Intravenous tissue plasminogen activator for acute ischemic stroke in patients with renal dysfunction.

OBJECTIVE: This study used the Taiwan Stroke Registry data to evaluate the efficacy and safety of intravenous tissue plasminogen activator (tPA) in treating acute ischemic stroke in patients with renal dysfunction. DESIGN: We identified 3525 ischemic stroke patients and classified them into two groups according to the estimated glomerular filtration rate (eGFR) at the emergency department: ≥60, and <60 ml/min/1.73 m2 or on dialysis and by the propensity score from August 2006 to May 2015. The odds ratio of poor functional outcome (modified Rankin Scale ≥2) was calculated for patients with tPA treatment (N = 705), compared to those without tPA treatment (N = 2820), by eGFR levels, at 1, 3 and 6 months after ischemic stroke. We also evaluated the risks of intracerebral hemorrhage, upper gastrointestinal bleeding, mortality, between the two groups by eGFR levels. RESULTS: Among patients with eGFR levels of <60 ml/min/1.73 m2, tPA therapy reduced the odds ratio of poor functional outcome to 0.60 (95% confidence interval = 0.42-0.87) at 6 months after ischemic stroke. The tPA therapy was not associated with increased overall risk of upper gastrointestinal bleeding, but with increased risk of intracerebral hemorrhage. The low eGFR was not a significant risk factor of intracerebral hemorrhage among ischemic stroke patients receiving tPA treatment. CONCLUSIONS: tPA for acute ischemic stroke could improve functional outcomes without increasing the risks of upper gastrointestinal bleeding for patients with or without renal dysfunction. The low eGFR was not a significant risk factor for intracerebral hemorrhage among patients receiving tPA treatment.

Increased incidence and recurrence rates of acute diverticulitis in patients with irritable bowel syndrome.

AIM: Acute diverticulitis (AD) is commonly diagnosed in outpatient and emergency departments and is associated with severe complications such as perforation and fistula. Symptoms of irritable bowel syndrome (IBS), such as abdominal pain, constipation and diarrhoea, are also common with AD. This study aimed to evaluate the strength of a possible association between IBS and AD. METHOD: This retrospective study analysed records from Taiwan's National Health Insurance Research Database and involved a total of 25 810 patients, including 12 905 IBS patients diagnosed between 2000 and 2012. The IBS and non-IBS cohorts were matched by propensity score for age, gender, comorbidities and medication, then compared for confounding variables by the chi-square test or Student's t-test. The association between AD and IBS was determined using Cox proportional hazards models. Kaplan-Meier curves assessed the cumulative incidence of AD in IBS patients. RESULTS: The overall incidence of AD was 3.95-fold higher in the IBS cohort than in the non-IBS cohort (63.34 vs 16.02 per 100 000 person-years, respectively) and IBS was an independent risk factor for subsequent diagnosis of AD in multivariate Cox proportional hazards regression model adjusted hazards ratio (aHR = 3.84, 95% CI = 2.29-6.44, P < 0.001) and Kaplan-Meier (log-rank test, P < 0.001) analysis. IBS was also associated with a high recurrence rate of AD (aHR = 8.30, 95% CI = 1.07-64.30, P = 0.04). CONCLUSION: The epidemiological evidence in this study demonstrates that patients with IBS are associated with a higher incidence of AD and also its recurrence.

Retrospective analysis of the association between tooth loss and dementia: a population-based matched case-control study.

OBJECTIVE: To clarify the association between multiple tooth loss and dementia. BASIC RESEARCH DESIGN: Case-control study based on the claims data from National Health Insurance Research Database (NHIRD). Patients were divided into two groups: the dementia groups and non-dementia group. For each case patient, one control patient was randomly selected and frequency matched by age (per 5 years) and sex. The case group comprised patients newly diagnosed with dementia, and the index date was the the date of dementia diagnosis, which became the baseline for comorbidity and age calculations. RESULTS: Among the 43,026 individuals, patients with dementia had a significantly higher extraction density at ages 60-69 (p ⟨ 0.0001) and 70-79 (p = 0.04) years compared with control patients. CONCLUSIONS: This population-based retrospective study demonstrated an association between tooth loss and dementia. Patients in Taiwan with more tooth extraction experience are likely to have an increased risk of dementia.

EZH2-mediated upregulation of ROS1 oncogene promotes oral cancer metastasis.

Current anti-epidermal growth factor receptor (EGFR) therapy for oral cancer does not provide satisfactory efficacy due to drug resistance or reduced EGFR level. As an alternative candidate target for therapy, here we identified an oncogene, ROS1, as an important driver for oral squamous cell carcinoma (OSCC) metastasis. Among tumors from 188 oral cancer patients, upregulated ROS1 expression strongly correlated with metastasis to lung and lymph nodes. Mechanistic studies uncover that the activated ROS1 results from highly expressed ROS1 gene instead of gene rearrangement, a phenomenon distinct from other cancers. Our data further reveal a novel mechanism that reduced histone methyltransferase EZH2 leads to a lower trimethylation of histone H3 lysine 27 suppressive modification, relaxes chromatin, and promotes the accessibility of the transcription factor STAT1 to the enhancer and the intron regions of ROS1 target genes, CXCL1 and GLI1, for upregulating their expressions. Down-regulation of ROS1 in highly invasive OSCC cells, nevertheless, reduces cell proliferation and inhibits metastasis to lung in the tail-vein injection and the oral cavity xenograft models. Our findings highlight ROS1 as a candidate biomarker and therapeutic target for OSCC. Finally, we demonstrate that co-targeting of ROS1 and EGFR could potentially offer an effective oral cancer therapy.

GATA3 interacts with and stabilizes HIF-1α to enhance cancer cell invasiveness.

This corrects the article DOI: 10.1038/onc.2017.8.

GATA3 interacts with and stabilizes HIF-1α to enhance cancer cell invasiveness.

GATA binding protein 3 (GATA3) is indispensable in development of human organs. However, the role of GATA3 in cancers remains elusive. Hypoxia inducible factor (HIF)-1 plays an important role in pathogenesis of human cancers. Regulation of HIF-1α degradation is orchestrated through collaboration of its interacting proteins. In this study, we discover that GATA3 is upregulated in head and neck squamous cell carcinoma (HNSCC) and is an independent predictor for poor disease-free survival. GATA3 promotes invasive behaviours of HNSCC and melanoma cells in vitro and in immunodeficient mice. Mechanistically, GATA3 physically associates with HIF-1α under hypoxia to inhibit ubiquitination and proteasomal degradation of HIF-1α, which is independent of HIF-1α prolyl hydroxylation. Chromatin immunoprecipitation assays show that the GATA3/HIF-1α complex binds to and regulates HIF-1 target genes, which is also supported by the microarray analysis. Notably, the GATA3-mediated invasiveness can be significantly reversed by HIF-1α knockdown, suggesting a critical role of HIF-1α in the underlying mechanism of GATA3-mediated effects. Our findings suggest that GATA3 stabilizes HIF-1α to enhance cancer invasiveness under hypoxia and support the GATA3/HIF-1α axis as a potential therapeutic target for cancer treatment.

5α-Reductase inhibitors increase acute coronary syndrome risk in patients with benign prostate hyperplasia.

BACKGROUND: This study explored the possible association between the use of two typical 5ARIs (finasteride and dutasteride) and the risk of acute coronary syndrome (ACS) in patients with benign prostate hyperplasia (BPH). METHODS: From the claims data of the Taiwan National Health Insurance (NHI) Taiwan, we identified 1843 ACS cases among BPH patients and randomly selected 7330 controls without ACS, with a similar mean age of 73 years. Multivariate logistic regression analysis estimated the odds ratio (OR) and 95 % confidence interval (CI) for the relationship between the 5ARIs medications and ACS risk. RESULTS: We found that BPH patients who had received treatment with both finasteride and dutasteride were at a higher risk of ACS with an OR of 3.47 (95 % CI 1.05-11.5), compared to patients without 5ARIs treatment. Furthermore, the dosage analysis showed that there were no significant associations between ACS risk and uses of a single drug medication regardless the dosages. The ORs for those who took only dutasteride were 1.07 (95 % CI 0.39-2.99) with low dose and 0.73 (95 % CI 0.38-1.44) with high dose. The ORs for those who took only finasteride were 1.30 (95 % CI 0.89-1.92) with low dose and 0.98 (95 % CI 0.19-5.13) with high dose. CONCLUSION: This population-based nested case-control study suggests that 5ARI use may increase ACS risk among patients with BPH when patients were exposed to both finasteride and dutasteride.

Decreased prevalence of dementia associated with statins: a national population-based study.

BACKGROUND AND PURPOSE: Dementia is a neurodegenerative disorder that presents a progressive decline in cognitive function and loss of short-term memory with age. Several studies have shown that statin, an oral lipid-lowering drug, may reduce the risk of developing dementia. The objective of this study is to explore the association between statin and the development of dementia. METHODS: The data analyzed in this study were retrieved from the National Health Insurance Research Database in Taiwan. The sample consisted of 123 300 patients ≥ 20 years of age, including 61 650 dementia patients with statin use and 61 650 patients without statin use who were eligible for inclusion in this study. Univariate and multivariate Cox proportional hazard regression analyses were performed to measure the effects of statin use on the risk of dementia. RESULTS: The beneficial effect of statin on dementia was significant after adjusting for sociodemographic factors and comorbidities (adjusted hazard ratio of 0.92, 95% confidence interval 0.86-0.98). The sex- and age-specific analysis of adjusted hazard ratios showed a higher beneficial effect from statin treatment in women than in men, and the effect became more significant with age. CONCLUSION: Statin therapy may help prevent the development of dementia, and both hydrophilic and lipophilic statins produce similar effects. However, the preventive characters and associated mechanisms must be further explored and identified.

A nationwide population-based retrospective cohort study: increased risk of acute coronary syndrome in patients with ankylosing spondylitis.

OBJECTIVES: To compare the risk of acute coronary syndrome (ACS) between patients with and without ankylosing spondylitis (AS). METHOD: This retrospective cohort study identified all patients with AS aged ≥ 18 years newly diagnosed from 2000 to 2009, registered in the National Health Insurance Research Database (NHIRD) in Taiwan. The non-AS cohort consisted of fourfold randomly selected control patients free of AS, frequency matched by age, sex, and diagnosis year. The incidence of ACS was determined for both AS and non-AS cohorts. RESULTS: We selected 6262 patients with AS and 25 048 patients without AS. The patients with AS were more prevalent than those without, with co-morbidities of hypertension, diabetes mellitus (DM), hyperlipidaemia, stroke, and peripheral vascular diseases. The overall incidence rate of ACS was higher in the AS cohort than in the non-AS cohort (4.4 vs. 2.9 per 1000 person-years), with an adjusted hazard ratio (aHR) of 1.36 [95% confidence interval (CI) 1.16-1.59]. AS patients with co-morbidities of hypertension, DM, and cancer had an aHR of 7.74 for ACS, compared to those without these co-morbidities. CONCLUSIONS: AS patients are at higher risk of ACS compared with non-AS subjects. Management of CV risk factors should be taken into account for the treatment of patients with AS, especially for patients with co-morbidities of hypertension, DM, and cancer.

A population-based cohort study in Taiwan--use of insulin sensitizers can decrease cancer risk in diabetic patients?

BACKGROUND: The purpose of the study was to explore the possible association between the use of insulin sensitizers (thiazolidinediones, TZDs) and the risk of cancer in Taiwanese diabetic patients. PATIENTS AND METHODS: From the National Health Insurance Research Database (NHIRD) of Taiwan, we identified 22 910 diabetic patients newly diagnosed from 2001 to 2009 and 91 636 non-diabetic comparisons frequency matched with age, sex, and calendar year, excluding those with cancer at the baseline. Among the diabetics, 4159 patients were treated with TZDs and the rest of 18 752 patients were on other anti-diabetic medications (non-TZDs). RESULTS: In comparison to the non-diabetes group, the non-TZDs group had an increased risk of developing cancer [the adjusted hazard ratio (HR): 1.20 and 95% confidence interval (CI) = 1.11-1.30]. The TZDs group had a HR of 1.18 (95% CI = 0.98-1.42). Analysis of site-specific cancer risks showed that both TZDs and non-TZDs groups with elevated risks of colorectal and pancreatic cancer. However, the non-TZDs group had an increased risk of liver cancer when comparing with TZD and non-diabetes groups. CONCLUSION: This study suggests that patients with diabetes are at an elevated risk of cancer (especially in colorectal and pancreatic cancers), and the use of TZDs might decrease the liver cancer risk in diabetic patients. Further investigation using large samples and rigorous methodology is warranted.

The clinical differences between dengue and scrub typhus with acute respiratory failure in southern Taiwan.

BACKGROUND: For both dengue and scrub typhus, acute respiratory failure (ARF) is a serious complication. The present study was carried out in order to investigate the clinical courses and outcomes of adult dengue and scrub typhus patients with ARF, and to identify the clinical differences between adult dengue and scrub typhus patients with ARF. METHODS: We conducted a retrospective study of the serologically confirmed adult dengue or scrub typhus patients admitted between 1998 and 2008 at Kaohsiung Chang Gung Memorial Hospital. A total of 980 dengue and 102 scrub typhus adult patients were included in our study. RESULTS: Eighteen of the 980 adult dengue patients and 8 of the 102 adult scrub typhus patients had ARF. There were significant differences that existed for eschar (P = 0.001; dengue 0%; scrub 62.5%), cough (P = 0.016; dengue 55.6%; scrub typhus 100%), white blood cell (WBC) count [P = 0.026; dengue 7.40 ± 5.74; scrub typhus 11.84 ± 4.95 (×10(3)/µL)], platelet count [P = 0.008; dengue 42.2 ± 33.9; scrub typhus 104.1 ± 93.3 (×10(9)/L)], prothrombin time (PT) [P = 0.007; dengue 12.82 ± 1.36; scrub typhus 10.74 ± 0.98 (s)], activated partial thromboplastin time (APTT) [P = 0.002; dengue 50.81 ± 10.08; scrub typhus 37.44 ± 4.06 (s)], blood urea nitrogen (BUN) [P < 0.001; dengue 64.6 ± 43.2; scrub typhus 20.9 ± 9.1 (mg/dL)], creatinine [P < 0.001; dengue 3.77 ± 3.37; scrub typhus 1.05 ± 0.37 (mg/dL)], admission day (A-day) [P = 0.027; dengue 2.9 ± 1.3; scrub typhus 5.4 ± 2.6 (days)], and ventilator duration [P = 0.022; dengue 9.4 ± 14.0; scrub typhus 14.8 ± 10.4 (days)] between both groups. CONCLUSIONS: This study provides relatively rare data regarding the clinical differences between adult dengue and scrub typhus patients with ARF.

The polymorphisms of C-reactive protein gene modify the association between central obesity and lung function in taiwan asthmatics.

High-sensitivity C-reactive protein (hs-CRP) concentrations and obesity are proposed to have a significant relationship with impairment of lung function, but little has been reported to date on the association between CRP gene and lung function. We studied the association of three tagSNPs (tag single nucleotide polymorphisms) of CRP gene and their interactions with central obesity on lung function. A total of 384 asthmatic adults and 384 controls who were 1:1 matched by sex and age were recruited for this study. Three tagSNPs polymorphisms for CRP rs1417938, rs1800947 and rs1205 were selected from HapMap data and genotyping by using TaqMan allelic discrimination assay. A questionnaire interview, body composition and pulmonary function tests were performed. CRP single nucleotide polymorphisms (SNPs) did not increase the risk of asthma, but CRP rs1205 CC genotype significantly decreased the predictive value of forced vital capacity (FVC) in the asthma group (adjusted mean change = -7.54%, 95% CI = -13.82 to -1.25%). Waist-to-hip ratio, not body mass index, also decreased the predictive value of FVC in asthmatics. The subjects with central obesity who carried CRP SNPs have a significant reduction effect in lung function. The current results suggest that central obesity may play a major role in lung function, and these effects were modified significantly by the polymorphisms for CRP gene.

Propofol inhibits lipopolysaccharide-induced lung epithelial cell injury by reducing hypoxia-inducible factor-1alpha expression.

BACKGROUND: Lipopolysaccharide (LPS) may activate hypoxia-inducible factor (HIF)-1α, which up-regulates cytokine expression and the lethality of LPS-induced shock. We investigated the effect of propofol on HIF-1α expression and acute lung injury in LPS-treated mice. METHODS: A series of both positive and negative control experiments were performed. We injected BALB/C mice with propofol or vehicle i.p. immediately and 12 h after an LPS challenge. After 24 h, we examined the lung wet/dry weight ratio, neutrophil infiltration, and HIF-1α mRNA expression and inflammatory cytokines in the lung tissue. Survival was determined for 48 h after LPS injection. In vitro, we determined the responses of A549 cells, with and without HIF-1α silenced, to treatment with LPS alone and LPS plus propofol. RESULTS: Propofol prolonged survival and attenuated acute lung injury and decreased the expression of HIF-1α, interleukin (IL)-6, keratinocyte-derived chemokine, and tumour necrosis factor-alpha (TNF-α) in the lungs of endotoxaemic mice. In HIF-1α knockdown-A549 cells, LPS-induced TNF-α, IL-6, and the pro-apoptotic gene, BNIP3 expression and apoptosis were reduced. Propofol, but not an inhibitor of nuclear factor κB, reduced HIF-1α expression in LPS-stimulated A549 cells. Propofol also down-regulated, in A549 cells, the expression of IL-6, IL-8, and TNF-α, Bcl-2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3), and apoptosis. CONCLUSIONS: Propofol reduces apoptosis in LPS-stimulated lung epithelial cells by decreasing HIF-1α, BNIP3, and cytokine production. Using propofol to inhibit HIF-1α expression may protect against the acute lung injury caused by LPS-induced sepsis.

Role of gender disparity of circulating high-sensitivity C-reactive protein concentrations and obesity on asthma in Taiwan.

BACKGROUND: Several studies have suggested that the association between obesity and asthma may be stronger in females than in males, but the reason is still unclear. OBJECTIVE: The aim of this study was to investigate whether differences in high-sensitivity C-reactive protein (hs-CRP) levels explain why obesity is associated with asthma in females but not in males. METHODS: This study prospectively enrolled 754 subjects ≥ 18 years old from hospital-based asthma patients and population-based controls. We measured adiposity factors [body mass index (BMI), waist circumference and waist-hip ratio], hs-CRP and total IgE levels. RESULTS: After adjusting for potential confounding factors, we found a significant association between BMI and asthma in females with a significant interaction of gender and BMI on asthma (χ(2) =10.2, P=0.004). If hs-CRP was added to the logistic model, the interaction was attenuated but still significant (χ(2) =7.02, P=0.03). After adjusting for BMI, we did not find that circulating hs-CRP concentrations were significantly associated with asthma in males and females. CONCLUSION: We found that BMI was associated with asthma in females, but our results do not support the suggestion that hs-CRP levels contribute significantly to the link between obesity and asthma with respect to gender disparity.

Benzene-di-N-substituted carbamates as conformationally constrained substrate analogs of cholesterol esterase.

Benzene-1,2-, 1,3-, and 1,4-di-N-substituted carbamates (1-15) are synthesized as the constrained analogs of gauche, eclipsed, and anti conformations, respectively, for the glycerol backbones of triacylglycerol. Carbamates 1-15 are characterized as the pseudo substrate inhibitors of cholesterol esterase. Long chain carbamates are more potent inhibitors than short chain ones. Comparison of different geometries for benzene-di-substituted carbamates, such as benzene-1,2-di-N-octylcarbamate (3) (ortho-3), benzene-1,3-di-N-octylcarbamate (8) (meta-8), and benzene-1,4-di-N-octylcarbamates (13) (para-13), indicates that inhibitory potencies are as followed: meta-8 > para-13 > ortho-3. Therefore, we suggest that the preferable conformation for the C(sn-1)-O/C(sn-2)-O glycerol backbone in the enzyme-triacylgycerol complex is the eclipsed conformation. Meanwhile, kinetic data indicate that among ortho, meta, and para carbamates, meta carbamates most resemble the substrate cholesterol ester.

Increased Ki-67 proliferative index and absence of P16INK4 in CIN-HPV related pathogenic pathways different from cervical squamous intraepithelial lesion.

BACKGROUND/AIM: It is generally assumed that similar pathways are involved in human papillomavirus (HPV) induced pathogenesis of cervical squamous intraepithelial lesions (SILs) and cancers and a subset of conjunctival intraepithelial neoplasm (CIN)-that the malignancies or pre-cancerous lesions arise through HPV oncoproteins E6 and E7, which disrupt the pathways of p53 and the product of the retinoblastoma (Rb) gene and, in turn, increase the protein product of gene p16INK4 through the mechanism of positive feedback. Several cell cycle molecules are detected to test this hypothesis. METHODS: Nine cases of CIN and eight non-CIN cases were analysed for the expression of Ki-67, pRb, p53, and p16INK4 via immunohistochemistry. Nine cases of cervical high grade squamous intraepithelial lesion (HSIL), and 10 cases of cervical low grade squamous intraepithelial lesion (LSIL) were included for stain control of p16INK4a, and comparison of p16INK4a expression to CIN cases. A nested polymerase chain reaction and a genechip HPV typing were used to detect HPV infection and types in the CIN and non-CIN samples RESULTS: HPV positivity was demonstrated in all of the CIN lesions but in none of the non-CIN lesions. The Ki-67 proliferative index (Ki-67 PI) was statistically higher in the CIN group than the non-CIN group; however, there were no differences of expression of pRb and p53 between the two groups and no expression of p16INK4 in all cases. All nine cases of HSIL, and seven out of 10 cases of LSIL used for stain control were immunoreactive for p16INK4a. There were statistically significant differences in overexpression of p16INK4a between the CINs and SILs CONCLUSIONS: The Ki-67 proliferative index may be a sensitive marker for CIN lesions and these results, with significant differences in overexpression of p16INK4a between CINs and SILs, may provide new evidence that HPV related mucosal dysplasia in different anatomical locations may lead to dissimilar molecular pathways.