Arthritic disorders can be the cause of hospitalizations, especially among individuals 60 years and older. The objective of this study is to investigate associations between health care resource utilization in arthritis patients with and without concomitant anemia in a secondary care setting in France.This retrospective cohort study utilized data on secondary care activity in 2001 from the Programme de Médicalisation des Systèmes d'Information database. Two cohorts were defined using ICD-10 codes: patients with an arthritis diagnosis with a concomitant diagnosis of anemia; and arthritis patients without anemia. Health care resource utilization for both populations was analyzed separately in public and private hospitals. Study outcomes were compared between the cohorts using standard bivariate and multivariable methods.There were 300,865 hospitalizations for patients with arthritis only, and 2,744 for those with concomitant anemia. Over 70% of patients with concomitant anemia were in public hospitals, compared with 53.5% of arthritis-only patients. Arthritis patients without anemia were younger than those with concomitant anemia . Patients with concomitant anemia/arthritis only had a mean length of stay of 11.91 (SD 14.07)/8.04 (SD 9.93) days in public hospitals, and 10.68 (SD 10.16)/9.83 (SD 7.76) days in private hospitals. After adjusting for confounders, the mean (95% CI) additional length of stay for arthritis patients with concomitant anemia, compared with those with arthritis only, was 1.56 (1.14-1.98) days in public and 0.69 (0.22-1.16) days in private hospitals. Costs per hospitalization were €;480 (227-734) greater for arthritis patients with anemia in public hospitals, and €;30 (-113-52) less in private hospitals, than for arthritis-only patients.Arthritis patients with concomitant anemia have a longer length of stay, undergo more procedures, and have higher hospitalization costs than nonanemic arthritis patients in public hospitals in France. In private hospitals, concomitant anemia was associated with modest increases in length of stay and number of procedures; however, this did not translate into higher costs. Such evidence of anemia-related health care utilization and costs can be considered as a proxy for the clinical significance of anemia. Arthritis and other rheumatic conditions are a significant public health issue, and are estimated to affect more than 21% of adults  and presAnemia, defined by the World Health Organization  as a hemInformation on the impact of anemia in arthritic populations is also limited, although there is evidence that anemic RA patients have more severe arthritic disease than nonanemic patients ,24,25. SAnemia has also been linked to increased health care costs and resource utilization , with diThe objective of this study was to assess differences in health resource utilization patterns among arthritis (OA and RA) patients with concomitant anemia compared with those without anemia. We analyzed data from French hospital admissions to test the hypothesis that arthritis patients with concomitant anemia are associated with more health care resource use than nonanemic arthritis patients.This retrospective cohort study utilized data on secondary care in France from the Programme de Médicalisation des Systèmes d'Information (PMSI) database. For public and private hospitals, two cohorts were identified from the hospitalizations that occurred during the 2001 calendar year: hospitalizations where there was a primary/secondary diagnosis of arthritis without anemia; and hospitalizations where there was both a primary/secondary diagnosis of arthritis and a primary/secondary diagnosis of anemia. Thus, both cohorts were comprised of arthritis patients, but differed in the presence or absence of anemia diagnosis, respectively. The cohorts were compared for the following measures of hospital resource utilization: length of stay, number of procedures, and mean total cost.The PMSI database covers more than 90% of private and public hospital activity in France and is used by government and regional health authorities as a tool to provide hospital activity indicators for allocating annual budget and forecasting medical needs and resources. Even though the PMSI database is not exhaustive of French hospitals, it guarantees a standardized collection of data that allows the unbiased identification of cases and controls for epidemiological studies. For each hospital stay, the PMSI database includes information on the patient's age, sex, and postal region; their primary, secondary, and related diagnoses; procedures undertaken; and length of stay. Use of PMSI to assess the epidemiological and economic burden of illness is recommended by the French guidelines for health economic evaluation .International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) codes  days) , and thoracic or abdominal investigations. In arthritic patients without anemia, procedures generally focused on the arthritis diagnosis, with major surgeries undertaken, such as hip and knee replacements, comprising 7.2% of all procedures in public hospitals. In patients with concomitant anemia, procedures were more focused on identifying the cause of anemia and its monitoring, with hip and knee replacements each representing <1% of procedures performed in public hospitals.Overall, the mean cost per hospitalization in public hospitals for the arthritis and anemia population was €;5,870  and €;4,190  for the arthritis without anemia population .As for public hospitalizations, the mean age of the arthritis with anemia population was slightly greater than that of the arthritis without anemia population, 72.2 years and 67.1 years, respectively , gonarthrosis , gonarthrosis (7.5%), and arthrosis (7.2%) were the most frequently reported. In patients with arthritis and anemia, the most common diagnoses were iron deficiency anemia , iron deficiency anemia (17.6%), RA , and coxarthrosis .Private hospital patients with arthritis and concomitant anemia also had, on average, a greater number of associated diagnoses (in addition to arthritis and/or anemia), than arthritis patients without anemia  days, versus 9.8 (95% CI 9.79-9.87) days for arthritis patients without anemia Table . In privAs for public hospitals, the types of procedures performed were mainly related to general anesthesia management/use of recovery room services, cardiovascular function monitoring , and thoracic or abdominal investigations. In arthritic patients without anemia, procedures generally focused on the arthritis diagnosis, with major surgeries undertaken, such as hip and knee replacements, comprising 12% of all procedures in private hospitals. In patients with concomitant anemia, procedures were more focused on identifying the cause of anemia and its monitoring, with hip and knee replacements (combined) representing 7% (hip and knee combined) of all procedures in private hospitals.In private hospitals, the mean cost per hospitalization for the arthritis and anemia population was €;2,700  compared with €;3,380  for the arthritis without anemia population  for anemic than nonanemic patients [P < 0.001) [To our knowledge, there are no previous studies looking specifically at the impact of anemia on health care resource use in hospitalized populations in Europe. However, studies assessing overall annual health care utilization have shown that anemia is associated with increased resource use and costs -34. In apatients . Penninxpatients  examined< 0.001) .The use of a national database representative of hospitalizations across France, in conjunction with the large size of the two study populations involved  adds weight to the findings regarding the impact of anemia in an arthritic population. In addition, the adjustment for key factors that could influence health care resource use, particularly the primary/secondary diagnosis and number of associated diagnoses, helps guard against the possibility that anemia is simply a marker for greater morbidity and severity of underlying disease. Indeed, analysis of the number and types of procedures performed in anemic and nonanemic patients suggests that, in this study, the anemic population has less severe arthritic disease than the nonanemic population.However, this study also has several limitations. First, as the analyzed data is derived from retrospective analysis of medical claims, the findings do not denote causality, but rather focus on identifying temporal association among patient outcomes. We are thus identifying association, not causality, between anemia and increased resource utilization. Second, care must be taken when using DRGs as these are sometimes re-coded for billing purposes and may, therefore, no longer accurately reflect the actual final diagnosis . Indeed,It is interesting that the results of this study show an anemia-attributable increase in resource utilization and cost in public but not in private hospitals. A small increase was observed in the length of stay of anemic versus nonanemic patients in the private sector, but this did not translate into increased costs, probably because of the less detailed way in which costs are reported for this sector. In private hospitals, because only total costs of stay per DRG  were available, part of the fixed costs such as, maintenance, logistics, and salaries, were not included in the private total costs per stay 0.In private hospitals, the anemia-related increase in length of stay was less than half that observed for public hospitals, and there was no difference in the number of procedures undergone by anemic and nonanemic patients. It is possible that the presence of anemia has a greater impact in patients who are generally more unwell than in those who are not as sick. In this study, diagnoses of patients in private hospitals were generally less severe  than those in public hospitals, reflecting the different characteristics of the two sectors: public hospitals, which are mostly teaching hospitals, offer more technical and innovative procedures and allow treatment of more severe cases than private centers, which are more sensitive to activity profitability. Furthermore, differences in financial incentives, corresponding to an increased stay in either public or private hospitals, may have also influenced these findings, though this is beyond the current scope of the paper and further studies are warranted.These study findings are important given that iron deficiency, which is an important cause of anemia in arthritis patients, is partially preventable. Although not proven, the upper GI complications associated with nonselective NSAID use, including ulceration, perforation, and bleeding, could contribute to iron deficiency anemia in arthritis patients using these drugs ,16,40. LIn conclusion, the study hypothesis was confirmed in French public hospital settings; a clear difference in health care resource use attributable to anemia, adjusting for five confounders, exists in public hospitalizations. In private hospital settings, the additional resource use due to anemia was not clearly shown. This was probably due to the fact that patients seen in private hospitals have a less severe condition than those in public settings. These French database analyses provide some of the first evidence of the health care utilization and costs related to anemia specifically in patients with arthritis, and can be considered as a measure for the clinical significance of anemia. Overall, these findings warrant closer consideration of anemic arthritis patients in the clinical setting, and further research to better clarify the impact of anemia in populations with arthritis. Analysis of hospital databases in other European and non-European countries would enhance the available evidence regarding the impact of anemia in patients with OA and/or RA.R. Diazaraque, G. Zlateva, and L. Niculescu are full-time employees of Pfizer Inc. M. Viala-Danten is a full-time employee of Mapi Values, France, who were paid consultants to Pfizer in connection with this research. This study was funded by Pfizer Inc.GZ contributed to the data analysis, interpretation and writing of the manuscript; RD contributed to the data interpretation and writing of the manuscript; MVD contributed to the statistical analysis, interpretation and writing of the manuscript; LN contributed to the study design, analysis, interpretation and writing of the manuscript. The manuscript has not been submitted or is not simultaneously being submitted elsewhere, and all authors have read and approved the final version of the manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2318/10/59/prepub


Elevated liver enzymes are markers of liver steatosis and metabolic syndrome. We aimed to investigate the association of Mediterranean diet on the relationship between aminotransferases  and the metabolic syndrome.The ATTICA study has randomly enrolled 1514 adult males (18–87 yrs) and 1528 females (18–89 yrs) from the greater area of Athens. Adherence to Mediterranean diet was assessed through the MedDietScore. According to NCEP III criteria, participants were classified into those with or without the metabolic syndrome.p < 0.001), while higher MedDietScore was associated with lower likelihood of having the metabolic syndrome in a multi-adjusted analysis . Stratified analysis by the level of adherence to the Mediterranean diet, revealed that only in subjects away or with moderate adherence to the Mediterranean diet, an increase in the AST/ALT ratio was associated with lower likelihood of having the metabolic syndrome ; however, when we focused in those with greater adherence to the Mediterranean diet, AST/ALT ratio was not associated with the presence of the syndrome . These findings remained similar in both genders, and even when the quantity of alcohol drinking was taken into account.Women with metabolic syndrome had higher γGT (p = 0.02) and lower AST/ALT levels (p = 0.018) than those without, and men with metabolic had a lower AST/ALT ratio (p = 0.01) compared to those without metabolic syndrome. The AST/ALT ratio was also positively correlated with MedDietScore (rho = 0.17, Aminotransferases ratio constitutes a marker of the metabolic syndrome among healthy adults; however, this relationship is moderated when individuals are close to the Mediterranean dietary pattern. The metabolic syndrome is a combination of metabolic disorders, such as dyslipidemia, hypertension, impaired glucose tolerance, compensatory hyperinsulinemia and the tendency to develop fat around the abdomen . People Alanine aminotranferase (ALT), aspartate aminotransferase (AST) and gamma -glutamyltransferase (γGT) are common markers of liver injury. Non alcoholic fatty liver disease (NAFLD) constitutes the most frequent explanation for abnormal liver tests results and accounts for asymptomatic elevation of aminotransferase levels in up to 90% of cases. ,3 It is Previous data from the ATTICA and other studies have shown that Mediterranean diet is related with lower prevalence of the metabolic syndrome. ,16 HowevThe ATTICA study is a health and nutrition survey, which is being carried out in the province of Attica , where Athens, is a major metropolis.  The sampAll participants were interviewed by trained personnel who used a standard questionnaire that evaluated lifestyle habits and various socio-demographic, clinical and biological characteristics. The study was approved by the Ethics Committee of our Institution and was carried in accordance with the declaration of Helsinki (1989) of the World Medical Association.Consumption of non-refined cereals and products, vegetables, legumes, fruits, olive oil, dairy products, fish, pulses, nuts, potatoes, eggs, sweets, poultry, red meat and meat products were measured as an average per week during the past year through a validated food-frequency questionnaire (the EPIC-Greek) . The freThe blood samples were collected from the antecubital vein between 8 to 10 a.m., in a sitting position after 12 hours of fasting and avoiding of alcohol. Serum was harvested immediately after admission. The biochemical evaluation was carried out in the same laboratory that followed the criteria of the World Health Organization Lipid Reference Laboratories. ALT, AST and γ-GT but also blood lipids were measured by using chromatographic enzymic method in an automatic analyzer . The intra-assay and inter-assay coefficient of variation was <5% for ALT, AST and γ-GT. An internal quality control was in place for assessing the validity of cholesterol, triglyceride and HDL methods. The intra and inter-assay coefficients of variation of cholesterol levels did not exceed 9%, triglycerides 4% and HDL 4%. Blood glucose levels were measured with a Beckman Glucose Analyzer. The intra-assay coefficient of variation was 9% and the limit of detection was 3 μU/mL.The study's questionnaire also included demographic characteristics like age, gender, and education level in years of school. Information about smoking habits was collected using a standardized questionnaire developed for the Study. Current smokers were defined as those who smoked at least 1 cigarette per day, former smokers were defined as those who had stopped smoking more than 1 year previously and the rest were defined as non-current smokers. For the ascertainment of physical activity status we used the International Physical Activity Questionnaire (IPAQ), as an index of weekly energy expenditure using frequency (times per week), duration (in minutes per time) and intensity of sports or other habits related physical activity (in MET/minutes) . Partici2, and obesity was defined as BMI 30 kg/m2. [th rib and iliac crest. Arterial blood pressure was measured three times at the end of the physical examination with subject in sitting position. Participants whose average blood pressure levels were greater or equal to 140/90 mmHg or were under antihypertensive medication were classified as hypertensive subjects [Body mass index (BMI) was calculated as weight (in kilograms) divided by height (in meters) squared. Based on the World Health Organization classification, overweight was defined as BMI between 25 and 29.9 kg/m0 kg/m2.  We also subjects .Participants were classified as having the metabolic syndrome or not, according to the definition provided by the National Cholesterol Education Panel -NCEP ATP III, consequently, if 3 or more of the following metabolic components are present: waist circumference ≥ 102 cm for males or ≥ 88 cm for females; triglyceride level ≥ 150 mg/dl; HDL cholesterol level <40 mg/dL for males or <50 mg/dL for females; blood pressure ≥ 130/85 mmHg; fasting blood glucose ≥ 100 mg/dL. p-values are based on two-sided tests and compared to a significance level of 5%. SPSS 14.0 software  was used for all the statistical calculations.Continuous variables are presented as mean values ± standard deviation, while categorical variables are presented as absolute number and frequencies. Associations between categorical variables were tested by the use of contingency tables and the calculation of chi-squared test. Differences between groups of study in normally distributed continuous variables were evaluated by the calculation of Student's t-test, while the Mann-Whitney test was used for the skewed variables. Correlations between biochemical markers and other continuous variables were tested using the Spearman or the Pearson's correlation coefficients. Binary and ordinal logistic regression analysis was used to evaluate the effect of selected aminotranferases levels on the likelihood of having the metabolic syndrome, as well as the number of metabolic disorders. The Wald statistic was used to hierarchy the effect of aminotranferases on the number of metabolic disorders in the ordinal logistic regression analyses. Multi-adjusted analysis has taken into consideration variables as age, sex, BMI, smoking habits, physical activity status and MedDietScore. Hosmer-Lemeshow statistic was used to evaluate models; goodness-of-fit. All reported AST levels were higher in males compared to females ; similarly ALT levels were higher in males , as well as γ-GT levels . The AST/ALT ratio was lower in males . Moreover, ALT, AST and γ-GT levels were positively correlated with BMI , while no associations were found regarding age, smoking habits and physical activity status of the participants.Table Unadjusted analysis revealed that 1 unit increase in AST/ALT ratio was associated with 0.37-times (95%CI 0.16–0.84) lower likelihood of having the syndrome in males and with 0.48-times lower likelihood in females (95%CI 0.28–0.86). Greater adherence to the Mediterranean diet was associated with lower likelihood of having the metabolic syndrome . Furthermore, the number of metabolic components of the participants was positively correlated with γ-GT , ALT  concentrations and inversely correlated with AST/ALT ratio . Further trend analysis, after adjusting for age, sex, physical activity and smoking habits revealed that γ-GT , followed by ALT , AST/ALT ratio , were positively associated with the number of metabolic components of the studied sample, while AST  showed no significant effect. No gender interactions were observed.p = 0.29 and p = 0.30, respectively). Furthermore, no significant interaction effect was observed between aminotransferases levels and gender, on the investigated outcome (p = 0.87). Thus, it was decided to perform a pooled analysis with genders combined, in order to increase the statistical power of the analyses.A multi-adjusted analysis, taking into consideration age, sex, BMI, smoking habits, physical activity status and MedDietScore, revealed that a higher AST/ALT ratio was associated with lower likelihood of having the metabolic syndrome . Additionally, when AST/ALT ratio was categorized in quartiles , only participants belonging in the highest quartile of AST/ALT ratio were less likely to have the metabolic syndrome, compared to those in the lowest quartile . No significant associations were observed when AST, ALT markers were tested separately for the presence of the syndrome (Table p < 0.001) and an inverse correlation with AST  and ALT levels . Moreover, a modified version of the MedDietScore without alcohol intake was also positively correlated with AST/ALT ratio , while it was inversely correlated with AST  and ALT levels . The previous findings suggest that greater adherence to the Mediterranean dietary prototype is associated with reduced aminotranferases levels, and lower ALT concentrations relatively to AST.Although unadjusted aminotransferase ratio did not differ between lower and higher tertile of MedDietScore, further data analysis in the whole population, after adjustment for BMI and alcohol drinking, revealed a positive correlation with AST/ALT ratio . In Figure However, a highly significant interaction was observed between AST/ALT ratio and MedDietScore p < 0.00. In Figup = 0.05, and p = 0.09, respectively), after adjusting for age, sex, body mass index, physical activity status, and smoking habits of the participants. Ïn the other hand, in people in the highest tertile of the diet score, the previous relationship was not significant (p = 0.51). The aforementioned relationships remained similar even when the quantity of alcohol drinking was taken into account.Thus, we stratified our analysis by tertile of the diet score . In Table Moreover, no significant associations were observed when AST, ALT and γ-GT were independently tested against the presence of the metabolic syndrome in a stratified by diet pattern analysis.6) in order to carry out the reaction of transfer of α-amino groups from aspartate and alanine to the α-keto group of ketoglutaric acid but pyridoxal-5'-phosphate affects more ALT. Finally, from observational studies ALT seems to correlate more with insulin resistance but the nature of this connection need to be elucidated [Studying a community-based representative sample of adult males and females without any clinical evidence of cardiovascular or other chronic disease, we observed that the metabolic syndrome was related with a lower AST/ALT ratio. However, the most interesting finding is that the latter relationship was altered when people were stratified by the level of adherence to the traditional Mediterranean diet. Particularly, AST/ALT ratio constitutes a marker of the metabolic syndrome only among people that report moderate to low adherence to the Mediterranean diet, irrespectively of the quantities of alcoholic beverages drinking and to the best of our knowledge, this is the first study to point out such a thing. Although it is known that a high AST/ALT ratio may be indicative of severe liver damage from alcohol, it is not the case in our study as the ratio of aminotransferases is not a combined with elevated liver enzymes but the mean aminotransferase levels both in people with or without metabolic syndrome were around 25 IU/L . Moreoveucidated ,29. The ucidated ,31. Partucidated . Liver eucidated -33. Neveucidated ,31. The ucidated ,35. In wIndeed, the favourable effect of Mediterranean diet to the metabolic syndrome has been demonstrated by a number of studies, including ATTICA ,16,36. HFurthermore, additional investigation is needed in order to comprehend how Mediterranean diet affects the relation of aminotransferase ratio with metabolic syndrome. A number of underlying mechanisms may interpret the phenomenon of the dissociation of the abovementioned parameters. It is already mentioned that ALT and AST/ALT are markers closely related to pathology of NAFLD, meaning with liver fat storage . AdherenOn the other hand, Mediterranean diet could minimize the contribution of hepatic inflammation secondary to liver steatosis, to the low-grade inflammation associated with the metabolic syndrome, by reducing, for example, the hepatic production of tumor necrosis factor-α, which triggers the production of other cytokines . By turnThe possible advantageous quality of Mediterranean diet to AST/ALT ratio and NAFLD should be further investigated by intervention studies. Additionally, the underlying mechanisms by which this type of diet modifies the relationship of aminotransferases ratio with metabolic syndrome need to be elucidated.This is a cross-sectional study, so it could not establish causal relationships, but only states hypotheses about the link between liver enzymes and aminotransferase ratio with metabolic syndrome and Mediterranean diet. In discussion, elevated liver enzymes and low AST/ALT ratio were utilized as an estimate of liver fat accumulation, assuming that most cases are markers for NAFLD. By excluding people with HBsAg+ or anti-HCV, this estimation is even more accurate and this is another limitation of our study, that participants did not underwent these measures. Although NAFLD is ideally diagnosed by liver biopsy, histological and ultrasonographic studies of patients referred for unexplained aminotransferase elevations indicate that fatty infiltration of the liver is the cause in 90% of cases and on top, the use of liver enzymes as NAFLD markers is a common methodology in epidemiological cross – sectional surveys, and therefore, our results are comparable. ,11 AlthoAdherence to the Mediterranean diet is positively correlated with AST/ALT ratio and should be further examined for its favorable impact to non alcoholic fat liver disease. Furthermore, this type of diet modifies the relationship of the liver enzymes ratio with metabolic syndrome; hence in people with a great adherence in Mediterranean diet, alterations in liver enzymes do not affect the likelihood of having metabolic syndrome and vice versa. Our findings pose the need for further investigation on whether Mediterranean diet may have a positive effect in liver biochemistry and liver fat accumulation by moderating metabolic syndrome related mechanisms or its beneficial role to metabolic syndrome could partially be explained by its consequences to liver fat and associated biomarkers.The authors declare that they have no competing interests.NT wrote the paper, DP, CP, CC, designed the study and supervised the data collection, YS, EP, CS critically reviewed the paper. All authors read and approved the final manuscript.


Smoking is highly addictive, and nicotine abstinence is associated with withdrawal syndrome in hospitalized patients. In this study, we aimed to evaluate the impact of sudden nicotine abstinence on the development of agitation and delirium, and on morbidities and outcomes in critically ill patients who required respiratory support, either noninvasive ventilation or intubation, and mechanical ventilation.We conducted a prospective, observational study in two intensive care units (ICUs). The 144 consecutive patients admitted to ICUs and requiring mechanical ventilation for >48 hours were included. Smoking status was assessed at ICU admission by using the Fagerström Test of Nicotine Dependence (FTND). Agitation, with the Sedation-Agitation Scale (SAS), and delirium, with the Intensive Care Delirium Screening Checklist (ICDSC), were tested twice daily during the ICU stay. Agitation and delirium were defined by SAS >4 and ICDSC >4, respectively. Nosocomial complications and outcomes were evaluated.n = 44) were younger and more frequently male and were more likely to have a history of alcoholism and to have septic shock as the reason for ICU admission than were nonsmokers. The incidence of agitation, but not delirium, increased significantly in the smoker group . Nicotine abstinence was associated with higher incidences of self-removal of tubes and catheters, and with more interventions, including the need for supplemental sedatives, analgesics, neuroleptics, and physical restraints. Sedation-free days, ventilator-free days, length of stay, and mortality in ICUs did not differ between groups. Multivariate analysis identified active smoking  as an independent risk factor for agitation. Based on a subgroup of 56 patients, analysis of 28 pairs of patients (smokers and nonsmokers in a 1:1 ratio) matched for age, gender, and alcoholism status found similar results regarding the role of nicotine withdrawal in increasing the risk of agitation during an ICU stay.Smokers (Nicotine withdrawal was associated with agitation and higher morbidities in critically ill patients. These results suggest the need to look specifically at those patients with tobacco dependency by using the FTND in ICU settings. Identifying patients at risk of behavioral disorders may lead to earlier interventions in routine clinical practice. Cigarette smoking is the main addiction in the world . TobaccoBehavioral disorders such as delirium and agitation in the critically ill occur with a high frequency, ranging from 15% to 80% of patients, and have been associated with increased morbidity and risk of mortality -13. ManyThus, we aimed to evaluate the nicotine-withdrawal syndrome in critically ill patients. We hypothesized that dependent smokers may have increased risk for agitation and delirium, and then increased morbidity, such as infections and accidental self-removal of tubes and catheters, related to these behavioral disorders.This prospective observational study was conducted over a period running from June 2007 to April 2008 in two adult ICUs . All patients admitted to the ICUs and mechanically ventilated with either noninvasive ventilation or intubation for respiratory support for longer than 48 hours were considered eligible for the investigation. Patients were excluded if they were younger than 18 years or were determined to have a history of chronic dementia and psychosis, or acute neurologic diseases on admission, such as severe traumatic brain injury, ischemic stroke, or cerebral hemorrhage. NRT was forbidden during the study period. The study was approved by the local ethics committee. Patients were included after informed consent of the patient or next-of-kin was obtained.The following demographic and clinical data were collected at ICU admission: age, gender, medical or surgical origin referring to the primary admission diagnosis, history of hypertension, chronic alcoholism and psychotropic therapy, smoking status, and primary diagnosis on admission to the ICUs. Alcohol consumption was considered chronic if it persisted for the whole year before admission, as defined by the National Institute on Alcohol Abuse and Alcoholism criteria for unhealthy alcohol use in the United States ,16. To aTabagism was evaluated according to the tobacco load, which is quantified in pack-years, and the nicotine dependence, as assessed by the Fagerström Test of Nicotine dependence (FTND)  Additio, obtaineDiagnostic and Statistical Manual of Mental Disorders (DSM) IV criteria [Agitation was assessed twice daily by nurses or physicians until ICU discharge, by using the modified Sedation-Agitation Scale (SAS)  additio. SAS liscriteria  and feat3 colony-forming units (CFUs)/ml; (2) colonization of central venous catheters: at least one organism at a concentration ≥103 CFUs/ml identified by culture of the catheter tip with the Brun-Buisson technique [4/ml with the presence of an organism at a concentration of 105 CFU/ml; (4) bacteremia: a positive hemoculture with the isolation of an organism or at least two positive hemocultures for a coagulase-negative Staphylococcus, according to the usual definitions [Nosocomial infections were defined as follows: (1) ventilator-acquired pneumonia: clinical suspicion of pneumonia , and at least one organism isolated by protective specimen brush at a concentration ≥10echnique ; (3) uriinitions .Primary end points were either one or more agitation or delirium events during the ICU stay. Secondary end points were ventilator-free days ; total dose of sedatives and analgesics administered during the ICU stay, including the extra doses needed to abort the episodes of agitation/delirium; and sedation-free days ; and complications related to agitation and delirium, such as requirement for supplemental sedation or physical restraints, use of additional antipsychotic medication; and self-extubation, self-removal of arterial, central venous and bladder catheters, nasogastric tubes, and nosocomial infections.2 test for categoric variables with continuity correction when appropriate, the Fisher's Exact test for proportions, and the Mann-Whitney test for quantitative variables. To determine the set of independent predictors of agitation, a multivariate logistic regression analysis was performed by using backward stepwise selection. In the multivariate model, the outcome variable studied was agitation, defined as success if agitation occurred at least once. Variables with a P value < 0.1 in univariate analysis were included in the regression analysis, and then a P value of 0.2 was used to remove variables from the model. To avoid analyses that might have resulted in biased conclusions because of redundancy of the included variables, SAPS II and SOFA scores were not included in the same model. The performance of the final model on the test set was assessed by using the c-index and its 95% CI. To ensure that our findings were robust, we also performed a case-control approach nested in our study to assess the relative risk (RR) of agitation, according to the smoking status. We matched each smoker with each nonsmoker in a 1:1 ratio. Each pair had to fulfill three conditions: same age (± 5 years), same gender, and same status regarding alcohol consumption . We analyzed this subset of patients by using the Wilcoxon test, the MacNemar χ2 test, and the pair-matched Mantel-Haenszel adjusted RR. Analysis was performed by using MedCalcSS version10.1 . The two-tailed significance level was set at P < 0.05.With a 30% baseline incidence of smokers in the general population, we calculated that a sample size of at least 134 patients was necessary to achieve a 30% absolute difference in agitation/delirium incidence among smokers and nonsmokers at a beta error of 0.2 and an alpha error of 0.05. For univariate analysis, we used the χP = 0.62, respectively), and in these cases, we have recorded the patient's test responses for analysis. Thus, only six (14%) FTND scores were obtained exclusively from next-of-kin, and were recorded as well.In total, 916 admissions were screened for enrollment. One hundred fifty consecutive patients met the inclusion criteria. Six patients were secondarily excluded, leaving 144 patients for analysis  patients in the overall cohort received noninvasive ventilation. In this subgroup of patients, the rate of intubation was 62% related to failure of noninvasive ventilation. Thus, only 17 patients (five smokers and 12 nonsmokers) were treated exclusively with noninvasive ventilation. Based on SAS and ICDSC scores, no statistical difference was recorded in the number of agitation events between both groups (data not shown).P = 0.0005), but delirium was not affected by smoking status. There was no central effect in the incidence of agitation. In a subgroup analysis comparing weak and strong tobacco dependencies according to FTND, no statistical difference was observed for the development of agitation . Similarly, tobacco-load distribution did not differ between smokers with and without agitation during the ICU stay. In patients in whom agitation developed, the median number of days with agitation events was greater for smokers than for nonsmokers. The rates of accidental removal of tubes and catheters were higher for smokers, as well as the need for supplemental sedative and analgesic medications, physical restraints, and neuroleptics in comparison with nonsmokers  , and then was not identified as independent predictor for agitation in the multivariate analysis.By univariate analysis, the risk factors associated with agitation were age, male gender, SOFA score, and active smoking Table . After a2 = 8.2; P = 0.004), and tobacco dependency was associated with an increased risk for agitation compared with a no-smoking history .Matching was possible in 62 patients representing 43% of the patients considered in the main analysis  ,38-40. HSome study limitations must be addressed. First, objective measurement of tobacco addiction, like urinary cotinine, was not performed, and conclusions drawn from this observational study in a small number of patients cannot be generalized. The lack of any association between the level of addiction and either agitation rate or most important outcomes  may also be the result of the small sample size. Second, tobacco-smoking status and end points were not collected in a blinded manner by nurses and staff, and this point may be considered a potential bias. Third, the use of sedative and analgesic drugs, as well as discontinuation of physical restraints, were left to the attending physician's judgment, and thus, were likely to be somewhat random. As a consequence, "organ failure" of the brain (delirium and agitation) may have been over- or underestimated in some cases. And fourth, adjusted analyses can potentially yield distorted associations by selection or omission of variables that influence outcome. Regarding age, gender, alcoholism, and septic shock, a large imbalance between smokers and nonsmokers was observed in our cohort study and may be considered as potential bias. These confounding factors are, however, taken into account in the matched analysis that confirms our finding.In mechanically ventilated patients, sudden nicotine abstinence was associated with severe agitation and its consequences, such as self-removal of tubes and catheters. These results suggest the need to be aware of nicotine-withdrawal syndrome in critically ill patients, and then support the necessity to improve strategies to prevent and treat agitation earlier. Based on these findings, the use of nicotine-replacement therapy should be tested by a well-designed, randomized controlled clinical trial in the ICU setting.• Agitation is a common event in critically ill patients.• Nicotine withdrawal was identified as risk factor of agitation, but not delirium, in multivariate and matched case-control analyses adjusted for confounding factors.• Agitation was associated with a higher adverse-event rate, such as accidental self-removal of tubes and catheters, and new interventions including supplemental sedation and physical restraint.• These results suggest the need to be aware of nicotine-withdrawal syndrome in critically ill patients, and then to support the necessity to improve strategies to prevent and treat agitation earlier.The authors declare that they have no competing interests.OL and DdC initiated the study and the design. DdC was involved in the interpretation of the results and wrote the manuscript. OL helped to draft the manuscript. AS, CD, MR, NT, PB and PC contributed to the conception of the study. All authors read and approved the final manuscript.This work was presented in part at the 37th Congress of the Société de Réanimation de Langue Française (SRLF) held in January 2009 in Paris, France.Fagerström Test for Nicotine Dependence (FTND).Click here for fileRiker Sedation-Agitation Scale (SAS).Click here for fileIntensive Care Delirium Screening Checklist (ICDSC).Click here for file


Background. Recent reports have found a positive relationship between periodontitis and the hormones cortisol and dehydroepiandrosterone (DHEA). We investigated the associations between those levels and periodontitis in never-smokers and smokers of elderly subjects. Subjects and Methods. Cortisol and DHEA levels in saliva were determined in 171 subjects , with clinical examinations including probing depth (PD) and clinical attachment loss (CAL) also performed. Results. Smoking had effects on cortisol and DHEA levels, and those were significantly associated with severe PD and CAL in never-smokers. According to ROC analysis, the cutoff values of cortisol and DHEA to obtain the optimal sensitivity and specificity for detecting severe periodontitis were 2.06 ng/mL and 60.24 pg/mL, respectively, for PD, and 2.12 ng/mL and 61.78 pg/mL, respectively, for CAL. Conclusions. Assessment of hormone levels may be a useful screening method for periodontitis, though limited to never-smokers. A number of investigators have proposed an association between periodontitis and psychosocial stress and the majority of studies in a systematic review  found a Smoking is associated with elevated cortisol and DHEA levels, as it increases the levels of adrenocorticotropin hormone (ACTH) . In addiThe subjects in this cross-sectional study were recruited from members of two senior citizen colleges in Kitakyushu City, Japan. The study sample consisted of community-dwelling, independently living elderly people aged 60 years old and older who attended lectures once a week. These colleges are part of the adult educational system supported by the government of Kitakyushu City, which enrolls students as volunteers for a period of one year. The course of study focused not only on health topics but also on other topics of interest to elderly people, such as finance and culture. The study population voluntarily participated in oral and systemic examinations and initially consisted of 231 subjects  residing in Fukuoka Prefecture, Japan. All of the subjects were independent in daily activities, with none hospitalized at the time of the study, as described previously . ExclusiBefore beginning the examinations, each subject was asked to respond to a survey conducted by a dental nurse that consisted of questions related to general medical condition, medication usage, lifestyle, oral health behavior, and oral hygiene habits, and each was also questioned verbally to obtain information regarding smoking status . The subjects were classified as either never-smokers or smokers  on the basis of their answers. Furthermore, a method that used face-scale scores was used to evaluate self-rated health status . From thSaliva samples were collected from all subjects between 11:00 AM and 1:00 PM to minimize any circadian rhythm effects, after they had refrained from oral intake for at least 2 hours prior to collection. Subjects with removable partial dentures kept them in their mouth during saliva collection. Collection of stimulated whole saliva was performed using sterile tubes. The subjects were first asked to swallow all saliva in the mouth, then chew paraffin for 3 minutes at a constant pace of 60 times per minute, which was monitored with an electric metronome. Collected samples were placed on ice immediately and the salivary flow rate (mL/min) was estimated by measuring the volume of saliva collected in the tube. Thereafter, the saliva samples were frozen at −30°C until further analysis. The concentration of cortisol in saliva (ng/mL) was measured using a salivary cortisol enzyme immunoassay kit , with a lower sensitivity limit of 0.07 ng/mL, while that of DHEA (pg/mL) was determined using a salivary DHEA enzyme immunoassay kit , with a lower sensitivity limit of 10 pg/mL.Periodontal status was evaluated using probing depth (PD), bleeding on probing (BOP), and clinical attachment loss (CAL). Periodontal examinations were conducted at two sites  of all teeth examined, using a standard periodontal probe  that was inserted into the periodontal pocket parallel to the long axis of all teeth fully erupted in the mouth, according to a modified method described in the Third National Health and Nutrition Examination Survey (NHANES III) , with soIn order to assess differences among the groups, a chi-square test was used for categorized variables and a Kruskal-Wallis test or ANOVA for continuous variables. If a normal distribution was not present according to the results of a Kolomogorov-Smirnov test, the former test was used.Receiver operating characteristics (ROCs) analyses were performed to determine the optimum cutoff values for the concentrations of cortisol and DHEA, which were used to screen for severe periodontal status. Subjects with severe periodontal status were dichotomized into periodontitis-negative  and periodontitis-positive , based on the PD and CAL levels. This dichotomy was then used to calculate the sensitivity and specificity for the cutoff values of cortisol and DHEA. ROC curves were plotted for cortisol and DHEA with PD and CAL and the area under the ROC curve (AUC) was calculated for each. The optimum sensitivity and corresponding specificity were determined from the point on the plot that was closest to the top left-hand corner of the axes. All statistical analyses were performed using SPSS 14.0 for Windows. The level of statistical significance was set at 0.05 for all of the analyses.Tables Among never-smokers, the median and 25th and 75th percentile values for cortisol were 1.87, 1.42, and 2.89 (ng/mL), respectively, while those for DHEA were 59.79, 32.69, and 89.52 (pg/mL), respectively. In contrast, among smokers, the median and 25th and 75th percentile values for cortisol were 2.18, 1.41, and 3.01 (ng/mL), respectively, while those for DHEA were 46.07, 30.07, and 89.77 (pg/mL), respectively. However, there were no significant differences regarding those hormone levels between smokers and never-smokers. We compared the levels of cortisol and DHEA between the with and without extensive periodontitis groups, which were defined by the number of teeth with PD  ≥5 mm or CAL  ≥6 mm.P = .001) and 0.69  for cortisol and DHEA, respectively (P < .001) and 0.68  for cortisol and DHEA, respectively  at various cutoff levels. The area under the curve (AUC) for PD was 0.68 (95% CI 0.58–0.78, ectively . For CALectively . As showIn the present cross-sectional study, we investigated cortisol and DHEA levels and periodontal status in elderly subjects and found that levels of the salivary stress-related hormones cortisol and DHEA were useful for screening for periodontitis in subjects who had never smoked. The association between periodontitis and stress-related hormones has been largely overlooked, with only two known human studies of the associations between cortisol in saliva and periodontitis reported. One of those was our own survey , while tSmoking is known to be associated with elevated cortisol and DHEA levels. In a recent report that compared cortisol profiles of smokers and nonsmokers over the day, cortisol levels were elevated in everyday life among smokers compared with nonsmokers, and the differences in values were quite substantial, averaging 35% or more on both working and weekend days . In the Measurement of biomarkers in saliva has many advantages, as the procedure is stress-free and noninvasive, and allows for frequent and rapid sampling, whereas diurnal rhythm, artificial changes due to food or drinking substances, and blood-contamination are some of the disadvantages. Thus, as described above in the Methods section, the sampling method must be carefully performed. In order to minimize any circadian rhythm effects, we selected the period between 11:00 AM and 1:00 PM for obtaining saliva samples, which has been reported to be stable in regard to daytime hormones levels in nonsmokers . A periodontal probe is generally used for periodontitis screening during community-based oral health check-ups, though several problems, including cost, burden on the subject, prevention of infection, and manpower needs, have been pointed out. Our analysis using ROC curves showed acceptable sensitivity and specificity for periodontitis screening with both of the salivary hormones tested in the present study. On the other hand, progress is being made in the development of various screening tests for periodontitis using enzymes , cytokinA limitation of the present study is that our subjects were generally in good health and noninstitutionalized. In addition, the percentage of subjects with severely extensive periodontitis among all subjects analyzed was low. Thus, these findings may indicate that the association exists primarily in systemically and orally healthy elderly individuals. Furthermore, it is possible that the periodontal examination method that utilized two sites per tooth in this study, which was based on NHANS III, may underestimate the severity and extent of periodontitis. Additional investigations are necessary to validate and extend the findings using other ages or outpatients. Further, the usefulness of cortisol and DHEA as predictors for periodontitis cannot be determined from our findings, and a longitudinal study is necessary to determine the relationships of those hormones to the progression of periodontitis. In summary, we found a significant association between the salivary steroid hormones cortisol and DHEA and periodontitis severity in community-dwelling elderly subjects who had never smoked. These results indicate that these stress-related hormones are useful indicators of the risk for periodontitis, as they showed moderate levels of sensitivity and specificity for periodontitis. Within the study limitations regarding smoking status, the present method of determining cortisol and DHEA levels may include a possibility as screening test for periodontal disease in the near future. Additional approaches to reveal a new type of screening test system for periodontitis as an alternative to the conventional probing method are required.


Introduction. The aim of this study is to compare outcomes in three groups of STS patients treated in our specialist centre: patients referred immediately after an inadequate initial treatment, patients referred after a local recurrence, and patients referred directly, prior to any treatment. Patients and methods. We reviewed all our nonmetastatic extremity-STS patients with a minimum follow-up of 2 years. We compared three patient groups: those referred directly to our centre (group A), those referred after an inadequate initial excision (group B), and patients with local recurrence (group C). Results. The study included 174 patients. Disease-free survival was 73%, 76%, and 28% in groups A, B, and C, respectively (P < .001). Depth, size, and histologic grade influenced the outcome in groups A and B, but not in C. Conclusion. Initial wide surgical treatment is the main factor that determines local control, being even more important than the known intrinsic prognostic factors of tumour size, depth, and histologic grade. The influence on outcome of initial wide local excision (WLE), which is made possible by referral to a specialist centre, is paramount. Soft tissue sarcomas (STSs) are a heterogeneous group of tumours that derive from mesodermal tissue and can occur anywhere in the body, although most are in the extremities (59%), trunk 19%), retroperitoneum (15%), or head and neck (9%) 9%, retro, but arewhoops procedure: the surgeon does not realise that the lump is a sarcoma until receiving the pathologist's report on the material that has already been excised [The main prognostic factors are intrinsic to the tumour: histologic grade, depth, and tumour size; however, advanced patient age and presence of metastases at diagnosis also affect the outcome . Surgery excised .whoops cases and even less on survival rates. The aim of this study is to compare outcomes in three groups of STS patients treated in our specialist centre, patients referred after a whoops procedure, patients referred after a local recurrence; and patients referred directly to our centre for a definitive diagnosis.Patients subjected to an IIE usually need further surgery, which increases the morbidity of the treatment. In addition, there is evidence that insufficient resection increases the risk of local recurrence , and it We reviewed all patients with a minimum follow-up of two years who had been treated for STS in our hospital between 1983 and 2006. We excluded cases of extraskeletal Ewing's Sarcomas, of STS when located anywhere other than in the extremities, and of patients with metastases at the time of diagnosis.whoops cases, included patients who had been referred to us immediately after an IIE; and group C, the local-recurrence group, included patients referred after having one or more local recurrences.Patients were assigned to one of the following three groups: group A, the virgin STS group, comprised those who had been referred directly to and first diagnosed at our hospital; group B, In all cases, all resected specimens had been examined histologically and the tumour had been evaluated as high or low grade. For group B patients, findings of residual tumour had been noted. From our records of each patient, the following data at the time of diagnosis were collected: gender, age, and tumour characteristics . For group C patients, we also assessed depth and histologic grade of the primary tumour; in most cases of group C, it was not possible to determine the primary tumour size. In accordance with the criteria of the American Joint Commission on Cancer Staging of STS , we regalocal recurrence to refer to any recurrence after the surgical treatment at our institution .Outcomes were analysed in terms of disease-free survival (DFS) and overall survival. Other outcome events, such as local recurrence and distant metastases, were not assessed. In this context of outcome events, for group C patients, we use the term The Chi-square test was used to compare phenotype frequencies between groups . A multivariate survival analysis (stepwise Cox regression) including prognostic factors  between groups A and B was performed.P < .05.Overall survival and disease-free survival data were expressed as Kaplan-Meier curves, and groups were compared by means of the logrank test (Mantel-Cox test). The statistical analysis was performed with the SPSS software v15.0 . In all cases statistical significance was defined as We treated a total of 236 STS patients between 1983 and 2006. Of them, 209 involved tumours in the extremities. We excluded 25 patients with metastases at diagnosis and 10 cases of extraskeletal Ewing's Sarcoma. The cases analysed then numbered were 174.The mean age of these patients was 43.74 years, with a standard deviation (SD) of 18.8 years. Mean follow-up was 91.95 months , with no differences between the three groups and a minimum follow-up of two years. Of the 174 cases, 57% were in group A, 22% were in group B , and 21%Patients were treated by surgery: radical excision with curative intention. Amputation as a primary therapeutical procedure was not performed. Wide local excision was complemented by radiation therapy and chemotherapy as standard treatment of deep, big, and/or high-grade STS. Of such patients, only 30% did not receive chemotherapy, because of a contraindication to the procedure (such as cardiologic disease). We now complement external radiotherapy with brachytherapy, but, in the patients treated between 1983 and 2001, we used an intraoperative boost dose of radiotherapy to the same end. Histologic analysis detected malignant cells in all the specimens from patients in groups A and C and residual tumour cells in 40% of specimens from group B cases.Analysis of previous operations, biopsies, or excisions suggested that oncologic surgery rules were frequently disregarded: in 39% of group B patients and 30% of group C patients. The most frequent indicator of disregard was an inappropriate transversal approach incision .P = .608); in group C the rate was 59%. This difference, A + B versus C, was statistically significant and was not related with depth and histologic grade . As shown in the Kaplan-Meier curves of P = .024).The rate of DFS was significantly lower in group C patients, 28%, than those in groups A and B patients, 73% and 76%, respectively (P > .05)  . The oveutaneous .The current view is that STS treatment in a referral centre, where diagnosis and treatment follow oncologic rules, improves results in terms of both quality of life and survival . HoweverThe retrospective series of patients we present and analyse here does not provide a representative sample of STSs. This is indicated, for example, by the fact that between 1980 and 2006 our centre treated over 1000 bone sarcomas but less than 300 STSs in the extremities.inadequate initial excision (IIE) and a whoops procedure [Without a biopsy, an STS, especially if it is subcutaneous and small, is sometimes misconstrued as a benign mass and surgically excised without the adequate margins for a malignant mass. Histologic study of the resected lump overturns the preoperative diagnosis and establishes the previously unsuspected diagnosis of sarcoma. Such an incident is known as rocedure . In the rocedure –11.To ensure early diagnosis and management of all suspected STS cases, developed countries such as the UK drew up referral guidelines  accordinwhoops procedures. These patients are often distressed by the unexpected diagnosis and, like their physicians, concerned about the prognosis and further management of the disease.In our practice, we still see patients referred after Wide local excision (WLE) is the correct primary treatment strategy for extremity STS. The overall approach to treatment should be multidisciplinary: with a specialist sarcoma surgeon, radiologists, pathologists, and clinical oncologists . Recent For patients with nonmetastatic STS, overall survival is 50%–70% , 16. TheIn our study we categorized patients into three groups to determine how an initial inadequate treatment of an STS affected the outcome. We found that patients diagnosed in and treated at our centre (group A) and patients referred immediately after an IIE (group B) presented similar results in terms of local recurrence rate, metastasis rate, disease-free survival, and overall survival Tables and 4. Giwhoops event had better outcomes than those who were diagnosed and treated directly in our institution  is needed; second, a greater volume of tissue is resected; third, a larger field is radiated; and fourth, soft tissue coverage procedures are more frequent [whoops patients needed adjuvant treatment. Therefore, to avoid complications, it is important that all patients with suspicious lumps be referred to a specialist centre. The situation with STS is the same as that asserted by Wafa and Grimer with regard to bone sarcoma [Although survival after wide reexcision in a frequent . In our  sarcoma : there iA patient with a lump which in any way raises a suspicion of STS should be referred to a specialist centre, where a multidisciplinary team with good experience of such infrequent lesions can assess the patient and determine the best treatment.whoops procedure, should be immediately followed by wide reexcision, which in our study resulted in survival rates similar to those for patients operated on directly with WLE. Reoperated patients suffered more radiotherapy related complications and a general increase in the morbidity rate. Patients presenting a local recurrence after an IIE had worse outcomes, especially in terms of disease-free survival.The unplanned excision of a malign mass, the Initial wide surgical treatment is the main factor that determines local control, being even more important than the known intrinsic prognostic factors of tumour size, depth, and histologic grade. The influence of initial WLE on outcome is paramount. However, these conclusions should be interpreted with caution, because the number of patients in each group is relatively small and important differences might be undetected.


The development of breast cancer is multifactorial. Hormonal, environmental factors and genetic predisposition, among others, could interact in the presentation of breast carcinoma. Human leukocyte antigen (HLA) alleles play an important role in immunity (cellular immunity) and may be important genetic traits. HLAAllele-specific interaction has not been well established. Recently, several studies had been conducted in order to do so, but the results are controversial and in some instances contradictory.We designed a case-control study to quantify the association of HLA class I and II genes and breast cancer. HLA typing was performed by high resolution sequence-specific oligotyping after DNA amplification (PCR-SSOP) of 100 breast cancer Mexican mestizo patients and 99 matched healthy controls.p = 0.031). HLA-Cw is not a marker neither for risk, nor protection for the disease, because we did not find significant statistical differences between the two groups. DRB1*1301, which is expressed in seven cases and in only one control, observing an risk increase of up to seven times and DRB1*1602, which behaves similarly in being present solely in the cases . DQ*0301-allele expression, which is much more common in the control group and could be protective for the presentation of the disease .HLA-A frequencies that we were able to observe that there was no difference between both groups from the statistical viewpoint. HLA-B*1501 was found three times more common in the case group (OR, 3.714; Our results reveal the role of the MHC genes in the pathophysiology of breast cancer, suggesting that in the development of breast cancer exists a disorder of immune regulation. The triggering factor seems to be restricted to certain ethnic groups and certain geographical regions since the relevant MHC alleles are highly diverse. This is the first study in Mexican population where high resolutions HLA typing has been performed in order to try to establish an association with malignancy. Breast cancer is a common neoplasm around the world with almost 1 million cases diagnosed every year, it is also considered the most frequent malignant neoplasm in developed countries, globally accounts for 18% of all female cancers .Multiple factors are associated with an increase in breast cancer development, including age, family history, exposure to hormones (endo – as well as exogenous), diet, benign mammary disease, and environmental and genetic factors. The majority of these factors moderately increase the risk of developing cancer. It is estimated that at least 50 and up to 80% of women who develop breast cancer do not possess predisposing factors in addition to gender and age .According to Rodríguez-Cuevas et al. , in MexiThis observation is similar to that for Japanese women, in whom 46.5% of women with this disease were aged < 50 years . AccordiOne of the predisposing factors can be genes located within the major histocompatibility complex (MHC) region; the association between human leukocyte antigen (HLA) gene products with a disease does not necessarily reflect the direct involvement of these molecules in the disease process , and becThe HLA system involvement in the development of cancer is poorly understood; nonetheless, it is widely recognized that MHC genetic variations lead to greater susceptibility to neoplasm development . NeoplasThe role of oncogene – and tumor suppressor gene-acquired changes is widely recognized; similarly, there is growing evidence suggesting that the immune system plays a protector role in tumorigenesis ,12. In pIf immunological surveillance is important during tumorigenesis, certain individuals who inherit specific HLA class I alleles, which are highly polymorphic, such as DRB or DQB, can be more susceptible to developing tumors, or contrariwise, more resistant to the growth of these ,14.p = 0.014) due to the disease in patients with negative auxiliary lymph nodes in comparison with patients demonstrating total negativity or positivity, especially after 5 years.In breast cancer, the study of HLA is reduced; the greatest number of studies is conducted on HLA class I expression. These studies have shown that up to 80% of tumors exhibit partial or total loss of HLA class I antigens ,17, whilp = 0.0072) as risk factor. At the same time, the authors concluded that DQB*03032 and DRB1*11 alleles represent resistance factors toward the disease. HLA polymorphisms appear to be responsible for the immune response variations in different individuals to different antigens and can contribute to susceptibility to the disease, specifically to non virus-related tumors, because breast cancer frequency in Mexico is high, thus considered a health problem, and the disease is present in any age group, with the characteristic of presenting at an earlier age than in other countries, and with the evidence that between 50 and 80%  at room temperature for 10 min, and twice at 60°C for 10 min. Dots were revealed using the Dig Nucleic Acid Detection Kit .HLA-A, HLA-B, HLA-C, allele and haplotype frequencies were estimated using the Arlequin program version 2.000 . SignifiAssociation between HLA haplotype and breast cancer was examined using statistical analysis from a 2 × 2 table according to the method described by Svejgaard and Ryder .During the study period, we included 100 patients who fulfilled inclusion and exclusion criteria with a confirmed diagnosis of breast cancer. Similarly, we obtained 99 samples of healthy control subjects.Age of patients with breast cancer ranged from 27 – 82 years ; distribution was normal. Seventy two cases did not present a familiar history of breast cancer, and in 28 cases, there was at least one first-degree family member with this neoplasm type; average age at menarche was 12.8 years. Seventy one percent of women used no family planning method, while use of oral hormones or another hormonal-therapy type was present only in 29 patients; the remainder of patients utilized some other family planning method. History of smoking as a risk factor was present in only 16% of patients.Locally advanced and advanced clinical stages were the most frequent (64%) stages in comparison with early stages. It is noteworthy that in 15% of cases, it was not possible to determine the clinical stage because the patients had been care for previously at another hospital. It was possible to determine tumor size in 89 cases, with an average of 5.2 cm ; in addition, it was possible to determine the distribution of clinical lymph node status in 94 patients, the most frequent lymph node status being N1 with 46 cases, and the second most frequent, N0 with 23 patients, according to the Tumor-Node-Metastasis (TNM) lymph node staging description.As expected due to neoplasm frequency, distribution by histological type obtained 94 cases of infiltrating ductal carcinoma and only six cases of infiltrating lobular carcinoma. Concerning differentiation degree, we found poorly differentiated carcinoma in 56% of cases, while moderately and well differentiated presented in 38 and 6% of cases, respectively. Distribution of differentiation degree with respect to the Scarff-Bloom-Richardson Index exhibited the presence of high-grade tumors in 67% of patients; the hormonal receptors of these tumors were distributed as follows: Positive estrogenic receptors in 54 cases; negative estrogenic receptors in 45 cases; positive pregestational receptors in 29 cases, and negative pregestational receptors in 70 cases. In one case, it was not possible to conduct hormonal receptor determination. Patient clinical characteristics were shown, as well as those of the neoplasms in Table At the moment of performing the present study, 61 patients were found without evidence of disease, while 39 cases presented disease recurrence .Table p = 0.031). After correction for multiple comparisons for the number of alleles of HLA-B locus (n = 17), the risk was not significant (Pc = 0.30).In Table HLA-Cw is a scarcely studied gene in this neoplasm type; we are able to say that at least in this group of women obtained from an ethnically similar population, HLA-Cw is not a marker for, nor a risk for, nor protection for the disease, because we did not find differences between the two groups.In Table Haplotypes were deduced both the results are highly heterogenic (data not show) therefore not conclusions could be drawn or associations performed.The origin of malignant neoplasms is multifactorial ; neverthBreast cancer has exhibited an increase in incidence in recent years, it is the tumor second only to lung cancer as cause of death by cancer in females, and is the number one cause of death by cancer in women 15 – 54 years of age worldwide . In MexiTo date, few studies have been conducted to attempt to determine the association and impact that these represent in the risk of presenting breast cancer and the different HLA, especially HLA class II, and some studies lack sufficient power due to a reduced number of studied cases .p = 0.0019; 95% CI, 1.337 – 3.409; Relative risk [RR], 2.135), explaining that in this geographical zone an environmental agent can be found  that can be associated with breast cancer. Our study reveals a significantly increased frequency of HLA-B*1501 in cancer patients in comparison to healthy controls  but not in other HLA-B alleles.In 2005 Lavado et al. , comparep = 0.02), and the second, found to be a protector. These protective or high risk alleles even though were frequent in our population (HLA-B*40 g.f.= 0.080 and -B*08 g.f. = 0.046) associations were not statistically significant neither for risk not for protection to the development of the neoplasm.Gopalkrishnan et al. , in a grp < 0.0001). These results reflect, at least in the patient group, that inheritance of the alleles of these genes (DQB*03032 and DRB1*11) represent alleles resistant to the presentation of early-age breast cancer.We found HLA-DQB1*0302 to be protective as well as HLA-DQB1*0301 but not associated with age, which is contrary to what was reported by Chaudhuri et al.  in 2000,Positive association of specific HLA class II alleles in any malignant-tumor type reflects the specific role of these molecules in the promotion of chronic inflammation. HLA expression suggests that immune-system evasion of certain cellular populations could be responsible for promoting survival of the neoplasm, thus rendering it necessary to continue evaluating these markers in different populations and to include greater numbers of patients to confirm the different associations and risks between alleles and haplotypes and to determine whether there are others that could be catalogued as risk factors for development of the neoplasm, and at a determined moment whether the fact that some allele, alleles, or haplotypes are found expressed consistently in some group of individuals affords the power to utilize HLA class II typifications as prognostic factors, at the present moment few authors had performed characterization of HLA in latin population, we could say this is the first attempt to characterize a Mexican mestizo population in order to try to find associations between HLA and breast cancer.The results obtained by our group demonstrate the role of genetics in the multifactorial pathophysiology of breast malignant neoplasms. It also reveals the role of the MHC genes in the pathophysiology, suggesting that in the development of breast cancer exists a disorder of immune regulation.Nevertheless, this triggering factor (MHC genes) seems to be restricted to certain ethnic groups as well as certain geographical regions since these relevant MHC alleles are highly diverse and confirms the relevance of HLA-DR alleles in the genetic susceptibility to develop this specific type of malignant disease.HLA: human leukocyte antigen; MHC: Major histocompatibility; ACS: American cancer society; PCR: Polymerase chain reaction;The authors declare that they have no competing interests.DCL: Study design, patient recruitment, article writing. DPM: Data collection, article writing. VV: Patient recruitment, data collection. AGC: Molecular analysis. AMB: Statistic evaluation and data analysis. VAA: Sample analysis. ALT: Molecular analysis. GVA: Sample analysis. RB: Sample analysis. NY: Genetic analysis. EJY: Study design, data analysis. JG: Study design, manuscript evaluation, data analysis. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/9/48/prepub


Vertical and horizontal trust, as dimensions of social capital, may be important determinants of health. As mass media campaigns have been used extensively to promote healthy lifestyles and convey health-related information, high levels of individual trust in the media may facilitate the success of such campaigns and, hence, have a positive influence on health. However, few studies have investigated the relationship between trust levels in mass media, an aspect of vertical trust, and health.Based on cross-sectional data of the general population from the AsiaBarometer Survey (2003–2006), we analyzed the relationship between self-rated health and trust in mass media, using a multilevel logistic model, adjusted for age, gender, marital status, income, education, occupation, horizontal trust, and trust in the healthcare system.In a total of 39082 participants , 26808 (69%) were classified as in good health. By the levels of trust in mass media, there were 6399 (16%) who reported that they trust a lot, 16327 (42%) reporting trust to a degree, 9838 (25%) who do not really trust, 3307 (9%) who do not trust at all, and 191 (0.5%) who have not thought about it. In the multilevel model, trust in mass media was associated with good health : the odds ratios (OR) of 1.16  = 1.05–1.27) for do not really trust; OR of 1.35 (95% CI = 1.23–1.49) for trust to a degree, and 1.57 (95% CI = 1.36–1.81) for trust a lot. Horizontal trust and trust in the healthcare system were also associated with health.Vertical trust in mass media is associated with better health in Asian people. Since mass media is likely an important arena for public health, media trust should be enhanced to make people healthier. Social capital has developed as a concept indicating the quantity and quality of social interactions in the community and has emerged recently as an important determinant of health . A socieAlthough social capital has been assessed as social participation or social trust , recent Social trust reflects the expectation that an individual or institution will act competently, fairly, openly, and with concern , and canPersons with high vertical trust consider public institutions or organizations as trustful social resources and the levels of this vertical trust may vary between societies with the level of social connectedness . For insHowever, little is known about the nature or role of vertical trust in terms of health determinants between other institutions and individuals in society. In addition to the healthcare system, mass media is also considered one of the most important public institutions, and may have a considerable effect on public health through the levels of trust the people have in this institution , and verMass media may function well with respect to improving health, along with relevant aspects of trust. A potential pathway from high trust in mass media to better health is increased acceptance of health-related messages and the resultant dissemination of good behavior related to health throughout communities. For instance, a recent study has shown that improvements in exercise and diet mediated by community-level projects are associated with better mental health . The autIn addition, a recent study has shown that public health agencies, using their communication and marketing resources effectively to support people in making healthful decisions and to foster health-promoting environments, have considerable opportunity to advance public health . Thus, tFurthermore, the links between vertical and horizontal trust are well founded and are positively correlated in an amplifying cycle . Indeed,Despite the importance of examining the relationships between vertical trust in mass media, few studies have addressed these issues. Therefore, in this study, we aim at evaluating the association between distrust in mass media and poor health among Asians, using data from the AsiaBarometer Survey, comprising trans-national and multidimensional surveys conducted throughout Asia.We used data from the AsiaBarometer Survey (2003–2006), which included information on individuals from 29 Asian countries on a vast range of subjects . The couWe used face-to-face interviews to administer structured questionnaires. The detailed content of the questionnaires has been published previously . Data coThe individual-level independent variables included gender, age (range between 20 and 69 years), marital status, religious belief, income, education, employment, and individual-level social trust. Age was categorized into five groups of 20–29, 30–39, 40–49, 50–59, and 60–69 years old. Categories of marital status included single, married, divorced/separated, or widowed.Annual household income was used as an income variable in this study. Categories of the income groups included low, middle, and high, based on the income distribution of each country  for very dissatisfied, somewhat dissatisfied, or neither satisfied nor dissatisfied; and good health (0) for very satisfied, or somewhat satisfied.Horizontal trust, a dimension of cognitive social capital, was measured by a composite index constructed from a factor  score of three questionnaire items related to general trust, interpersonal trust, and mutual help. The general trust question was, "Would you say that most people can be trusted or that you can't be too careful in dealing with people?". The question for interpersonal trust in merit-based utility was, "Would you say that most of the time people try to be helpful or that they are mostly looking out for themselves?". The question for mutual help was, "If you saw somebody on the street looking lost, would you stop to help?". For the last question, the responses were: "I would always stop to help", "I would help if nobody else did", and "It is highly likely I wouldn't stop to help". These questions have been widely used in previous studies to measure cognitive social trust ,5,22,23.Trust in institutions  is an item that reflects the participant's trust in the healthcare system and in mass media (specified as newspapers and television). The item "Please indicate to what extent you trust the following institutions to operate in the best interests of society" offered the alternatives (a) the healthcare system and (b) mass media, with the six alternative responses: (1) "Trust a lot"; (2) "Trust to a degree"; (3) "Don't really trust"; (4) "Don't trust at all"; (5) "Haven't thought about it"; and (6) "I don't know".Descriptive statistics were calculated and presented as the mean with standard deviation or the count number in proportion to the overall sample population where appropriate. Bivariate correlation analyses were conducted among the trust variables using Pearson's correlation coefficients.We used the multilevel (mixed-effects) logistic regression model to analyze the relationship of individual characteristics to self-rated health by considering individuals nested in each country, as data structures in the Asia Barometer Survey were hierarchical multilevels . The data provide information on individuals, while the individuals are also grouped in their countries. Analyzing hierarchical data at the individual level by conventional regression models does not meet the assumption of independence of observations. When ignoring the nesting of individuals in countries, the estimated standard errors would be smaller, thus inflating the risk of Type I errors . The mixThe model was constructed to evaluate the relations of trust in the healthcare system and mass media to self-rated health, adjusted for age, gender, marital status, income, education, occupation, and horizontal trust. We constructed a total of six models, including only baseline sociodemographic variables (base), such as age, gender, marital status, income, education, and occupation (Model 1), base plus horizontal trust (Model 2), base plus trust in the healthcare system (Model 3), base plus trust in mass media (Model 4), base minus income and education plus horizontal trust, trust in the healthcare system and trust in mass media (Model 5), and base plus horizontal trust, trust in the healthcare system and trust in mass media . Model 5 was constructed by eliminating income and education from the full model for examining the possible endogeneity to health of income and education.P-values less than 0.05 were considered statistically significant.No interaction terms were included in the model. To check the robustness of the model, we also conducted the logistic regression analysis including country fixed effects as well as the ordered probit model analysis using original dependent variable . The odds ratios (ORs) along with 95% confidence interval (CIs) were estimated in each variable for poor health. An OR value greater than one indicates greater effects that were positively related to poor health. All statistical analyses were performed using STATA 10.0 . Two-tailed Table In terms of self-rated health, 68.6% considered themselves to be in good health, while 30.9% were in poor health. More than half (55.4%) of the participants were classified as having low horizontal trust Table . For theP < 0.001). For trust in the healthcare system, 22.3% of the participants with good health and 12.8% with poor health reported as "having trust a lot" (P < 0.001). In addition, for trust in mass media, 17.9% of the participants with good health and 12.9% with poor health reported as "having trust a lot" (P < 0.001).For horizontal trust, 37.9% of the participants with good health and 34.8% with poor health had high trust (P < 0.001). The correlation coefficients between horizontal trust and trust in the healthcare system and between horizontal trust and trust in mass media were 0.0159 and 0.0160, respectively (P < 0.001 for both).The correlation coefficient between trust in the healthcare system and trust in mass media was 0.3434 , horizontal trust was associated significantly with good health, with an OR of 1.27 (95% CI = 1.17–1.38). For institutional trust , trust in the healthcare system was associated significantly with good health, with ORs of 1.29 (95% CI = 1.14–1.45) for "don't really trust", 1.75 (95% CI = 1.54–1.99) for "trust to a degree", and, similarly, 2.29 (95% CI = 1.95–2.68) for "trust a lot". Overall, these results indicate a linear relationship between the levels of trust in the healthcare system and the ORs for good health  trust in the healthcare system and health. Further, significant sociodemographic determinants for health include younger age, male gender, marital status, high income, and high education.Although the current study has inferential limitations for causal direction due to the cross-sectional study design, the interpretation could be made that the levels of trust in mass media may be able to influence the individual's health status. Enhancement of trust in mass media among the general population could be utilized to promote people's health.Regarding causal pathways for how trust in mass media operates to influence health, the following mechanism can be considered: greater media trust may lead to higher use of mass media for health information; this in turn may lead to higher awareness of important health information and may result in better health-related decision-making and behavior. Alternatively, media trust could reflect higher credibility of public information on health issues, and may lead to greater dissemination of accurate health information, which may, in turn, lead to better health-related behavior. However, since there may be intermediate variables that underlie the relationship between media trust and health, further studies are needed to explore these causal mechanisms.Mass media can have beneficial effects on people's health through conveying useful information related to health by various approaches, such as educational campaigns, series programs, and advertisements. In particular, mass media campaigns can have beneficial effects on public health, because mass media, particularly newspaper and television, can reach population-wide consumers throughout Asian countries. Given the widespread influence of mass media, well-designed mass media campaigns can have beneficial effects not only on health knowledge and attitudes, but also on health behaviors, with a potentially huge public health impact .TV advertisements can increase public knowledge and awareness of the important symptoms of various diseases. For instance, TV delivery of information regarding the early warning symptoms of stroke increases the number of presentations to the emergency department during the early stages of stroke, providing increased opportunity to receive potentially life-saving thrombolytic therapies that are only indicated during the early stage ,27. A USDespite increased interest in obtaining health information by the public, a significant proportion of those diagnosed with a serious disease, such as cancer, report that they do not seek health information beyond that given by healthcare providers. One study, based on a national survey of American adults, demonstrated that compared with information-seeking groups, non-seeker patients showed low trust in mass media and paid less attention to health information in mass media . Thus, tThere are several strengths of our study. This may be one of the first studies to suggest a significant association between trust in mass media and health. Second, our results are based on the multilevel and multivariable model adjusted for potential confounders, such as demographic and socioeconomic factors. In evaluating the relationship between trust and well-being, these factors should be adjusted for to avoid confounding effects. Individuals with higher socioeconomic status may perceive their societies as being friendly and may have high trust in most public institutions, compared with those with a lower socioeconomic status . FurtherThird, we assessed the potential association between sociodemographic factors and health after accounting for horizontal and vertical trust. The results of our study confirmed previous reports that found several factors for good health: including younger age, marital status, high income, high education, horizontal trust, and trust in the healthcare system ,6,41. InOur study is based on the analysis of cross-sectional data and thus it has inferential limitations. It is possible that poor health leads to social isolation and distrust in any institutions due to psychosocial mechanisms. In addition, health and trust may reflect different facets of a common underlying psychological construct of general well-being. Alternatively, media trust might act as a surrogate marker for other types of output vertical trust, economic development or income equity in a country, or it might approximate the political systems, such as democracy, freedom of the press, and multi-ethnic cohesion. These parameters are known to be related to health status. Another limitation of our study was the use of the self-reported health satisfaction measure. It would have been more accurate to obtain more explicit self-reported health dimensions, such as those from the SF-36, although these data were not available in the AsiaBarometer Survey. Finally, our study has both cross-sectional causality problems and the absence of objective measures of physical health . Future In summary, this study is the first to analyze the relationship between high institutional trust in mass media and good health. These results indicate that individuals with high trust in mass media have better health. Mass media programs may contribute towards better health, especially among those people who have trust in mass media. Mass media may need to recognize the importance of their social role in terms of public health. Further research is necessary to determine the characteristics of high-quality mass media with high trust among the public.The authors declare that they have no competing interests.YT was involved in the analysis and interpretation of data, critical revision of the manuscript for important intellectual content, statistical analysis, and also had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. SF was involved in the acquisition, analysis, and interpretation of data and critical revision of the manuscript for important intellectual content. MJ was involved in interpretation of data and critical revision of the manuscript for important intellectual content. TI was responsible for the study concept and design, obtaining funds, administrative, technical, and material support, and study supervision, and was also involved in the acquisition, analysis, and interpretation of data and critical revision of the manuscript for important intellectual content.The pre-publication history for this paper can be accessed here:Appendix A and Appendix BClick here for file