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Chi-Ling Wu,1 Oswald Ndi Nfor,1 Disline Manli Tantoh,1,2 Wen-Yu Lu,1 Yung-Po Liaw1– 3 1Department of Public Health, Institute of Public Health, Chung Shan Medical University, Taichung City, Taiwan; 2Department of Medical Imaging, Chung Shan Medical University Hospital, Taichung City, Taiwan; 3Institute of Medicine, Chung Shan Medical University, Taichung City, TaiwanCorrespondence: Yung-Po Liaw, Department of Public Health and Institute of Public Health, Chung Shan Medical University, No.110 Sec. 1 Jianguo N.Road, Taichung City, Taiwan, Tel +886436097501, Fax +886423248179, Email Liawyp@csmu.edu.twPurpose: Osteoporosis is a degenerative disease that affects women and men of all races. We studied the association between body mass index (BMI), rs2908004 polymorphism of the WNT16 gene, and osteoporosis using data from Taiwan Biobank (TWB).Patients and Methods: We analyzed data from 10,942 subjects aged 30 to 70. We defined osteoporosis based on a mean T-score of − 2.5 and below in the hip. Body mass index was classified following the guidelines of the Health Promotion Administration. Imputation was carried out using the IMPUTE2 (v2.3.1) program. Multiple logistic regression was used for analysis. The odds ratios (ORs) and 95% confidence interval (CI) for osteoporosis were determined.Results: In the multivariate regression model, variant rs2908004 had a significant association with osteoporosis. That is, the rs2908004-GA+AA genotype was associated with lower osteoporosis risk than the GG genotype (OR, 0.651; 95% CI = 0.544 to 0.780). Compared to normal-weight, underweight was significantly associated with a higher risk of osteoporosis (OR, 6.517; 95% CI = 4.624 to 9.186) while overweight and obesity were protective (OR, 0.176; 95% CI = 0.140 to 0.221 and 0.057; 95% CI = 0.039 to 0.083, respectively). There was an interaction between rs2908004 and BMI (p = 0.0148). Subgroup analyses (using rs2908004-GG/normal-weight as the reference group) indicated ORs of 7.66 (95% CI = 5.153 to 11.394) in the rs2908004-GG/underweight group and 3.002 (95% CI = 1.509 to 5.974) in the rs2908004-GA+AA/underweight group (95% CI = 1.509 to 5.974). Odds ratios were substantially lower in rs2908004-GG/obese, rs2908004-GG/overweight, GA+AA/normal-weight, rs2908004-GA+AA/overweight, and rs2908004-GA+AA/obese groups, respectively.Conclusion: According to our study, underweight was associated with an increased risk of osteoporosis irrespective of WNT16 rs2908004 genotypes, while overweight and obesity were associated with a lower risk.Keywords: bone health, SNP, osteoporosis, anthropometric measures

Chunli Wu,1–3 Liang Yang,4 Xun Qi,2 Taifang Wang,3 Meng Li,3 Ke Xu1,2 1Department of Radiology, The First Affiliated Hospital of China Medical University, Shenyang, China; 2Key Laboratory of Diagnostic Imaging and Interventional Radiology of Liaoning Province, The First Affiliated Hospital of China Medical University, Shenyang, China; 3Department of Radiation Oncology, The Fourth Affiliated Hospital of China Medical University, Shenyang, China; 4Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang 110032, China Background: Resistance to radiation therapy is still a challenge for treatment of pancreatic cancer (PC). Long non-coding RNAs (lncRNA) HOTAIR has been found to play a oncogenic role in several cancers. However, the correlation between HOTAIR and radiotherapy in PC is still unclear.Methods: TCGA data was collected to analyze the expression of HOTAIR and its relationship with PC progression. A series of functional experiments were conducted to explore the role of HOTAIR in PC radiosensitivity and its underlying molecular mechanisms.Results: By the analysis of the TCGA data, we found HOTAIR expression in PC tissues was significantly higher than normal tissues and associated with tumor progression. The function analysis showed HOTAIR was enriched in biological regulation and response to stimulus.And in vitro study, the expression of HOTAIR was increased in PANC-1 and AsPC-1 cells after radiation. We identified that HOTAIR knockdown could enhance radiosensitivity and influence autophagy by up-regulating ATG7 expression in PC cells. By futher rescue experiments using rapamycin, activation of autophagy could reversed the the inhibition of cell proliferation and colony formation, as well as promotion of apoptosis mediated by HOTAIR knockdown, indicating that HOTAIR knockdown promoted radiosensitivity of PC cells by regulating autophagy. Conclusion: Our finding revealed the the regulatory role of HOTAIR in radiosensitivity and provided a a new sight to improve radiotherapy effciency in PC. Keywords: HOTAIR, pancreatic cancer, radiosensitivity, autophagy, Atg7

I-Chieh Mao,1 Ching-Yeh Lin,2 Chia-Lin Wu,3,4 Chew-Teng Kor,5,6 Chia-Chu Chang3,7–9 1Division of Critical Care, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan; 2Division of Hematology and Oncology, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan; 3Division of Nephrology, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan; 4Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; 5Internal Medicine Research Center, Changhua Christian Hospital, Changhua, Taiwan; 6Graduate Institute of Statistics and Information Science, National Changhua University of Education, Changhua, Taiwan; 7Department of Internal Medicine, Kuang Tien General Hospital, Taichung, Taiwan; 8School of Medicine, Chung-Shan Medical University, Taichung, Taiwan; 9Department of Nutrition, Hungkuang University, Taichung, Taiwan Background: Hydroxychloroquine (HCQ), one of the disease-modifying antirheumatic drugs, may lead to an inhibition of autophagy. Autophagy, an intracellular self-defense mechanism for the lysosomal degradation of cytoplasmic components such as damaged organelles, plays a role in protecting against neoplasm growth but is also vital for cancer cells due to an increased intracellular metabolic waste. Methods: Taiwan National Health Insurance Database was subjected to analysis to investigate the effect of HCQ exposure on cancer risk in patients with autoimmune diseases. Cancer incidence between patients with or without at least 12-month HCQ use was compared by propensity score-matched landmark analysis. A total of 100,000 participants were enrolled, including 7,662 patients who were diagnosed with autoimmune diseases between January 1, 2000, and December 31, 2012. Results: After propensity score matching, HCQ user and nonuser groups consist of 1,933 patients with a mean follow-up time of 7.82 and 6.7 years, respectively. During the follow-up period, 93 HCQ users and 77 HCQ nonusers developed cancers. Meanwhile, Kaplan–Meier estimates showed no difference in the overall incidence of cancer between HCQ users and nonusers. Conclusion: This propensity score-matched study of Taiwanese patients with autoimmune diseases suggested that HCQ exposure did not increase the cancer risk. Keywords: hydroxychloroquine, autophagy, cancer, autoimmune diseases, propensity score

Chia-Chu Chang,1,2 Hung-Hsiang Liou,1 Chia-Lin Wu,1 Chirn-Bin Chang,1,2 Yu-Jun Chang,3 Ping-Fang Chiu,1,2 Ching-Hui Huang41Division of Nephrology, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan; 2School of Medicine, Chung Shan Medical University, Taichung, Taiwan; 3Epidemiology and Biostatistics Center, 4Division of Cardiology, Department of Internal Medicine, Changhua Christian Hospital, Changhua, TaiwanBackground: The purpose of this study was to examine whether long-term use of anticoagulants in elderly patients with atrial fibrillation (AF) and chronic kidney disease (CKD) influences renal function.Methods: In this retrospective observational study, we reviewed the records of 2023 patients who attended our institution for treatment of CKD between January 2001 and September 2012. Inclusion criteria were having been under review for three months or more, age older than 60 years, permanent AF, a CHADS2 score > 2, and National Kidney Foundation Kidney Disease Outcomes Quality Initiative CKD stage 3–5. Sixty-one patients fulfilled these criteria, and were divided into those receiving antiplatelet anticoagulation (group A) and those receiving warfarin (group B). The results of laboratory investigations and estimated glomerular filtration rate (GFR) were recorded at months 3, 6, 12, and 18 from treatment initiation. We also recorded the occurrence of serious cardiovascular and neurological events, significant bleeding, and survival beyond 12 years.Results: Of the 61 patients enrolled, 35 were in group A and 26 were in group B. The mean international normalized ratio (INR) was 1.95 ± 1.01 (goal < 3.0). After adjustment for potential confounding variables, we found that patients in group B had a higher estimated GFR (6.06 ± 2.36 mL per minute, P = 0.01). Over a 12-year observation period, group B patients had significantly (P = 0.013) better survival than group A, with an adjusted hazard ratio for mortality of 0.318 (P = 0.022).Conclusion: Warfarin therapy may delay deterioration in renal function and improve survival of elderly patients with CKD and AF.Keywords: aged, atrial fibrillation, chronic kidney disease, vitamin K antagonists, warfarin

We present results from N-body simulations of self-interacting dark matter (SIDM) subhalos, which could host ultra-faint dwarf spheroidal galaxies, inside a Milky-Way-like main halo. We find that high-concentration subhalos are driven to gravothermal core collapse, while low-concentration subhalos develop large (kpc-sized) low-density cores, with both effects depending sensitively on the satellite's orbit and the self-interaction cross section over mass σ/m. The overall effect for σ/m ≳ 3 cm2/g is to increase the range of inner densities, potentially explaining the observed diversity of Milky Way satellites, which include compact systems like Draco and Segue 1 that are dense in dark matter, and less dense, diffuse systems like Sextans and Crater II . We discuss possible ways of distinguishing SIDM models from collisionless dark matter models using the inferred dark matter densities and stellar sizes of the dwarf spheroidal galaxies.

Objective: Immune cells are involved in the pathogenesis of osteoarthritis (OA). We examined the effects of T helper (Th) cells, which induce the expression of macrophage inflammatory protein (MIP-1γ), on the progression of OA.Design: Using anterior cruciate ligament-transection (ACLT), we induced OA in one hind-leg knee joint of B6 mice. The CD4(+) T cells from splenocytes and synovium were flow-cytometrically and immunochemically evaluated, respectively. The knee joints were histologically assessed for manifestations of OA. MIP-1γ levels and nuclear factor-κB (NF-κB) in the knee joints were measured using enzyme-linked immunosorbent and immunoblotting assays, respectively; osteoclastogenesis was detected by tartrate-resistant acid phosphatase (TRAP) staining. The inflammatory responses and MIP-1γ expression were examined using immunohistochemistry.Results: The number of CD4(+) T cells and the expression of interferon-γ (IFN-γ) increased during OA onset (30 days after ACLT) and then decreased at a later stage of OA (90 days after ACLT). Tissue damage induced by CD4(+) T cells was evident at the later stage. The activation of CD4(+) T cells induced the expression of MIP-1γ and NF-κB. The expression of MIP-1γ can be detected in synovium which CD4(+) T cells were infiltrated. The increased MIP-1γ expression caused an increase in the number of osteoclasts in joints. The regulation of CD4(+) T cells was accompanied by increased macrophage infiltration and matrix metalloproteinase (MMP)-9 expression. Histopathological examinations revealed that CD4(+) T cell knockout (CD4(-/-)) mice had less expression of MIP-1γ and slower cartilage degeneration than control mice had.Conclusions: CD4(+) T cells were activated during the onset of OA, but cartilage damage was more prominent at a later stage. CD4(+) T cells were involved in the pathogenesis of OA: they induced MIP-1γ expression and subsequent osteoclast formation. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Synovial fibroblasts (SFs) play a pivotal role in the pathogenesis of rheumatoid arthritis (RA). It has been documented that the phenotype of rheumatoid synovium is similar, in many respects, to that of an aggressive tumor. In this study, a novel, genetically engineered adenovirus was designed to lyse SFs that exhibit high telomerase activity and p53 mutations, and its effects as a novel therapeutic strategy were assessed in an experimental arthritis model. METHODS: An E1B-55-kd-deleted adenovirus driven by the human telomerase reverse transcriptase promoter was constructed (designated Ad.GS1). Cytolysis of SFs and productive replication of Ad.GS1 in the SFs of rats with collagen-induced arthritis (CIA), as well as the SFs of patients with RA (RASFs), were assessed in vitro and in vivo. Treatment responses, as well as the presence of disease-related cytokines and enzymes in the ankle joints, were determined in the murine model. RESULTS: Ad.GS1 replicated in and induced cytolysis of human RASFs and SFs from arthritic rats, but spared normal fibroblasts. Bioluminescence imaging in vivo also demonstrated replication of Ad.GS1 in arthritic rat joints, but not in normal rat joints. Intraarticular administration of Ad.GS1 significantly reduced the ankle circumference, articular index scores, radiographic scores, and histologic scores and decreased the production of interleukin-1beta, matrix metalloproteinase 9, and prolyl 4-hydroxylase in rats with CIA compared with their control counterparts. CONCLUSION: This study is the first to demonstrate the amelioration of arthritic symptoms by a novel, telomerase-dependent adenovirus in the rat CIA model, an experimental model that resembles human RA. In addition, the results suggest that because of its ability to induce cytolysis of SFs, this virus may be further explored as a therapeutic agent in patients with RA. [ABSTRACT FROM AUTHOR]

Progress continues on American Society of Regional Anesthesia (ASRA) AcutePOP. Highlights include selection of data fields and creation of definitions for complications jointly accepted by clinical registries for ASRA, American Society of Anesthesiologists, Regional Anesthesia Surveillance System, Society for Obstetric Anesthesia and Perinatology, and Society for Pediatric Anesthesia. Development of a Web site and applications continues, and a demonstration is planned for the ASRA 2009 meeting. [ABSTRACT FROM AUTHOR]

Background and Objectives: Painful diabetic peripheral neuropathy (DPN) is an increasingly prevalent disorder that is best managed through a multimodal approach. We examined the effects of pregabalin on pain control, sleep disturbance, and the patient's global impression of change (PGIC) for the treatment of this disorder.Methods: Studies were identified using the National Library of Medicine's PubMed and EMBase databases (1966 to July 15, 2007). Inclusion criteria were randomized trials comparing pregabalin to placebo in the treatment of DPN for adult patients. A total of 13 abstracts were identified of which 3 met inclusion criteria. Data were collected from each article and results were recorded. Primary outcome was pain at the conclusion of the study. Secondary outcomes included number of patients with 50% reduction in mean pain score, PGIC ratings at endpoint, and adverse events. A random-effects model was used.Results: The 3 studies yielded 728 total subjects from 5 centers, of which 476 received pregabalin (dose range 75 to 600 mg/day) and 252 received placebo. Pregabalin treatment was associated with a significant decrease in pain scores (weighted mean difference, 1.15), higher likelihood to achieve at least a 50% reduction in mean pain score (relative risk [RR], 4.05), and improved PGIC ratings (RR = 1.45). Pregabalin was associated with an increased risk of somnolence, dizziness, and edema.Conclusions: Pregabalin has significant effects on the pain associated with DPN as well as secondary endpoints that affect patients' quality of life. [ABSTRACT FROM AUTHOR]

Background: Stump and phantom pains are debilitating sequelae of amputations that are often resistant to treatment. The efficacy of pharmacologic therapies, including opioids and sodium channel blockers, for postamputation pain is uncertain.Methods: The authors conducted a double-blind, randomized, placebo-controlled, crossover study in adult patients with postamputation pain of 6 months or longer and greater than 3 on a 0-10 numeric pain rating scale. Each of the three treatment periods (morphine, mexiletine, or placebo) included a 1-week drug-free interval followed by 4-week titration, 2-week maintenance, and 2-week drug-taper phases. The primary outcome measure was change in average pain intensity from the drug-free baseline to the last week of maintenance.Results: Sixty amputees were enrolled; data were analyzed from 56 subjects for one drug period, 45 subjects for two drug periods, and 35 subjects who completed all three drug periods. The mean morphine and mexiletine dosages were 112 and 933 mg, respectively. Morphine treatment provided lower pain scores compared with placebo and mexiletine (P = 0.0003). The mean percent pain relief during treatment with placebo, mexiletine, and morphine was 19, 30, and 53%, respectively (P < 0.0001, morphine vs. placebo and mexiletine). The numbers needed to treat to obtain 50% and 33% decreases in pain intensity with morphine were 5.6 and 4.5, respectively. Treatment with morphine was associated with a higher rate of side effects.Conclusions: Therapy with morphine, but not mexiletine, resulted in a decrease in intensity of postamputation pain but was associated with a higher rate of side effects and no improvement in self-reported levels of overall functional activity and pain-related interference in daily activities. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The phosphatidylinositol 3-kinase (PI 3-kinase)/Akt pathway is known to be activated in rheumatoid arthritis (RA) synovial tissue, which impacts cell growth, proliferation, survival, and migration. Phosphatase and tensin homolog deleted from chromosome 10 (PTEN) functions as a negative regulator of PI 3-kinase signaling, thus blocking Akt activation. The aim of this study was to examine the effect of PTEN gene transfer in rats with collagen-induced arthritis (CIA). METHODS: Adenoviral vectors encoding human PTEN (AdPTEN) or beta-galactosidase (AdLacZ) were injected intraarticularly into rats with CIA, and their treatment responses were monitored by measures of clinical, radiographic, and histologic changes. The expression of phosphorylated Akt, total Akt, vascular endothelial growth factor (VEGF), proinflammatory cytokines, and chemokines, as well as the extent of microvessel density in the ankle joints were determined. RESULTS: AdPTEN treatment reduced Akt phosphorylation and decreased VEGF production in human RA synovial fibroblasts. Compared with AdLacZ treatment of the rats with CIA, AdPTEN treatment significantly reduced ankle circumference, articular index scores, radiography scores, and histology scores, and also decreased microvessel density and levels of VEGF and interleukin-1beta. Furthermore, PTEN gene transfer led to down-regulation of Akt activation and increased apoptosis in the ankle joints. CONCLUSION: This study is the first to demonstrate the in vivo effect of intraarticular gene delivery of PTEN on amelioration of arthritis symptoms in rats with CIA, which involved antiangiogenic, antiproliferative, and antiinflammatory effects of PTEN via inhibition of the PI 3-kinase/Akt signaling pathway. Our findings also implicate the PI 3-kinase/Akt pathway as a therapeutic target for the treatment of RA or other inflammatory diseases. [ABSTRACT FROM AUTHOR]

Background: Clinical outcome of internal carotid artery (ICA) occlusion is highly variable and the reason is uncertain.Aim: To study the predictive factors of clinical outcome and stroke recurrence in patients with ischemic stroke associated with unilateral atherosclerosis-related ICA occlusion.Settings and Design: Prospective study in neurology department of a single hospital.Materials and Methods: We prospectively studied 66 patients who suffered from first-ever ischemic stroke associated with unilateral atherosclerosis-related ICA occlusion over a period of two years. The end point was death or stroke recurrence.Statistical Analysis: Chi-square or Fisher's exact test was used to analyze predictors of early functional outcome. Multivariate analysis was used to analyze predictors of death or stroke recurrence within two years.Result: Higher age (>or=70 years) predicted a worse functional outcome (P=0.049). Total anterior circulation syndrome (TACS) was associated with a poor functional outcome (P<0.001), but lacunar syndrome had a better outcome (P=0.001). Stroke in evolution predicted a poor outcome (P=0.001), while those with symptom improvement had a better outcome (P=0.016). Pneumonia predicted a poor outcome (P=0.021). Five patients expired and 22 patients suffered from recurrent stroke in the following 24 months. Previous transient ischemic attack (TIA) and anemia were associated with a higher risk of death or recurrent stroke within two years (P=0.036, P=0.012).Conclusion: High age, TACS, stroke in evolution and pneumonia were predictors for poor functional outcome. Previous TIA and anemia were predictors for death and recurrent stroke within two years. [ABSTRACT FROM AUTHOR]

PURPOSE: Acute respiratory failure requiring mechanical ventilation in severe community-acquired pneumonia has been shown to be a significant negative prognostic factor. We analyzed the early evolution of the Pao(2)/Fio(2) ratio and evaluated its clinical value as an outcome predictor. MATERIALS AND METHODS: This is a prospective study conducted in a tertiary referral hospital. In 62 adult patients requiring early mechanical ventilation due to severe community-acquired pneumonia, we measured serial changes in Pao(2)/Fio(2) ratio and other clinical variables within the first 48 hours of mechanical ventilation and compared the difference between survivors and nonsurvivors. RESULTS: The initial Pao(2)/Fio(2) ratio was lower in nonsurvivors (n = 27) than in survivors (n = 35) (158.0 +/- 55.8 vs 117.9 +/- 50.6, P = .025). Over the next 48 hours, the ratio increased significantly in survivors but not in nonsurvivors (analysis of variance, P < .001). An increase in Pao(2)/Fio(2) ratio greater than 56 mm Hg had a sensitivity of 75% and a specificity of 81% of survival. A definite causative pathogen was identified in 36 patients (58%) and the 3 most commonly isolated pathogens were Streptococcus pneumoniae, Staphylococcus aureus, and Klebsiella pneumoniae. Ten patients received inadequate initial empirical antimicrobial therapy, in which the Pao(2)/Fio(2) ratio change was significantly less than those who were adequately treated (analysis of variance, P < .001). Mortality was much higher (86% [6/7]) in patients who received inadequate antibiotics and where Pao(2)/Fio(2) ratio change was less than 56 mm Hg. On multivariate analysis, trend changes in Pao(2)/Fio(2) ratio over 48 hours, shock, and Acute Physiology and Chronic Health Evaluation II score were documented to be independent predictors of mortality. CONCLUSIONS: A progressive improvement of Pao(2)/Fio(2) ratio during the first 48 hours of mechanical ventilation indicates favorable outcome. Serial measurement of this ratio should be considered in decision making for therapeutic strategy.Copyright © 2007 by Elsevier Inc. [ABSTRACT FROM AUTHOR]

The Acute Pain Summit 2005 was convened to critically examine the perceptions of physicians about current methods used to control postoperative pain and to compare those perceptions with the available scientific evidence. Clinicians with expertise in treatment of postsurgical pain were asked to evaluate 10 practice-based statements. The statements were written to reflect areas within the field of acute-pain management, where significant questions remain regarding everyday practice. Each statement made a specific claim about the usefulness of a specific therapy (eg, PCA or epidural analgesia) or the use of pain-control modalities in specific patient populations (eg, epidural analgesia after colon resection). Members of the American Society of Regional Anesthesia and Pain Medicine (ASRA) were asked, via a Web-based survey, to rate their degree of agreement with each of the 10 statements; 22.8% (n = 632) of members responded. In preparation for the pain summit, a panel member independently conducted a literature search and summarized the available evidence relevant to each statement. Summit participants convened in December 2005. The assigned panel member presented the available evidence, and workshop participants then assigned a category for the level of evidence and recommendation for each statement. All participants then voted about each statement by use of the same accept/reject scale used earlier by ASRA members. This manuscript details those opinions and presents a critical analysis of the existing evidence supporting new and emerging techniques used to control postsurgical pain. [ABSTRACT FROM AUTHOR]