Sensitization with Fungal Protease Allergen Establishes Long-Lived, Allergenic Th Cell Memory in the Lung.

Allergic asthma is a chronic inflammatory disease that affects millions of individuals worldwide. Exposure to allergens produced by a variety of otherwise harmless microbes, including fungi, predisposes individuals to immunopathologic disease upon subsequent encounters with allergen. We developed a mouse model that employs a purified protease produced by Aspergillus (Asp f 13) to investigate the contributions of CD4+ Th cells to recurrent lung inflammation. Notably, memory CD4+ T cells enhanced the eosinophil response of sensitized/rechallenged animals. In addition, memory CD4+ T cells maintained allergenic features, including expression of GATA-binding protein 3 and IL-5. Th2 memory T cells persisted in the peribronchiolar interstitium of the lung and expressed markers of tissue residence, such as CD69, CCR8, and IL-33R. Lastly, we identified a peptide epitope contained within Asp f 13 and generated a peptide-MHC class II tetramer. Using these tools, we further demonstrated the durability and exquisite sensitivity of memory T cells in promoting lung eosinophilia. Our data highlight important features of memory T cells that strengthen the notion that memory T cells are principal drivers of eosinophilic disease in murine models of allergic sensitization and episodic airway inflammation.

The application of six dietary scores to a Middle Eastern population: a comparative analysis of mortality in a prospective study.

Background The associations between dietary indices and mortality have not been evaluated in populations from the Middle East, which have different dietary patterns compared to the US and Europe. In this study, we evaluated the association between six dietary indices and mortality in the Golestan Cohort Study (GCS) in Iran, which is the largest prospective study in the Middle East with 50,045 participants. Methods The six dietary indices, namely the Healthy Eating Index (HEI-2015), Alternative Healthy Eating Index (AHEI-2010), Alternative Mediterranean Diet (AMED), Dietary Approach to Stop Hypertension created by Fung (DASH-Fung) and Mellen (DASH-Mellen), and the World Cancer Research Fund (WCRF/AICR) index, were applied to data from a food frequency questionnaire, computed and divided into quintiles. Adjusted Cox models were used to estimate hazards ratio (HR) and 95% confidence intervals (CI) for overall and cause-specific mortality, using the lowest quintile as a reference group. Results Among 42,373 participants included in the current analyses, 4424 subjects died during 10.6 years of follow-up. Participants with the highest quintile dietary scores, compared with the lowest quintile dietary scores, had significantly decreased overall mortality in the AHEI-2010, AMED, DASH-Fung, and WCRF/AICR indices (HR 0.88, 95% CI = 0.80-0.97; 0.80, 0.70-0.91; 0.77, 0.70-0.86; and 0.79, 0.70-0.90, respectively). A reduced cardiovascular mortality was found for high AHEI-2010 and DASH-Fung scores (17% and 23%, respectively), and a reduced cancer mortality for high HEI-2015, AMED, and DASH-Fung scores (21, 37 and 25%, respectively). Conclusion Various indices of dietary quality are inversely associated with overall mortality, and selectively with cancer and cardiovascular mortality in the GCS, which contribute to the generalizability and validity of dietary guidelines.

Turmeric, Pepper, Cinnamon, and Saffron Consumption and Mortality.

Background Previous studies have reported the beneficial effects of spice consumption on lipid profiles, fasting glucose, and blood pressure, which suggests that spice consumption could affect the risk of cardiovascular disease, diabetes mellitus, and consequently mortality. The objective of this study was to evaluate the relationship between consumption of turmeric, black or chili pepper, cinnamon, and saffron with overall and cause-specific mortality in an adult population in Iran. Methods and Results We used data from the Golestan Cohort Study, which has followed 50 045 participants aged 40 to 75 years from baseline (2004-2008). After establishing the exclusion criteria, 44 398 participants were included in the analyses. Spice consumption data were extracted from the baseline Food Frequency Questionnaire. Cox models were used to estimate hazard ratios (HR) and 95% CI for overall and cause-specific mortality, comparing the ever consumers to the never consumers as a reference group for each type of spice (adjusted for known and suspected confounders). During 11 years of follow-up, 5121 people died. Turmeric consumption was associated with significantly reduced risk of overall mortality (HR=0.90, 95% CI=0.85-0.96) and cardiovascular mortality (HR=0.91, 95% CI=0.82-0.99). Black or chili pepper consumption was associated with significantly reduced risk of overall mortality (HR=0.91, 95% CI=0.86-0.98). Saffron consumption was associated with significantly reduced risk of overall (HR=0.85, 95% CI=0.77-0.94) and cardiovascular mortality (HR=0.79, 95% CI=0.68-0.92). We found no associations with cinnamon consumption or between any of these spices and cancer mortality. Conclusions Consuming turmeric or saffron was associated with decreased risk of overall and cardiovascular mortality. The hypothesis of a protective effect of spice consumption on mortality should be tested in other prospective studies.

Nut consumption and the risk of oesophageal squamous cell carcinoma in the Golestan Cohort Study.

BACKGROUND: Nut consumption has been inversely associated with gastric cancer incidence in US-based studies, but not with oesophageal cancer. However, there is aetiologic heterogeneity, among oesophageal squamous cell carcinoma (ESCC) cases in low-risk vs. high-risk populations. The objective of this study was to evaluate the association between nut consumption and risk of ESCC in a high-risk population. METHODS: The Golestan Cohort Study enroled 50,045 participants in Northeastern Iran, between 2004 and 2008. Intake of peanuts, walnuts and mixed nuts (including seeds) were assessed using a validated food frequency questionnaire at baseline. Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals for subsequent ESCC adjusted for potential confounders. Non-consumers of nuts were used as the reference category and the consumers were categorised into tertiles. RESULTS: We accrued 280 incident ESCC cases during 337,983 person-years of follow up. Individuals in the highest tertiles of total nut consumption, and mixed nut consumption were significantly associated with lower risk of developing ESCC compared to non-consumers (HR = 0.60, 95% CI = 0.39-0.93, p-trend = 0.02, and HR = 0.52, 95% CI = 0.32-0.84, p trend = 0.002, respectively). CONCLUSIONS: We found a statistically significant inverse association between total nut consumption and the risk of ESCC in this high-risk population.

Toenail mineral concentration and risk of esophageal squamous cell carcinoma, results from the Golestan Cohort Study.

Studies conducted in China linked selenium deficiency to higher risk of esophageal squamous cell carcinoma (ESCC), but this has not been widely tested outside that selenium-deficient region. The aim of this study was to investigate the association between selenium and other mineral concentrations in toenails and risk of ESCC in a region with high incidence rates. In this nested case-control study, we identified 222 cases of ESCC from the Golestan Cohort Study, Iran, which has followed up 50,045 participants since enrollment (2004-2008). We randomly selected one control for each case matched by age and sex, using incidence density sampling. We used toenail samples collected at baseline to measure the concentration of selenium, zinc, chromium, mercury, and scandium using instrumental neutron activation analysis. Multivariate adjusted logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals. Median nail selenium, zinc, chromium, and mercury levels were 1.01, 74.59, 0.77, and 0.018 µg/g in cases and 1.02, 75.71, 0.71, and 0.023 µg/g in controls, respectively. The adjusted odds ratios comparing each fourth quartile of mineral status versus the first quartile were as follows: selenium = 0.78 (95% CI, 0.41-1.49); zinc=0.80 (95% CI, 0.42-1.53); chromium = 0.91 (95% CI, 0.46-1.80); and mercury=0.61 (95% CI, 0.27-1.38), and all trend tests were non-significant. The nail selenium concentration in our controls reflects relatively high selenium status. No evidence of association between selenium or chromium concentrations in toenails and the risk of ESCC was detected in this population.

Oral health and mortality in the Golestan Cohort Study.

Background: Previous studies have found associations between oral health and mortality, but the majority of previous studies have been conducted in high-income countries. Methods: We used data from the Golestan Cohort Study, a study of 50 045 people aged 40 to 75 years in north eastern Iran, recruited from January 2004 to June 2008. Tooth loss and decayed, missing and filled teeth (DMFT) were assessed by trained physicians. Frequency of tooth brushing and use of dentures were self-reported. Cause-specific mortality was ascertained through March 2014. We calculated hazard ratios (HRs) and 95% confidence intervals (95% CIs) for the associations between the oral health variables, overall mortality and cause-specific mortality. Results: Participants with the greatest tooth loss had increased overall mortality (HR 1.43; 95% CI: 1.28, 1.61) compared with those with the least tooth loss; similar estimates were observed for DMFT score. For cause-specific mortality, an increased risk of death was found for tooth loss and mortality from cardiovascular disease (HR 1.33; 95% CI: 1.13, 1.56), cancer (HR 1.30; 95% CI: 1.03, 1.65) and injuries (HR 1.99; 95% CI: 1.28, 3.09). The associations between oral health and injury mortality were strongly attenuated after exclusion of participants with comorbid conditions at baseline. No statistical interaction was found between denture use and tooth loss or DMFT on mortality. Conclusions: Poor oral health appears to predict overall and cause-specific mortality in populations in economic transition. Investigation of the underlying mechanisms might provide an important contribution to reducing mortality.

Dietary intake of minerals and risk of esophageal squamous cell carcinoma: results from the Golestan Cohort Study.

BACKGROUND: Dietary factors have been hypothesized to affect the risk of esophageal cancer via different mechanisms, but the intake of minerals is understudied and the evidence is conflicting. OBJECTIVE: The objective was to evaluate the associations of dietary intake of minerals with risk of esophageal squamous cell carcinoma (ESCC). DESIGN: We used data from the Golestan Cohort Study, which was launched in a high-risk region for esophageal cancer in Iran. Participants were enrolled in 2004-2008 and were followed to 2014. Intakes of minerals were assessed with a validated food-frequency questionnaire. A Cox proportional hazards model was used to estimate HRs and 95% CIs of ESCC for dietary intakes of selected minerals. RESULTS: We identified 201 ESCC cases among 47,405 subjects. Calcium intake was significantly inversely associated with the risk of ESCC (HR per 100-mg/d increase: 0.88; 95% CI: 0.81, 0.96; P = 0.005; quartile 4 vs. quartile 1 HR: 0.49; 95% CI: 0.29, 0.82; P-trend = 0.013). Zinc intake was also inversely associated with ESCC, but the quartile association did not reach significance (HR per 1-mg/d increase: 0.87; 95% CI: 0.77, 0.98; P = 0.027; quartile 4 vs. quartile 1 HR: 0.56; 95% CI: 0.28, 1.12; P-trend = 0.097). The relations between dietary intakes of selenium, magnesium, and copper and risk of ESCC were nonlinear (P-nonlinear trend = 0.001, 0.016, and 0.029, respectively). There was no relation between dietary intake of manganese and the risk of ESCC. CONCLUSION: The results suggest that higher intakes of calcium and zinc are associated with a lower risk of ESCC in a high-risk region of Iran.

Circulating biomarkers of tryptophan and the kynurenine pathway and lung cancer risk.

BACKGROUND: Imbalances in tryptophan metabolism have been linked to cancer-related immune escape and implicated in several cancers, including lung cancer. METHODS: We conducted a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) that included 893 incident lung cancer cases and 1,748 matched controls. Circulating levels of tryptophan and six of its metabolites were measured and evaluated in relation to lung cancer risk. RESULTS: Tryptophan (Ptrend = 2 × 10(-5)) and the kynurenine/tryptophan ratio (KTR; Ptrend = 4 × 10(-5)) were associated with lung cancer risk overall after adjusting for established risk factors. The ORs comparing the fifth and first quintiles (OR5th vs. 1st) were 0.52 [95% confidence interval (CI), 0.37-0.74] for tryptophan and 1.74 (95% CI, 1.24-2.45) for KTR. After adjusting for plasma methionine (available from previous work, which was strongly correlated with tryptophan), the associations of tryptophan (adjusted Ptrend = 0.13) and KTR (Ptrend = 0.009) were substantially attenuated. KTR was positively associated with squamous cell carcinoma, the OR5th vs. 1st being 2.83 (95% CI, 1.62-4.94, Ptrend = 3 × 10(-5)) that was only marginally affected by adjusting for methionine. CONCLUSIONS: This study indicates that biomarkers of tryptophan metabolism are associated with subsequent lung cancer risk. Although this result would seem consistent with the immune system having a role in lung cancer development, the overall associations were dependent on methionine, and further studies are warranted to further elucidate the importance of these metabolites in lung cancer etiology. IMPACT: This is the first prospective study investigating the tryptophan pathway in relation to lung cancer risk.

Diabetes mellitus and its correlates in an Iranian adult population.

The rising epidemic of diabetes imposes a substantial economic burden on the Middle East. Using baseline data from a population based cohort study, we aimed to identify the correlates of diabetes mellitus (DM) in a mainly rural population from Iran. Between 2004 and 2007, 50044 adults between 30 and 87 years old from Golestan Province located in Northeast Iran were enrolled in the Golestan Cohort Study. Demographic and health-related information was collected using questionnaires. Individuals' body sizes at ages 15 and 30 were assessed by validated pictograms ranging from 1 (very lean) to 7 in men and 9 in women. DM diagnosis was based on the self-report of a physician's diagnosis. The accuracy of self-reported DM was evaluated in a subcohort of 3811 individuals using fasting plasma glucose level and medical records. Poisson regression with robust variance estimator was used to estimate prevalence ratios (PR's). The prevalence of self-reported DM standardized to the national and world population was 5.7% and 6.2%, respectively. Self-reported DM had 61.5% sensitivity and 97.6% specificity. Socioeconomic status was inversely associated with DM prevalence. Green tea and opium consumption increased the prevalence of DM. Obesity at all ages and extreme leanness in childhood increased diabetes prevalence. Being obese throughout life doubled DM prevalence in women (PR: 2.1; 95% CI: 1.8, 2.4). These findings emphasize the importance of improving DM awareness, improving general living conditions, and early lifestyle modifications in diabetes prevention.

Alcohol-related cancers and genetic susceptibility in Europe: the ARCAGE project: study samples and data collection.

Cancers of the upper aerodigestive tract (UADT) include those of the oral cavity, pharynx (other than nasopharynx), larynx, and esophagus. Tobacco smoking and consumption of alcoholic beverages are established causes of UADT cancers, whereas reduced intake of vegetables and fruits are likely causes. The role of genetic predisposition and possible interactions of genetic with exogenous factors, however, have not been adequately studied. Moreover, the role of pattern of smoking and drinking, as well as the exact nature of the implicated dietary variables, has not been clarified. To address these issues, the International Agency for Research on Cancer initiated in 2002 the alcohol-related cancers and genetic susceptibility (ARCAGE) in Europe project, with the participation of 15 centers in 11 European countries. Information and biological data from a total of 2304 cases and 2227 controls have been collected and will be used in a series of analyses. A total of 166 single nucleotide polymorphisms of 76 genes are being studied for genetic associations with UADT cancers. We report here the methodology of the ARCAGE project, main demographic and lifestyle characteristics of the cases and controls, as well as the distribution of cases by histology and subsite. About 80% of cases were males and fewer than 20% of all cases occurred before the age of 50 years. Overall, the most common subsite was larynx, followed by oral cavity, oropharynx, esophagus and hypopharynx. Close to 90% of UADT cancers were squamous cell carcinomas. A clear preponderance of smokers and alcohol drinkers among UADT cases compared with controls was observed.

Prehospital electrocardiogram and early helicopter dispatch to expedite interfacility transfer for percutaneous coronary intervention.

Care provision and benchmarking for patients with ST-elevation myocardial infarction (STEMI) have focused on streamlining time between initial hospital presentation and opening of theinfarct-related artery. In a Boston-area regional system already characterized by expedited advanced life support (ALS) dispatch and paramedic performance of prehospital electrocardiogram (EKG), a critical pathway was designed that allows for helicopter dispatch based on ground ALS providers' STEMI diagnosis. The pathway dictates that as soon as ALS crews make the diagnosis of STEMI from their 12-lead EKG, they will contact Boston MedFlight (BMF) and a helicopter will be immediately dispatched to the participating community hospital (Lawrence General Hospital [LGH]). Based on historical and predicted time patterns, it is expected that BMF will arrive at LGH soon after the ALS ambulance delivers the patient to the LGH emergency department (ED). The patient will then undergo BMF transport from the ED into central Boston with direct transfer into an awaiting cardiac catheterization suite (ie, bypassing the receiving hospital ED). The pathway minimizes the delay between patient arrival at LGH and BMF arrival for transport to the catheterization laboratory. It is hoped that implementation of the critical pathway will allow the region's patients with STEMI to achieve coronary arterial patency within 90 minutes of LGH presentation. If the pathway proves effective, it can serve as a model for other regions and programs with similar clinical and logistic situations and advance the concept of "diagnosis-to-balloon" time.