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Yi-Wen Chen,1,2 Ai-Chia He,3 Tzu-Yun Huang,1,3 De-Hao Lai,3 Yi-Ping Wang,1 Wei-Wen Liu,1,3 Wei-Ting Kuo,1,3 Hsin-Han Hou,1,3 Shih-Jung Cheng,1,3 Chen-Yi Lee,1 Wei-Chun Chuang,1 Che-Chen Chang,4 Bor-Shiunn Lee1,3 1Department of Dentistry, National Taiwan University Hospital, Taipei, 100229, Taiwan; 2Graduate Institute of Clinical Dentistry, School of Dentistry, National Taiwan University, Taipei, 100229, Taiwan; 3Graduate Institute of Oral Biology, School of Dentistry, National Taiwan University, Taipei, 100229, Taiwan; 4Department of Chemistry, National Taiwan University, Taipei, 10617, TaiwanCorrespondence: Bor-Shiunn Lee, Graduate Institute of Oral Biology, School of Dentistry, National Taiwan University, No. 1, Changde Street, Taipei, 100229, Taiwan, Tel +886-2-23123456 ext 66846, Fax +886-2-2383-1346, Email leebs@ntu.edu.twIntroduction: Cisplatin is one of the most effective chemotherapeutic drugs used in oral cancer treatment, but systemic administration has side effects. The purpose of this study was to evaluate the effect of iontophoresis on the enhancement of cisplatin release from cisplatin-encapsulated chitosan nanoparticles.Methods: The effect of different mass ratios of chitosan to tripolyphosphate (TPP) (5:1, 10:1, 15:1, 20:1) on the encapsulation efficiency of cisplatin was investigated. Uptake of cisplatin-encapsulated chitosan by cells was observed using a confocal laser scanning microscope. The cell viability at different cisplatin concentrations was examined using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Three iontophoresis methods, namely constant-current chronopotentiometry (CCCP), cyclic chronopotentiometry (CCP), and differential pulse voltammetry (DPV), were used to enhance cisplatin release from cisplatin-encapsulated chitosan nanoparticles. In addition, mouse oral squamous cell carcinoma cell lines were implanted into the mouse oral mucosa to induce oral cancer. The effects of enhanced cisplatin release by CCCP, CCP, and DPV on tumor suppression in mice were evaluated. Tumors and lymph nodes were isolated for hematoxylin-eosin staining and immunohistochemistry staining including Ki-67 and pan CK after sacrifice. Inductively coupled plasma mass spectrometry was conducted to quantify the platinum content within the tumors.Results: The results showed that nanoparticles with a mass ratio of 15:1 exhibited the highest cisplatin encapsulation efficiency (approximately 15.6%) and longest continued release (up to 35 days) in phosphate buffered saline with a release rate of 100%. Cellular uptake results suggested that chitosan nanoparticles were delivered to the cytoplasm via endocytosis. The results of the MTT assay revealed that the survival rate of cells decreased as the cisplatin concentration increased. The CCP (1 mA, on:off = 1 s: 1 s) and DPV (0– 0.06 V) groups were the most effective in inhibiting tumor growth, and both groups exhibited the lowest percentage of Ki-67 positive and pan CK positive.Conclusion: This study is the first to investigate and determine the efficacy of DPV in enhancing in vivo drug release from nanoparticles for the treatment of cancer in animals. The results suggest that the CCP and DPV methods have the potential to be combined with surgery for oral cancer treatment. Keywords: oral cancer, cisplatin, chitosan, nanoparticle, iontophoresis

Shih Ping Lin,1– 3 Ching-Wein Chang,4 Chun-Yi Wu,1,5 Chun-Shih Chin,1,6 Cheng-Hsien Lin,1,7 Sz-Iuan Shiu,1,8 Yun-Wen Chen,1,9 Tsai-Hung Yen,1,9 Hui-Chi Chen,4 Yi-Hung Lai,4 Shu-Chin Hou,4 Ming-Ju Wu,3,5 Hsin-Hua Chen1,3,9– 11 1Division of General Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; 2Division of Infection, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; 3Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan; 4Department of Nursing, Taichung Veterans General Hospital, Taichung, Taiwan; 5Division of Nephrology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; 6Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; 7Division of Hematology and Oncology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; 8Gastroenterology and Hepatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; 9Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; 10Institute of Biomedical Science and Rong Hsing Research Centre for Translational Medicine, Big Data Center, Chung Hsing University, Taichung, Taiwan; 11School of Medicine, National Yang Ming Chiao Tung University, Taipei, TaiwanCorrespondence: Hsin-Hua Chen, Division of General Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, 1650 Taiwan Boulevard Sect. 4, Taichung, 40705, Taiwan, Email shc5555@hotmail.comObjective: Huddles are short, regular debriefings that are designed to provide frontline staff and bedside caregivers environments to share problems and identify solutions. Daily huddle implementation could improve medical safety work, problem identification and improvement, situation awareness and teamwork enhancement, the collaboration and communication between professionals and departments, and patient safety. This study aimed evaluated the effectiveness of a hospital-based huddle at a general medical ward in Taiwan.Methods: A Continuous Integration team was conducted by combining multidisciplinary frontline staff to huddle at a 74-bed general medical ward. Team Huddles started twice a week. A physical huddle run board was created, which contained four parts, including idea submitted, idea approved, working on an idea and standardizing. Problems were submitted to the board to be identified, and the solutions were evaluated through huddle discussion. We divided the problems into two groups: quick hits (resolved within 24– 48hrs) and complex issues (resolved > 48hrs). An anonymous questionnaire was designed to evaluate the huddle response.Results: A total of 44 huddles occurred from September 9th, 2020, to September 30th, 2021, and 81 issues were identified and resolved. The majority issues were policy documentation (n=23; 28.4%). Sixty-seven (82.7%) issues were defined as quick hits, and the other fourteen (17.3%) issues were complex. The mean hours to the resolution of quick hits was 5.17 hours, median 3.5 hours, and range from 0.01– 15.4 hours. The mean days to resolve completion issues were 19.73 days, median 7.5 days, and range 3.57– 26.14 days. An overwhelming 92.9% of staff responded that huddles help to expedite the process to reach treatment goals, reduce clinical mistakes, near misses, reduce patient incidences, and help teamwork enhancement, with rating of 4.52 (on a 5-point Likert scale).Conclusion: Implementing of multidisciplinary team huddle improved the accountability of issue identification, problem-solving and teamwork enhancement.Keywords: huddle run, safety culture, teamwork, patient safety

Yi-Ju Liao,1 Tzu-Hung Hsiao,2– 4 Ching-Heng Lin,2,3,5,6 Chun-Sheng Hsu,7– 10 Yen-Lin Chang,1,8 Yu-Wei Chen,11 Chiann-Yi Hsu,2,12 Yi-Ming Chen,2,10,13– 15,* Ming-Fen Wu1,* 1Department of Pharmacy, Taichung Veterans General Hospital, Taichung, Taiwan; 2Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan; 3Department of Public Health, Fu Jen Catholic University, New Taipei City, Taiwan; 4Institute of Genomics and Bioinformatics, National Chung Hsing University, Taichung, Taiwan; 5Institute of Public Health and Community Medicine Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan; 6Department of Industrial Engineering and Enterprise Information, Tunghai University, Taichung, Taiwan; 7Department of Physical Medicine and Rehabilitation, Taichung Veterans General Hospital, Taichung, Taiwan; 8Department of Public Health and Institute of Public Health, Chung Shan Medical University, Taichung, Taiwan; 9School of Medicine, National Defense Medical Center, Taipei, Taiwan; 10Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan; 11Cardiovascular Center, Taichung Veterans General Hospital, Taichung, Taiwan; 12Biostatistics Task Force of Taichung Veterans General Hospital, Taichung, Taiwan; 13Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; 14Rong Hsing Research Center for Translational Medicine & Ph.D. Program in Translational Medicine, National Chung Hsing University, Taichung, Taiwan; 15School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan*These authors contributed equally to this workCorrespondence: Yi-Ming ChenDivision of Allergy, Immunology and Rheumatology, Department of Internal Medicine, Taichung Veterans General Hospital, 1650, Section 4, Taiwan Boulevard, Xitun Dist., Taichung, 407, Taiwan, Tel +886-4-2359-2525 ext. 4400, Fax +886-4-2359-2705, Email ymchen1@vghtc.gov.twPurpose: Clopidogrel is widely used in coronary artery, peripheral arterial, and cerebrovascular disease. We aimed to study the association of the CYP2C19 phenotype with cardiovascular outcomes and interventional procedures in a hospital-based population.Patients and Methods: This cross-sectional, retrospective study enrolled patients with prior exposure to clopidogrel at the Taichung Veterans General Hospital (TCVGH) using data extracted from the Taiwan Precision Medicine Initiative (TPMI). Data on the CYP2C19 phenotype, drug-prescription profile, comorbidities, vascular intervention procedures, and hospitalization due to acute myocardial infarction (AMI) or stroke of clopidogrel users were analyzed.Results: From the 32,728 patients in the TCVGH-TPMI cohort, we selected 2687 clopidogrel users. A total of 400 (14.9%) clopidogrel poor metabolizers (PMs), 1235 (46.0%) intermediate metabolizers (IMs), and 1052 (39.2%) extensive metabolizers (EMs) were identified. The predominant loss-of-function allele is *2. In 2687 patients with clopidogrel exposure, the CYP2C19 PM phenotype was unassociated with hospitalization due to AMI or stroke after adjusting for comorbidities and carotid angiographies. Among the 1554 clopidogrel users who underwent cardiovascular intervention, 193 (12.4%) received two or more types of interventional procedures. Compared with non-PMs, patients with the PM phenotype had a higher risk of multiple carotid interventions (OR: 3.13, 95% CI: 1.19– 8.22).Conclusion: In this hospital-wide cohort, 8.2% were clopidogrel users, of which 14.9% were CYP2C19 PMs. The result of this study does not support universal genotyping of CYP2C19 in all clopidogrel users to identify risks for stroke and AMI. CYP2C19 PMs are more likely to undergo multiple carotid interventions than non-PMs. Prospective studies to investigate the association of the CYP2C19 genotype and carotid interventions and outcomes are needed to validate our results.Keywords: pharmacogenomics, clopidogrel, CYP2C19, Taiwan precision medicine initiative, TPMI, carotid intervention

Ming-Ta Hsieh,1– 3 Li-Hui Lu,2 Chi-Wei Lin,1,4 Yun-Wen Chen5 1Department of Family Medicine and Community Medicine, E-Da Hospital, Kaohsiung City, Taiwan; 2College of Law, National University of Kaohsiung, Kaohsiung City, Taiwan; 3Department of Nursing, College of Medicine, I-Shou University, Kaohsiung City, Taiwan; 4School of Medicine for International Students, College of Medicine, I-Shou University, Kaohsiung City, Taiwan; 5Pediatrician, Local Clinic, Kaohsiung City, TaiwanCorrespondence: Ming-Ta HsiehDepartment of Family Medicine and Community Medicine, E-Da Hospital, No. 1, Yida Road, Jiao-su Village, Yan-chao District, Kaohsiung City, 82445, TaiwanEmail kaplan210@yahoo.com.twBackground: The annual medical litigation rate has increased yearly since 1987 in Taiwan. Policy makers keep going medical legislation reforms. The effectiveness of legislation reforms to reduce malpractice litigation risk is uncertain.Objective: To determine whether medical legislation reform helps reduce the risk of medical litigation.Design, Setting, and Participants: This retrospective study used national data obtained from Ministry of Health and Welfare in Taiwan. The period analyzed was from 1987 to 2018. The annual medical litigation rate was determined, types of medical negligence litigation were compared, medical appraisal results were summarized, and the importance of medical legislation was identified.Interventions: After legislation reform vs before legislation reform.Measurements: The main outcome showed trends in medical dispute assessments over time by adjusting for the general population (per 1,  000,  000 people). We established 2004 and 2012 as the 2 cut-points for further analysis of medical appraisal results due to legislation reform.Results: With legislation reforms, the annual medical litigation rate decreased from 26.68 cases per million people in 2012 to 16.41 cases per million people in 2018. The annual medical litigation rate declined by approximately 38% from 2012 to 2018. Medical appraisal results were malpractice cases in 22.1% before Medical Care Act (2004 Reform) compared with 18.8% from 2004 to 2012 (odds ratio [OR], 0.82; 95% CI, 0.727– 0.924; p=0.001), and 6.4% after mediation system introduced in 2012 (odds ratio [OR], 0.243; 95% CI, 0.205– 0.288; p< 0.001).Conclusion: Medical legislation reform has reduced the risk of malpractice litigation over time.Keywords: medical malpractice, medical legislation reform, health policy

Yun-Chen Chang,1 Ta-Jen Lee,1 Chi-Che Huang,1,2 Po-Hung Chang,1,2 Yi-Wei Chen,1 Chia-Hsiang Fu1,2 1Department of Otolaryngology-Head and Neck Surgery, Linkou Chang Gung Memorial Hospital, Taoyuan City, 333, Taiwan; 2Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan City, 333, TaiwanCorrespondence: Chia-Hsiang FuDivision of Rhinology, Department of Otolaryngology-Head and Neck Surgery, Linkou Chang Gung Memorial Hospital and Chang Gung University, No. 5 Fu-Shin Street, Guishan District, Taoyuan City, 333, TaiwanTel +886-3-3281200, ext.: 8465Fax +886-3-3979361Email fufamily@adm.cgmh.org.twBackground: Screening for the existence of aeroallergens in patients with possible allergic rhinitis using venous blood samples has become more popular, with advantages of increased convenience and less consumption of time.Objective: The aim of this study was to investigate the sensitivities and specificities of Phadiatop tests and total immunoglobulin E (IgE) levels in both adults and children.Methods: This study was conducted prospectively in a tertiary center. The process of recruitment took place from Jan 2015 to Dec 2019, and patients with clinical symptoms that suggested persistent allergic rhinitis were recruited and their serum samples collected. The results of the total IgE and Phadiatop tests as well as the positive items in the ImmunoCAP assay were recorded and analyzed.Results: A total of 9174 cases with complete data were enrolled, including 576 children and 8598 adults. A positive result in the ImmunoCAP assay was considered a positive atopic status towards aeroallergens. While using the total IgE levels to predict positive aeroallergens, the sensitivities and specificities were 65.7% and 85.7%, respectively, for adults and 86.3% and 77.4%, respectively, for children. When we used Phadiatop tests for allergy screening, the sensitivities and specificities was 94.5% and 98.2%, respectively, for the adult group and 98.5% and 96.8%, respectively, for the pediatric group.Conclusion: The Phadiatop test had better diagnostic power for aeroallergen detection than the serum total IgE levels, or even the dual test, for both the adult and pediatric groups in this hospital-based study. We suggest that the Phadiatop test is more cost-effective in aeroallergen screening for patients with suspected atopic airway diseases.Keywords: Phadiatop test, ImmunoCAP, total immunoglobulin E, IgE, aeroallergens

Sheng-Feng Sung,1,* Chien-Chou Su,2– 4,* Cheng-Yang Hsieh,2,3,5 Ching-Lan Cheng,2– 4,6 Chih-Hung Chen,7 Huey-Juan Lin,8 Yu-Wei Chen,9,10 Yea-Huei Kao Yang2– 4,6 1Division of Neurology, Department of Internal Medicine, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi, Taiwan; 2Department of Pharmacy, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 3School of Pharmacy, Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 4Health Outcome Research Center, National Cheng Kung University, Tainan, Taiwan; 5Department of Neurology, Tainan Sin Lau Hospital, Tainan, Taiwan; 6School of Pharmacy, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 7Department of Neurology, National Cheng Kung University Hospital and College of Medicine, Tainan, Taiwan; 8Department of Neurology, Chi Mei Medical Center, Tainan, Taiwan; 9Department of Neurology, Landseed International Hospital, Taoyuan, Taiwan; 10Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan*These authors contributed equally to this workCorrespondence: Yea-Huei Kao YangSchool of Pharmacy, Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, TaiwanTel +886-6-2353535 ext.5688Fax +886-6-2373149Email yhkao@mail.ncku.edu.twPurpose: Home-time has been found to correlate well with modified Rankin Scale (mRS) scores in patients with stroke. This study aimed to determine its correlations in patients with different types of stroke at various time points after stroke in a non-Western population.Methods: This study used linked data from multi-center stroke registry databases and a nationwide claims database of health insurance. Functional outcomes as measured with the modified Rankin Scale were obtained from the registry databases and home-time was derived from the claims database. Spearman correlation coefficients were used to assess the correlation between home-time and mRS scores. The area under the receiver operating characteristic curve (AUC) was used to evaluate the performance of home-time in predicting good functional outcome.Results: This study included 7959 patients hospitalized for stroke or transient ischemic attack (TIA), for whom mRS scores were available in 6809, 6694, and 4330 patients at 90, 180, and 365 days, respectively. Home-time was highly correlated with mRS scores at the three time-points in patients with ischemic (Spearman’s rho − 0.69 to − 0.83) or hemorrhagic (Spearman’s rho − 0.86 to − 0.88) stroke, but the correlation was only weak to moderate in those with TIA (Spearman’s rho − 0.32 to − 0.58). Home-time predicted good functional outcome with excellent discrimination in patients with ischemic (AUCs > 0.8) or hemorrhagic (AUCs > 0.9) stroke but less so in those with TIA (AUCs > 0.7).Conclusion: Home-time was highly correlated with mRS scores and showed excellent discrimination in predicting good functional outcome in patients with ischemic or hemorrhagic stroke. Home-time could serve as a valid surrogate measure for functional outcome after stroke.Keywords: home-time, stroke, disability

Xi Chen,* Bei Feng,* Di-Qi Zhu, Yi-Wei Chen, Wei Ji, Tian-Ji Ji, Fen LiDepartment of Cardiology, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiaotong University, Shanghai, People’s Republic of China*These authors contributed equally to this workBackground: Electrospun gelatin/polycaprolactone (Gt/PCL) nanofibrous scaffolds loaded with graphene are novel nanomaterials with the uniquely strong property of electrical conductivity, which have been widely investigated for their potential applications in cardiovascular tissue engineering, including in bypass tracts for atrioventricular block.Purpose: Electrospun Gt/PCL/graphene nanofibrous mats were successfully produced. Scanning electron micrography showed that the fibers with graphene were smooth and homogeneous. In vitro, to determine the biocompatibility of the scaffolds, hybrid scaffolds with different fractions of graphene were seeded with neonatal rat ventricular myocytes. In vivo, Gt/PCL scaffolds with different concentrations of graphene were implanted into rats for 4, 8 and 12 weeks.Results: CCK-8 assays and histopathological staining (including DAPI, cTNT, and CX43) indicated that cells grew and survived well on the hybrid scaffolds if the mass fraction of graphene was lower than 0.5%. After implanting into rats for 4, 8 or 12 weeks, there was no gathering of inflammatory cells around the nanomaterials according to the HE staining results.Conclusion: The results indicate that Gt/PCL nanofibrous scaffolds loaded with graphene have favorable electrical conductivity and biological properties and may be suitable scaffolds for use in the treatment of atrioventricular block. These findings alleviate safety concerns and provide novel insights into the potential applications of Gt/PCL loaded with graphene, offering a solid foundation for comprehensive in vivo studies.Keywords: gelatin, polycaprolactone, graphene, electrical conductivity, toxicity, atrioventricular block

Jinfang Ma,1 Jinping Zheng,1 Nanshan Zhong,1 Chunxue Bai,2 Haoyan Wang,3 Juan Du,4 Fenglei Li,5 Yanwei Chen,6 Zhe Shi,7 Xin Li,8 Pingyan Chen9 1State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 2Department of Respiratory Medicine, Zhongshan Hospital Affiliated to Fudan University, Shanghai, People’s Republic of China; 3Department of Respiratory Medicine, Beijing Friendship Hospital Affiliated to Capital Medical University, Beijing, People’s Republic of China; 4Department of Respiratory Medicine, The Affiliated Hospital of Guizhou Medical University, Guiyang, People’s Republic of China; 5Department of Respiratory Medicine, The Liwan Hospital of the Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 6Department of Respiratory Medicine, Nanshan People’s Hospital, Shenzhen, People’s Republic of China; 7Department of Respiratory Medicine, The First People’s Hospital, Huizhou, People’s Republic of China; 8Department of Respiratory Medicine, China Resource and Wisco General Hospital, Wuhan, People’s Republic of China; 9Department of Biostatistics, Southern Medical University, Guangzhou, People’s Republic of China Purpose: Recurrence of acute exacerbations has a major impact on patients with COPD. Therefore, effective prevention and treatment of exacerbation is crucial in the management of COPD, especially for patients with moderate to severe disease. This study evaluated the effectiveness of YuPingFeng granule administration in preventing exacerbation and improving symptom score, as well as its long-term (1 year) safety profile, in patients with COPD. Patients and methods: This was a randomized, double-blind, parallel, placebo-controlled study of 240 patients from eight centers in China. Participants were eligible if they had mild to severe COPD as defined by Global Initiative for Chronic Obstructive Lung Disease, had a history of at least two COPD exacerbations or one hospitalization within the previous year, and had remained clinically stable for over 4 weeks before the study. They were randomly assigned to receive 5 g of YuPingFeng or placebo, three times per day, for 1 year. The primary end point was the exacerbation rate over 1 year, and the analysis was by intention to treat. Secondary end points included symptom score, which was assessed by COPD assessment test (CAT) score and safety profiles. This trial was registered in the Chinese Clinical Trial Registry (http://www.chictr.org.cn; registration number: ChiCTR-IPR-15007023). Results: The YuPingFeng group had a significantly lower exacerbation rate than the placebo group (1.15 vs 1.55; risk ratio=0.677 [95% CI 0.531–0.863]; P=0.002) and a significantly reduced risk of second exacerbation (95% CI 0.326–0.772; P=0.002). After treatment, the mean change in the CAT score in the YuPingFeng group (-4.41±7.01) differed significantly from that in the placebo group (-2.49±5.31; P=0.001). YuPingFeng was well tolerated. Conclusion: YuPingFeng granules can be considered as a treatment option for COPD; this treatment prevents acute exacerbations of COPD and has a good safety profile. Keywords: COPD, exacerbation, treatment, YuPingFeng

Jun-Hao Shih,1,2,* Bing-Yan Zeng,3,* Pao-Yen Lin,4,5 Tien-Yu Chen,6,7 Yen-Wen Chen,8 Ching-Kuan Wu,9 Ping-Tao Tseng,10 Ming-Kung Wu4 1Department of Occupational and Environmental Health Consultation, EMHA Consulting International Incorporation, Hsinchu, Taiwan; 2Certified Occupational Medicine Physician & Deputy Secretary General, Taiwan Environmental and Occupational Medicine Association, Tainan, Taiwan; 3Department of Internal Medicine, E-Da Hospital, Kaohsiung, Taiwan; 4Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; 5Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; 6Department of Psychiatry, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan; 7Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan; 8Prospect Clinic for Otorhinolaryngology and Neurology, Kaohsiung, Taiwan; 9Department of Psychiatry, Tsyr-Huey Mental Hospital, Kaohsiung Jen-Ai’s Home, Kaohsiung, Taiwan; 10WinShine Clinics in Specialty of Psychiatry, Kaohsiung, Taiwan *These authors contributed equally to this work Abstract: Evidence has suggested that dysregulation of the dopaminergic system may play a significant role in the pathogenesis of attention-deficit/hyperactivity disorder (ADHD) in children. Manganese, a neurotoxicant, has been reported to exert its neurotoxicity by affecting the dopaminergic system. However, the association between peripheral manganese levels and ADHD has not been comprehensively reviewed. This study aimed to investigate the association between peripheral manganese levels and ADHD in children. An electronic search was performed on databases including PubMed, ProQuest, ClinicalKey, Cochrane Library, ClinicalTrials.gov, Embase, Web of Science, and ScienceDirect with last search on March 25th, 2018. As per the inclusion criteria, human observational studies investigating peripheral manganese levels in children with ADHD and controls were included. The meta-analysis was performed using a random-effects model, and possible confounders were examined by subgroup analysis. In total, four articles with 175 ADHD children and 999 controls were recruited. The manganese levels were significantly higher in ADHD children than in controls (p=0.033), when studies investigating blood levels and those investigating hair levels were included. However, when only studies investigating blood levels were included, there was no significant difference between ADHD children and controls (p=0.076). Our results support higher peripheral manganese levels in children diagnosed with ADHD than those in controls. Further primary studies are needed to clarify this association. Keywords: meta-analysis, manganese, ADHD, pediatric psychiatry, review

Yi-Yen Lee,1,2,* Aliaksandr A Yarmishyn,3,4,* Mong-Lien Wang,3,4 Hsiao-Yun Chen,4,5 Shih-Hwa Chiou,3–5 Yi-Ping Yang,4,5 Chun-Fu Lin,1,2 Pin-I Huang,2,6 Yi-Wei Chen,2,6 Hsin-I Ma,7 Ming-Teh Chen1,2 1Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, 2Faculty of Medicine, National Yang-Ming University, 3Institute of Pharmacology, National Yang-Ming University, 4Department of Medical Research, Taipei Veterans General Hospital, 5Institute of Clinical Medicine, National Yang Ming University, 6Cancer Center, Radiation Oncology Division, Taipei Veterans General Hospital, 7Department of Neurological Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan *These authors contributed equally to this work Background: Glioblastoma multiforme (GBM) is the most malignant brain tumor, and there is no effective treatment strategy. Patients with GBM have a median overall survival of only 14.6 months. Current treatment consists of safe and maximal surgical excision, followed by concurrent chemoradiotherapy and maintenance chemotherapy. There are several obstacles that hinder the effectiveness of this aggressive treatment. Temozolomide (TMZ) is an oral alkylating drug that acts through alkylating the O6 position of guanine in DNA that leads to cell death. However, the expression and enzymatic activity of the DNA repair protein MGMT limits the therapeutic benefit from treatment with TMZ. MGMT reduces the efficacy of alkylating drugs by removing the methyl or alkyl group from damaged O6-methylguanine. Expression levels of MGMT play an important role in the outcome of GBM patients. miRNAs are a group of small regulatory RNAs that control target gene expression by binding to mRNAs. miR-142-3p has been found to be an important factor in the development and maintenance of the oncogenic state. Results: In this study, we sought to investigate whether miR-142-3p can regulate MGMT gene expression in GBM cells. Here, we show that miR-142-3p downregulates MGMT expression through binding to the 3′-UTR of MGMT mRNA, thus affecting protein translation. Responsiveness to TMZ was significantly enhanced after transfection with miR-142-3p. Overexpression of miR-142-3p also sensitized GBM cells to alkylating drugs. Conclusion: Above all, our findings demonstrate that miR-142-3p plays a critical role in regulating MGMT expression, has great potential for future clinical applications, and acts as a new diagnostic marker for this intractable disease. Keywords: glioblastoma, O6-methylguanine-DNA methyltransferase, miR-142-3p, carmustine, temozolomide

Yu-Shian Cheng,1 Ping-Tao Tseng,1,2 Yen-Wen Chen,3 Brendon Stubbs,4–6 Wei-Chieh Yang,7 Tien-Yu Chen,8,9 Ching-Kuan Wu,1 Pao-Yen Lin10,11 1Department of Psychiatry, Tsyr-Huey Mental Hospital, Kaohsiung Jen-Ai’s Home, 2WinShine Clinics in Specialty of Psychiatry, 3Prospect Clinic for Otorhinolaryngology & Neurology, Kaohsiung, Taiwan, Republic of China; 4Physiotherapy Department, South London and Maudsley NHS Foundation Trust, 5Health Service and Population Research Department, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, 6Faculty of Health, Social Care and Education, Anglia Ruskin University, Chelmsford, UK; 7Department of Pediatrics, DA-AN Women and Children Hospital, Tainan, 8Department of Psychiatry, Tri-Service General Hospital, Taipei, 9School of Medicine, National Defense Medical Center, Taipei, 10Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 11Institute for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan, Republic of China Aim: Deficiency of omega 3 fatty acids may be linked to autism spectrum disorder (ASD). Evidence about the potential therapeutic effects of supplementation of omega 3 fatty acids is lacking in ASD patients.Methods: We searched major electronic databases from inception to June 21, 2017, for randomized clinical trials, which compared treatment outcomes between supplementation of omega 3 fatty acids and placebo in patients with ASD. An exploratory random-effects meta-analysis of the included studies was undertaken.Results and conclusion: Six trials were included (n=194). Meta-analysis showed that supplementation of omega 3 fatty acids improved hyperactivity (difference in means =-2.692, 95% confidence interval [CI] =-5.364 to -0.020, P=0.048, studies =4, n=109), lethargy (difference in means =-1.969, 95% CI =-3.566 to -0.372, P=0.016, studies =4, n=109), and stereotypy (difference in means =-1.071, 95% CI =-2.114 to -0.029, P=0.044, studies =4, n=109). No significant differences emerged between supplementation of omega 3 fatty acids and placebo in global assessment of functioning (n=169) or social responsiveness (n=97). Our preliminary meta-analysis suggests that supplementation of omega 3 fatty acids may improve hyperactivity, lethargy, and stereotypy in ASD patients. However, the number of studies was limited and the overall effects were small, precluding definitive conclusions. Future large-scale randomized clinical trials are needed to confirm or refute our findings. Keywords: poly-unsaturated fatty acid, omega 3, autism, pediatric

Ming-Ming Li,* Jia Cao,* Jia-Chun Yang, Yu-Jie Shen, Xiao-Lei Cai, Yuan-Wen Chen, Chun-Ying Qu, Yi Zhang, Feng Shen, Lei-Ming Xu Department of Gastroenterology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, People’s Republic of China *These authors contributed equally to this work Abstract: Quantum dots (QDs) conjugated with integrin antagonist arginine–glycine–aspartic acid (RGD) peptides (QDs-RGD) are novel nanomaterials with a unique optical property: a high molar extinction coefficient. Previously, we have shown that QDs-RGD demonstrate a photodynamic therapy (PDT) effect as new photosensitizers for the pancreatic cancer cell line SW1990 in vitro. Here, we investigate the application of QDs-RGD in mice bearing pancreatic tumors using PDT. To ensure that more photosensitizers accumulated in tumors, QDs-RGD were injected intratumorally. After selection of an adequate dosage for injection from analyses of biodistribution images captured by an IVIS system, PDT was initiated. Three groups were created according to different PDT procedures. In group 1, mice were injected with QDs-RGD intratumorally, and an optical fiber connected to a laser light was inserted directly into the tumor. Irradiation was sustained for 20 min with a laser light (630 nm) at 100 mW/cm2. In group 2, the laser optical fiber was placed around, and not inserted into, tumors. In group 3, PDT was conducted as in group 1 but without injection of QDs-RGD. After 28 days of observation, tumors on the back of mice in group 1 grew slowly (V/V0 =3.24±0.70) compared with the control groups, whose tumors grew quickly, and the mean V/V0 reached 6.08±0.50 (group 2) and 7.25±0.82 (group 3). Histology of tumor tissues showed more necrotic tissues, more inflammatory cells, and less vascular tissue in the PDT group than those in the control groups. These results suggest that QDs-RGD-mediated PDT, with illumination using an optical fiber inserted directly into the tumor, can inhibit the growth of SW1990 tumors with high efficiency in nude mice. Keywords: quantum dots, RGD peptides, pancreatic neoplasm, intratumoral injection, photodynamic therapy

Po-Chou Liliang,1 Kang Lu,1 Cheng-Loong Liang,1 Ya-Wen Chen,2,3 Yu-Duan Tsai,1 Yuan-Kun Tu4 1Department of Neurosurgery, E-Da Hospital, 2Department of Nursing, I-Shou University, 3School of Nursing, Kaohsiung Medical University, 4Department of Orthopedic Surgery, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan Purpose: Nucleoplasty is a minimally invasive technique that is considered efficacious in alleviating lumbar disk degenerative low back pain (LBP). The efficacy of nucleoplasty and identified variables that can predict pain relief for nucleoplasty was reported. Patients and methods: Between December 2013 and November 2015, 47 nucleoplasty procedures on 47 lumbar disks in 31 consecutive patients were performed. The outcome was evaluated using a visual analog scale (VAS) score. Improvements of ≥50% in VAS scores were considered substantial pain relief. The variables associated with pain relief after nucleoplasty included: 1) age; 2) sex; 3) body mass index; 4) hyperintensity zone at the rear of the disk; 5) hypointensity of the disk; 6) Modic changes of the end plates; 7) spinal instability pain; and 8) discography results. Results: Twenty-one patients (67.7%) experienced substantial pain relief. The most common side effects following nucleoplasty were soreness at the needle puncture site (64.5%), numbness in the lower leg (12.9%), and increased intensity of back pain (9.7%). All side effects were transient. Multivariate analysis revealed that the discography results were the most critical predictor for substantial pain relief of nucleoplasty (P=0.03). The sensitivity and specificity of discography were 92.8% and 62.5%, respectively. Conclusion: Discography results could improve the success rate of nucleoplasty in the treatment of disk degenerative LBP. Keywords: low back pain, lumbar disk degenerative, nucleoplasty, discography

Bor-Shiunn Lee,1 Chien-Chen Lee,2 Yi-Ping Wang,2 Hsiao-Jan Chen,3 Chern-Hsiung Lai,4 Wan-Ling Hsieh,1 Yi-Wen Chen2 1Graduate Institute of Oral Biology, 2Graduate Institute of Clinical Dentistry, School of Dentistry, National Taiwan University and National Taiwan University Hospital, 3Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, 4College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan Abstract: Chronic periodontitis is characterized by inflammation of periodontal tissues, leading to bone resorption and tooth loss. The goal of treatment is to regenerate periodontal tissues including bone and cementum lost as a consequence of disease. The local delivery of tetracycline was proven to be effective in controlling localized periodontal infection without apparent side effects. Previous studies suggested that lovastatin has a significant role in new bone formation; however, the local delivery of lovastatin might enhance its therapeutic effects. A number of local delivery devices have been developed recently, including poly(D,L-lactide-co-glycolide acid) (PLGA) nanoparticles. The aim of this study was to develop a local delivery device, PLGA-lovastatin-chitosan-tetracycline nanoparticles, which allows the sequential release of tetracycline and lovastatin to effectively control local infection and promote bone regeneration in periodontitis. The size and microstructure of nanoparticles were examined by transmission electron microscopy, Nanoparticle Size Analyzer, and Fourier transform infrared spectroscopy. The release of tetracycline and lovastatin was quantified using a UV-Vis spectrophotometer. Furthermore, the cytotoxic effect and alkaline phosphatase activity of the nanoparticles in osteoblast cell cultures as well as antibacterial activity against periodontal pathogens were investigated. Finally, the bone regeneration potential of PLGA nanoparticles in three-walled defects in beagle dogs was investigated. The results indicated that PLGA-lovastatin-chitosan-tetracycline nanoparticles showed good biocompatibility, antibacterial activity, and increased alkaline phosphatase activity. The volumetric analysis from micro-CT revealed significantly increased new bone formation in defects filled with nanoparticles in dogs. This novel local delivery device might be useful as an adjunctive treatment in periodontal regenerative therapy. Keywords: lovastatin, tetracycline, chitosan, poly(d,l-lactide-co-glycolide acid), periodontal regeneration

Ya-Wen Chen,1,2 Gunn-Guang Liou,3 Huay-Ben Pan,4,5 Hui-Hwa Tseng,5,6 Yu-Ting Hung,4 Chen-Pin Chou4,5,7,8 1National Institute of Cancer Research, National Health Research Institutes, Miaoli, 2Graduate Institute of Basic Medical Science, China Medical University, Taichung, 3Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli, 4Department of Radiology, Kaohsiung Veterans General Hospital, Kaohsiung, 5School of Medicine, National Yang-Ming University, Taipei, 6Department of Pathology, Kaohsiung Veterans General Hospital, Kaohsiung, 7Department of Medical Laboratory Sciences and Biotechnology, Fooyin University, Kaohsiung, 8School of Medicine, National Defense Medical Center, Taipei, Taiwan Background: The use of ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles to visualize cells has been applied clinically, showing the potential for monitoring cells in vivo with magnetic resonance imaging (MRI). USPIO conjugated with anti-CD133 antibodies (USPIO-CD133 Ab) that recognize the CD133 molecule, a cancer stem cell marker in a variety of cancers, was studied as a novel and potent agent for MRI contrast enhancement of tumor cells. Materials and methods: Anti-CD133 antibodies were used to conjugate with USPIO via interaction of streptavidin and biotin for in vivo labeling of CD133-positive cells in xenografted tumors and N-ethyl-N-nitrosourea (ENU)-induced brain tumors. The specific binding of USPIO-CD133 Ab to CD133-positive tumor cells was subsequently detected by Prussian blue staining and MRI with T2-weighted, gradient echo and multiple echo recombined gradient echo images. In addition, the cellular toxicity of USPIO-CD133 Ab was determined by analyzing cell proliferation, apoptosis, and reactive oxygen species production. Results: USPIO-CD133 Ab specifically recognizes in vitro and labels CD133-positive cells, as validated using Prussian blue staining and MRI. The assays of cell proliferation, apoptosis, and reactive oxygen species production showed no significant differences in tumor cells with or without labeling of USPIO-CD133 Ab. In vivo imaging of CD133-positive cells was demonstrated by intravenous injection of USPIO-CD133 Ab in mice with HT29 xenografted tumors. The MRI of HT29 xenografts showed several clusters of hypotensive regions that correlated with CD133 expression and Prussian blue staining for iron. In rat, brain tumors induced by transplacental ENU mutagenesis, several clusters of hypointensive zones were observed in CD133-expressing brain tumors by MRI and intravenously administered USPIO-CD133 Ab. Conclusion: Combination of USPIO-CD133 Ab and MRI is valuable in recognizing CD133-expressing tumor cells in vitro, extracellularly labeling for cell tracking and detecting CD133-expressing tumors in xenografted tumors as well as ENU-induced rat brain tumors. Keywords: MRI, USPIO, CD133, USPIO-CD133 Ab, molecular imaging

Yu-Wei Chen,1 Anita C Bundy,1 Reinie Cordier,2 Yi-Ling Chien,3 Stewart L Einfeld1,4 1Faculty of Health Sciences, The University of Sydney, Sydney, NSW, Australia; 2School of Occupational Therapy and Social Work, Faculty of Health Sciences, Curtin University, Perth, WA, Australia; 3Department of Psychiatry, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan; 4Brain and Mind Research Institute, The University of Sydney, Sydney, NSW, Australia Objective: The purpose of the present study was to examine motivation for the contextual nature of motivations for social participation in cognitively able adolescents and adults with autism spectrum disorder, using self-determination theory as a theoretical framework.Methods: Fourteen Australians and 16 Taiwanese (aged 16–45 years) with Asperger’s syndrome and high functioning autism were asked to carry a device which prompted them seven times/day for 7 days, to record what they were doing, with whom, perceived difficulty and social reciprocity, and the reasons for engaging in a situation, which were then coded into degree of self-determination.Results: Multilevel analyses showed that participants were more likely to be self-determined while engaging in “solitary/parallel leisure” and “social activities” than in other types of activities. Interactions with “family members” and “casual/intimate friends” were also positively associated with self-determined motivation. Further, participants were more likely to perceive higher levels of being listened to during interaction with casual/intimate friends than in interaction with other people. Global social anxiety served as a moderator for their perceptions of difficulty and social reciprocity during social engagement.Conclusion: The findings highlight the context-dependent motivations for social engagement of cognitively able individuals with autism spectrum disorder. Keywords: autism, real-life experience, social motivation, social interaction, ecological momentary assessment

Chun-Ying Qu,1,* Min Zhou,1,* Ying-wei Chen,2 Mei-mei Chen,3 Feng Shen,1 Lei-Ming Xu11Digestive Endoscopic Diagnosis and Treatment Center, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, People’s Republic of China; 2Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, People’s Republic of China; 3Digestive Department, Xinhua Hospital, School of medicine, Shanghai Jiaotong University, Shanghai, People’s Republic of China*These authors contributed equally to this workPurpose: The first-line chemotherapy treatment protocol for gastric cancer is combination chemotherapy of 5-fluorouracil (5-FU) and cisplatin (CDDP). The aim of this study was to engineer prodrug-based nanostructured lipid carriers (NLC) platform for codelivery of 5-FU and CDDP to enhance therapy and decrease toxicity.Methods: First, 5-FU-stearic acid lipid conjugate was synthesized by two steps. Second, 5-FU-stearic acid prodrug and CDDP were loaded in NLC. Finally, hyaluronic acid (HA) was coated onto NLC surface. Average size, zeta potential, and drug loading capacity of NLC were evaluated. Human gastric cancer cell line BGC823 (BGC823 cells) was used for the testing of in vitro cytotoxicity assays. In vivo antitumor activity of NLC was evaluated in mice bearing BGC823 cells model.Results: HA-coated 5-FU-stearic acid prodrug and CDDP-loaded NLC (HA-FU/C-NLC) showed a synergistic effect in combination therapy and displayed the greatest antitumor activity than all of the free drugs or uncoated NLC in vitro and in vivo.Conclusion: This work reveals that HA-coated NLC could be used as a novel carrier to codeliver 5-FU and CDDP for gastric cancer therapy. HA-FU/C-NLC could be a promising targeted and combinational therapy in nanomedicine.Keywords: gastric cancer, nanostructured lipid carriers, hyaluronic acid, combination chemotherapy, lipid prodrug

Yen-Wen Chen,1 Pao-Yen Lin,2,3 Kun-Yu Tu,4 Yu-Shian Cheng,4 Ching-Kuan Wu,4 Ping-Tao Tseng4 1Department of Neurology, E-Da Hospital, 2Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 3Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, 4Department of Psychiatry, Tsyr-Huey Mental Hospital, Kaohsiung Jen-Ai’s Home, Kaohsiung, Taiwan Introduction: Since its discovery several decades ago, nerve growth factor (NGF) has been found to play roles in different areas, such as neurology, endocrinology, and immunology. There is some evidence linking NGF and psychiatry, including the role of NGF in subjects’ response to stress, the alteration of NGF in different emotional states, and the penetration of NGF across the blood–brain barrier under specific conditions. There are many inconsistent findings regarding the differences in NGF in patients with major depressive disorder (MDD) at the present time. The aim of our study was to clarify whether NGF levels are different in MDD compared with healthy controls (HCs).Methods: We conducted a thorough literature search and compared peripheral NGF levels between MDD and HC through meta-analysis, and investigated possible confounding variables through meta-regression.Results: Seven studies were brought into the current meta-analysis comparing peripheral NGF in MDD and HCs. The main result was that the NGF levels were significantly lower in MDD than in HCs and that this had an inverse correlation with mean age and disease severity. In addition, meta-analysis of four articles found that the peripheral NGF levels did not change significantly before and after treatment.Conclusion: Our study highlights the significant differences in peripheral NGF levels in patients with MDD. However, further exploration of the dynamic changes in peripheral NGF along with the disease course, and specific studies investigating the correlation of NGF in the peripheral and CNS environments are still needed. Keywords: psychiatry, NGF, mood disorder, neurotrophic factor

Cien-Leong Chye,1 Cheng-Loong Liang,1 Kang Lu,1 Ya-Wen Chen,2,3 Po-Chou Liliang1 1Department of Neurosurgery, E-Da Hospital, I-Shou University, 2Department of Nursing, I-Shou University, 3School of Nursing, Kaohsiung Medical University, Kaohsiung, Taiwan Purpose: Chronic hip pain is a common symptom experienced by many people. Often, surgery is not an option for patients with multiple comorbidities, and conventional drugs either have many side effects or are ineffective. Pulsed radiofrequency (PRF) is a new method in the treatment of pain. We attempt to compare the efficacy of PRF relative to conservative management for chronic hip pain.Patients and methods: Between August 2011 and July 2013, 29 patients with chronic hip pain were divided into two groups (PRF and conservative treatment) according to consent or refusal to undergo PRF procedure. Fifteen patients received PRF of the articular branches of the femoral and obturator nerves, and 14 patients received conservative treatment. Visual analog scale (VAS), Oxford hip scores (OHS), and pain medications were used for outcome measurement before treatment and at 1 week, 4 weeks, and 12 weeks after treatment.Results: At 1 week, 4 weeks, and 12 weeks after treatment initiation, improvements in VAS were significantly greater with PRF. Improvements in OHS were significantly greater in the PRF group at 1 week, 4 weeks, and 12 weeks. Patients in the PRF group also used less pain medications. Eight subjects in the conservative treatment group switched to the PRF group after 12 weeks, and six of them had >50% improvement.Conclusion: When compared with conservative treatment, PRF of the articular branches of the femoral and obturator nerves offers greater pain relief for chronic hip pain and can augment physical functioning. Keywords: pulsed radiofrequency, obturator and femoral nerves, hip joint pain, osteoar­thritis

W Darlene Reid,1,2 Cristiane Yamabayashi,1 Donna Goodridge,3 Frank Chung,4 Michael A Hunt,1 Darcy D Marciniuk,5 Dina Brooks,6 Yi-Wen Chen,1 Alison Hoens,1,7 Pat Camp1,21Department of Physical Therapy, University of British Columbia, Vancouver, 2Institute of Heart and Lung Health, University of British Columbia, Vancouver, 3College of Nursing, University of Saskatchewan, 4Physiotherapy, Burnaby Hospital, Fraser Health, British Columbia, 5Division of Respirology, Critical Care and Sleep Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, 6Department of Physical Therapy, University of Toronto, Toronto, ON, 7Providence Health Care, Vancouver, BC, CanadaIntroduction: The prescription of physical activity for hospitalized patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) can be complicated by the presence of comorbidities. The current research aimed to synthesize the relevant literature on the benefits of exercise for people with multimorbidities who experience an AECOPD, and ask: What are the parameters and outcomes of exercise in AECOPD and in conditions that are common comorbidities as reported by systematic reviews (SRs)?Methods: An SR was performed using the Cochrane Collaboration protocol. Nine electronic databases were searched up to July 2011. Articles were included if they (1) described participants with AECOPD, chronic obstructive pulmonary disease (COPD), or one of eleven common comorbidities, (2) were an SR, (3) examined aerobic training (AT), resistance training (RT), balance training (BT), or a combination thereof, (4) included at least one outcome of fitness, and (5) compared exercise training versus control/sham.Results: This synthesis examined 58 SRs of exercise training in people with AECOPD, COPD, or eleven chronic conditions commonly associated with COPD. Meta-analyses of endurance (aerobic or exercise capacity, 6-minute walk distance – 6MWD) were shown to significantly improve in most conditions (except osteoarthritis, osteoporosis, and depression), whereas strength was shown to improve in five of the 13 conditions searched: COPD, older adults, heart failure, ischemic heart disease, and diabetes. Several studies of different conditions also reported improvements in quality of life, function, and control or prevention outcomes. Meta-analyses also demonstrate that exercise training decreases the risk of mortality in older adults, and those with COPD or ischemic heart disease. The most common types of training were AT and RT. BT and functional training were commonly applied in older adults. The quality of the SRs for most conditions was moderate to excellent (>65%) as evaluated by AMSTAR scores.Conclusion: In summary, this synthesis showed evidence of significant benefits from exercise training in AECOPD, COPD, and conditions that are common comorbidities. A broader approach to exercise and activity prescription in pulmonary rehabilitation may induce therapeutic benefits to ameliorate clinical sequelae associated with AECOPD and comorbidities such as the inclusion of BT and functional training.Keywords: pulmonary disease, chronic obstructive, comorbidity, exercise, physical fitness

To maximize the light yield of the liquid scintillator (LS) for the Jiangmen Underground Neutrino Observatory (JUNO), a 20 t LS sample was produced in a pilot plant at Daya Bay. The optical properties of the new LS in various compositions were studied by replacing the gadolinium-loaded LS in one antineutrino detector. The concentrations of the fluor, PPO, and the wavelength shifter, bis-MSB, were increased in 12 steps from 0.5 g/L and

Tiam1 (T-lymphoma invasion and metastasis 1) is one of the known guanine nucleotide (GDP/GTP) exchange factors (GEFs) for Rho GTPases (e.g., Rac1) and is expressed in breast tumor cells (e.g., SP-1 cell line). Immunoprecipitation and immunoblot analyses indicate that Tiam1 and the cytoskeletal protein, ankyrin, are physically associated as a complex in vivo. In particular, the ankyrin repeat domain (ARD) of ankyrin is responsible for Tiam1 binding. Biochemical studies and deletion mutation analyses indicate that the 11-amino acid sequence between amino acids 717 and 727 of Tiam1 ((717)GEGTDAVKRS(727)L) is the ankyrin-binding domain. Most importantly, ankyrin binding to Tiam1 activates GDP/GTP exchange on Rho GTPases (e.g., Rac1). Using an Escherichia coli-derived calmodulin-binding peptide (CBP)-tagged recombinant Tiam1 (amino acids 393-728) fragment that contains the ankyrin-binding domain, we have detected a specific binding interaction between the Tiam1 (amino acids 393-738) fragment and ankyrin in vitro. This Tiam1 fragment also acts as a potent competitive inhibitor for Tiam1 binding to ankyrin. Transfection of SP-1 cell with Tiam1 cDNAs stimulates all of the following: (1) Tiam1-ankyrin association in the membrane projection; (2) Rac1 activation; and (3) breast tumor cell invasion and migration. Cotransfection of SP1 cells with green fluorescent protein (GFP)-tagged Tiam1 fragment cDNA and Tiam1 cDNA effectively blocks Tiam1-ankyrin colocalization in the cell membrane, and inhibits GDP/GTP exchange on Rac1 by ankyrin-associated Tiam1 and tumor-specific phenotypes. These findings suggest that ankyrin-Tiam1 interaction plays a pivotal role in regulating Rac1 signaling and cytoskeleton function required for oncogenic signaling and metastatic breast tumor cell progression.

The opioid system is known to enhance motivated behaviors, including ethanol drinking and food ingestion, by acting in various reward-related brain regions, such as the nucleus accumbens, ventral tegmental area and medial hypothalamus. There is indirect evidence, however, suggesting that opioid peptides may act differently in the perifornical lateral hypothalamus (PF/LH), causing a suppression of consummatory behavior. Using brain-cannulated Sprague-Dawley rats trained to voluntarily drink 7% ethanol, the present study tested the hypothesis that opioids in the PF/LH can reduce the consumption of ethanol, with animals receiving PF/LH injections of the δ-opioid receptor agonist D-Ala2-met-enkephalinamide (DALA), the μ-receptor agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO), the κ-receptor agonist (±)-trans-U-50,488 methanesulfonate (U-50,488H), or the general opioid antagonist methylated naloxone (m-naloxone). The consumption of ethanol, lab chow, and water was monitored for 4 h after injection. The results showed that the three opioid receptor agonists injected into the PF/LH specifically and significantly reduced ethanol intake, while causing little change in chow or water intake, and the opposite effect, enhanced ethanol intake, was observed with the opioid antagonist. Of the three opioid agonists, the δ-agonist appears to produce the most consistent and long-lasting suppression of consumption. This effect was not observed with injections 2 mm dorsal to this area, focusing attention on the PF/LH as the main site of action. These results suggest that the opioid peptides have a specific role in the PF/LH of reducing ethanol drinking, which is distinct from their more commonly observed appetitive actions in other brain areas. The additional finding, that m-naloxone in the PF/LH stimulates ethanol intake in contrast to its generally suppressive effect in other regions, focuses attention on this hypothalamic area and its distinctive role in contributing to the variable effects sometimes observed with opioid antagonist therapy for alcoholism. [ABSTRACT FROM AUTHOR]

We investigated whether overexpression of catalase (CAT) in renal proximal tubular cells (RPTCs) could prevent the programming of hypertension and kidney disease in the offspring of dams with maternal diabetes. Male offspring of nondiabetic and diabetic dams from two transgenic (Tg) lines (Hoxb7-green fluorescent protein [GFP]-Tg [controls] and Hoxb7/CAT-GFP-Tg, which overexpress CAT in RPTCs) were studied from the prenatal period into adulthood. Nephrogenesis, systolic blood pressure, renal hyperfiltration, kidney injury, and reactive oxygen species (ROS) generation were assessed. Gene expression of transforming growth factor-β1 (TGF-β1), nuclear factor erythroid 2p45-related factor-2 (Nrf2), and heme oxygenase-1 (HO-1) was tested in both in vitro and in vivo studies. Renal dysmorphogenesis was observed in offspring of Hoxb7-GFP-Tg dams with severe maternal diabetes; the affected male offspring displayed higher renal ROS generation and developed hypertension and renal hyperfiltration as well as renal injury with heightened TGF-β1 expression in adulthood. These changes were ameliorated in male offspring of diabetic Hoxb7/CAT-GFP-Tg dams via the Nrf2-HO-1 defense system. CAT promoted Nrf2 nuclear translocation and HO-1 gene expression, seen in both in vitro and in vivo studies. In conclusion, CAT overexpression in the RPTCs ameliorated maternal diabetes-induced perinatal programming, mediated, at least in part, by triggering the Nrf2-HO-1 defense system. [ABSTRACT FROM AUTHOR]

Background and Objectives: The aims of this study were to establish the potencies of epinephrine, bupivacaine, dextromethorphan, 3-methoxymorphinan, and dextrorphan and evaluate interactions of epinephrine with bupivacaine, dextromethorphan, 3-methoxymorphinan, or dextrorphan as an infiltrative anesthetic. Bupivacaine, a common and long-acting local anesthetic, was used as control.Methods: Dose-dependent responses of epinephrine, dextromethorphan, 3-methoxymorphinan, and dextrorphan on cutaneous analgesia were compared with bupivacaine in rats. The interactions of drugs were evaluated via an isobolographic analysis.Results: We found that epinephrine, bupivacaine, dextromethorphan, 3-methoxymorphinan, and dextrorphan produced a dose-dependent local anesthetic effect as infiltrative cutaneous analgesia. Relative potencies were epinephrine > bupivacaine > dextromethorphan > 3-methoxymorphinan > dextrorphan (P < .01 for each comparison). Coadministration of bupivacaine with epinephrine produced a synergistic effect, and coadministration of dextromethorphan, 3-methoxymorphinan, or dextrorphan with epinephrine produced an additive effect.Conclusions: Epinephrine, dextromethorphan, 3-methoxymorphinan, and dextrorphan are known to have local anesthetic effects as infiltrative cutaneous analgesia in rats. Epinephrine increased the potency of bupivacaine, but not dextromethorphan, 3-methoxymorphinan, or dextrorphan as an infiltrative anesthetic. The cutaneous analgesic effects of adding epinephrine to dextromethorphan, 3-methoxymorphinan, or dextrorphan, are similar to combinations of 2 local anesthetics. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to identify risk factors for redialysis in postoperative patients with acute renal failure (ARF) who had previously been weaned from acute dialysis. Although recovery of renal function is anticipated in patients with ARF, no data have been reported on successful weaning from acute dialysis.Design and Setting: Retrospective observational case-control study in a 64-bed surgical ICU.Patients and Methods: Success in discontinuing dialysis was defined as cessation from dialysis for at least 30 days. A total of 304 postoperative patients who underwent acute renal replacement therapy in a surgical ICU between July 2002 and April 2005 were included. SOFA score biochemical data and renal function parameters were assessed on the day after the last session of renal replacement therapy, designated as day 0 (D0).Results: We could wean 94 patients (30.9%) from acute dialysis for more than 5 days, and 64 of these (21.1%) were successfully weaned for at least 30days. The independent predictors for resuming dialysis within 30 days were: (a) longer duration of dialysis (OR 1.06), (b) higher SOFA score on D0 (OR 1.44), (c) oliguria (urine output <100cc/8h; OR 4.17) on D1, and (d) age over 65 years (OR 6.35). The area under the ROC curve was 0.880. Two-way analysis of variance with repeated measurements over time showed a larger decline in SOFA score and an increase in urine output in patients with successful cessation of dialysis. Kaplan-Meier analysis showed a significant difference in early resumption of dialysis between patients with or without oliguria at D0.Conclusions: More than two-thirds of patients weaned from postoperative acute dialysis for more than 5 days were free of dialysis for at least 30 days. Less urine output, longer duration of dialysis, age over 65 years, and higher disease severity score are predictive of a patient's redialysis after initial weaning from acute dialysis. [ABSTRACT FROM AUTHOR]