywords: saliva, inflammation, type 2 diabetes, biomarkers, metabolic syndrome, oxidative stress

Jun Yeob Kim,1 Rusia Lee,1,2 Gu Xiao,1 Dominique Forbes,1 Jill Bargonetti1– 3 1The Department of Biological Sciences, Hunter College, City University of New York, New York, NY, USA; 2Biology PhD Program, The Graduate Center of Biology, City University of New York, New York, NY, USA; 3Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10021, USACorrespondence: Jill Bargonetti The Department of Biological SciencesHunter College, Belfer Building, 413 East 69 th Street, New York, NY 10021, USATel +1 212-896-0465Email bargonetti@genectr.hunter.cuny.eduBackground: Mouse double minute 2 (MDM2) is an E3 ubiquitin ligase that is over-expressed in many cancers and regulates target proteins through ubiquitination. Full-length MDM2 (MDM2-FL) is best known for targeting wild-type p53 for degradation by the proteasome, but the functions of the many splice variants of MDM2 are under-explored. The three well-studied alternative MDM2 isoforms are MDM2-A/ALT2, MDM2-B/ALT1, and MDM2-C/ALT3. MDM2-A and MDM2-B are capable of down-regulating MDM2-FL activity and have transforming activity in cancers with mutant p53. The MDM2 isoform MDM2-C is over-expressed in breast cancer and correlates with decreased survival in the context of mutant p53 expression. Therefore, MDM2-C requires further study to determine if it has biochemical activities similar to MDM2-FL. Hypothesis: We hypothesized that like MDM2-FL, the MDM2-C isoform (lacking exons 5– 9 and containing a full C-terminal RING finger sequence) would maintain E3 ubiquitin ligase activity.Materials and Methods: In order to explore the biochemical function of MDM2-C, we used an in vitro ubiquitination assay and a glutaraldehyde cross-linking assay.Results: Here we report, for the first time, that MDM2-C has E3 auto-ubiquitin ligase activity, which can promote ubiquitination of wild-type p53 and mutant p53 R273H, and also can form a protein–protein interaction with p53 proteins.Conclusion: This information strongly positions MDM2-C as a protein with biochemical activities that may explain the varied outcomes observed in patients with high-level expression of MDM2-C in the presence of wild-type p53 versus mutant p53.Keywords: MDM2 splice variants, mutant p53, wild-type p53, breast cancer

Jae Hee Won,1 Sung Min Kim,1 Jong Wan Kim,1 Jun Ho Park,2 Jeong Yeon Kim1 1Department of Surgery, Dongtan Sacred Hospital, Hallym University College of Medicine, KyungKee, Korea; 2Department of Surgery, Kangdong Sacred Hospital, Hallym University College of Medicine, KyungKee, KoreaCorrespondence: Jeong Yeon KimDepartment of Surgery, Dongtan Sacred Hospital, Hallym University College of Medicine, Seokwoodong 42, kyungkee 18450, Republic of KoreaTel +82 031 8 086 2430Fax +82 031 8 086 2029Email imanisia@hallym.or.krBackground: Colorectal mucosa-associated lymphoid tissue (MALT) lymphoma (cMALToma) is rare and comprises only 2.5% of the MALT lymphomas. Its etiology and treatment have not been well established. The aim of this systematic literature review was to try to characterize cMALToma and analyze the risk factors for treatment failure with various therapeutic strategies.Methods: We retrospectively reviewed 50 case reports from 1993 to 2017 through a PubMed search of English medical literature, describing cMALToma. We included 67 patients from previous case reports and we added 6 patients treated for cMALToma in our multicenter institutes. Risk factor analysis was done for treatment failure, defined as remission failure and recurrence.Results: Of 73 patients diagnosed with cMALToma, tumors were located in 54 patients (74.0%) in the rectum, in 10 patients (13.6%) in the right colon, in 3 patients (4.1%) in the transverse colon, and in 6 patients (8.2%) in the sigmoid colon. In first-line treatment, patients achieved complete remission (CR) with surgery (18/19 cases), local resection (18/19 cases), chemotherapy (12/13 cases), radiation therapy (4/5 cases), antibiotics therapy including Helicobacter pylori eradication (12/15 cases), and no treatment (1/2 cases). Among these, eight cases (10.9%) needed second-line treatment, and there was overall remission failure in 3 cases (4.1%). Of the remaining 70 patients with CR, the tumor recurred in 5 patients (6.8%). The multivariable analysis showed that male sex, multiple tumors, and first-line treatment failure were significantly related to treatment failure (p=0.03, p=0.05, p=0.03, respectively).Conclusion: CR of primary cMALToma was achieved using various therapeutic strategies. First-line treatment failure and multiple tumors were associated with treatment failure, although the numbers of cases that failed are too small to draw definitive conclusions.Keywords: MALT-associated lymphoma, colon, rectum, prognosis

Hong-Goo Lee,*,1 Yun-Sang Park,*,1 Jin-Hyuk Jeong,1 Yong-Bin Kwon,1 Dae Hwan Shin,1 Ju-Young Kim,2 Yun-Seok Rhee,3 Eun-Seok Park,4 Dong-Wook Kim,5 Chun-Woong Park11College of Pharmacy, Chungbuk National University, Cheongju 28160, South Korea; 2College of Pharmacy, Woosuk University, Wanju 55338, South Korea; 3College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju 52828, South Korea; 4School of Pharmacy, Sungkyunkwan University, Suwon 16419, South Korea; 5Department of Pharmaceutical Engineering, Cheongju University, Cheongju 28530, South Korea*These authors contributed equally to this workIntroduction: In this study, a dual release bi-layer tablet containing Fesoterodine fumarate (Fst) 5 mg and Mirabegron (Mrb) 50 mg was prepared to investigate the different release behavior of each drug in bilayer tablet. The bilayer tablet was prepared based on monolayer-tablet formulation of each drug.Methods: The optimized bi-layer tablet showed an in vitro dissolution profile similar to commercial reference tablets Toviaz and Betmiga, based on a satisfactory similarity factor. Drug-release kinetics of each drug in the bilayer tablet were evaluated based on dissolution profiles. Drug-release behavior was evaluated by observing the surface of each layer by scanning electron microscopy and measuring the changes in weight and volume of the tablet during dissolution. Drug transfer between each layer was also investigated by Fourier -transform infrared spectroscopic imaging by observing the cross-section of the bilayer tablet cut vertically during dissolution.Results: The release of Fst was well suited for the Higuchi model, and the release of Mrb was well suited for the Hixson-crowell model. Compared with dissolution rate of each monolayer tablet, that of Fst in the bilayer tablet was slightly reduced (5%), but the dissolution rate of Mrb in bilayer tablet was dramatically decreased (20%). Also, a drug-release study confirmed that polymer swelling was dominant in Fst layer compared with polymer erosion, and degradation was dominant in MRB layer. Fourier-transform infrared imaging and 3-D image reconstruction showed that drug transfer in the bilayer tablet correlates with the results of drug-release behavior.Conclusion: These findings are expected to provide scientific insights in the development of a dual-release bilayer drug-delivery system for Fst and Mrb.Keywords: mirabegron, fesoterodine fumarate, swelling property, erosion property, bilayer tablet, FT-IR imaging

Ji-Youn Kim,1 Hyun Chul Song,1 Hyeon-Gun Jee21Division of Oral & Maxillofacial Surgery, Department of Dentistry, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; 2Healthcare Innovation Park, Seoul National University Bundang Hospital, Seongnam, Republic of KoreaPurpose: Osteonecrosis of the jaw (ONJ), both medication-related and non medication-related, mainly occurs in aged patients. It needs surgical intervention. Refractory healing after an operation of ONJ can significantly lower the quality of life of elderly patients. The purpose of this study was to determine risk factors associated with refractory healing in aged patients.Patients and methods: We performed a retrospective study of ONJ in aged patients who underwent surgical treatments in a single institute during a 12-year period. Multiple logistic regression analysis was used to determine independent risk factors associated with refractory healing.Results: A total of 122 patients were included. Of them, 25 patients were identified as the refractory group and 97 patients as the control group. Diabetes mellitus (DM) (AOR=5.03, 95% CI: 1.74–14.52) and glucocorticoid administration (AOR=7.97, 95% CI: 2.52–25.23) were found to be significant risk factors for refractory healing of ONJ.Conclusion: DM and medication of glucocorticoid might be risk factors for refractory healing of ONJ.Keywords: osteomyelitis, osteonecrosis, medication-related osteonecrosis of the jaw, surgical therapy, refractory healing, diabetes mellitus, glucocorticoid

Seung Jun Lee,1 Sang Suk Yun,1 Sunmi Ju,1 Jung Wan You,1 Yu Ji Cho,1 Yi Yeong Jeong,1 Ju-Young Kim,2 Ho Cheol Kim,2 Jong Deog Lee11Division of Pulmonology and Allergy, Department of Internal Medicine, Gyeongsang National University Hospital, Gyeongsang National University School of Medicine, Jinju, Republic of Korea; 2Division of Pulmonology and Allergy, Department of Internal Medicine, Gyeongsang National University Changwon Hospital, Changwon, Gyeongsang National University School of Medicine, Jinju, Republic of KoreaBackground: The Global Initiative for Chronic Obstructive Lung Disease (GOLD) released an updated document in 2017 that excluded the spirometric parameter in the classification of patients. The validity of this new classification system in predicting mortality and respiratory hospitalization is still uncertain.Methods: Outpatients (n=149) with chronic obstructive pulmonary disease (COPD) who underwent spirometry and six-minutes walking test from October 2011 to September 2013 were enrolled. The overall mortality and rate of respiratory hospitalization over a median of 61 months were analyzed. Kaplan-Meier survival analyses, receiver operaing curve analyses with areas under the curve (AUCs), and logistic regression analyses for GOLD 2007, GOLD 2011, GOLD 2017, and/or BODE index were performed to evaluate their abilities to predict mortality and respiratory hospitalization.Results: Forty-two (53.2%) patients in 2011 GOLD C or D group were categorized into 2017 GOLD A or B group. The odds ratios of GOLD 2017 group C and group D relative to group A were 7.55 (95% CI, 1.25–45.8) and 25.0 (95% CI, 6.01–102.9) for respiratory hospitalization. Patients in GOLD 2017 group A and group B had significantly better survival (log-rank test, p

Minkyung Oh,1 Jae-Gook Shin,1,2 Sangzin Ahn,1 Bo Hoon Kim,3 Ji Yeon Kim,3 Hyun Ju Shin,4 Hyun Ju Shin,4 Jong-Lyul Ghim1,21Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, Republic of Korea; 2Department of Clinical Pharmacology, Inje University Busan Paik Hospital, Busan, Republic of Korea; 3Formulation Research Team, Seoul, Daewoong Pharma, Republic of Korea; 4Clinical Research Team, Daewoong Pharma, Seoul, Republic of KoreaObjective: The aim of this study was to compare the pharmacokinetic (PK) and safety profiles of a fixed dose combination (FDC) formulation and co-administration of amlodipine, olmesartan, and rosuvastatin.Materials and methods: This study was an open-label, randomized, cross-over design conducted in healthy male volunteers. All subjects received either a single FDC tablet containing amlodipine 10 mg/olmesartan 40 mg/rosuvastatin 20 mg, or were co-administered an FDC tablet containing amlodipine 10 mg/olmesartan 40 mg and a tablet containing rosuvastatin 20 mg, for each period, with 14-day washout periods. Plasma concentrations of amlodipine, olmesartan, and rosuvastatin were measured by liquid chromatography tandem mass spectrometry. Safety was evaluated by measuring vital signs, clinical laboratory parameters, physical examinations, and medical interviews.Results: Sixty-four subjects were enrolled, and 54 completed the study. The geometric mean ratios and 90% CI for the maximum plasma concentration (Cmax) and area under the curve from time zero to the last sampling time (AUCt) were 1.0716 (1.0369,1.1074) and 1.0497 (1.0243,1.0757) for amlodipine, 1.0396 (0.9818,1.1009) and 1.0138 (0.9716,1.0578) for olmesartan, and 1.0257 (0.9433,1.1152) and 1.0043 (0.9453,1.0669) for rosuvastatin. Fourteen cases of adverse events occurred in 12 subjects. There was no statistically significant clinical difference between the formulation groups.Conclusion: The 90% CI of the primary PK parameters were within the acceptance bioequivalence criteria, which is ln (0.8) and ln (1.25). These results indicate that the FDC formulation and co-administration of amlodipine, olmesartan and rosuvastatin are pharmacokinetically bioequivalent and have similar safety profiles.Keywords: fixed-dose combination, pharmacokinetics, amlodipine, olmesartan, rosuvastatin

Moon SU, Kim J, Bokara KK, et al. Int J Nanomedicine. 2012;7:2751– 2765. The authors have advised Figure 5 on page 2760 is incorrect. Due to an error at the time of figure assembly the images for Figure 5B and 5F were duplicated. The authors did not pick this error up during the proof-reading stage of the publication. The correct Figure 5 is shown in Download Article. Figure 5 Doublecortin and bromodeoxyuridine staining was performed to detect the migrating exogenous subventricular zone neural progenitor cells in the hydrophilic or hydrophobic carbon nanotubes transplantation groups (A and D) 3 weeks or (E and H) 5 weeks after middle cerebral artery occlusion injury. The images show (A and E) the experimental control group (without subventricular zone neural progenitor cell transplantation), (B and F) injury-subjected rats transplanted with subventricular zone neural progenitor cells, (C and G) injury-subjected rats transplanted with hydrophilic carbon nanotubes impregnated with subventricular zone neural progenitor cells, and (D and H) injury-subjected rats transplanted with hydrophobic carbon nanotubes impregnated with subventricular zone neural progenitor cells. Notes: Doublecortin and bromodeoxyuridine double positive immunostained cells are indicated by yellow. Scale bars = 50 µm.Abbreviations: BrdU, bromodeoxyuridine; DAPI, 4′,6-diamidino-2-phenylindole; DCX, doublecortin. The authors apologize for this error and advise that this does not affect the results of the paper. Read the original article

Dae Hun Kim,1,* Jae Yeol Kim,1,* Rae Man Kim,1 Pooja Maharjan,1 Yu-Geun Ji,2 Dong-Jin Jang,3 Kyoung Ah Min,1 Tae-Sung Koo,2 Kwan Hyung Cho1 1Department of Pharmacy, Inje Institute of Pharmaceutical Sciences and Research, Inje University, Gimhae, Republic of Korea; 2Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon, Republic of Korea; 3Department of Pharmaceutical Engineering, Inje University, Gimhae, Republic of Korea *These authors contributed equally to this work Background: The present study aimed to develop orlistat-loaded solid self-nanoemulsifying drug delivery system preconcentrate (SSP) with the minimum use of lipid excipients for the enhanced solubility, in vitro dissolution, lipase inhibition, and in vivo performance. Materials and methods: In the screening of solubilizing vehicles, Solutol HS15 and Lauroglycol 90 were selected as the surfactant and oil phase, respectively. A pseudo-ternary phase diagram composed of Solutol HS15, Lauroglycol 90, and orlistat as an anti-obesity agent and lipid component was constructed, and the SSP regions were confirmed in terms of the particle size distribution in water, melting point by differential scanning calorimetry, and crystallinity by X-ray diffraction. Results: Physicochemical interaction between Solutol HS15 and orlistat resulted in SSP with various melting points in the range of 26°C~33°C. The representative maximum orlistat-loaded SSP (orlistat/Solutol HS15/Lauroglycol 90=55/40/5, weight ratio) showed the melting point of 32.23°C and constructed uniform nanoemulsion with the particle size of 141.7±1.1 nm dispersed in water. In the dissolution test at pH 1.2 without any detergent, the SSP reached 98.12%±0.83% until 45 minutes, whereas raw orlistat showed no significant dissolution rate. The dissolution samples containing SSP showed a lipase inhibition of 90.42%±1.58% within 45 minutes. In terms of the reduction level of fat absorption in rats, the intake group of SSP gave a significantly higher fat excretion into stool than the one observed in the raw orlistat group (P

Francis O Obiweluozor,1,2,* Gladys A Emechebe,3,* Arjun Prasad Tiwari,3 Ju Yeon Kim,1 Chan Hee Park,1,3 Cheol Sang Kim1,3 1Division of Mechanical Design Engineering, Chonbuk National University, Jeonju City, Republic of Korea; 2Department of Chemical Engineering, Enugu State University of Science and Technology, Enugu State, Nigeria; 3Department of Bionanosystem Engineering Graduate School, Chonbuk National University, Jeonju City, Republic of Korea *These authors contributed equally to this work Background: The objective of this study was to evaluate the efficacy of a combination of Photothermal therapy (PTT) and chemotherapy in a single nano-fiber platform containing lethal polydopamine nano-pheres (PD NPs) for annihilation of CT 26 cancer cells.Method: Polydioxanone (PDO) nano-fiber containing PD and bortezomib (BTZ) was fabricated via electrospinning method. The content of BTZ and PD after optimization was 7% and 2.5% respectively with respect to PDO weight. PD NPs have absorption band in near-infrared (NIR) with resultant rapid heating capable of inducing cancer cell death. The samples was divided into three groups – PDO, PDO+PD, and PDO+PD-BTZ for analysis.Results: In combined treatment, PDO nano-fiber alone could not inhibit cancer cell growth as it neither contain PD or BTZ. However, PDO+PD fiber showed a cell viability of approximately 20% after 72 hr of treatment indicating minimal killing via hyperthermia. In the case of PDO composite fiber containing BTZ, the effect of NIR irradiation reduced the viability of cancer cells down to around 5% after 72 h showing the efficiency of combination therapy on cancer cells elimination. However, due to higher photothermal conversion that may negatively affect normal cells above 46°C, we have employed 1 s “OFF” and 2 s “ON” after initial 9 s continuous irradiation to maintain the temperature between 42 and 46°C over 3 mins of treatment using 2 W/cm2; 808 nm laser which resulted to similar cell death.Conclusion: In this study, combination of PTT and chemotherapy treatment on CT 26 colon cancer cells within 3 min resulted in effective cell death in contrast to single treatment of either PTT and chemotherapy alone. Our results suggest that this nano-fiber device with efficient heating and remote control drug delivery system can be useful and convenient in the future clinical application for localized cancer therapy. Keywords: electrospinning, polydopamine nanospheres, chemotherapy, photothermal therapy, electrospun nano-fiber, Bortezomib, local treatment, combination cancer therapy

Yeon-Mok Oh,1,* Keu Sung Lee,2,* Yoonki Hong,3,* Sung Chul Hwang,2 Jae Yeol Kim,4 Deog Keom Kim,5 Kwang Ha Yoo,6 Ji-Hyun Lee,7 Tae-Hyung Kim,8 Seong Yong Lim,9 Chin Kook Rhee,10 Hyoung Kyu Yoon,11 Sang Yeub Lee,12 Yong Bum Park,13 Jin Hee Jung,14 Woo Jin Kim,3 Sang-Do Lee,1 Joo Hun Park2 1Department of Pulmonary and Critical Care Medicine and Clinical Research Center for Chronic Obstructive Airway Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; 2Department of Pulmonary and Critical Care Medicine, Ajou University School of Medicine, Suwon, Korea; 3Department of Internal Medicine and Environmental Health Center, Kangwon National University, Kangwon National University Hospital, Chuncheon, Korea; 4Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea; 5Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea; 6Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea; 7Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea; 8Division of Pulmonology, Department of Internal Medicine, Hanyang University College of Medicine, Guri, Korea; 9Division of Pulmonary and Critical Care Medicine, Department of Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea; 10Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Seoul St Mary’s Hospital, Catholic University of Korea, Seoul, Korea; 11Division of Respiratory and Critical Care Medicine, Department of Internal Medicine, College of Medicine, Korea University Anam Hospital, Seoul, Korea; 12Division of Respiratory and Critical Care Medicine, Department of Internal Medicine, College of Medicine, Korea University Anam Hospital, Seoul, Korea; 13Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Hallym University Kangdong Sacred Heart Hospital, Seoul, Korea; 14Department of Biomedical Informatics, Ajou University School of Medicine, Suwon, Korea *These authors contributed equally to this work Background: High blood eosinophil count is a predictive biomarker for response to inhaled corticosteroids in prevention of acute exacerbation of COPD, and low blood eosinophil count is associated with pneumonia risk in COPD patients taking inhaled corticosteroids. However, the prognostic role of blood eosinophil count remains underexplored. Therefore, we investigated the associated factors and mortality based on blood eosinophil count in COPD.Methods: Patients with COPD were recruited from 16 hospitals of the Korean Obstructive Lung Disease cohort (n=395) and COPD in Dusty Area cohort (n=234) of Kangwon University Hospital. The two merged cohorts were divided based on blood eosinophil count into three groups: high (≥5%), middle (2%–5%), and low (

Do-Hyeong Kim,1 Seokyung Shin,1 Ji Young Kim,1 Seung Hyun Kim,2 Minju Jo,2 Yong Seon Choi1 1Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea; 2Department of Anesthesiology and Pain Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea Background: This study investigated the ability of pulse pressure variation (PPV) and pleth variability index (PVI) to predict fluid responsiveness of patients undergoing spinal surgery in the prone position.Patients and methods: A total of 53 patients undergoing posterior lumbar spinal fusion in the prone position on a Jackson table were studied. PPV, PVI, and hemodynamic and respiratory variables were measured both before and after the administration of 6 mL/kg colloid in both the supine and prone positions. Fluid responsiveness was defined as a 15% or greater increase in stroke volume index, as assessed by esophageal Doppler monitor after fluid loading.Results: In the supine position, 40 patients were responders. The areas under the receiver operating characteristic (ROC) curves for PPV and PVI were 0.783 [95% CI 0.648–0.884, P

Hye Jung Park,1 Min Kwang Byun,1 Hyung Jung Kim,1 Jae Yeol Kim,2 Yu-Il Kim,3 Kwang-Ha Yoo,4 Eun Mi Chun,5 Ji Ye Jung,6 Sang Haak Lee,7 Chul Min Ahn1 On behalf of the Korean Smoking Cessation Study Group 1Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, 2Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, 3Department of Internal Medicine, Chonnam National University Hospital, Gwangju, 4Department of Internal Medicine, Konkuk University School of Medicine, 5Department of Internal Medicine, Ewha Womans University School of Medicine, 6Division of Pulmonology, Department of Internal Medicine, Institute of Chest Disease, Severance Hospital, Yonsei University College of Medicine, 7Division of Pulmonology, Critical Care and Sleep Medicine, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea Background: Vitamin C, as an antioxidant, has recently been suggested to provide protection against COPD; however, only few national cohort studies have investigated these effects. We aimed to confirm the protective effects of vitamin C against COPD in Korean patients. Patients and methods: We analyzed the data of 3,283 adults aged ≥40 years (representing 23,541,704 subjects) who underwent pulmonary function tests and responded to questionnaires on smoking history and vitamin C intake, with stratification variables and sampling weight designated by the Korea 2012 National Health and Nutrition Examination Survey. Results: Among all the subjects, 512 (representing 3,459,679 subjects; 15.6%) were diagnosed as having COPD based on pulmonary function test results. Male gender, old age, residence in suburban/rural regions, low household income, low educational level, an occupation in agriculture or fisheries, and heavy smoking were significantly associated with COPD. Low intake of nutrients, including potassium, vitamin A, carotene, retinol, and vitamin C, was significantly associated with COPD. The prevalence of COPD in heavy smokers with the lowest quartile (Q1, 141.63 mg; 32.6%) of vitamin C intake (P=0.015). In multivariate analysis, male gender, old age, heavy smoking, and a low intake of vitamin C were significant independent risk factors for COPD. A significant reduction of 76.7% in COPD risk was observed with a Q3 vitamin C intake compared to Q1 vitamin C intake (odds ratio, 0.233; 95% confidence interval, 0.094-0.576) in heavy smokers. Conclusion: This large-scale national study suggests that dietary vitamin C provides protection against COPD, independent of smoking history, in the general Korean population. Keywords: chronic obstructive lung disease, vitamin C, nutrition, risk factor, smoking

Ji Young Yoo,1 Jong Yeop Kim,1 Hyun Jeong Kwak,2 Dong Chul Lee,2 Go Wun Kim,1 Sook Young Lee,1 Yun Jeong Chae1 1Department of Anaesthesiology and Pain Medicine, Ajou University School of Medicine, Suwon, 2Department of Anaesthesiology and Pain Medicine, Gachon University, Gil Medical Center, Incheon, Korea Purpose: Prevention of cough during emergence after nasal surgery is important for avoiding surgical site bleeding. We investigated the remifentanil effect-site concentration in 50% (EC50) of the elderly patients undergoing nasal surgery for smooth emergence without cough and compared it with that of adult patients.Methods: Twenty-two elderly (aged 65–80 years) and 25 adult patients (aged 20–60 years) with an American Society of Anesthesiologists physical status I/II undergoing nasal surgery were enrolled. Anesthesia was maintained with sevoflurane and remifentanil. Remifentanil EC50 and EC95 for preventing cough were determined using the modified Dixon’s up-and-down method and isotonic regression with bootstrapping approach. Recovery profiles were also recorded.Results: With Dixon’s up-and-down method, the EC50 of remifentanil in elderly patients (2.40±0.25 ng/mL) was not significantly different from that of adults (2.33±0.30 ng/mL) (P=0.687). With isotonic regression, the EC95 of remifentanil in elderly patients (3.32 [95% confidence interval: 3.06–3.38] ng/mL) was not significantly different from that of adults (3.30 [95% confidence interval: 2.96–3.37] ng/mL). However, eye opening time (14.1±3.8 vs 12.0±2.9 seconds), extubation time (17.2±4.1 vs 14.0±3.0 seconds), and postanesthesia care unit duration (44.5±7.6 vs 38.7±3.4 minutes) in elderly patients were significantly longer than those in adults (P

Jong Hwa Jun,1 Wern-Joo Sohn,2 Youngkyun Lee,2 Jae-Young Kim21Department of Ophthalmology, School of Medicine, Dongsan Medical Center, Keimyung University, 2Department of Oral Biochemistry, School of Dentistry, IHBR, Kyungpook National University, Daegu, South KoreaAbstract: The molecular and cellular effects of anti-vascular endothelial growth factor monoclonal antibody (bevacizumab) on lens epithelial cells (LECs) were examined using both an immortalized human lens epithelial cell line and a porcine capsular bag model. After treatment with various concentrations of bevacizumab, cell viability and proliferation patterns were evaluated using the water-soluble tetrazolium salt assay and 5-bromo-2'-deoxyuridine enzyme-linked immunosorbent assay, respectively. The scratch assay and Western blot analysis were employed to validate the cell migration pattern and altered expression levels of signaling molecules related to the epithelial–mesenchymal transition (EMT). Application of bevacizumab induced a range of altered cellular events in a concentration-dependent manner. A 0.1–2 mg/mL concentration demonstrated dose-dependent increase in proliferation and viability of LECs. However, 4 mg/mL decreased cell proliferation and viability. Cell migrations displayed dose-dependent retardation from 0.1 mg/mL bevacizumab treatment. Transforming growth factor-β2 expression was markedly increased in a dose-dependent manner, and α-smooth muscle actin, matrix metalloproteinase-9, and vimentin expression levels showed dose-dependent changes in a B3 cell line. Microscopic observation of porcine capsular bag revealed changes in cellular morphology and a decline in cell density compared to the control after 2 mg/mL treatment. The central aspect of posterior capsule showed delayed confluence, and the factors related to EMT revealed similar expression patterns to those identified in the cell line. Based on these results, bevacizumab modulates the proliferation and viability of LECs and induces morphological alterations through the modulation of expression patterns of specific factors related to the EMT.Keywords: avastin, bevacizumab, lens epithelial cell, transforming growth factor, vascular endothelial growth factor

Ju-Young Kim,1,* Sung-Hoon Lee,2,3,* Chun-Woong Park,4 Yun-Seok Rhee,5 Dong-Wook Kim,6 Junsang Park,3 Moonseok Lee,3 Jeong-Woong Seo,2 Eun-Seok Park2 1College of Pharmacy, Woosuk University, Wanju-gun, Republic of Korea; 2School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea; 3GL Pharmtech, Seongnam, Republic of Korea; 4College of Pharmacy, Chungbuk National University, Cheongju, Republic of Korea; 5College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju, Republic of Korea; 6Department of Pharmaceutical Engineering, Cheongju University, Cheongju, Republic of Korea *These authors contributed equally to this work Abstract: The aim of present study was to design oxycodone once-a-day controlled-release (CR) tablets and to perform in vitro/in vivo characterizations. Release profiles to achieve desired plasma concentration versus time curves were established by using simulation software and reported pharmacokinetic parameters of the drug. Hydroxypropyl methylcellulose (HPMC) 100,000 mPa·s was used as a release modifier because the polymer was found to be resistant to changes in conditions of the release study, including rotation speed of paddle and ion strength. The burst release of the drug from the CR tablets could be suppressed by applying an additional HPMC layer as a physical barrier. Finally, the oxycodone once-a-day tablet was comprised of two layers, an inert HPMC layer and a CR layer containing drug and HPMC. Commercial products, either 10 mg bis in die (bid [twice a day]) or once-a-day CR tablets (20 mg) were administered to healthy volunteers, and calculated pharmacokinetic parameters indicated bioequivalence of the two different treatments. The findings of the present study emphasize the potential of oxycodone once-a-day CR tablets for improved patient compliance, safety, and efficacy, which could help researchers to develop new CR dosage forms of oxycodone. Keywords: pharmacokinetics, oral delivery, in vitro–in vivo correlation, double-layer tablet

Hyun Ho Kim,1 Jae Young Kim,1 Sung Jun Kim,1,2 Eun Su Park,3 Seok Joon Shin,1,2 Kwi Young Kang,1,4 Yeon Sik Hong,1,4 Hye Eun Yoon1,21Department of Internal Medicine, College of Medicine, The Catholic University of Korea, 2Division of Nephrology, Department of Internal Medicine, Incheon St Mary's Hospital, 3Department of Pathology, Incheon St Mary's Hospital, 4Division of Rheumatology, Department of Internal Medicine, Incheon St Mary's Hospital, Incheon, Republic of KoreaAbstract: Polymyositis is a rare and gradually progressive autoimmune disease of skeletal muscle. Two main types of renal involvement have been described: acute tubular necrosis related to rhabdomyolysis and glomerulonephritis. However, cases of overflow proteinuria related to polymyositis have rarely been reported. Herein, we report a case of a 41-year-old male who presented with edema of both lower extremities. Laboratory studies revealed elevated creatine phosphokinase level, hypoalbuminemia, and a moderate amount of proteinuria, although albuminuria was not dominant. Urine electrophoresis showed an abnormally restricted zone in the β-fraction, which suggested overflow proteinuria of non-glomerular origin. Despite intravenous hydration, his serum creatine phosphokinase level did not decrease and his symptoms did not improve. Electromyography showed myopathy, and muscle biopsy revealed findings consistent with polymyositis. After corticosteroid therapy, his creatine phosphokinase level and proteinuria decreased and his clinical symptoms improved. This case demonstrates an atypical presentation of polymyositis manifested by overflow proteinuria.Keywords: polymyositis, proteinuria, rhabdomyolysis

Joo-Yeon Kim,1,* Mak-Soon Lee,1,* Sunyoon Jung,1 Hyunjin Joo,1 Chong-Tai Kim,2 In-Hwan Kim,3 Sangjin Seo,1 Soojung Oh,1 Yangha Kim11Department of Nutritional Science and Food Management, Ewha Womans University, Seoul, Republic of Korea; 2Functional Materials Research Group, Korea Food Research Institute, Seongnam, Gyeonggi, Republic of Korea; 3Department of Food and Nutrition, Korea University, Seoul, Republic of Korea *These authors contributed equally to this workPurpose: This study determined the effects of oleoresin capsicum (OC) and nanoemulsion OC (NOC) on obesity in obese rats fed a high-fat diet.Methods: The rats were randomly separated into three groups: a high-fat (HF) diet group, HF + OC diet group, and HF + NOC diet group. All groups were fed the diet and water ad libitum for 14 weeks.Results: NOC reduced the body weight and adipose tissue mass, whereas OC did not. OC and NOC reduced mRNA levels of adipogenic genes, including peroxisome proliferator-activated receptor (PPAR)-γ, sterol regulatory element-binding protein-1c, and fatty acid-binding protein in white adipose tissue. The mRNA levels of genes related to β-oxidation or thermogenesis including PPAR-α, palmitoyltransferase-1α, and uncoupling protein-2 were increased by the OC and NOC relative to the HF group. Both OC and NOC clearly stimulated AMP-activated protein kinase (AMPK) activity. In particular, PPAR-α, palmitoyltransferase-1α, uncoupling protein-2 expression, and AMPK activity were significantly increased in the NOC group compared to in the OC group. NOC decreased glycerol-3-phosphate dehydrogenase activity whereas OC did not.Conclusion: From these results, NOC could be suggested as a potential anti-obesity agent in obese rats fed a HF diet. The effects of the NOC on obesity were associated with changes of multiple gene expression, activation of AMPK, and inhibition of glycerol-3-phosphate dehydrogenase in white adipose tissue.Keywords: oleoresin capsicum, nanoemulsion, anti-obesity, gene expression, AMP-activated protein kinase, rats

Ho Il Yoon,1 Chang-Hoon Lee,2 Deog Kyeom Kim,3 Geun Min Park,4 Sang-Min Lee,2 Jae-Joon Yim,2 Jae-Yeol Kim,5 Jae Ho Lee,1 Choon-Taek Lee,1 Hee Soon Chung,3 Young Whan Kim,2 Sung Koo Han,2 Chul-Gyu Yoo2 1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine and Lung Institute, Seoul National University Bundang Hospital, Seongnam-si, Republic of Korea; 2Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine and Lung Institute, Seoul National University College of Medicine, Seoul, Republic of Korea; 3Division of Pulmonology, Department of Internal Medicine, Seoul National University Boramae Hospital, Seoul, South Korea; 4Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine, Dongguk University Ilsan Hospital, Dongguk University College of Medicine, Goyang, Republic of Korea; 5Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Republic of Korea Background: Antibiotic treatment is one of the major pharmacologic treatments for acute exacerbation of chronic obstructive pulmonary disease (AECOPD). However, the choice of antibiotic depends on the local resistance pattern. A multicenter, randomized, controlled trial was done in patients with AECOPD to compare the efficacy of levofloxacin with that of cefuroxime axetil. Methods: Patients with AECOPD and without radiographic evidence of pneumonia were enrolled and randomized to either levofloxacin 500 mg daily or cefuroxime 250 mg twice daily in the mild-moderate exacerbation group, or 500 mg twice daily in the severe exacerbation group, for seven days. Clinical efficacy and microbiologic response were evaluated 5–7 days after the last dose. Results: Treatment was clinically successful in 90.4% of patients in the levofloxacin group, and in 90.6% of patients in the cefuroxime group (95% confidence interval -9.40 to 10.91), within a noninferiority margin of 10%. The microbiologic response appeared to be higher in the levofloxacin group, but the difference was not statistically significant. The safety profile was similar in both groups. Conclusion: Levofloxacin is not inferior to cefuroxime with regard to clinical efficacy in treating AECOPD. Keywords: chronic obstructive pulmonary disease, acute exacerbation, levofloxacin, cefuroxime

Sung Ung Moon,1,* Jihee Kim,1,2,* Kiran Kumar Bokara,1,* Jong Youl Kim,1 Dongwoo Khang,3,4 Thomas J Webster,3,4 Jong Eun Lee1,21Department of Anatomy, 2Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea; 3School of Engineering, 4Department of Orthopedics, Brown University, Providence, RI, USA*These authors contributed equally to this workAbstract: The present in vivo study was conducted to evaluate whether hydrophilic (HL) or hydrophobic (HP) carbon nanotubes (CNTs) impregnated with subventricular zone neural progenitor cells (SVZ NPCs) could repair damaged neural tissue following stroke. For this purpose, stroke damaged rats were transplanted with HL CNT-SVZ NPCs, HP CNT-SVZ NPCs, or SVZ NPCs alone for 1, 3, 5, and 8 weeks. Results showed that the HP CNT-SVZ NPC transplants improved rat behavior and reduced infarct cyst volume and infarct cyst area compared with the experimental control and the HL CNT-SVZ NPC and SVZ NPCs alone groups. The transplantation groups showed an increase in the expression of nestin (cell stemness marker) and proliferation which was evident with the increased number of doublecortin and bromodeoxyuridine double-stained immunopositive cells around the lesion site. But, these effects were more prominent in the HP CNT-SVZ NPC group compared with the other transplantation groups. The HP CNT-SVZ NPC and HL CNT-SVZ NPC transplants increased the number of microtubule-associated protein 2 (marker for neurons) and decreased the number of glial fibrillary acidic protein (marker for astroglial cells) positive cells within the injury epicenter. The majority of the transplanted HP CNT-SVZ NPCs collectively broadened around the ischemic injured region and the SVZ NPCs differentiated into mature neurons, attained the synapse morphology (TUJ1, synaptophysin), and decreased microglial activation (CD11b/c [OX-42]). For these reasons, this study provided the first evidence that CNTs can improve stem cell differentiation to heal stroke damage and, thus, deserve further attention.Keywords: biocompatibility, brain, in vivo, stem cell, wettability, carbon nanotubes, stroke

The high-precision X-ray diffraction setup for work with diamond anvil cells (DACs) in interaction chamber 2 (IC2) of the High Energy Density instrument of the European X-ray Free-Electron Laser is described. This includes beamline optics, sample positioning and detector systems located in the multipurpose vacuum chamber. Concepts for pump-probe X-ray diffraction experiments in the DAC are described and their implementation demonstrated during the First User Community Assisted Commissioning experiment. X-ray heating and diffraction of Bi under pressure, obtained using 20 fs X-ray pulses at 17.8 keV and 2.2 MHz repetition, is illustrated through splitting of diffraction peaks, and interpreted employing finite element modeling of the sample chamber in the DAC.

As a baryon number violating process with ΔB=2, neutron-antineutron oscillation (n→n¯) provides a unique test of baryon number conservation. We have performed a search for n→n¯ oscillation with bound neutrons in Super-Kamiokande, with the full dataset from its first four run periods, representing an exposure of 0.37 Mton-years. The search used a multivariate analysis trained on simulated n→n¯ events and atmospheric neutrino backgrounds and resulted in 11 candidate events with an expected background of 9.3 events. In the absence of statistically significant excess, we derived a lower limit on n¯ appearance lifetime in O16 nuclei of 3.6×1032 years and on the neutron-antineutron oscillation time of τn→n¯>4.7×108 s at 90% C.L.

We have searched for proton decay via p→e+π0 and p→μ+π0 modes with the enlarged fiducial volume data of Super-Kamiokande from April 1996 to May 2018, which corresponds to 450 kton·years exposure. We have accumulated about 25% more livetime and enlarged the fiducial volume of the Super-Kamiokande detector from 22.5 kton to 27.2 kton for this analysis, so that 144 kton·years of data, including 78 kton·years of additional fiducial volume data, has been newly analyzed. No candidates have been found for p→e+π0 and one candidate remains for p→μ+π0 in the conventional 22.5 kton fiducial volume and it is consistent with the atmospheric neutrino background prediction. We set lower limits on the partial lifetime for each of these modes: τ/B(p→e+π0)>2.4×1034 years and τ/B(p→μ+π0)>1.6×1034 years at 90% confidence level.

We present a search for an excess of neutrino interactions due to dark matter in the form of weakly interacting massive particles (WIMPs) annihilating in the Galactic center or halo based on the data set of Super-Kamiokande-I, -II, -III and -IV taken from 1996 to 2016. We model the neutrino flux, energy, and flavor distributions assuming WIMP self-annihilation is dominant to νν¯, μ+μ-, bb¯, or W+W-. The excess is in comparison to atmospheric neutrino interactions which are modeled in detail and fit to data. Limits on the self-annihilation cross section σ are derived for WIMP masses in the range 1 GeV to 10 TeV, reaching as low as 9.6×10-23 cm3 s-1 for 5 GeV WIMPs in bb¯ mode and 1.2×10-24 cm3 s-1 for 1 GeV WIMPs in νν¯ mode. The obtained sensitivity of the Super-Kamiokande detector to WIMP masses below several tens of GeV is the best among similar indirect searches to date.

A search for proton decay into three charged leptons has been performed by using 0.37 Mton·years of data collected in Super-Kamiokande. All possible combinations of electrons, muons, and their antiparticles consistent with charge conservation were considered as decay modes. No significant excess of events has been found over the background, and lower limits on the proton lifetime divided by the branching ratio have been obtained. The limits range between 9.2×1033 and 3.4×1034 years at 90% confidence level, improving by more than an order of magnitude upon limits from previous experiments. A first limit has been set for the p→μ-e+e+ mode.

We report a search for astronomical neutrinos in the energy region from several GeV to TeV in the direction of the blazar TXS 0506+056 using the Super-Kamiokande detector following the detection of a 100 TeV neutrinos from the same location by the IceCube collaboration. Using Super-Kamiokande neutrino data across several data samples observed from 1996 April to 2018 February we have searched for both a total excess above known backgrounds across the entire period as well as localized excesses on smaller timescales in that interval. No significant excess nor significant variation in the observed event rate are found in the blazar direction. Upper limits are placed on the electron-and muon-neutrino fluxes at the 90% confidence level as 6.0 × 10-7 and 4.5 × 10-7-9.3 × 10-10 [erg cm-2 s-1], respectively.

Supernova detection is a major objective of the Super-Kamiokande (SK) experiment. In the next stage of SK (SK-Gd), gadolinium (Gd) sulfate will be added to the detector, which will improve the ability of the detector to identify neutrons. A core-collapse supernova (CCSN) will be preceded by an increasing flux of neutrinos and antineutrinos, from thermal and weak nuclear processes in the star, over a timescale of hours; some of which may be detected at SK-Gd. This could provide an early warning of an imminent CCSN, hours earlier than the detection of the neutrinos from core collapse. Electron antineutrino detection will rely on inverse beta decay events below the usual analysis energy threshold of SK, so Gd loading is vital to reduce backgrounds while maximizing detection efficiency. Assuming normal neutrino mass ordering, more than 200 events could be detected in the final 12 hr before core collapse for a 15-25 solar mass star at around 200 pc, which is representative of the nearest red supergiant to Earth, α-Ori (Betelgeuse). At a statistical false alarm rate of 1 per century, detection could be up to 10 hr before core collapse, and a pre-supernova star could be detected by SK-Gd up to 600 pc away. A pre-supernova alert could be provided to the astrophysics community following gadolinium loading.

A new event reconstruction algorithm based on a maximum likelihood method has been developed for Super-Kamiokande. Its improved kinematic and particle identification capabilities enable the analysis of atmospheric neutrino data in a detector volume 32% larger than previous analyses and increase the sensitivity to the neutrino mass hierarchy.Analysis of a 253.9 kton•year exposure of the Super-Kamiokande IV atmospheric neutrino data has yielded a weak preference for the normal hierarchy, disfavoring the inverted hierarchy at 74% assuming oscillations at the best fit of the analysis.

Neutral current (NC) interactions of atmospheric neutrinos on oxygen form one of the major backgrounds in the search for supernova relic neutrinos with water-based Cherenkov detectors. The NC channel is dominated by neutrino quasielastic (NCQE) scattering off nucleons inside O16 nuclei. In this paper we report the first measurement of NCQE cross section using atmospheric neutrinos at Super-Kamiokande (SK). The measurement used 2,778 live days of SK-IV data with a fiducial volume of 22.5 kiloton water. Within the visible energy window of 7.5-29.5 MeV, we observed 117 events compared to the expected 71.9 NCQE signal and 53.1 background events. Weighted by the atmospheric neutrino spectrum from 160 MeV to 10 GeV, the flux averaged NCQE cross section is measured to be (1.01±0.17(stat.)-0.30+0.78(sys.))×10-38 cm2.

A series of semi-crystalline, wide band gap (WBG) photovoltaic polymers were synthesized with varying number and topology of fluorine substituents. To decrease intramolecular charge transfer and to modulate the resulting band gap of D-A type copolymers, electron-releasing alkoxy substituents were attached to electron-deficient benzothiadiazole (A) and electron-withdrawing fluorine atoms (0-4F) were substituted onto a 1,4-bis(thiophen-2-yl)benzene unit (D). Intra- and/or interchain noncovalent Coulombic interactions were also incorporated into the polymer backbone to promote planarity and crystalline intermolecular packing. The resulting optical band gap and the valence level were tuned to 1.93-2.15 eV and -5.37 to -5.67 eV, respectively, and strong interchain organization was observed by differential scanning calorimetry, high-resolution transmission electron microscopy and grazing incidence X-ray scattering measurements. The number of fluorine atoms and their position significantly influenced the photophysical, morphological and optoelectronic properties of bulk heterojunctions (BHJs) with these polymers. BHJ photovoltaic devices showed a high power conversion efficiency (PCE) of up to 9.8% with an open-circuit voltage of 0.94-1.03 V. To our knowledge, this PCE is one of the highest values for fullerene-based single BHJ devices with WBG polymers having a band gap of over 1.90 eV. A tandem solar cell was also demonstrated successfully to show a PCE of 10.3% by combining a diketopyrrolopyrrole-based low band gap polymer.

A search for neutron-antineutron (n-n¯) oscillation was undertaken in Super-Kamiokande using the 1489 live-day or 2.45×1034 neutron-year exposure data. This process violates both baryon and baryon minus lepton numbers by an absolute value of two units and is predicted by a large class of hypothetical models where the seesaw mechanism is incorporated to explain the observed tiny neutrino masses and the matter-antimatter asymmetry in the Universe. No evidence for n-n¯ oscillation was found; the lower limit of the lifetime for neutrons bound in O16, in an analysis that included all of the significant sources of experimental uncertainties, was determined to be 1.9×1032years at the 90% confidence level. The corresponding lower limit for the oscillation time of free neutrons was calculated to be 2.7×108s using a theoretical value of the nuclear suppression factor of 0.517×1023s-1 and its uncertainty.

A search for the dinucleon decay pp → K+ K+ has been performed using 91.6  kton·yr data from Super-Kamiokande-I. This decay provides a sensitive probe of the R-parity-violating parameter λ112''. A boosted decision tree analysis found no signal candidates in the data. The expected background was 0.28±0.19 atmospheric neutrino induced events and the estimated signal detection efficiency was 12.6%±3.2%. A lower limit of 1.7×10(32)  years has been placed on the partial lifetime of the decay O16 → C14K+ K+ at 90% C.L. A corresponding upper limit of 7.8×10(-9) has been placed on the parameter λ112''.

A search for neutron-antineutron (n-n¯) oscillation was undertaken in Super-Kamiokande using the 1489 live-day or 2.45×1034 neutron-year exposure data. This process violates both baryon and baryon minus lepton numbers by an absolute value of two units and is predicted by a large class of hypothetical models where the seesaw mechanism is incorporated to explain the observed tiny neutrino masses and the matter-antimatter asymmetry in the Universe. No evidence for n-n¯ oscillation was found; the lower limit of the lifetime for neutrons bound in O16, in an analysis that included all of the significant sources of experimental uncertainties, was determined to be 1.9×1032years at the 90% confidence level. The corresponding lower limit for the oscillation time of free neutrons was calculated to be 2.7×108s using a theoretical value of the nuclear suppression factor of 0.517×1023s-1 and its uncertainty.

As the resident immune cells of the central nervous system, microglia rapidly respond to brain insults, including stroke and traumatic brain injury. Microglial activation plays a major role in neuronal cell damage and death by releasing a variety of inflammatory and neurotoxic mediators. Their activation is an early response that may exacerbate brain injury and many other stressors, especially in the acute stages, but are also essential to brain recovery and repair. The full range of microglial activities is still not completely understood, but there is accumulating knowledge about their role following brain injury. We review recent progress related to the deleterious and beneficial effects of microglia in the setting of acute neurological insults and the current literature surrounding pharmacological interventions for intervention.

Inflammation is an important event in ischemic injury. These immune responses begin with the expression of pro-inflammatory genes modulating transcription factors, such as nuclear factor-κB (NF-κB), activator protein-1 (AP-1), and signal transducers and activator of transcription-1 (STAT-1). The 70-kDa heat shock protein (Hsp70) can both induce and arrest inflammatory reactions and lead to improved neurological outcome in experimental brain injury and ischemia. Since Hsp70 are induced under heat stress, we investigated the link between Hsp70 neuroprotection and phosphorylation of inhibitor of κB (IκB), c-Jun N-terminal kinases (JNK) and p38 through co-immunoprecipitation and enzyme-linked immunosorbent assay (ELISA) assay. Transcription factors and pro-inflammatory genes were quantified by immunoblotting, electrophoretic-mobility shift assay and reverse transcription-polymerase chain reaction assays. The results showed that heat stress led to Hsp70 overexpression which rendered neuroprotection after ischemia-like injury. Overexpression Hsp70 also interrupts the phosphorylation of IκB, JNK and p38 and blunts DNA binding of their transcription factors (NF-κB, AP-1 and STAT-1), effectively downregulating the expression of pro-inflammatory genes in heat-pretreated astrocytes. Taken together, these results suggest that overexpression of Hsp70 may protect against brain ischemia via an anti-inflammatory mechanism by interrupting the phosphorylation of upstream of transcription factors.

The 70-kDa heat shock protein (HSP70) is known to protect the brain from injury through multiple mechanisms. We investigated the effect of pharmacological HSP70 induction in experimental traumatic brain injury (TBI). 3-month-old male C57/B6 mice were given 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) intraperitoneally (IP, 2 mg/kg) or intracerebroventricularly (ICV, 1 μg/kg) to determine whether HSP70 could be induced in the brain. Mice were subjected to TBI via cortical controlled impact, and were treated with 17-AAG (or vehicle) IP according to one of two treatment regimens: (1) 2 mg/kg at the time of injury, (2) a total of three doses (4 mg/kg) at 2 and 1d prior to TBI and again at the time of injury. Brains were assessed for HSP70 induction, hemorrhage volume at 3 d, and lesion size at 14 d post-injury. Immunohistochemistry showed that both IP and ICV administration of 17-AAG increased HSP70 expression primarily in microglia and in a few neurons by 24 h but not in astrocytes. 17-AAG induced HSP70 in injured brain tissue as early as 6 h, peaking at 48 h and largely subsiding by 72 h after IP injection. Both treatment groups showed decreased hemorrhage volume relative to untreated mice as well as improved neurobehavioral outcomes. These observations indicate that pharmacologic HSP70 induction may prove to be a promising treatment for TBI.