How mycobacterium tuberculosis infection could lead to the increasing risks of chronic fatigue syndrome and the potential immunological effects: a population-based retrospective cohort study.

BACKGROUND: Chronic fatigue syndrome (CFS) has been shown to be associated with infections. Tuberculosis (TB) is a highly prevalent infectious disease. Patients with chronic fatigue syndrome and post-tuberculosis experience similar symptoms. Furthermore, chronic fatigue syndrome and tuberculosis share similar plasma immunosignatures. This study aimed to clarify the risk of chronic fatigue syndrome following the diagnosis of Mycobacterium tuberculosis infection (MTI), by analyzing the National Health Insurance Research Database of Taiwan. METHODS: 7666 patients aged 20 years or older with newly diagnosed Mycobacterium tuberculosis infection during 2000-2011 and 30,663 participants without Mycobacterium tuberculosis infection were identified. Both groups were followed up until the diagnoses of chronic fatigue syndrome were made at the end of 2011. RESULTS: The relationship between Mycobacterium tuberculosis infection and the subsequent risk of chronic fatigue syndrome was estimated through Cox proportional hazards regression analysis, with the incidence density rates being 3.04 and 3.69 per 1000 person-years among the non-Mycobacterium tuberculosis infection and Mycobacterium tuberculosis infection populations, respectively (adjusted hazard ratio [HR] = 1.23, with 95% confidence interval [CI] 1.03-1.47). In the stratified analysis, the Mycobacterium tuberculosis infection group were consistently associated with a higher risk of chronic fatigue syndrome in the male sex (HR = 1.27, 95% CI 1.02-1.58) and age group of ≥ 65 years old (HR = 2.50, 95% CI 1.86-3.38). CONCLUSIONS: The data from this population-based retrospective cohort study revealed that Mycobacterium tuberculosis infection is associated with an elevated risk of subsequent chronic fatigue syndrome.

Estimating the incidence rate ratio of common cold among patients with non-apnea sleep disorders: a retrospective cohort study.

The purpose was to explore the potential effects of nonapnea sleep disorders (NSDs) and hypnotic use on the incidence of common cold. This study adapted population-based retrospective cohort study designed. We used the data from the Taiwan National Health Insurance Research Database between 1998 and 2011. In total, 59,476 patients with NSDs were included in the study cohort, and the reference cohort comprised 59,476 propensity score-matched patients. We conducted a Poisson regression analysis to assess the incidence of common cold. The overall incidence of common cold was significantly higher than that in the reference cohort. Compared with the patients of the reference cohort without hypnotic use, those of the NSDs cohort with benzodiazepines and zolpidem use had higher incidence of common cold. In conclusion, study cohort had a higher incidence of developing common cold, and particularly pronounced in NSDs with hypnotic use.

Positive association of Parkinson's disease with ankylosing spondylitis: a nationwide population-based study.

BACKGROUND: Ankylosing spondylitis (AS) is characterized by excessive production of inflammatory cytokines. Recent evidence suggests that inflammation underlies the neurodegenerative process of Parkinson's disease (PD). Whether AS has an influence on the development of PD is unclear. We aimed to examine a relationship, if any exists between AS and PD. METHODS: A population-based matched cohort study was performed using data from the 2000-2010 Taiwan National Health Insurance database. 6440 patients with AS and 25,760 randomly selected, age- and sex-matched controls were included in this study. The risk of PD in the AS cohort was evaluated by using a Cox model. RESULTS: This study revealed a positive association between AS and the risk of PD regardless of sex and age (aHR 1.75, p < .001). Particularly, AS cohort to non-AS cohort relative risk of PD significantly increased for the patients aged below 49 and above 65 years (aHR 4.70, p < .001; aHR 1.69, p < .001, respectively) and the patients with and without comorbidities (aHR 1.61, p < .001; aHR 2.71, p < .001, respectively). Furthermore, NSAID use was associated with lower risk of PD (aHR 0.69, p < .05). However, the risk of PD was higher (aHR 2.40, p < .01) in patients with AS receiving immunosuppressants than in those not receiving (aHR 1.70, p < .001). CONCLUSIONS: Patients with AS had an increased risk of PD which might be related to underlying chronic inflammation. Further research is required to elucidate the underlying mechanism.

Increased risk of chronic fatigue syndrome in patients with inflammatory bowel disease: a population-based retrospective cohort study.

BACKGROUND: Similarities in the symptoms of chronic fatigue syndrome (CFS) and inflammatory bowel disease (IBD) have been observed as follows: severe disease activity in IBD correlates with severe fatigue, major psychiatric signs, the common use of medication, and bacterial translocation. One of several hypotheses for explaining the mechanisms underlying CFS suggests a similarity to the impaired intestinal mucosa of IBD. "This study investigated the risk of incident CFS among patients with IBD". METHODS: We conducted a population-based retrospective cohort study by using Taiwan's National Health Insurance Research Database to evaluate the subsequent risk of CFS in patients with IBD, according to demographic characteristics and comorbidities. The exposure cohort comprised 2163 patients with new diagnoses of IBD. Each patient was randomly selected and frequency matching according to gender and age with four participants from the general population who had no history of CFS at the index date (control cohort). Cox proportional hazards regression analysis was conducted to estimate the relationship between IBD and the subsequent risk of CFS. RESULTS: The exposure cohort had a significantly higher overall risk of subsequent CFS than that of the control group [adjusted hazard ratio (Christophi in Inflamm Bowel Dis 18(12):2342-2356, 2012) = 2.25, 95%, confidence interval (Aaron and Buchwald in Ann Intern Med 134(9 Pt 2):868-881, 2001; Farraye et al. in Am J Gastroenterol 112:241, 2017) 1.70-2.99]. Further analysis indicated a significantly higher risk of CFS in patients who were male (HR = 3.23, 95% CI 2.12-4.91), were older than 35 years, and had IBD but without comorbidity status, e.g. Cancers, diabetes, obesity, depression, anxiety, sleep disorder, renal disease (HR = 2.50, 95% CI 1.63-3.84) after adjustment. CONCLUSION: The findings from this population-based retrospective cohort study suggest that IBD, especially Crohn's disease, is associated with an increased risk of subsequent CFS.

Increased risk of chronic fatigue syndrome following psoriasis: a nationwide population-based cohort study.

BACKGROUND: The onset of chronic fatigue syndrome (CFS) has been shown to be associated with several immunological conditions such as infections or atopy. The aim of this study was to clarify the risk of chronic fatigue syndrome following the diagnosis of psoriasis, an immune-related dermatological disease, by analyzing the National Health Insurance Research Database of Taiwan. METHOD: 2616 patients aged 20 years or older with newly diagnosed psoriasis during 2004-2008 and 10,464 participants without psoriasis were identified. Both groups were followed up until the diagnoses of CFS were made at the end of 2011. RESULTS: The relationship between psoriasis and the subsequent risk of CFS was estimated through Cox proportional hazards regression analysis, with the incidence density rates being 2.27 and 3.58 per 1000 person-years among the non-psoriasis and psoriasis populations, respectively (adjusted hazard ratio [HR] = 1.48, with 95% confidence interval [CI] 1.07-2.06). In the stratified analysis, the psoriasis group were consistently associated with a higher risk of CFS in male sex (HR = 2.05, 95% CI 1.31-3.20) and age group of ≥ 60 years old (HR = 2.32, 95% CI 1.33-4.06). In addition, we discovered that the significantly increased risk of CFS among psoriasis patients is attenuated after they receive phototherapy and/or immunomodulatory drugs. CONCLUSIONS: The data from this population-based retrospective cohort study revealed that psoriasis is associated with an elevated risk of subsequent CFS, which is differentiated by sex and age.

Hypoglycemic effects of Trichosanthes kirilowii and its protein constituent in diabetic mice: the involvement of insulin receptor pathway.

BACKGROUND: Diabetes is a serious chronic metabolic disorder. Trichosanthes kirilowii Maxim. (TK) is traditionally used for the treatment of diabetes in traditional Chinese medicine (TCM). However, the clinical application of TK on diabetic patients and the hypoglycemic efficacies of TK are still unclear. METHODS: A retrospective cohort study was conducted to analyze the usage of Chinese herbs in patients with type 2 diabetes in Taiwan. Glucose tolerance test was performed to analyze the hypoglycemic effect of TK. Proteomic approach was performed to identify the protein constituents of TK. Insulin receptor (IR) kinase activity assay and glucose tolerance tests in diabetic mice were further used to elucidate the hypoglycemic mechanisms and efficacies of TK. RESULTS: By a retrospective cohort study, we found that TK was the most frequently used Chinese medicinal herb in type 2 diabetic patients in Taiwan. Oral administration of aqueous extract of TK displayed hypoglycemic effects in a dose-dependent manner in mice. An abundant novel TK protein (TKP) was further identified by proteomic approach. TKP interacted with IR by docking analysis and activated the kinase activity of IR. In addition, TKP enhanced the clearance of glucose in diabetic mice in a dose-dependent manner. CONCLUSIONS: In conclusion, this study applied a bed-to-bench approach to elucidate the hypoglycemic efficacies and mechanisms of TK on clinical usage. In addition, we newly identified a hypoglycemic protein TKP from TK. Our findings might provide a reasonable explanation of TK on the treatment of diabetes in TCM.

Effects of Arsenic in Drinking Water on Risk of Hepatitis or Cirrhosis in Persons With and Without Chronic Viral Hepatitis.

BACKGROUND & AIMS: Arsenic in drinking water is associated with hepatomegaly and death from liver cancer. However, confounding factors related to liver diseases have not been carefully studied. We examined associations between exposure of arsenic in drinking water and risk of hepatitis and cirrhosis, and the interaction with chronic viral hepatitis, in people living in the Lanyang Basin of northeastern Taiwan, where well water has an arsenic content that ranges from undetectable to 3590 µg/L. METHODS: We tested blood samples from 4387 people who lived in arseniasis-endemic areas in northeastern Taiwan from 1991 through 1994 for hepatitis B virus DNA, hepatitis B surface antigen (HBsAg), and antibodies against hepatitis C virus (anti-HCV). We measured arsenic concentrations in well water and collected information on residents' histories of major chronic diseases. Reports of chronic hepatitis or cirrhosis were ascertained using the Taiwan National Health Insurance database. Reports of liver cancer were ascertained using the Taiwan National Cancer Registry. RESULTS: Prevalence odds ratios in the overall study population for chronic hepatitis or cirrhosis for well water arsenic concentrations of ≤10 µg/L were 1.00 (reference), 0.93 for 10.1-49.9 µg/L (95% confidence interval [CI], 0.57-1.52), 1.24 for 50.0-99.9 µg/L (95% CI, 0.68-2.23), 0.98 for 100.0-299.9 (95% CI, 0.52-1.85), and 1.86 for ≥300.0 µg/L (95% CI, 1.08-3.20). Increasing levels of arsenic in drinking water were associated with increasing prevalence of chronic hepatitis or cirrhosis in residents who were seronegative for HBsAg and seronegative for anti-HCV, but not for seropositive for either HBsAg or anti-HCV. In individuals who were seropositive for HBsAg or anti-HCV, we observed an inverse association between hepatitis or cirrhosis and consumption of water with levels of arsenic ≥100.0 µg/L. Among participants who were seropositive for HBsAg or anti-HCV, consumption of water with levels of arsenic ≥100.0 µg/L was associated with a reduced risk of liver cancer (multivariate-adjusted hazard ratio, 0.29; 95% CI, 0.09-0.95; P < .05). A higher proportion of individuals exposed to cumulative arsenic level >14,000 µg/L ×year were carriers of inactive hepatitis B virus (DNA <10,000 copies/mL) and were positive for HBsAg (60%) than individuals exposed to water below this arsenic level (35%). CONCLUSIONS: Concentrations of arsenic concentration in drinking water ≥300.0 µg/L significantly increase risk of hepatitis or cirrhosis in people without chronic viral hepatitis. However, in people with chronic viral hepatitis, levels of arsenic ≥100.0 µg/L in drinking water significantly reduce the risk of chronic hepatitis or cirrhosis.

[18F]-Fluorodeoxyglucose Positron Emission Tomography Standardized Uptake Value as a Predictor of Adjuvant Chemotherapy Benefits in Patients With Nasopharyngeal Carcinoma.

BACKGROUND: The role of adjuvant chemotherapy for the treatment of nasopharyngeal carcinoma (NPC) is controversial, and the identification of adequate predictive factors is warranted. Therefore, we aimed to investigate whether the mean standardized uptake value (SUV) measured on [(18)F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) could predict the survival benefits for NPC patients that receive adjuvant chemotherapy. MATERIALS AND METHODS: The data for 174 NPC patients who underwent PET/computed tomography before chemoradiation between January 2004 and January 2012 were reviewed. The SUV75% was recorded for primary tumors. All patients received intensity-modulated radiotherapy and cisplatin-based chemotherapy. Adjuvant chemotherapy consisted of 3 cycles of 75 mg/m(2) cisplatin and 1,000 mg/m(2) fluorouracil for 4 days. RESULTS: The optimal cutoff value was 8.35 for SUV75%, with 112 (64.4%) patients having lower SUV75% and 62 (35.6%) having higher SUV75%. Patients with lower SUV75% had significantly better 5-year overall survival (OS) and distant metastasis-free survival. Multivariate analysis revealed that tumor stage, SUV75%, and adjuvant chemotherapy were significant prognostic factors for OS. Patients with higher SUV75% had significantly higher 5-year OS rates with adjuvant chemotherapy than without adjuvant chemotherapy (84.3% vs. 32.4%, respectively; p < .001). However, in the lower SUV75% group, no differences in 5-year OS were observed between patients who received and those who did not receive adjuvant chemotherapy (92.4% vs. 93.3%, respectively; p = .682). CONCLUSION: The SUV75% on FDG PET for primary tumors could successfully identify NPC patients who may benefit from adjuvant chemotherapy.

Comparison of genome-wide DNA methylation in urothelial carcinomas of patients with and without arsenic exposure.

BACKGROUND: Arsenic is a well-documented carcinogen of human urothelial carcinoma (UC) with incompletely understood mechanisms. OBJECTIVES: This study aimed to compare the genome-wide DNA methylation profiles of arsenic-induced UC (AsUC) and non-arsenic-induced UC (Non-AsUC), and to assess associations between site-specific methylation levels and cumulative arsenic exposure. METHODS: Genome-wide DNA methylation profiles in 14 AsUC and 14 non-AsUC were analyzed by Illumina Infinium methylation27 BeadChip and validated by bisulfite pyrosequencing. Mean methylation levels (߯) in AsUC and non-AsUC were compared by their ratio (߯ ratio) and difference (Δ߯). Associations between site-specific methylation levels in UC and cumulative arsenic exposure were examined. RESULTS: Among 27,578 methylation sites analyzed, 231 sites had ߯ ratio >2 or <0.5 and 45 sites had Δ߯ >0.2 or <-0.2. There were 13 sites showing statistically significant (q<0.05) differences in ߯ between AsUC and non-AsUC including 12 hypermethylation sites in AsUC and only one hypermethylation site in non-AsUC. Significant associations between cumulative arsenic exposure and DNA methylation levels of 28 patients were observed in nine CpG sites of nine gens including PDGFD (Spearman rank correlation, 0.54), CTNNA2 (0.48), KCNK17 (0.52), PCDHB2 (0.57), ZNF132 (0.48), DCDC2 (0.48), KLK7 (0.48), FBXO39 (0.49), and NPY2R (0.45). These associations remained statistically significant for CpG sites in CTNNA2, KLK7, NPY2R, ZNF132 and KCNK17 in 20 non-smoking women after adjustment for tumor stage and age. CONCLUSIONS: Significant associations between cumulative arsenic exposure and methylation level of CTNNA2, KLK7, NPY2R, ZNF132 and KCNK17 were found in smoking-unrelated urothelial carcinoma. Arsenic exposure may cause urothelial carcinomas through the hypermethylation of genes involved in cell adhesion, proteolysis, transcriptional regulation, neuronal pathway, and ion transport. The findings of this study, which are limited by its small sample size and moderate dose-response relation, remain to be validated by further studies with large sample sizes.

Use of arsenic-induced palmoplantar hyperkeratosis and skin cancers to predict risk of subsequent internal malignancy.

Hyperpigmentation, hyperkeratoses, and Bowen's disease are hallmarks of chronic arsenic exposure. The association between arsenic-induced skin lesions and subsequent internal cancers is examined by using a community-based prospective study. The cohort was enrolled from an arseniasis-endemic area in southwestern Taiwan, where 2,447 residents participated in skin examinations during the late 1980s. The number of participants diagnosed with hyperpigmentation was 673; with hyperkeratosis, 243; and with skin cancer (Bowen's disease or non-melanoma skin cancer), 378. Newly diagnosed internal cancers were ascertained through linkage with National Cancer Registry profiles. Cox regression was performed to estimate hazard ratios with 95% confidence intervals for potential risk predictors. Compared with participants without skin lesions, patients affected with skin cancers had a significantly increased risk of lung cancer (hazard ratio = 4.64, 95% confidence interval: 2.92, 7.38) and urothelial carcinoma (hazard ratio = 2.02, 95% confidence interval: 1.23, 3.30) after adjustment for potential confounders and cumulative arsenic exposure. Hyperkeratosis is significantly associated with an increased lung cancer risk (hazard ratio = 2.76, 95% confidence interval: 1.35, 5.67). A significant interactive effect on lung cancer risk between hyperkeratosis and cigarette smoking was identified, which suggests that patients with hyperkeratosis who have been exposed to arsenic should cease smoking.

Epithelial polarization in the 3D matrix requires MST3 signaling to regulate ZO-1 position.

Apical-basal cell polarity must be tightly controlled for epithelial cyst and tubule formation, and these are important functional units in various epithelial organs. Polarization is achieved through the coordination of several molecules that divide cells into an apical domain and a basolateral domain, which are separated from tight and adherens junctions. Cdc42 regulates cytoskeletal organization and the tight junction protein ZO-1 at the apical margin of epithelial cell junctions. MST kinases control organ size through the regulation of cell proliferation and cell polarity. For example, MST1 relays the Rap1 signal to induce cell polarity and adhesion of lymphocytes. Our previous study showed that MST3 was involved in E-cadherin regulation and migration in MCF7 cells. In vivo, MST3 knockout mice exhibited higher ENaC expression at the apical site of renal tubules, resulting in hypertension. However, it was not clear whether MST3 was involved in cell polarity. Here, control MDCK cells, HA-MST3 and HA-MST3 kinase-dead (HA-MST3-KD) overexpressing MDCK cells were cultured in collagen or Matrigel. We found that the cysts of HA-MST3 cells were fewer and smaller than those of control MDCK cells; ZO-1 was delayed to the apical site of cysts and in cell-cell contact in the Ca2+ switch assay. However, HA-MST3-KD cells exhibited multilumen cysts. Intensive F-actin stress fibers were observed in HA-MST3 cells with higher Cdc42 activity; in contrast, HA-MST3-KD cells had lower Cdc42 activity and weaker F-actin staining. In this study, we identified a new MST3 function in the establishment of cell polarity through Cdc42 regulation.

Genetic polymorphisms in glutathione S-transferase (GST) superfamily and risk of arsenic-induced urothelial carcinoma in residents of southwestern Taiwan.

BACKGROUND: Arsenic exposure is an important public health issue worldwide. Dose-response relationship between arsenic exposure and risk of urothelial carcinoma (UC) is consistently observed. Inorganic arsenic is methylated to form the metabolites monomethylarsonic acid and dimethylarsinic acid while ingested. Variations in capacity of xenobiotic detoxification and arsenic methylation might explain individual variation in susceptibility to arsenic-induced cancers. METHODS: To estimate individual susceptibility to arsenic-induced UC, 764 DNA specimens from our long-term follow-up cohort in Southwestern Taiwan were used and the genetic polymorphisms in GSTM1, GSTT1, GSTP1 and arsenic methylation enzymes including GSTO1 and GSTO2 were genotyped. RESULTS: The GSTT1 null was marginally associated with increased urothelial carcinoma (UC) risk (HR, 1.91, 95% CI, 1.00-3.65), while the association was not observed for other GSTs. Among the subjects with cumulative arsenic exposure (CAE) ≥ 20 mg/L*year, the GSTT1 null genotype conferred a significantly increased cancer risk (RR, 3.25, 95% CI, 1.20-8.80). The gene-environment interaction between the GSTT1 and high arsenic exposure with respect to cancer risk was statistically significant (multiplicative model, p = 0.0151) and etiologic fraction was as high as 0.86 (95% CI, 0.51-1.22). The genetic effects of GSTO1/GSTO2 were largely confined to high arsenic level (CAE ≥ 20). Diplotype analysis showed that among subjects exposed to high levels of arsenic, the AGG/AGG variant of GSTO1 Ala140Asp, GSTO2 5'UTR (-183)A/G, and GSTO2 Asn142Asp was associated with an increased cancer risk (HRs, 4.91, 95% CI, 1.02-23.74) when compared to the all-wildtype reference, respectively. CONCLUSIONS: The GSTs do not play a critical role in arsenic-induced urothelial carcinogenesis. The genetic effects of GSTT1 and GSTO1 on arsenic-induced urothelial carcinogenesis are largely confined to very high exposure level.

Leptin Is Associated with Poor Clinical Outcomes and Promotes Clear Cell Renal Cell Carcinoma Progression.

Emerging evidence has shown the oncogenic roles of leptin in modulating cancer progression in addition to its original roles. Analyses of transcriptomic data and patients' clinical information have revealed leptin's prognostic significance in renal cell carcinoma (RCC). However, its biological effects on RCC progression have not yet been explored. Clinical and transcriptomic data of a RCC cohort of 603 patients were retrieved from The Cancer Genome Atlas (TCGA) and analyzed to reveal the correlation of leptin with clinical outcomes and the hierarchical clustering of gene signatures based on leptin levels. In addition, cox univariate and multivariate regression analyses, cell migration upon leptin treatment, identification of putative leptin-regulated canonical pathways via ingenuity pathway analysis (IPA), and the investigation of induction of Wnt5a, ROR2, and Jun N-terminal Kinases (JNK) phosphorylation activation were performed. We first observed a correlation of high leptin levels and poor outcomes in RCC patients. Knowledge-based analysis by IPA indicated the induction of cancer cell migration by leptin, which was manifested via direct leptin treatment in the RCC cell lines. In RCC patients with high leptin levels, the planar cell polarity (PCP)/JNK signaling pathway was shown to be activated, and genes in the axis, including CTHRC1, FZD2, FZD10, ROR2, WNT2, WNT4, WNT10B, WNT5A, WNT5B, and WNT7B, were upregulated. All of these genes were associated with unfavorable clinical outcomes. WNT5A and ROR2 are pivotal upstream regulators of PCP/JNK signaling, and their correlations with leptin expression levels were displayed by a Pearson correlation analysis. The inhibition of signal transduction by SP600125 reversed leptin-mediated cell migration properties in RCC cell lines. The results indicate the prognostic impact of leptin on RCC patients and uncover its ability to promote cell migration via PCP/JNK signaling.

GT-repeat polymorphism in the heme oxygenase-1 gene promoter and the risk of carotid atherosclerosis related to arsenic exposure.

BACKGROUND: Arsenic is a strong stimulus of heme oxygenase (HO)-1 expression in experimental studies in response to oxidative stress caused by a stimulus. A functional GT-repeat polymorphism in the HO-1 gene promoter was inversely correlated to the development of coronary artery disease in diabetics and development of restenosis following angioplasty in patients. The role of this potential vascular protective factor in carotid atherosclerosis remains unclear. We previously reported a graded association of arsenic exposure in drinking water with an increased risk of carotid atherosclerosis. In this study, we investigated the relationship between HO-1 genetic polymorphism and the risk of atherosclerosis related to arsenic. METHODS: Three-hundred and sixty-seven participants with an indication of carotid atherosclerosis and an additional 420 participants without the indication, which served as the controls, from two arsenic exposure areas in Taiwan, a low arsenic-exposed Lanyang cohort and a high arsenic-exposed LMN cohort, were studied. Carotid atherosclerosis was evaluated using a duplex ultrasonographic assessment of the extracranial carotid arteries. Allelic variants of (GT)n repeats in the 5'-flanking region of the HO-1 gene were identified and grouped into a short (S) allele (< 27 repeats) and long (L) allele (≥ 27 repeats). The association of atherosclerosis and the HO-1 genetic variants was assessed by a logistic regression analysis, adjusted for cardiovascular risk factors. RESULTS: Analysis results showed that arsenic's effect on carotid atherosclerosis differed between carriers of the class S allele (OR 1.39; 95% CI 0.86-2.25; p = 0.181) and non-carriers (OR 2.65; 95% CI 1.03-6.82; p = 0.044) in the high-exposure LMN cohort. At arsenic exposure levels exceeding 750 µg/L, difference in OR estimates between class S allele carriers and non-carriers was borderline significant (p = 0.051). In contrast, no such results were found in the low-exposure Lanyang cohort. CONCLUSIONS: This exploratory study suggests that at a relatively high level of arsenic exposure, carriers of the short (GT)n allele (< 27 repeats) in the HO-1 gene promoter had a lower probability of developing carotid atherosclerosis than non-carriers of the allele after long-term arsenic exposure via ground water. The short (GT)n repeat in the HO-1 gene promoter may provide protective effects against carotid atherosclerosis in individuals with a high level of arsenic exposure.

Risk of aortic dissection, congestive heart failure, pneumonia and acute respiratory distress syndrome in patients with clinical vertebral fracture: a nationwide population-based cohort study in Taiwan.

OBJECTIVE: Studies on the association between clinical vertebral fractures (CVFs) and the subsequent risk of cardiopulmonary diseases, including aortic dissection (AD), congestive heart failure (CHF), pneumonia and acute respiratory distress syndrome (ARDS) are scarce. Therefore, we used the National Health Insurance Research Database to investigate whether patients with CVF have a heightened risk of subsequent AD, CHF, pneumonia and ARDS. DESIGN: The National Health Insurance Research Database was used to investigate whether patients with CVFs have an increased risk of subsequent AD, CHF, pneumonia and ARDS. PARTICIPANTS: This cohort study comprised patients aged ≥18 years with a diagnosis of CVF and were hospitalised at any point during 2000-2010 (n=1 08 935). Each CVF patient was frequency-matched to a no-CVF hospitalised patients based on age, sex, index year and comorbidities (n=1 08 935). The Cox proportional hazard regressions model was used to estimate the adjusted effect of CVF on AD, CHF, pneumonia and ARDS risk. RESULTS: The overall incidence of AD, CHF, pneumonia and ARDS was higher in the CVF group than in the no-CVF group (4.85 vs 3.99, 119.1 vs 89.6, 283.3 vs 183.5 and 9.18 vs 4.18/10 000 person-years, respectively). After adjustment for age, sex, comorbidities and Charlson comorbidity index score, patients with CVF had a 1.23-fold higher risk of AD (95% CI=1.03-1.45), 1.35-fold higher risk of CHF (95% CI=1.30-1.40), 1.57-fold higher risk of pneumonia (95% CI=1.54-1.61) and 2.21-fold higher risk of ARDS (95% CI=1.91-2.57) than did those without CVF. Patients with cervical CVF and SCI were more likely to develop pneumonia and ARDS. CONCLUSIONS: Our study demonstrates that CVFs are associated with an increased risk of subsequent cardiopulmonary diseases. Future investigations are encouraged to delineate the mechanisms underlying this association.

Ghrelin Upregulates Oncogenic Aurora A to Promote Renal Cell Carcinoma Invasion.

Ghrelin is a peptide hormone, originally identified from the stomach, that functions as an endogenous ligand of the growth hormone secretagogue receptor (GHSR) and promotes growth hormone (GH) release and food intake. Increasing reports point out ghrelin's role in cancer progression. We previously characterized ghrelin's prognostic significance in the clear cell subtype of renal cell carcinoma (ccRCC), and its pro-metastatic ability via Snail-dependent cell migration. However, ghrelin's activity in promoting cell invasion remains obscure. In this study, an Ingenuity Pathway Analysis (IPA)-based investigation of differentially expressed genes in Cancer Cell Line Encyclopedia (CCLE) dataset indicated the potential association of Aurora A with ghrelin in ccRCC metastasis. In addition, a significant correlation between ghrelin and Aurora A expression level in 15 ccRCC cell line was confirmed by variant probes. ccRCC patients with high ghrelin and Aurora A status were clinically associated with poor outcome. We further observed that ghrelin upregulated Aurora A at the protein and RNA levels and that ghrelin-induced ccRCC in vitro invasion and in vivo metastasis occurred in an Aurora A-dependent manner. Furthermore, MMP1, 2, 9 and 10 expressions are associated with poor outcome. In particular, MMP10 is significantly upregulated and required for the ghrelin-Aurora A axis to promote ccRCC invasion. The results of this study indicated a novel signaling mechanism in ccRCC metastasis.

Association between intensive periodontal treatment and spontaneous intracerebral hemorrhage-a nationwide, population-based cohort study.

Periodontal disease is a chronic inflammation of periodontium and has a high prevalence. Periodontal disease has been discovered to be a possible risk factor for cerebrovascular diseases. The available evidence are not enough to set up a causal relationship between periodontal disease and cerebrovascular diseases. Patients with spontaneous intracerebral hemorrhage have high mortality rates. The present study investigated whether intensive periodontal treatment is a protective factor of spontaneous intracerebral hemorrhage and can reduce the risk of spontaneous intracerebral hemorrhage.In total, 64,960 patients with a history of periodontal disease were picked out from the National Health Insurance Research Databases as a case-cohort from January 01, 2000 to December 31, 2010. They were divided on the basis of whether periodontal disease patients received intensive surgical treatment (treatment cohort) or not (control cohort). The periodontal disease patients in treatment and control cohorts were selected by propensity score matching at a ratio of 1:1. Incidences of spontaneous intracerebral hemorrhage in both cohorts were analyzed and compared.The total hazard of spontaneous intracerebral hemorrhage was significantly decreased in the treatment cohorts compared with the control cohorts (adjusted hazard ratio = 0.60, 95% confidence interval = 0.45-0.79).Compared with the control cohort, intensive periodontal treatment may reduce the overall incidence of spontaneous intracerebral hemorrhage, particularly in elderly patients, males, and those who received more than 2 intensive treatments.

Effects of endogenous inflammation signals elicited by nerve growth factor, interferon-γ, and interleukin-4 on peripheral nerve regeneration.

BACKGROUND: Large gap healing is a difficult issue in the recovery of peripheral nerve injury. The present study provides in vivo trials of silicone rubber chambers filled with collagen containing IFN-γ or IL-4 to bridge a 15 mm sciatic nerve defect in rats. Fillings of NGF and normal saline were used as the positive and negative controls. Neuronal electrophysiology, neuronal connectivity, macrophage infiltration, location and expression levels of calcitonin gene-related peptide and histology of the regenerated nerves were evaluated. RESULTS: At the end of 6 weeks, animals from the groups of NGF and IL-4 had dramatic higher rates of successful regeneration (100 and 80%) across the wide gap as compared to the groups of IFN-γ and saline controls (30 and 40%). In addition, the NGF group had significantly higher NCV and shorter latency compared to IFN-γ group (P < 0.05). The IL-4 group recruited significantly more macrophages in the nerves as compared to the saline controls and the NGF-treated animals (P < 0.05). CONCLUSIONS: The current study demonstrated that NGF and IL-4 show potential growth-promoting capability for peripheral nerve regeneration. These fillings in the bridging conduits may modulate local inflammatory conditions affecting recovery of the nerves.

Risk of Parkinson disease in Sjögren syndrome administered ineffective immunosuppressant therapies: A nationwide population-based study.

To determine the incidence and risk of Parkinson disease (PD) in patients with Sjögren syndrome (SS) according to a nationwide population-based database.In total, 12,640 patients in the SS cohort and 50,560 in the non-SS cohort were enrolled from Taiwan's National Health Insurance Research Database from 2000 to 2010. We used the Cox multivariable proportional hazards model to determine the risk factors for PD in the SS cohort.We observed an increased incidence of PD in patients with SS, with a crude hazard ratio (HR) of 1.40 and an adjusted HR (aHR) of 1.23. The cumulative incidence of PD was 1.95% higher in the SS cohort than in the non-SS cohort. The SS cohort had an elevated HR under medication use, namely cevimeline and pilocarpine (crude HR, 1.28), hydroxychloroquine (crude HR, 1.43; aHR, 1.46), and methylprednisolone (crude HR, 2.21; aHR, 1.49). Patients receiving other non-hydroxychloroquine immunosuppressant therapies had a lower risk (aHR, 0.86) of PD. Furthermore, patients with SS aged 20 to 49 years had a 1.93-fold higher risk of PD than did those without SS (aHR, 1.93). The risk of PD was higher (aHR, 2.20) in patients with SS without comorbidities than in those with comorbidities. The aHR of PD significantly increased when the follow-up period exceeded 9 years (aHR, 1.93).We determined an increased risk of PD in patients with SS. Further investigation is warranted to determine the possible underlying mechanisms and the potential role of non-hydroxychloroquine immunosuppressants in ameliorating PD.