Angiotensin converting enzyme inhibitors (ACE inhibitors) reduce peripheral vascular resistance via blockage of angiotensin converting enzyme (ACE). ACE inhibitors are commonly used to treat congestive heart failure and high blood pressure, but other effects have been reported. In this study, we explored the association between ACE inhibitor therapy and the prevalence of comorbid conditions in adults with diabetesWe surveyed 1003 adults with diabetes randomly selected from community practices. Patients were interviewed at home and self-reported their personal and clinical characteristics including comorbidity. Current medications were obtained by direct observation of medication containers. We built logistic regression models with the history of comorbidities as the outcome variable and the current use of ACE inhibitors as the primary predictor variable. We adjusted for possible confounding by social  and clinical factors , glycosolated hemoglobin (A1C), number of comorbid conditions, and number of prescription medications).vs. 15%; odd ratio = 0.59; 95% confidence interval ; P = 0.01); and a history of stomach ulcers or peptic ulcer disease less frequently than non-users . After correcting for potential confounders, ACE inhibitors remained significantly inversely associated with a personal history of cancer  and peptic ulcer disease .ACE users reported a history of any cancer (except the non-life-threatening skin cancers) less frequently than non-users (10% ACE inhibitor use is associated with a lower likelihood of a history of cancer and peptic ulcers in patients with diabetes. These findings are limited by the cross sectional study design, self-report of comorbid diagnoses, and lack of information on the timing and duration of ACE inhibitor use. Further research is needed to confirm these associations and understand their mechanisms. EvidencThis study is part of a larger project, the Vermont Diabetes Information System (VDIS), a study of 8,855 adults with diabetes in primary care practices . The subSubjects completed a questionnaire at home and were visited by a trained research assistant who reviewed the questionnaire responses, assisted the subject with any missing or unacceptable responses, reviewed the subject's medications, and measured their blood pressure, height and weight using a portable sphygmomanometer, stadiometer, and scale. Race, education, income, marital status, functional status, smoking, alcohol consumption, and comorbid conditions were obtained by questionnaire. Prior to the interview, patients were instructed to gather all current medications, including over the counter preparations, for review by the research assistant. The medication list was ascertained by direct observation of the medication container with recording of the drug name, dose, frequency, and route of administration. Duration of therapy was not recorded.To determine comorbidity, we used a modification of the Self-Administered Comorbidity Questionnaire  in whichThe interviews occurred between July 2003 and March 2005. Most laboratory data were obtained from the patients' local clinical laboratories, which all use the same Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications high performance, liquid chromatography (HPLC) method for the determination of glycosylated hemoglobin (A1C). Less than 1% of A1C tests were done using the Bayer DCA 2000 immunoassay point of care instrument, which has been shown to compare favorably with the HPLC method .The research protocol was carried out in compliance with the Helsinki Declaration and was approved by the Committee on Human Research of the University of Vermont. The interviewed subjects provided written informed consent. The full study protocol and variables, and the medication profiles of the subjects have been previously reported ,14.2), current alcohol use (yes/no), current cigarette use (yes/no), number of comorbidities, and number of prescription medications. The selection of these potential confounding conditions was based on clinical and epidemiologic judgment and not on statistical determinants. We used Stata/SE 9.2  for all analyses.We performed a cross sectional analysis of the interviewed subjects at the time of their enrollment in the VDIS trial. We explored the association between rheumatic disease, asthma/COPD, CAD, cancer, CHF, cirrhosis, CVA, depression, paresis, PUD, PVD, and the use of ACE inhibitors therapy using logistic regression with each condition as the outcome variable and the use of ACE inhibitors as the primary predictor variable. We then adjusted for possible confounding by social and clinical factors including gender, age (years), systolic blood pressure (mmHg), glycosylated hemoglobin level (A1C in mg%), body mass index (BMI in kg/mThe study population was representative of adults with diabetes in primary care practices in Northern New England. See Table 2), having higher number of prescription medications, and being a non-drinker.Table 2), alcohol drinking (yes/no), cigarette smoking (yes/no), number of comorbidities, and number of prescription medications. This model showed a significant association between cancer and the use of ACE inhibitors    Table . Other vThese data suggest a negative association of ACE inhibitor use with both cancer and PUD in a community based population of adults with diabetes.Evidence from animal models suggests that angiotensin II stimulates neovascularization  and promet al. [et al. [Very few reports have looked at the association between ACE inhibitors and peptic ulcers. One study found that captopril significantly reduced the development of gastric ulcers in pylorus-ligated rats . Anotheret al.  determinet al.  indicate [et al.  suggesteThe mechanisms of the observed associations between ACE inhibition and the two diagnoses are unknown. It is possible that ACE inhibitors protect against the development of cancer or ulcer disease, although confirmation of these hypotheses must await additional investigation. Another interpretation of our results is the "treatment-risk paradox" in which the history of cancer or ulcer disease inhibits the use of ACE inhibitors, perhaps due to concerns of polypharmacy or intolerance of the medication due to the underlying disease. However, the prescribing information for ACE inhibitors does not discourage their use in either cancer or PUD and univariate analysis shows no significant differences between the number of comorbidities in ACE inhibitor users and non-users. These facts argue against the "treatment-risk paradox" theory, although not conclusively.This study has several strengths. First, the interviewed subjects were a randomly selected subset of a large population of patients receiving care in the Northeast, and are therefore likely to be representative of primary care patients generally. Second, all data on medications were obtained by direct observation in the patient's home and not from secondary sources. Third, multiple potential confounders were assessed and found to have no significant effect on the apparent associations between ACE inhibition and PUD and cancer.This study has several limitations including lack of clinical confirmation of the comorbid diagnoses, and lack of information on the timing and duration of ACE inhibitor treatment relative to the onset of the comorbidities. As in any cross-sectional study, unmeasured confounders may be responsible for the apparent associations found.These data suggest a potential protective association of ACE inhibitors for cancer and peptic ulcer disease in patients with diabetes. Further research is needed to confirm these associations and understand their mechanisms.The authors declare that they have no competing interests.MERN, CDM and BL contributed equally to all aspects of this work.The pre-publication history for this paper can be accessed here:


P<0.001), but not in the absence of CAC. Additionally, rs1333049 was not associated with simple CAC or CAC severity/extent in CAD patients with CAC. 849 CAD patients undergoing revascularization (660 with CAC and 189 without CAC) were enrolled in a cohort study to test its association with cardiovascular events in CAD patients with and without CAC in a 3-year follow-up. rs1333049 was significantly associated with the incidence of cardiovascular events in non-target vessels in patients with CAC , but not in those without CAC. The variants at the 9p21 locus were related to CAD and post-revascularization events only in the presence of CAC, suggesting that they may confer risk of calcification-related coronary atherosclerosis.Variants at the 9p21 locus have been associated with coronary artery disease (CAD); coronary artery calcification (CAC) is related to CAD and other cardiovascular events. To determine the association of the 9p21 locus with CAD in the presence and absence of CAC, 4 groups were enrolled in a case-control study, including 527 CAD patients without CAC, 692 CAD patients with CAC, 585 individuals with simple CAC but no CAD, and 725 healthy controls. The rs1333049 representing the locus was associated with CAD in the presence of CAC (odds ratio = 1.38 in allelic analysis, 95%CI, 1.19–1.60,  Genome-wide association studies (GWAS) have revealed a highly significant association between the variation on chromosome 9p21 and the risk of coronary artery disease (CAD)CAD is a chronic multistage inflammatory disease which can progress to acute coronary syndrome  and sudden cardiac death. Multiple cellular pathways in different tissues contribute to the pathogenic processes resulting in CAD. Genetic factors can affect CAD by acting at different stages in its clinical evolution, such as in plaque rupture or the subsequent thrombosis resulting in an increase in the risk of myocardial infarction, and coronary atherosclerosis, resulting in CAD.Variants of the 9p21 locus have been associated with coronary artery calcification (CAC), premature atherosclerosis, and cardiovascular events (CV events), such as myocardial infarction (based on studies in multiple ethnic groups) The conserved sequence within the 9p21 locus has functional enhancer activity which controls the expression of nearby genes modulating inflammation and cell proliferation, therefore promoting atherosclerosis and CAC Previous GWAS have demonstrated that rs1333049, which is most strongly associated with CAD and its major complication myocardial infarction, is the lead variant at the 9p21 locus All subjects provided written informed consent. The study protocol was conducted in accordance with the Declaration of Helsinki Principles (revised in 1983), and was reviewed and approved by the Ethics Committee of Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Beijing, China.Subjects in the first study were enrolled from an outpatient cohort, aged 45–70 years, who underwent coronary computed tomography angiography (CCTA) in Fuwai Hospital for CAD from April 2007 to December 2010. The main complaints and symptoms of these patients included angina, atypical chest pain, and chest distress with multiple risk factors. CCTA was performed with the use of a 64-slice multidetector scanner as previously described Patients treated with coronary artery bypass grafting surgery (CABG) or drug-eluting stents (DES) at Fuwai Hospital were enrolled from April 2006 to December 2006. Patients with previous revascularization or other cardiac surgery, liver disease, or malignant tumor were excluded from the study. The inclusion criteria also included regular antiplatelet therapy, aspirin (100 mg) plus clopidogrel (75 mg) daily post-operation; other antiplatelet therapy or warfarin users were excluded. CV events were defined as reinfarction, coronary revascularization, and cardiovascular death. The follow-up started from the date of revascularization until the date of the first CV events, or the end of the 3 year follow-up period. Major events were recorded based on hospital records, direct telephone contact, and computer records. Supplemental information was obtained from the patient's family and their physicians. In contrast to the results published by Hoppmann et al. in 2009 Blood samples were collected after a 12-hour fast before cardiovascular procedures. The plasma and cell buffy coat were kept at −70°C. Genomic DNA was extracted and biological variables were determined within 3 months. A complete clinical history was obtained from all subjects. In addition to neurological history and family history of hypertension, CAD, and diabetes mellitus (DM), the following vascular risk factors were also recorded: history of vascular disease, cigarette smoking, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), blood glucose, high density lipoprotein-cholesterol (HDL-C), total plasma cholesterol (TC), and triglycerides (TG). Plasma biochemical parameters were assayed by an automatic analyzer . LDL-C was calculated using the Friedewald formula. Hypertension was based on 3 independent measures of blood pressure >140/90 mmHg or the use of antihypertensive drugs. DM was diagnosed if the subject had a fasting glucose >7.0 mmol/L or >11.1 mmol/L at 2 hours after oral glucose challenge, or both. All lipid measurements were determined by a CDC qualified laboratory at Fuwai hospital.A DNA isolation kit, RelaxGene Blood DNA System , was used for preparing genomic DNA following the recommendations of the manufacturer. Genotyping was performed by using MassARRAY high-throughput DNA analysis with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry . The primers were designed by MassARRAY Assay Design software (Version 3.1). rs1333049 was genotyped using iPLEX Gold technology (Sequenom) followed by an automated data analysis with the TYPER RT software Version 4.0. Reproducibility of genotyping was confirmed by bidirectional sequencing in random 10% population, and the reproducibility was 99.1%.Quantitative variables were compared with the one-way ANOVA test. A chi-square test was used to test for qualitative variables, genotype/allele frequencies, and the Hardy-Weinberg equilibrium of the variants. The effect of rs1333049 on CAD was expressed as odds ratio. Relative risk analysis was carried out with 2×2 cross tabulation (crude OR) and logistic regression (adjusted OR) for the adjustment of conventional risk factors. A linear regression model was used to assess the correlation between rs1333049 and CAC extent/severity and CAD extent, ln(CAC score+1), the number of calcified arteries was as the dependent variable; all analyses were performed under an additive genetic model. Cox proportional-hazards models were used to examine the association between rs1333049 and CV event incidence after adjustment for age, gender, and other covariates, in which the allele coding was defined as the number of minor alleles. Analyses were performed using SPSS 13.0 for Windows.The statistical power of our study was estimated by G*power and SAS programs. In the case-control study, minor allele frequency was 0.468 and 0.522 in controls and CAD cases, respectively. Our study could reach >85% power. In the cohort study, our sample size could also get >85% power according to the frequency of events in non-target vessels.The clinical characteristics of the case-control study population are shown in In CAD patients, we analyzed the association between rs1333049 and the number of affected coronary arteries (defined as main stenosis ≥50%). No association was found in CAD patients. When the CAD patients were partitioned to the presence or absence of CAC, no association was found in either subgroup as well .The correlation between rs1333049 and CAC severity/extent in CAD patients was determined by analyzing rs1333049 and ln(CAC score+1) and the number of coronary calcified vessels both in subjects with simple CAC and in CAD patients. rs1333049 was correlated with the 2 indices of CAC in the whole CAD patient group, including patients with CAC and patients without CAC; however, in the subgroup analysis, the correlation disappeared in the subgroup with CAC .The clinical characteristics of the cohort study population are shown in To eliminate the interference of coronary revascularization, we also analyzed the association of rs1333049 with the incidence of CV events which occurred in non-target vessels. rs1333049 was significantly associated with the incidence of CV events which occurred in non-target vessels in patients with CAC, but not in patients without CAC .This is the first clinical investigation on the effects of variants at 9p21 locus on CAD subtypes in presence and in absence of CAC. We found that the rs1333049 allele increased the risk of CAD and CV events in the presence, but not in the absence, of CAC. We also found that the variant was not associated with simple CAC or with the extent or severity of CAC in CAD patients; therefore, calcification may be involved in the mechanism by which the 9p21 locus affects the susceptibility to CAD.CAC is thought to be a precursor to, or complication of, CAD. Some have postulated that calcified plaques may represent “older, healed” plaques, as compared to calcified components within a mixed calcified plaque which have been proposed as intermediary in age between non-calcified and calcified plaques; however, this assertion, to date, has not been proven Different mechanisms were involved in the two CAD subtypes, in the absence and presence of CAC. Hyperlipidemia may be associated with the extent of non-calcified plaques As a degenerative and inflammatory disease of elderly patients, about 80% of abdominal aortic aneurysms show considerable wall calcification It is interesting to note that variants at the 9p21 locus robustly predict angiographic CAD prevalence, independent of standard risk factors, but do not predict CAD extent or myocardial infarction Another interesting finding was that this locus was only associated with the incidence of CV events which occurred in non-target vessels. Previous studies reported that this locus is not related to the clinical and angiographic outcomes after the placement of DES in coronary arteries There were some limitations in our study. At first, the phenotype CAD and CAC were only determined by CCTA. CCTA has been shown to be a sensitive and specific tool for the detection of significant coronary stenosis and has also allowed for the visualization and characterization of plaque subtypes In conclusion, the variant on the 9p21 locus was only associated with CAD and CV events in the presence of CAC. This locus may only confer risk of calcification related to coronary atherosclerosis.


Indonesia is one of the largest consumers of tobacco in the world, however there has been little work done on the economics addiction of tobacco. This study provides an empirical test of a rational addiction (henceforth RA) hypothesis of cigarette demand in Indonesia.Four estimators  were explored to test the RA hypothesis. The author adopted several diagnostics tests to select the best estimator to overcome econometric problems faced in presence of the past and future cigarette consumption (suspected endogenous variables). A short-run and long-run price elasticities of cigarettes demand was then calculated. The model was applied to individuals pooled data derived from three-waves a panel of the Indonesian Family Life Survey spanning the period 1993-2000.p-value < 1%, implying that cigarettes indeed an addictive goods. The rational addiction hypothesis was rejected in favour of myopic ones. The short-run cigarette price elasticity for male and female was estimated to be-0.38 and -0.57, respectively, and the long-run one was -0.4 and -3.85, respectively.The past cigarette consumption coefficients turned out to be a positive with a Health policymakers should redesign current public health campaign against cigarette smoking in the country. Given the demand for cigarettes to be more prices sensitive for the long run  than the short run , an increase in the price of cigarettes could lead to a significant fall in cigarette consumption in the long run rather than as a constant source of government revenue. The World Health Organization has developed the WHO Framework Convention on Tobacco Control . This frIncreasing cigarette prices via excise taxes has been recognized as one of several strategies to curb tobacco consumption . To contEconomists have increasingly examined addictive behaviors of smoking in theoretical and empirical economic models. A standard economic model assumes that consumers demand goods (including cigarettes and other tobacco products) in order to maximize their utility subject to a set of constraints such as prices, income, and other factors. This implies consumption decisions at a given point in time are independent of past choices . Since cChaloupka and Warner  have divOn this other hand, psychological studies of harmful addiction also have introduced three basic dimensions of: tolerance, withdrawal and reinforcement (positive effects of habits) that are now part of the formal economic models of addictive behavior . ToleranAddicts in public health point of view refer to psychological disorder, i.e. smokers acquire habit formation to the act of smoking, and physical addiction to nicotine. This view starts from the observation that smoking is bad for the smoker's health, and then goes on to conclude that individuals do not derive benefits from smoking. Whilst in economic sense, addicts is in fact a combination of habit and preference adaptation which starts with subjective individual preferences where individual's smokers reveal that they gain net utility (or satisfaction) from tobacco consumption. From the above perspectives, it implies that addicts in public health are among the addicts in the economist sense where addicts in the latter's construct picks out a larger dimension.This study provides an empirical test of the RA of cigarette demand in Indonesia, a country that represents a significant contributor to the global burden of disease from tobacco-related illnesses. With the fourth largest population in the world, Indonesia in 2002 ranked as the fifth largest consumers of cigarettes 182 billion) behind China (1.7 trillion), USA 463 billion), Russia 375 billion), and Japan (299 billion) . Cigarettes consumed increased from 33 billion in 1970 to 217 billion in 2004. Our study adds evidence to the existing empirical works for testing the RA hypothesis which yield mixed results, and are often described as less than convincing due to implausible discount rates, unsteady demand and low price elasticities [ billion,3 billion2 billionThe RA models assume that consumers take into account all future effects of their present consumption to maximize life-time utility or happiness . Consumei is an individual, t is time, C is consumption of cigarettes, Pc and Pa is the price of cigarettes and alcohol, respectively, x' is a vector of exogenous variable that affect consumption of cigarettes, υi is individual fixed effects that control for the agent time invariant preferences and marginal utility of wealth, t dare time fixed effects to control unanticipated changes in wealth, and it εis the error term.where Ct+1, together with a reasonable estimate of the discount rate, gives a direct test of a RA model against an alternative model in which consumers are myopic addicts [β1. Similarly, given the assumption of rational behavior and the symmetry present in the model, future consumption (β2) has a positive impact on current consumption.Equation (1) allows for direct tests of addiction and rationality. The statistical significance of the coefficient of future consumption,  addicts ,9,10. Fo2/β1β, gives an estimate of the discount factor [1/β2 β- 1). The effects of price on demand for cigarette can be obtained from the solution to the second-order difference equation (1). Coefficient estimate of the cigarette prices indicates the short run elasticity, whilst the long run elasticity is computed using the following expression: The ratio of the coefficient on the lead to that on the lags, t factor . The impit εmay be serially correlated with and through suspected endogenous variable Cit-1 and Cit+1. Second, equation (1) was derived assuming perfect certainty on prices and other variables [Cit+1 should be seen as the planned future consumption, which may or may not be equal to the realized future consumption if there unexpected changes in period t + 1, implying there is measurement error when we use actual values of Cit+1.Applying ordinary least squares (OLS) in equation (1) could lead to biased parameter estimates for two reasons. First, ariables , and thuCit-1 and Cit+1 are regressed in the first stage on known, observed personal characteristics (exogenous right hand side equation (1)) and the instruments iz, as follows:Instrumental variables (IV) techniques are often used to estimate equation (1) due to endogenous of lagged and future consumption variables . Here, wCit* are Cit-1 and Cit+1; i zare the potential instruments, and all else is as defined in equation (1). This stage generates predicted values for the endogenous proxy variables. The dependent variable is then regressed on all exogenous right hand side variables and the predicted values derived from the first stage regressions.where it Pand it x, and does not eliminate i υin (1). Thus, the endogeneity of Cit-1 and Cit+1 are likely to be worse. A within transformation of equation (1) was done to eliminate i υwith the following transformation in first-differences [The 2SLS only assumes simultaneous exogeneity for ferences :t = 3,...,T-1. Equation (3) allows one to apply instrumental variable techniques without assuming strict exogeneity of it Pand where it that are uncorrelated with Δit εand correlated with the regressors, and apply GMM to equation (3) using the orthogonality condition that E = 0. The GMM estimator produces consistent estimate where hetersoskedasticity (or non-constant variance) arise, and asymptotically efficient estimates of the parameters of interest when the errors are serially independent [Our strategy is to find a set of instruments zependent . The estependent .GMM and system-GMM are also used to deal with errors-in-variables and unobservable heterogeneity,14. GiveCit-1 and Cit+1 indeed exogenous, we would opt to OLS, otherwise either 2SLS, GMM or system-GMM call for. While to single out between 2SLS and GMM estimator, a various Pagan and Hall's (1983) test for heteroskedasticity was adopted [We utilized several diagnostic tests to evaluate the overall specifications of the models, and to select the most appropriate estimator. An endogeneity test was employed using the Hausman specification tests. If both  adopted . Since wet al. (2004) described more fully IFLS1, IFLS2 and IFLS3, respectively [This study used individual aggregated data obtained from three-wave a panel of the Indonesian Family Life Survey (IFLS) data, conducted in 1993 (IFLS1), 1997 (IFLS2) and 2000 (IFLS3). Frankenberg and Karoly (1995), Frankenberg and Thomas (2001), and Straus ectively -19.Ct-1) and in the next wave (Ct+1) from the current interview. These variables measure the effects of past and future cigarette consumption on current marginal utility of cigarette consumption. We included measures of cigarette (tPc) and alcohol (tPa) prices at the time of the interview. Other time-varying explanatory variables included a monthly income proxy , expressed as a real value with 2,000 CPI data. To obtain a per-equivalent adult measure of consumption, all income proxy data was adjusted for family size.IFLS contains measures of smoking behavior from individuals aged 15 and above. Table itε. We avoided lagged values of cigarette consumption as instruments for lead consumption due to concerns about serial correlation in the errors. Other dummy variables, which we consider to be proxies for wealth or economic stability, were also included as potential instruments: dwelling walls are brick; dwelling floor is permanent; dwelling is owned (1/0); and individual's religion.Instrumental variable techniques can only be applied if one finds instruments that satisfy two requirements: they (the instruments) must be correlated with the endogenous variable(s) and are orthogonal . ApproprSeventy-seven percent of male age above 15 years reported to have ever smoked habit in 1993, compared to 69 percent in 1997 and 70 percent in 2000 . The figure is consistent in all data. Average number of cigarettes smoked per day is about 12. There are no significant changes in the number of cigarettes smoked between 1993, 1997 and 2000. But, male smoke approximately 30-40 percent higher in the average number of cigarettes smoked per day than female. Since female differ substantially in the frequency and amount of cigarette consumed from males, we perform our analysis separately for male and female.p-value of 0.031 , suggesting OLS results in inconsistent parameter estimates.The endogeneity test, Durbin-Wu-Hausman and Wu-Hausman, for the entire samples was 3.5 and 6.9, respectively, with a To discriminate either 2SLS or GMM, we utilize results of the Pagan and Hall's test for heteroskedasticity . For femSelecting either GMM or system-GMM for male sample, and choosing either 2SLS or system-GMM for female sample are performed based on several instrumental variables tests. A reduced form regression of the lags and leads consumption (equation 2) on the full set of instruments was estimated. The results are presented in Table R2 in the first-stage regression of equation (2) [R2 reveals the models explained a relatively high proportion of the variation for the suspected endogenous. For the entire samples, R2 for the lagged and future consumption was 13% and 12%, respectively. As our models have two suspected endogenous variables, relying only on R2 and F-test may not be enough to detect the relevance of the instruments. Hence, we used a Shea partial R2 measure, which takes into account the inter-correlations among the instruments [R2 and Shea Partial R2. An estimated equation that yields a large value of the Partial R2 and a small value of the Shea measure indicating the instruments lack sufficient relevance to explain all the endogenous regressors, and the model may be essentially unidentified [R2 and Shea partial R2 is considerably low, and thus our models are well-identified.The relevancy of instruments was investigated by evaluating tion (2) . Our R2 truments ,23. Tablentified . With thF-test to determine whether they correlated with the potentially endogenous regressors [F-test that the parameters of the covariates are jointly equal to zero was rejected, indicating the instruments are jointly significant. However, values of the F-test gives little doubt on the relevance of the instruments. A conservative rule of thumb for a single endogenous regressor is that the F-test less than 10 is an indicator of a weak instrument [F-test all instruments for the lagged and lead consumption were 25 and 23, respectively, whilst F-test excluded instrument F- were 8 and 5 for the lagged and lead consumption, respectively. For female sample, results of the F-test even yielded worse performance, less than 2.The relevance of the instruments was also investigated using gressors . The nulstrument . In our J-statistic, and both Sargan's and Basmaan's statistic tests were used in the case of GMM and 2SLS respectively , they will also need to satisfy an orthogonal requirement , i.e. thResults for cigarette demand equation (1) are shown in Table Pooled OLS with robust cluster standard errors, for the entire sample as well as for male and female separately are reported in Table Table p-value < 1%) and alcohol price  turned out to be statistically significant. A positive value of the lagged consumption  suggests that the effect of dependence, reinforcement and tolerance is significant. However, the lead consumption coefficient term turned out to be a negative, suggesting the RA model is rejected in favor of the myopic one. For male sample, the short and long run price elasticity of cigarette was estimated to be -0.38 and -0.39, respectively, and is significant at the 1% percent level, while for female, it was estimated to be -0.57 and -3.89 for short and long run elasticity, respectively.Our primary results are displayed in Table This study tests the RA hypothesis using OLS, 2SLS, GMM, and system-GMM estimators. The former estimator produces consistent estimates of the coefficients and of their standard errors only when the regressors are exogenous and the error term is homoskedastic and serially uncorrelated . The thrF-test less than 10 [We find the evidence for endogeneity of both lagged and future consumption. This led us to apply the methods that treat regressor as endogenous. While 2SLS has been applied widely to test the RA model ,27-30, a than 10 . The latThe RA hypothesis is accepted when the coefficient of the future consumption is a positive and significant, and when the discount rate has a reasonable value ,9,31. OuA rational smoker engages in a rational learning process, balances the utility value of smoking with expected utility loss and selects the efficient risk level . This beNevertheless, the findings that Indonesian smokers are irrational, e.g. they are myopic addicts, are an important message for public health policy. Anecdotal, tobacco industries in the county provide more attractive and thorough advertisement as well as provide many favorable messages about smoking on their products than public health campaign do. If we believed that smokers are misinformed about a key risk of smoking, our findings would imply that policy makers may need strategies that would change smokers' perceptions about a key risk of smoking. In light of this view, the promotion of more informed and responsible smoking should become policy objective. Policy makers have to redesign current public health campaign against cigarette smoking in the country.Another important finding from this analysis is very interesting. Cigarette consumption is found to be negatively related to price, and the long-run cigarette price effects (or equilibrium multiplier) exceeded the short-run effects. From a public health perspective, these findings are of substantial interest, suggesting an increase in the price of cigarettes via excise taxes could lead to a significant fall in cigarette consumption in the long-run. Future increase in the tax will reduce the number of ex-smokers returning to cigarettes and will reduce consumption among continuing smokers. They also will induce some smokers to quit and prevent others from becoming regular or persistent smokers . EmpiricOur study also finds the long-run cigarette price effects for female are greater than one, in absolute value, implying the demand to be more elastic in the long-run than in the short-run. A long-run price elasticity of -3.85 among female smokers indicates that increasing cigarette prices via excise taxes can be an effective tool to reduce cigarette consumption for this population. However, since the demand for cigarettes is more elastic in the long-run, further excise tax increases are more likely to act as a tobacco control mechanism in the long-run rather than as a constant source of government revenue. In such a case, price increases brought about by higher taxes would cause government revenue to decrease as the proportionate change in prices would lower the proportionate change in consumption.The short-run elasticity of cigarette demand gives the percentage variation in the consumption of cigarette in the first year after a permanent change in the current price and all future prices, with past consumption held constant. Whilst Hu and Mao  argue thThis study estimates the demand for cigarette in Indonesia according to the rational addiction framework. The demand equation is tested on individuals aggregated data taken from three-wave a panel of the Indonesian Family Life Survey covering the periods 1993-2000. We explore several estimators, and select the best alternative one to overcome the econometric problems faced in presence of endogenous or predetermined variable. Findings confirm that while the effect of dependency, reinforcement and tolerance is significant (and hence cigarette is an addictive good), the rational addiction hypothesis is rejected in favor of myopic one. This finding calls health policymakers to redesign current public health campaign against cigarette smoking. We also find demand to be more price sensitive in the long-run  than the short-run , suggesting an increase in the price of cigarettes could lead to a significant fall in cigarette consumption in the long-run. The short-run cigarette price elasticity for male and female is estimated to be-0.38 and -0.57, respectively, and the long-run one is -0.4 and -3.85, respectively.The authors declare that they have no competing interests.BH participated in the design of the study, managed the data, performed the statistical analysis, interpretation of the results, drafted the manuscript and revised it critically for important intellectual content. HT contributed to conception of this study, helped to draft the manuscript and revised it. All authors read and approved the final manuscript.


The acute effects of grape polyphenols on endothelial function in adults are inconsistent. Here, we performed meta-analyses to determine these acute effects as measured by flow-mediated dilation (FMD).Trials were searched in PubMed, Embase and the Cochrane Library database. Summary estimates of weighted mean differences (WMDs) and 95% CIs were obtained by using random-effects models. Meta-regression and subgroup analyses were performed to identify the source of heterogeneity. The protocol details of our meta-analysis have been submitted to the PROSPERO register and our registration number is CRD42013004157.Nine studies were included in the present meta-analyses. The results showed that the FMD level was significantly increased in the initial 120 min after intake of grape polyphenols as compared with controls. Meta-regression and subgroup analyses were performed and showed that a health status was the main effect modifier of the significant heterogeneity. Subgroups indicated that intake of grape polyphenols could significantly increase FMD in healthy subjects, and the increased FMD appeared to be more obviously in subjects with high cardiovascular risk factors. Moreover, the peak effect of grape polyphenols on FMD in healthy subjects was found 30 min after ingestion, which was different from the effect in subjects with high cardiovascular risk factors, in whom the peak effect was found 60 min after ingestion.Endothelial function can be significantly improved in healthy adults in the initial 2 h after intake of grape polyphenols. The acute effect of grape polyphenols on endothelial function may be more significant but the peak effect is delayed in subjects with a smoking history or coronary heart disease as compared with the healthy subjects. Atherosclerosis is the primary pathophysiological basis for most cardiovascular diseases In vitro studies have indicated that grape polyphenols can enhance the endothelial nitric oxide synthase and increase the production of nitric oxide in endothelial cells in vitro and animal studies encouraged people to investigate the effects of grape polyphenols on endothelial function in adults. Due to the rapidly metabolized feature of polyphenols Extracted grape polyphenols contain high concentrations of epicatechin, catechin, quercetin, gallic acid and resveratrol as well as other compounds et al. published 4 trials (before 2007) and conducted a meta-analysis Hooper Flow-mediated vasodilation (FMD) of the brachial artery, a noninvasive ultrasound method to assess endothelial function http://www.crd.york.ac.uk/prospero/. Our registration number is CRD42013004157. Meanwhile, the protocol details and the PRISMA checklist have also been provided in The protocol details of our present meta-analyses have been submitted to the PROSPERO register and this record has been published on the database at The present meta-analyses were conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines Studies were chosen for analysis if they met the following criteria: (i) the article was published in English; (ii) studies were controlled trials in adults; (iii) the endothelial function was evaluated by the flow-mediated vasodilation method; (iv) FMD was measured after fasting and at fixed times  after the intake of the grape polyphenols; (v) the values of FMD were reported at the start and end of the intervention.The search, data extraction, and quality assessment were completed independently by two reviewers according to the inclusion criteria. Any discrepancies between the two reviewers were resolved through discussion until a consensus was reached. The extracted data included the study characteristics, population information, and the baseline and final FMD values. If red wine and de-alcoholized red wine were both used as the supplementation of grape polyphenols, both the alcoholized and de-alcoholized data were extracted and separated into two independent trials .The quality of the studies was judged by concealment of treatment allocation, quality of randomization, blinding, reporting of withdrawals, and generation of random numbers. Trials were scored one point for each area addressed, with a possible score of 0 to 5  P<0. 1). The I2 statistic was also examined, and we considered an I2 value >50% to indicate significant heterogeneity between the trials The primary outcome was the percentage change in FMD between baseline and final levels due to grape polyphenols supplementation. If the percentage change in FMD was not reported in the study, we calculated it according to the Cochrane Handbook for Systematic Review and Follman D’s theory for overview of clinical trials with continuous variables Publication bias was assessed with the Egger regression test and funnel plots in vitro, or because the objectives were not related to the present meta-analyses. Therefore, 27 potentially relevant articles were selected for full text evaluation The identification process of eligible studies is shown in Nine studies were included in the present meta-analyses. The characteristics of the included trials are shown in There were five trials The quality score of the nine studies ranged from 1 to 4. Six were randomized, controlled studies P<0.00001) . Meta-regression was performed to detect the sources of heterogeneity, and the results indicated that health status might be the main effect modifier (P<0.05). The dose of grape polyphenols, the intervention with alcohol or without alcohol, the baseline FMD level and the average age of the participants were not effect modifiers.In the included nine studies, five 0.00001) . SignifiP<0.0001). In the subgroup with high cardiovascular risk factors, intake of grape polyphenols appeared to be a more significant influence on FMD when compared to the healthy subgroup 30 min after the intervention . Furthermore, the heterogeneity of the effect has been largely explained by the health status, and there was no significant heterogeneity in the healthy subgroup   .P<0.00001) . Meta-regression indicated that health status might also be the main effect modifier (P<0.05). The dose of grape polyphenols, the intervention with alcohol or without alcohol, the baseline FMD level and the average age of the participants were not effect modifiers.Six studies 0.00001) . SignifiP = 0.0001). The percentage change in FMD in the subgroup with high cardiovascular risk factors 60 min after intervention  was much higher than in the healthy subgroup. Furthermore, there was no significant heterogeneity in the healthy subgroup   .P = 0.0002) .Four studies  0.0002) . No signP = 0.43) .Only two studies  = 0.43) . SignifiP = 0.651; the meta-analysis 60 min after the intervention: P = 0.470; the meta-analysis 120 min after the intervention: P = 0.605; the meta-analysis 180 min after the intervention: P = 0.770).Statistical analyses of the Egger test and funnel plots were performed to detect the publication bias. No publication bias was found in the three meta-analyses , cytokines  and adipokines  might be also influenced by the supplementation of grape polyphenols, because recent study has indicated grape polyphenols might improve the inflammatory status in patients with cardiovascular disease Fifth, although there were 7 trials investigating the chronic effect of grape polyphenols on endothelial function In conclusion, the present meta-analyses reveal that endothelial function can be significantly improved in the initial two hours after intake of grape polyphenols in healthy adults. The acute effects of grape polyphenols on endothelial function may be more significant but the peak effect is delayed in subjects with a history of smoking or coronary heart disease as compared with healthy subjects. Additional well-designed trials, especially in patients with dyslipidemia or cardiovascular diseases, are required to verify our present results.Table S1The protocol of the present meta-analyses.(DOC)Click here for additional data file.Table S2PRISMA 2009 checklist.(DOC)Click here for additional data file.Table S3Subgroup analyses for the 30 min effect of grape polyphenols on endothelial function.(DOC)Click here for additional data file.Table S4Subgroup analyses for the 60 min effect of grape polyphenols on endothelial function.(DOC)Click here for additional data file.


Objectives: The aim of this study was to estimate the prevalence of dental erosion and to investigate possible associations among dental erosion and medical history, dietary and lifestyle habits in a sample of adolescents in Greece. Study design: The study sample consisted of 770 adolescents, 374 boys and 396 girls aged 13 to 16 years. All individuals were clinically examined and answered questions regarding their medical history, rate and frequency of drinks and food consumption and lifestyle habits. Statistical analysis of the questionnaire items was performed by using the multiple logistic regression analysis model. Results: Two hundreds and sixty adolescents were diagnosed as having dental erosion, giving a prevalence rate 33.8%. The habit of holding drinks in the mouth before swallowing  (p=0.002), the ingestion of acidic drinks at bedtime  (p=0.000), the consumption of car- bonated drinks  (p=0.011) and fruit juices  (p=0.000) were the most important associated factors of dental erosion. Conclusions: The prevalence of dental erosion in the study sample was 33.8% while dental erosion experience was associated with frequency and habits of consumption of some dietary components. Key words:Prevalence, tooth erosion, risk factors, adolescents.  Tooth erosion (TE) has been defined as the physical result of a localized, chronic, pathologic and irreversible loss of dental hard tissue caused by acids or chelants without bacterial involvement .TE is frequently encountered in dental practice, affected people of all ages and describes the condition of dental hard tissue. It may also be associated with dentine hypersensitivity, root caries, abrasion and gingival recession in case of the exposure of the root surface to the oral environment .The aetiology of TE is multi-factorial and the result of more than one factor acting together. A wide range of factors has been identified as significantly associated with TE including chemical, biological and behavioural factors -5.These The most important factors that have been associated with TE are intrinsic and extrinsic, however interactions between individuals susceptibility factors, such as salivary characteristics and tooth/ tissue anatomy may play an important role in the development of erosive lesions ,4,6.The intrinsic factors include diseases that cause vomiting or regurgitation, such as gastro-oesophageal reflux, anorexia and bulimia nervosa, or illnesses that cause a reduction in saliva flow  while thA number of epidemiological studies have investigated the role of the mentioned factors in the development of erosive lesions in children and adolescents ,8-10. HoSubject populationStudy population consisted of 770 adolescents, 374 boys and 396 girls, 13 to 16 years of age. The sample were adolescents attending maintained schools who had reached the age of 13 to 16 years old but had not attained their 17th birthday on the date of examination.The Greek Ministry of Health and the Greek Dental Association organize dental surveys for schoolchildren and adults annually, in order to assess the prevalence of diseases such as dental caries and periodontitis, the oral hygiene level and the treatment needs of the Greek population. All the participants complete an oral health questionnaire and undergo an oral clinical examination in several private practices without charge. This precondition is an important motivation in order to create a representative random study sample.As part of the mentioned National Oral Health Survey the present study was carried out between November 2010 to May 2011. It is important to highlight that the topic of the present study was not included in the National Oral Health Survey. Therefore, the participants of the present study completed an additional questionnaire and underwent an oral clinical examination in a private practice.Study population divided into two groups: erosion presence group (EPG) which showed erosion in at least one tooth surface and erosion absence group (EAG) which did not show any type of erosive lesion.Selection CriteriaThe selection criteria of the participants comprised adolescents who were not with orthodontic appliances, enamel defect accompanied by a loss of tooth substance, and fractured or missing teeth of the incisors or the first maxillary molars. These situations could lead to overor underestimate the prevalence of TE and the possible associations that are under consideration. The participants were in good general health as estimated by a general health questionnaire and confirmed by their parents/guardians.QuestionnaireBefore the clinical examination all adolescents filled in a selfadministered questionnaire regarding that aimed to establish which aetiological factors were associated with TE.The questionnaire included variables such as age, gender, data regarding the general medical history of the sam-ple with reference to medication and chronic disorders, drink and food items which had erosive potential and the consumption of intake, which was classified as: low consumption (1-7 times per week) and high consumption (22 or more times per week).Questions regarding chronic disorders included gastric disorders, diabetes mellitus, asthma, juvenile rheumatoid arthritis and medication included drugs for asthma treatment, aspirin , vitamin C, and drugs that causes reduction in salivary flow rate Other questions asked whether acidic drinks were consumed at bedtime and if existed the habit of holding the drink in the mouth before swallowing and the habit of swimming in chlorinated pools. Regarding the habit of holding the drink in mouth, it was not possible to estimate the period (in seconds) that the dietary component (drink) was kept in mouth before swallowing. Consequently, the question was if they consume the examined drinks as they consume water .Clinical examinationThe clinical examinations were performed in a private dental practice, using a conventional dental unit and illumination. One well-trained and calibrated dentist who was also registered as an active member in the Hellenic Society of Periodontology (HSP) and the European Federation of Periodontology (EFP) performed the examinations.The clinical examination included the evaluation of the labial and palatal surfaces of the maxillary permanent incisors # 11,12,21,22) and the occlusal surface of the first permanent molars  according to validated index proposed by the UK National Diet and Nutrition Survey (NDNS ) .An informed consent letter regarding the aim and importance of the study was signed by the adolescents and the parents/guardians before starting the survey, which assured that children participated in the study on their own accord.ReproducibilityA randomly chosen sample of 80 (10%) adolescents was reexamined clinically by the same dentist in order to establish the intra-examiner variance. After consideration of the code numbers of the double examined adolescents no differences were recorded between the 1st and the 2nd clinical assessment.Statistical AnalysisThe individual was the statistical unit in order to estimate the prevalence of TE.Statistical analysis of questionnaire items was performed by using a multiple logistic regression analysis model to identify which variables were best associated with TE.A stepwise selection procedure was used to investigate the influence of risk factors to the outcome of erosion. A two-step approach was used for this aim. First, bivariate analysis was used to test the relationship between TE and the associated factors. Thereby, the criterion for the independent variables to enter the model was set at 0.25. In addition, odds ratios with 95% confidence intervals (CI) were used to assess the bivariate relationships among the examined variables. Then, the mentioned model was used to analyse the factors that were independently related to the presence of TE. The variables after the bivariate analysis were entered into the model in a forward process and then in a back-ward fashion in order to find out which final variables could be considered as risk factors of TE.The data analysis was performed using the statistical package of SPSS ver.17.0 . A p value less than 5% (p<0.05) was considered to be statistically significant.The total number of the adolescents who visited the private practice during the determined period for their an-nual dental follow-up was 834; however, 770 of them met the mentioned selection criteria giving a response rate 92.32%. The mean age of the sample of the study was 14.2 ± 0.4 years.A sample of questions for the questionnaire relating medical history, dietary habits and lifestyle factors is shown in A total of 260 patients were diagnosed as having TE giving an overall prevalence of 33.8% , while the overall boys to girls ratio was 1:1.1 (p= 0.852) .The EP group was consisted of 124 boys and 136 girls and the EA group was consisted of 250 boys and 260 girls. The results showed that factors such as gastric disorders (p= 0.927) and medication (p= 0.521) were not associated with TE according to the bivariate analysis model. .The consumption of drinks and food was dichotomized in high  and low  consumption.Also, the consumption of other acidic components is shown in A significant association was recorded between the intake of fruit juice (p= 0.001), carbonated drinks (p= 0.000), sport drinks (p= 0.045), fruit consumption (p= 0.050) and the occurrence of TE , Table 3Consumption of an acidic drink at bedtime was reported by 40.5% of the adolescents. A statistically significant difference in the experience of erosion between those who consumed an acidic drink at bedtime and those who did not, was recorded (p=0.000). The habit of retaining the drink in mouth before swallowing was observed in 40.3% of the adolescents and it could be related to the occurrence of TE (p=0.000) . A groupThe association between TE and the possible risk factors was analysed by the multiple logistic regression analy-sis model. The variables that entered the model (step one) were the following: consumption of fruit juice, carbo-nated and sport drinks, consumption of fruits and the habits of ingestion acidic drink at bedtime and holding drinks in mouth . The finThe prevalence of TE in the current study was not similar to the results of other investigations. However, the prevalence ranging from 5.5 % to 100.0 % was determined during recent studies on children and adolescent samples in different countries ,8,12-15.The variation in prevalence among these studies may be explained by several factors. First, the different criteria used in the various studies could be at least partly the reason for this discrepancy. The tooth wear index (TWI) is the most extensively adopted index to measure TE, but it can overestimate the prevalence of this condition because it is not specific for TE and consequently measures different types of tooth wear. In addition, it is often difficult to distinguish the three main forms of tooth wear, i.e. erosion, attrition and abrasion and it isOn the other hand the permanent dentition analysed in different investigations shows TE at ages ranging from 3 to 65+ years and this finding may also influence the results through differences in the time of exposure to risk factors. Standardization of the indices, ages and the teeth examined would facilitate such comparisons. Furthermore, socioeconomic, cultural and geographical factors could influence the outcome of prevalence data . In thisGastric disorders and diseases such as anorexia nervosa and bulimia in which vomit is the main symptom are causative factors of TE according to previous studies ,18, findAccording to the literature the use of chronic medication with an acidic composition such as aspirin (for use by active juvenile rheumatoid arthritis patients), vitamin C, drugs prescribed for the treatment of asthma or that causes reduction in salivary flow rate could increase the risk for TE ,19,20.The consumption of vitamin C has been considered a risk factor for TE, whereas previous investigations showed that the risk for TE is increased by the chronic consumption of vitamin C ,21. No fIt is also important to highlight that few studies have been carried out regarding the influence of the mentioned medication on TE in children and adolescents.The frequent consumption of carbonated drinks was shown to be strongly associated with TE, finding that was in agreement with those observed in previous studies ,12,21,22Mungia et al. and OwenThe modern lifestyle has changed the quality of dietary habits and has caused an increase in the consumption of carbonated beverages, fruit juices and sport drinks among children and adolescents. Especially, the consumption of carbonated drinks was increased substantially in the last years in all around the world mainly in children and adolescents because of low cost and high availability . Citric acid which is the main component of citrus fruits and its juices has higher potential to cause TE, than other types of acids, possibly because its chelating action on calcium enamel continues with the pH increases .The freqThe consumption of sport drinks has been increased mainly in adolescents who frequently take physical activities, because it rehydrates the organism and rapidly replace the mineral loss that is lost during transpiration. Owens  observedThese discrepancies among the juice fruits and sport drinks consumption and TE could be attributed to the limitations mentioned above.Milk has a protective effect against erosion, since it contains high concentration of calcium and phosphate in its composition and has a neutral pH (7.0)  . SimilaIn the present study TE was present in individuals with low and high consumption and this factor could not be considered as a protector factor against TE. In addition, El Aidi et al.  recordedOn the other hand yoghurt or another milk-based food may have an erosive potential, in case it has a low content of calcium and/or phosphate and a low pH ,27. In tVinegar consumption has a high potential to cause TE as has low pH, according to several studies ,21,26. HThe consumption of fruits was related to TE in the present study. Similarly, some authors observed that citric fruits are dietary components of high impact in the occurrence of erosive lesions ,10,18, wThe results of the current study showed no significant difference in TE prevalence between vegetarian and non-vegetarian adolescents which was in agreement with the study by Al-Dlaigan et al.. HoweverIn the literature, many studies have shown that individuals with the habit of holding drinks in the mouth especially, carbonated beverages, before swallowing could have a greater susceptibility to TE ,9,11,27.These observations were in agreement with the results of the present study. Holding drinks in the mouth before swallowing causes a marked pH drop at the tooth surface and increases the risk of erosion .Only in a study by Wang et al.  no assocAnother condition that could predispose to TE is the ingestion of acidic drinks at bedtime. Zero et al.  reportedIn the current study the consumption of acidic drinks at bedtime was associated with TE, finding that was in agreement with the findings reported in a study by Moazzez et al. , whereasAs mentioned, some possible risk factors such as consumption of tea, coffee, iron tonics, amino acids supplementaries and swimming in chlorinated pools were excluded from the statistical analysis as the number of adolescents which consume those components or swim in pools was extremely low.However, previous investigations have recorded that the mentioned factors were, in many cases, associated with the occurrence of TE ,27,29-30TE is a multi-factorial condition and there are many factors that were not investigated in the present study and could be associated with TE, such as the protective effect of saliva and the association between TE and abra-sion/attrition. It could be assumed also that other factors such as cultural, social, occupational and interand intra-individual host factors might be relevant in the occurrence of TE.The identification of aetiological factors associated with TE is very important for the establishment of preventive measures. Epidemiological and case-control studies have been developed in the last years to elucidate possible causal determinants for TE.These studies could show associations and indicative risk factors but they could not identify the aetiological factors, because for this a prospective study could be necessary. Other studies are still necessary to explain the aetiology of TE, focusing in the biological, chemical and behavioural factors involved in order to implement adequate preventive policies.In conclusion, the present investigation provided evidence that TE is a significant problem in Greek adolescents. TE should receive more attention that promotes awareness in dentists to make an early diagnosis and to identify the different aetiological factors of this condition. Adolescents with high consumption of fruit juices and carbonated drinks and had the habits to consume acidic drinks at bedtime and holding these drinks in the mouth before swallowing tended to have more TE.A strategy of offering preventive care, including more campaigns promoting a healthier lifestyle for those at risk of TE and a regular dental follow-up, should be conducted for school-children and adolescents in order to eliminate the medical burden of the government and families.


The insertion/deletion (I/D) polymorphism of the gene encoding angiotensin converting enzyme is a controversial risk factor for restenosis after percutaneous transluminal coronary angioplasties (PTCA) in patients. Genetic association studies can be problematic to reproduce due to insufficient power, phenotypic heterogeneity, population stratification, small effect of the variant and even publication biases. To derive a more precise estimation of the relationship as well as to quantify the between-study heterogeneity and potential bias, a meta-analysis including 11,193 patients from 33 published cohort studies was performed. In a combined analysis, the summary per-allele odds ratio for restenosis was 1.31 , and 1.22 , for PTCA-stent and PTCA-balloon, respectively. In the subgroup analysis by ethnicity, significantly increased restenosis risks after PTCA-stent were found in Asians for the polymorphism; whereas no significant associations were found among Caucasians. As for restenosis risks after PTCA-balloon, no evidence of any gene-disease association was obtained in the stratiﬁed analyses according to ethnicity and study size. In conclusion, this meta-analysis demonstrated that the DD homozygous of ACE I/D polymorphism was significantly associated with elevated restenosis susceptibility after PTCA-stent among Asian populations. Coronary artery disease represents the most important cause of sudden cardiac death. Percutaneous coronary intervention (PCI) for unblocking a narrowed coronary artery is a widely used technique for treating patients with angina or an acute coronary event. Initially, PCI was performed only with balloon catheters, but technical advances made it possible to improve patient outcome by the placement of bare metal stents (BMS), or later, drug eluting stents (DES) at the site of blockage –3. The u One ubiquitous system that may influence the restenosis process is the renin-angiotensins system (RAS). Angiotensin II is a potent vascular smooth muscle mitogen and may therefore play a pivotal role in the restenosis process . Angiote After the first report of an association between the I/D polymorphism and restenosis after PTCA , a numbeOur analysis included all genetic association studies of the angiotensin converting enzyme insertion or deletion polymorphism in coronary restenosis after a percutaneous coronary intervention, with or without coronary stenting, conducted before the end of Sep. 2013. To accomplish this task, the MEDLINE, PubMed, ISI Web of Science, EMBASE, EBSCO, Cochrane Library databases, Wanfang and CNKI  databases were searched. For the electronic searches we used combinations of key words relating to the angiotensin converting enzyme gene  and to restenosis . To reduce the likelihood of publication bias, unpublished data, negative data from candidate gene studies, and GWAS (genome-wide association studies) data were also actively sought. Articles were selected on the basis of the abstract, before examining the full text. In addition, the reference lists of selected articles were hand-searched to identify additional relevant reports. Case reports, case-only studies, editorials, and review articles were excluded. Articles in languages other than English were translated. An eligible study for inclusion was restricted to prospective cohort studies and case-control studies in which the relative risk (RR) or odds ratio (OR) of coronary restenosis in relation to the ACE I/D polymorphism was reported or exact figures were available that permitted estimation of the OR. Restenosis was defined as a narrowing of the coronary diameter by 50% or more at follow up compared with the minimal luminal diameter immediately after intervention. Only articles that actually did report angiographic follow-up data were included in the analysis. Because restenosis is a time-related phenomenon, a follow-up window from 3 to 12 months was chosen ,28. If mTwo investigators extracted information from all eligible publications independently according to the inclusion criteria listed above. Data were collected on the authors, journal, year of publication, ethnicity of participants, studies design (prospective cohort study or case-control study), coronary intervention procedure, genotype distribution in the case and control group for II, I/D, and DD genotypes, consistency of genotype frequencies with Hardy-Weinberg equilibrium (HWE), restenosis definition criteria, age, sex, duration of follow up and genotyping methods. Disagreements were resolved by discussion among all authors.For association studies with inconsistent results on the same polymorphisms, the methodological quality should be assessed by appropriate criteria to limit the risk of introducing bias into meta-analyses or systematic reviews. A procedure known as ‘extended-quality score’, has been developed to assess the quality of association studies. The procedure scores each paper categorizing it as having ‘high’, ‘median’ or ‘poor’ quality. Detailed procedure of the quality assessment was previously described .2 based Q test, and the quantity of heterogeneity was assessed by the inconsistency index I2 statistic (ranging from 0 to 100%), which is deﬁned as the percentage of the observed between-study variability that is due to heterogeneity rather than chance [2 values <25% correspond to no or little heterogeneity, values 25–50% correspond to moderate heterogeneity, and values >50% correspond to strong heterogeneity between studies. The pooled OR was estimated using random effects (RE) models [The OR for restenosis risk associated with the ACE I/D variant was assessed in each study, along with its 95% confidence interval (CI). The meta-analysis examined the association between the polymorphism and the risk of restenosis, for the: (i) allele contrast, (ii) heterozygous contrast, (iii) homozygote contrast, (iv) dominant, and (v) recessive models . Genotypn chance ,32. Hete) models . RE mode) models . The sigSubgroup analysis was stratiﬁed by the study characteristic of ethnicity (Asian vs. Caucasian), and study size, respectively. Ethnic group, study size, duration of follow up, age and sex were analyzed as covariates in meta-regression. A cumulative meta-analysis was performed to evaluate the trend of OR in time . In cumuBased on our search strategy, the primary screening produced 221 potentially relevant articles. 188 articles were excluded because they clearly did not meet the inclusion criteria or overlapping references. Study selection process was shown in -4)  with statistically signiﬁcant between-study heterogeneity (P<10-4) . Signiﬁc-4) ; similar-4) . In view-4) . Meta-regression was used to explore the cause of heterogeneity, and it was found that follow up (P = 0.07), mean age of cases (P = 0.11), sex distribution (P = 0.19), did not significantly correlated with the magnitude of the genetic effect. However, a slight effect in heterogeneity for ethnicity (P = 0.02) and sample size (P = 0.007) were found. 2=0%; Angiotensin converting enzyme inhibitors have been evaluated as prophylactic treatment against restenosis in several studies, but the relationship between the ACE I/D polymorphism and ACE inhibitors using in modifying restenosis risk was not established yet. Genotype counts of the ACE I/D polymorphism among patients stratiﬁed by ACE inhibitors treatment were available in 5 studies including 438 restenosis cases after PTCA-stent. Patients on ACE inhibitor treatment with the DD genotype of the ACE gene had similar in-stent restenosis risk compared with those patients without this treatment with an OR of 1.25 [95% CI: 0.82-1.89, P(Z)=0.30, P(Q)=0.48, I Retrospective analysis based on the publication year showed that the cumulative results (asymptote lines) tended to be stable for the eight studies after 2002, but more replications would be necessary for complete conﬁrmation . Sensitivity analysis was performed by excluding one study at a time. The results confirmed the significant association between the DD homozygous and the risk of restenosis, with ORs and 95% CIs ranging from 1.42 (95% CI: 1.02-1.12) to 1.67 (95%CI: 1.11-2.50). Funnel plot and Egger’s test were performed to evaluate the publication bias of the literature reviewed. The shape of the funnel plots seemed symmetrical, suggesting no publication bias among the studies included . The EggSignificant heterogeneity was present among the 12 datasets of the ACE I/D polymorphism . In metaAlthough cumulative meta-analysis for I/D polymorphism in restenosis indicated a downward trend of association in the whole studied period  were not provided. Ideally we would like to pool individual-level data. However this is not possible for the present study. Sampling variability and stratiﬁcation in genetic association studies could be a possible confounding factor on the role of genetic markers. The strict selection criteria ensure a clear case and control deﬁnition for meta-analysis, because when the possibility for a case to be considered as a control is minimized, then the estimation of risk is unbiased. The cases and controls of each study were well deﬁned with similar inclusion criteria, although they unavoidably cover a wide spectrum of disease, in terms of duration, demographics, and other clinical manifestations. The existence of diversity of these factors across studies may result to the presence of heterogeneity. In addition, the risk effect may depend on the interaction with other risk factors: smoking, alcohol consumption, exercise, control of diabetes, and body mass index, all of which modulate the development of restenosis ,89. Prev Limited statistical power is a common problem in complex genetic studies. In this meta-analysis, to obtain as much literature as possible, we put equal emphasis on the positive and negative literature, which reduced potential publication bias and helped to maximize statistical power and robustness. Documentation of the nature of the study group and full angiographic follow-up are also essential in any study on restenosis. When restenosis is described as a binary variable, it is rational to incorporate a measure of the loss of the gain attained by PTCA or the loss of lumen from the time of PTCA into a discrete criterion rather than using 50% of lumen diameter as a single criterion. The influence of genetic polymorphisms in the development of restenosis has been investigated by means of candidate gene approaches. Spectacular advance was made in identifying susceptible genes involved in various types of diseases through genome-wide association strategy (GWAS). In the future, GWAS may be of great importance when establishing a comprehensive picture of the relationship between genetic variant and post-PTCA outcome. In summary, findings from this meta-analysis indicate that the DD homozygous of ACE I/D polymorphism was significantly associated with increased risk of restenosis after PTCA-stent among Asian populations. More work is needed to further investigate the association of the polymorphism across different ethnic populations. Besides, future studies are recommended to identify the possible gene-gene and gene-environmental interactions. Checklist S1PRISMA 2009 Checklist.(DOC)Click here for additional data file.Figure S1Flow chart of literature search for studies examining ACE I/D polymorphism and risk of restenosis after PTCA.(TIF)Click here for additional data file.Figure S2Association between ACE I/D polymorphism and restenosis risk after PTCA-stent by ACE inhibitors treatment.(TIF)Click here for additional data file.Figure S3Cumulative meta-analysis for restenosis after PTCA-stent and ACE I/D polymorphism: the random effects pooled odds ratio (OR) with the corresponding 95% confidence interval (CI) at the end of each year-information step is shown.(TIF)Click here for additional data file.Figure S4Begg’s funnel plot for publication bias in studies on ACE I/D polymorphism and restenosis after PTCA-stent.(TIF)Click here for additional data file.Figure S5Cumulative meta-analysis for restenosis after PTCA-balloon and ACE I/D polymorphism.(TIF)Click here for additional data file.Figure S6Begg’s funnel plot for publication bias in studies on ACE I/D polymorphism and restenosis after PTCA-balloon.(TIF)Click here for additional data file.


Studies about Schroth exercises show that they may be effective in slowing curve progression and improving outcomes in individuals with adolescent idiopathic scoliosis (AIS), howeverThe goal of this study was to determine the effect of Schroth exercises on curve progression using questionnaire scores of patients with AIS who were randomly assigned to spend six months as controls. We included patients with AIS, 10-18 years, with curves of 10-45o, wearing a brace or not, and randomized initially into the standard-care group (observation or bracing) of an ongoing RCT. After receiving standard care for 6 months, controls received the 6-month Schroth intervention. Patients completed five introductory individual visits followed by 1-hour weekly supervised group sessions combined with daily home exercises prescribed using an algorithm (45 minutes). Outcomes were recorded at baseline, 6 and 12 months. Effect sizes were estimated using Cohen’s d , which corresponds to the difference between groups divided by the pooled standard deviation of the individual differences[Of 13 subjects, 2 dropped out while controls and 2 while in Schroth therapy. Of the nine subjects who completed all follow-ups, the mean age and Cobb angle at baseline were 14.0±1.8yrs and 31±10.5o (17-43o), respectively. The recruitment rate was 14% among eligible participants, with time constraints limiting participation. All effect sizes favored Schroth except the Spinal Appearance Questionnaire (SAQ) waist score (0.14). Effect sizes for the SRS-22r questionnaire were as follows: self-image=0.92, pain=0.60, function=0.18 and total=0.56. Pain, self-image and total scores improvements were statistically significant (repeated measures ANOVA). SAQ effect sizes were as follows: general=0.23, chest=0.96, kyphosis=1.43, shoulders=0.40, trunk shift=0.44, prominence=0.77 and curve=0.89. Effect sizes for curve measures were as follows: major Cobb angle=0.00 and combined Cobb angles=0.13. Global ratings of change were significantly higher after Schroth therapy . All but one effect size favored Schroth and nearly half of the effect sizes were moderate or large. Of 70 patients, a change of 0.3-effect size would be considered to be a significant finding. Although only minor effects were observed on curve angles, Schroth exercises can positively affect appearance perception and quality of life, which are deemed priorities with scoliosis conservative treatments[


The polymorphism rs6313 (T102C) has been associated with suicidal behavior in case–control and meta-analysis studies, but results and conclusions remain controversial. The aim of the present study was to examine the association between T102C with suicidal behavior in a case–control study and, to assess the combined evidence – this case–control study and available data from other related studies – we carried out a meta-analysis.We conducted a case–control study that included 161 patients with suicide attempts and 244 controls; we then performed a meta-analysis. The following models were evaluated in the meta-analysis: A) C allele vs T allele; B) T allele vs C allele; C) Caucasian population, D) Asian population, and E) suicide attempters with schizophrenia.We found an association between attempted suicide and control participants for genotype  and allele  frequencies in the case–control study. The meta-analysis, comprising 23 association studies (including the present one), showed that the rs6313 polymorphism is not associated with suicidal behavior for the following comparisons:T allele vs C allele =0.44); C allele vs T allele: =0.22); Caucasians , and Asians .Our results showed association between the rs6313 (T102C) polymorphism and suicidal behavior in the case–control study. However, the meta-analysis showed no evidence of association. Therefore, more studies are necessary to determine conclusively an association between T102C and suicidal behavior. Suicidal behavior is a major health problem worldwide. Several recent studies have been carried out that support a possible relationship between genetic factors and suicidal behavior ,2. HistoFourteen known serotonin receptor subtypes are involved in serotonin action . One canTo our knowledge, up to the present moment, there are no association studies of 5HTR2A and suicidal behavior in the Mexican population. Therefore, we examined the association between 5HTR2A and suicidal behavior in this population. This work focuses on investigating the genetic basis of suicide attempters by assessing the rs6313 genotype. Finally, we used the combined evidence to carry out a meta-analysis of all published data.A total of 161 patients were consecutively recruited from the outpatient service of the General Hospital of Comalcalco in the state of Tabasco, Mexico. These patients had attempted suicide between January and December 2011. In addition, 247 unrelated controls participated in this study. They were recruited from the Blood Donor Center of the General Hospital of Comalcalco and from the general population of the Comalcalco city area in the state of Tabasco, México. Subjects were physically healthy on medical evaluation; none manifested psychiatric problems, as assessed in brief interviews by psychiatrists. To reduce ethnic variation and stratification effects, only Mexican subjects descending from Mexican parents and grandparents participated in this study. However, no structured methods were used to assess genetic heterogeneity.After they were given a verbal and written explanation of the research objectives, all subjects signed an informed consent to participate in the study; they did not receive any economical remuneration. This study complied with the principles convened in the Helsinki Declaration. In addition, this study was approved by the DAMC-UJAT Ethics and Research Committee (P.O.A. 20110237).Suicide attempt patients were evaluated by a trained psychiatrist or clinical psychologists with at least a master's degree level, using the Structured Clinical Interview for DSM-IV Axis-I and II diagnoses, in the Spanish version. We defined suicide attempt as a self-harm behavior with at least some intent to end one’s life . SubjectGenomic DNA was extracted from peripheral blood leukocytes using a modified version of the protocol by Lahiri . The 5HTHardy-Weinberg equilibrium was tested using Pearson's goodness-of-fit chi-squared test. Chi-squared test or Fisher's Exact test was used to compare genotype and allele frequencies between groups. The power to detect associations given the sample size was analyzed by using the Quanto 1.2 software. The power of the analysis was 0.43 . The level of significance was set at p=0.05.This meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria .A literature search was performed that covered from 1997 to 2012. Relevant publications were identified using the following search terms in Medline, Ebsco and Web of Science databases: “HTR2A and suicidal behavior”, “HTR2A and suicide”, “rs6313 and suicide”, “5-hydroxytryptamine-receptor 2A” and “serotonin receptor 2A”. These words were combined to retrieve the summaries. The search also implicated the review of the bibliography cited at the end of various research articles to identify additional papers not covered by the electronic search of abstracts. The publications had to fulfill the following selection criteria: (1) to be studies on the relationship between rs6313 and suicidal behavior , (2) to be published in peer-reviewed journals, (3) to contain independent data, (4) to be case–control association studies in which the frequencies of three genotypes were clearly stated or could be calculated, (5) the use of healthy individuals as controls, and (6) to provide sufficient data to enable the estimation of an odds ratio with 95% confidence interval.Two investigators (González-Castro TB and Tovilla-Zárate CA) working independently screened each of the titles, abstracts and full texts to determine their inclusion. The results were compared and disagreements were resolved by consensus.The same authors mentioned in the last paragraph carefully extracted the information from all the included publications; they worked in an independent manner and in accordance with the inclusion criteria listed above. The following data were obtained from each of the studies: authors, year of publication, region, number of cases and controls, age, and ethnical origin of the participants. The outcomes of the meta-analysis were built by taking into consideration the following categories: a) exposed sick, b) exposed not-sick, c) not-exposed sick and d) not-exposed not-sick. The “sick” term refers to subjects exhibiting suicidal behavior and the “exposed” term to the allele of risk.http://dxsp.sergas.es). This software is freely available for epidemiologic analysis of tabulated data. Data were analyzed with the random-effects model following the reports in the literature [2) analysis was used to calculate the Hardy-Weinberg equilibrium to assess genotype distribution.For the meta-analysis procedures, we used the EPIDAT 3.1 program  were recruited; mean age was 25.5 (9.56) years old (range: 14–56 years of age). Control subjects consisted of 244 volunteers ; mean age was 33.1 (13.0) years old (range: 14–61 years of age). Both groups (cases p=0.06 and controls p=0.06) showed Hardy-Weinberg equilibrium for the analyzed genetic variability. From the 161 suicide attempters, 11 (7%) exhibited the T102T genotype, 80 (50%) the T102C, and 70 (43%) the C102C type. On the other hand, in the control group, 9 individuals (4%) presented the T102T genotype, 100 (41%) the T102C type, and 135 (55%) the C102C type. We observed significant differences in genotype  and allele  frequencies between patients and the control group.The selection process in this study is detailed in Figure We measured the Hardy-Weinberg equilibrium in all genotyped populations. Both patients and controls were in equilibrium (p>0.05), with the exception of the control group in Du et al. (p=0.004), Turecki et al. (0.009) and Crawford et al. (0.01) ,30,35, aFigure Given that our results in the association study suggested an association with the T allele, we performed a meta-analysis using the allelic model for this allele Table . We did In addition, we performed an analysis in two population groups: Caucasian  polymorphism of the 5-HTR2A gene with suicidal behavior. First, a case–control study was conducted. Subsequently, we performed a meta-analysis to assess the current evidence of association between rs6313 and suicidal behavior. In the first part, we found an association between rs6313 and suicidal behavioral in a Mexican sample. To our knowledge, this is the first study addressing the genetic association between the T102C allele and suicidal behavior in a Mexican population.The genetic analysis revealed a slight preponderance of the T allele in the cases group. In 2000, Du et al. described an association between the 102C allele and ideation suicide . Since 2There are several possible explanations for the discrepancies in the results regarding this association. First, there are differences in the populations of patients. For example, Du et al.  and otheIn the current meta-analysis we utilized the allelic model and ethnicity groups. There are two previous meta-analyses -the last including 25 studies- that have explored the association between rs6313 and suicidal behavior ,45. BothWe performed a meta-analysis for the C  and T  alleles separately; however, no association was observed. The results suggest no association between rs6313 (T102C) and suicidal behavior. One possibility for this lack of association may lie in the different criteria used in the selection of patients. In addition, samples sizes of several of the studies included in our meta-analysis are in the low range compared with genetic studies for other diseases ,46.There is the possibility that the C allele may be regarded as a factor risk in the Caucasian population, because in a first analysis we observed an association when we considered a fixed effects with heterogeneity. However, we adopted the random effects, which accounts for additional sources of inter-study variation when heterogeneity exists. This model is more conservative than the fixed effects, since the latter assumes the same true genetic effects, whereas the former assumes normally distributed effects and parametrizes inter-studies variation . When weFinally, we recognize some limitations in the present study; 1) the sample size of the case–control study is small and may not have sufficient power to detect an association between suicidal behavior and small effects polymorphism. In relation to our meta-analysis, there are also some considerations to bear in mind: first; included studies were limited to published articles; second, we did not perform sub-analyses including attempted or completed suicide; third, we did not carry out a subgroup analysis based on gender, and fourth, we did not report psychopathologies related to suicide attempters.In conclusion, we encountered a significant association between the T102C polymorphism and suicidal behavior in a Mexican population. However, this result was not observed in the meta-analysis. Nonetheless, our meta-analysis provides pooled data on a substantial number of cases and controls that may provide a better understanding in the association between rs6313 and suicidal behavior. However, more comprehensive studies and larger samples are necessary to determine conclusively the presence of this association.PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses; DSM-IV: Diagnostic and Statistical Manual of Mental Disorders-IV; SA: Suicide attempters; SC: Suicide completers; SI: Suicide ideation.The authors declare not to have any competing interests.TZC and GCTB conceived the study, participated in its design, and helped to draft the manuscript. TZC, JRI, LNL and NH helped to perform the statistical analysis and to draft the manuscript. PGS and VSMP recruited participants and helped with data integration and analysis. GA, TZC and HN coordinated and supervised the integration of data. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-244X/13/25/prepub


There are few rigorous methods for combining qualitative and quantitative findings from studies with complex interventions using multiple research methods and giving appropriate weight to each without introducing bias to the overall conclusions.Method for Aggregating The Reporting of Interventions in Complex Studies (MATRICS) for the ENIGMA study  – a multi-centre, mixed-methods study to evaluate the impact of the Modernising Endoscopy Services programme [We developed a rogramme , funded We developed a template that requires researchers to follow the steps outlined below:effects identified by the study (from the aims objectives and outcome measures), and divide them between effects on: sample population ; on the specialty being investigated  and on the rest of the organisation and society and give each a unique number.1. List the types of methods used to explore each effect listed in step 1 and give each a unique letter .2. List the 3. Create an alphanumeric code by cross matching the effects identified and the methods used to investigate them (eg patient satisfaction “1” was investigated using a patient questionnaire “A” = 1A).findings of the study and label them using the alphanumeric code (eg “patients were dissatisfied with waiting times – A1”).4. List the explicit 5. Synthesise all consistent findings and list their alphanumeric codes alongside to characterise mutually confirmatory findings. Synthesis is best done independently by at least two researchers.6. Reorder all contradictory findings and their alphanumeric codes adjacent to one another to better illustrate all conflicting findings.The MATRICS tool greatly facilitated the unbiased factual reporting of findings from multiple methods for ENIGMA . AdditioWe have also applied the MATRICS successfully to other complex studies using multiple methods.If the experience of the study team regarding the MATRICS approach to synthesising results in complex studies is reflected by others, it could provide a formal structure for reporting the results of complex and/or multiple-method studies. Further application of this methodology will provide evidence of whether this reporting tool will improve a reader’s understanding of a study and its findings.