The incidence of liver injury in Uyghur patients treated for TB in Xinjiang Uyghur autonomous region, China, and its association with hepatic enzyme polymorphisms nat2, cyp2e1, gstm1 and gstt1.

BACKGROUND AND OBJECTIVE: Of three first-line anti-tuberculosis (anti-TB) drugs, isoniazid is most commonly associated with hepatotoxicity. Differences in INH-induced toxicity have been attributed to genetic variability at several loci, NAT2, CYP2E1, GSTM1and GSTT1, that code for drug-metabolizing enzymes. This study evaluated whether the polymorphisms in these enzymes were associated with an increased risk of anti-TB drug-induced hepatitis in patients and could potentially be used to identify patients at risk of liver injury. METHODS AND DESIGN: In a cross-sectional study, 2244 tuberculosis patients were assessed two months after the start of treatment. Anti-TB drug-induced liver injury (ATLI) was defined as an ALT, AST or bilirubin value more than twice the upper limit of normal. NAT2, CYP2E1, GSTM1 and GSTT1 genotypes were determined using the PCR/ligase detection reaction assays. RESULTS: 2244 patients were evaluated, there were 89 cases of ATLI, a prevalence of 4% 9 patients (0.4%) had ALT levels more than 5 times the upper limit of normal. The prevalence of ATLI was greater among men than women, and there was a weak association with NAT2*5 genotypes, with ATLI more common among patients with the NAT2*5*CT genotype. The sensitivity of the CT genotype for identifying patients with ATLI was 42% and the positive predictive value 5.9%. CT ATLI was more common among slow acetylators (prevalence ratio 2.0 (95% CI 0.95,4.20) )compared to rapid acetylators. There was no evidence that ATLI was associated with CYP2E1 RsaIc1/c1genotype, CYP2E1 RsaIc1/c2 or c2/c2 genotypes, or GSTM1/GSTT1 null genotypes. CONCLUSIONS: In Xinjiang Uyghur TB patients, liver injury was associated with the genetic variant NAT2*5, however the genetic markers studied are unlikely to be useful for screening patients due to the low sensitivity and low positive predictive values for identifying persons at risk of liver injury

Genetic diversity in Indian isolates of Fusarium oxysporum f. sp. ciceris, chickpea wilt pathogen

Forty-eight isolates of FOC collected from different chickpea growing regions in India were evaluated for genetic variations using amplified fragment length polymorphism (AFLP). Out of 48 isolates, 41 werefound pathogenic and seven non-pathogenic. Pathogenic isolates differ in their virulence however; there was no apparent correlation between geographical origin and virulence of the isolates. The genetic variation was evaluated by the AFLP analysis. A total 339 fragments were scored following selective amplification with five EcoR1 and Mse1 primer combinations E-TC/M-CAT, E-TC/M-CAC, EAC/ M-CAG, E-TA/MCAG, E-TA/M-CAG, out of which 331 fragments were polymorphic. UPGMA cluster analysis and principle coordinate analysis distinctly classified 48 isolates into two major groups; pathogenic and non-pathogenic. The pathogenic isolates could be further clustered into six majorgroups at 0.77 genetic similarities. Region specific grouping was observed with in few isolates. The results of the present study provide evidence of the high discriminatory power of AFLP analysis,suggesting the applicability of this method to the molecular characterization of Fusarium oxysporum f.sp. ciceris

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Six sigma, absorptive capacity and organisational learning orientation

"This is an Accepted Manuscript of an article published by Taylor & Francis in International Journal of Production Research, available online: http://wwww.tandfonline.com/10.1080/00207543.2010.543175."The importance of the Six Sigma methodology in industry is growing constantly. However, there are few empirical studies that analyze the advantages of this methodology and its positive effects on organizational performance. The purpose of this paper is to extend understanding of the success of Six Sigma quality management initiatives by investigating the effects of Six Sigma teamwork and process management on absorptive capacity. It also seeks to understand the relation between absorptive capacity and organizational learning as two sources of sustainable competitive advantage. The information used comes from a larger study, the data for which were collected from a random sample of 237 European firms. Of these 237 organizations, 58 are Six Sigma organizations. Structural Equation Modelling (SEM) was used to test the hypotheses. The main findings show that Six Sigma teamwork and process management positively affect the development of absorptive capacity. A positive and significant relationship is also observed between absorptive capacity and organizational learning orientation. The findings of this study justify Six Sigma implementation in firms. This study provides us with an in-depth understanding of some structural elements that characterize the Six Sigma methodology, enabling us to provide an explanation for its success

Membrane diffusion- and capillary blood volume measurements are not useful as screening tools for pulmonary arterial hypertension in systemic sclerosis: a case control study

<p>Abstract</p> <p>Background</p> <p>There is no optimal screening tool for the assessment of pulmonary arterial hypertension (PAH) in patients with systemic sclerosis (SSc). A decreasing transfer factor of the lung for CO (TLCO) is associated with the development of PAH in SSc. TLCO can be partitioned into the diffusion of the alveolar capillary membrane (Dm) and the capillary blood volume (Vc). The use of the partitioned diffusion to detect PAH in SSc is not well established yet. This study evaluates whether Dm and Vc could be candidates for further study of the use for screening for PAH in SSc.</p> <p>Methods</p> <p>Eleven SSc patients with PAH (SScPAH+), 13 SSc patients without PAH (SScPAH-) and 10 healthy control subjects were included. Pulmonary function testing took place at diagnosis of PAH. TLCO was partitioned according to Roughton and Forster. As pulmonary fibrosis in SSc influences values of the (partitioned) TLCO, these were adjusted for fibrosis score as assessed on HRCT.</p> <p>Results</p> <p>TLCO as percentage of predicted (%) was lower in SScPAH+ than in SScPAH- (41 ± 7% <it>vs</it>. 63 ± 12%, p < 0.0001, respectively). Dm% in SScPAH+ was decreased as compared with SScPAH- (22 ± 6% <it>vs</it>. 39 ± 12%, p < 0.0001, respectively), also after adjustment for total fibrosis score (before adjustment: B = 17.5, 95% CI 9.0–25.9, p = < 0.0001; after adjustment: B = 14.3, 95% CI 6.0–21.7, p = 0.008). No difference was found in Vc%. There were no correlations between pulmonary hemodynamic parameters and Dm% in the PAH groups.</p> <p>Conclusion</p> <p>SScPAH+ patients have lower Dm% than SScPAH- patients. There are no correlations between Dm% and hemodynamic parameters of PAH in SScPAH+. These findings do not support further study of the role of partitioning TLCO in the diagnostic work- up for PAH in SSc.</p

Design of the Anti-tuberculosis Drugs induced Adverse Reactions in China National Tuberculosis Prevention and Control Scheme Study (ADACS)

<p>Abstract</p> <p>Background</p> <p>More than 1 million tuberculosis (TB) patients are receiving the standard anti-TB treatment provided by China National Tuberculosis Prevention and Control Scheme (CNTS) in China every year. Adverse reactions (ADRs) induced by anti-TB drugs could both do harm to patients and lead to anti-TB treatment failure. The ADACS aimed to explore ADRs' incidences, prognoses, economical and public health impacts for TB patients and TB control, and build a DNA bank of TB patients.</p> <p>Methods/Design</p> <p>Multiple study designs were adopted. Firstly, a prospective cohort with 4488 sputum smears positive pulmonary tuberculosis patients was established. Patients were followed up for 6-9 months in 52 counties of four regions. Those suspected ADRs should be checked and confirmed by Chinese State Food and Drug Administration (SFDA). Secondly, if the suspected ADR was anti-TB drug induced liver injury (ATLI), a nested case-control study would be performed which comprised choosing a matched control and doing a plus questionnaire inquiry. Thirdly, health economical data of ADRs would be collected to analyze financial burdens brought by ADRs and cost-effectiveness of ADRs' treatments. Fourthly, a drop of intravenous blood for each patient was taken and saved in FTA card for DNA banking and genotyping. Finally, the demographic, clinical, environmental, administrative and genetic data would be merged for the comprehensive analysis.</p> <p>Discussion</p> <p>ADACS will give an overview of anti-TB drugs induced ADRs' incidences, risk factors, treatments, prognoses, and clinical, economical and public health impacts for TB patients applying CNTS regimen in China, and provide suggestions for individualized health care and TB control policy.</p

Body mass index in early adulthood and colorectal cancer risk for carriers and non-carriers of germline mutations in DNA mismatch repair genes

BACKGROUND: Carriers of germline mutations in DNA mismatch repair (MMR) genes have a high risk of colorectal cancer (CRC), but the modifiers of this risk are not well established. We estimated an association between body mass index (BMI) in early adulthood and subsequent risk of CRC for carriers and, as a comparison, estimated the association for non-carriers. METHODS: A weighted Cox regression was used to analyse height and weight at 20 years reported by 1324 carriers of MMR gene mutations (500 MLH1, 648 MSH2, 117 MSH6 and 59 PMS2) and 1219 non-carriers from the Colon Cancer Family Registry. RESULTS: During 122,304 person-years of observation, we observed diagnoses of CRC for 659 carriers (50%) and 36 non-carriers (3%). For carriers, the risk of CRC increased by 30% for each 5 kg m(-2) increment in BMI in early adulthood (hazard ratio, HR: 1.30; 95% confidence interval, CI: 1.08-1.58; P=0.01), and increased by 64% for non-carriers (HR: 1.64; 95% CI: 1.02-2.64; P=0.04) after adjusting for sex, country, cigarette smoking and alcohol drinking (and the MMR gene that was mutated in carriers). The difference in HRs for carriers and non-carriers was not statistically significant (P=0.50). For MLH1 and PMS2 (MutLα heterodimer) mutation carriers combined, the corresponding increase was 36% (HR: 1.36; 95% CI: 1.05-1.76; P=0.02). For MSH2 and MSH6 (MutSα heterodimer) mutation carriers combined, the HR was 1.26 (95% CI: 0.96-1.65; P=0.09). There was no significant difference between the HRs for MutLα and MutSα heterodimer carriers (P=0.56). CONCLUSION: Body mass index in early adulthood is positively associated with risk of CRC for MMR gene mutation carriers and non-carriers

Body mass index in early adulthood and colorectal cancer risk for carriers and non-carriers of germline mutations in DNA mismatch repair genes

BACKGROUND: Carriers of germline mutations in DNA mismatch repair (MMR) genes have a high risk of colorectal cancer (CRC), but the modifiers of this risk are not well established. We estimated an association between body mass index (BMI) in early adulthood and subsequent risk of CRC for carriers and, as a comparison, estimated the association for non-carriers. METHODS: A weighted Cox regression was used to analyse height and weight at 20 years reported by 1324 carriers of MMR gene mutations (500 MLH1, 648 MSH2, 117 MSH6 and 59 PMS2) and 1219 non-carriers from the Colon Cancer Family Registry. RESULTS: During 122,304 person-years of observation, we observed diagnoses of CRC for 659 carriers (50%) and 36 non-carriers (3%). For carriers, the risk of CRC increased by 30% for each 5 kg m(-2) increment in BMI in early adulthood (hazard ratio, HR: 1.30; 95% confidence interval, CI: 1.08-1.58; P=0.01), and increased by 64% for non-carriers (HR: 1.64; 95% CI: 1.02-2.64; P=0.04) after adjusting for sex, country, cigarette smoking and alcohol drinking (and the MMR gene that was mutated in carriers). The difference in HRs for carriers and non-carriers was not statistically significant (P=0.50). For MLH1 and PMS2 (MutLα heterodimer) mutation carriers combined, the corresponding increase was 36% (HR: 1.36; 95% CI: 1.05-1.76; P=0.02). For MSH2 and MSH6 (MutSα heterodimer) mutation carriers combined, the HR was 1.26 (95% CI: 0.96-1.65; P=0.09). There was no significant difference between the HRs for MutLα and MutSα heterodimer carriers (P=0.56). CONCLUSION: Body mass index in early adulthood is positively associated with risk of CRC for MMR gene mutation carriers and non-carriers