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Abstract Aims: In regard to increasing greenhouse area in Iran followed by increased use of pesticides and contaminated crops, this study aimed to determine the frequency and types of consumed pesticides in Kashan region, Iran, greenhouses. Instrument & Methods: In this descriptive study in 2011-2012, samples was entered by census method. At the first step, a list of greenhouses was obtained from agricultural organization, 39 active greenhouses were detected, thereafter the questionnaires have been completed in detail by direct interview; obtained data were analyzed in SPSS 23 by descriptive statistics. Findings: 87.1% of greenhouses used chemical methods for controlling pest and diseases of products and 43.5% used non-chemical methods. The most frequent used chemical pesticides were Deltamethrin (37.9%) and Permethrin (28.3%) as pyrethroid insecticides, Diazinon (23.1%) as an organophosphate insecticide and Carbendazim (23.2%) as a fungicides. Conclusion: 87.1% of the greenhouses’ owners of Kashan region, Iran, use chemical pesticide for pest control.

We studied fertility indices of Iranian and non-Iranian populations which were covered by 23 Rays health houses. This cross-sectional study aimed to prove the effect of increasing number of non-Iranian immigrants on health indices of the area covered by Tehran university of medical sciences and health services, consequently giving attention to specific health programs. The data collection method was census of permanent residents of the villages by means of vital horoscopes. 8494 of 27611 persons were non-Iranian. Dependency ratio and natural growth rate was 75%, 1.14% in Iranians and 98%, 1.74% in non-Iranians, respectively. Mortality in non-Iranians was 1.24 times more than Iranians. General fertility rate in Iranians was 60 and in non-Iranians was 110 live births in 1000 women of child bearing age. Total fertility rate in Iranians was 1.73 and in non-Iranians 3.27 neonates for each woman. Age-specific fertility rates were absolutely higher in non-Iranians. Gross eproductive rate was 0.87 in Iranians and 1.59 in non-Iranians. Mean number of girls born by a non-Iranian mother will be double times of an Iranian mother (P

Previous studies have reported inconsistent findings regarding paternal addiction to cigarettes, alcohol, and opium with psychological distress in youths. This study examined the association between paternal addiction to cigarettes, alcohol, and opium and the psychological distress of youths in southeast Iran. This cross-sectional study was conducted on 895 youths (aged 15-35) from the baseline phase of the Rafsanjan Youth Cohort Study (RYCS) whose fathers also participated in the Rafsanjan Cohort Study (RCS). The RYCS is a part of the RCS, a branch of prospective epidemiological research studies in Iran (PERSIAN). Smoking, alcohol consumption, and opium usage in youths and their fathers were assessed using a self-reported questionnaire. Psychological distress was assessed using the Kessler Psychological Distress Scale (K6 and K10). Fathers who used opium were more likely to have youth with psychological distress based on the K6 score (OR:1.37, CI:1.01-1.86) and K10 score (OR:1.34, CI: 1.01-1.80). The duration of opium consumption lower than or equal to the median was associated with increased odds of having a youth with psychological distress based on the K6 or K10 scores (OR:1.62, CI:1.14-2.31, OR:1.44, CI:1.01-2.03 respectively), but there was no significant association with duration above the median. In addition, consuming opium more than the median dosage increased the chance of having a psychologically distressed youth up to 1.47 times based on the K6 score (OR 1.47, CI 1.01-2.14) and 1.55 times based on the K10 score (OR 1.55, CI:1.08-2.22). Smoking cigarette duration lower than or equal to the median increased the chance of having a psychologically distressed youth to 1.52 times more based on the K6 score (OR 1.52, CI 1.07-2.15). There was no significant association between paternal alcohol consumption and the odds of having a psychologically distressed youth. Parental addiction to opium can lead to an increase in psychological distress in youths in the absence however of a consistent dose and duration relationship., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: Written informed consent was obtained from the participants. The ethics committee of Rafsanjan University of Medical Sciences (IR.RUMS.REC.1401.252) approved this study. All methods were carried out in accordance with relevant guidelines and regulations. Interviews, measurements, and physical examinations were done according to the PERSIAN cohort protocol. Questionnaires were validated in the PERSIAN cohort study., (© 2024. The Author(s).)

Birt-Hogg-Dubé (BHD) syndrome patients are uniquely susceptible to all renal tumour subtypes. The underlying mechanism of carcinogenesis is unclear. To study cancer development in BHD, we used human proximal kidney (HK2) cells and found that long-term folliculin (FLCN) knockdown was required to increase their tumorigenic potential, forming larger spheroids in non-adherent conditions. Transcriptomic and proteomic analysis uncovered links between FLCN, cell cycle control and the DNA damage response (DDR) machinery. HK2 cells lacking FLCN had an altered transcriptome profile with cell cycle control gene enrichment. G 1 /S cell cycle checkpoint signaling was compromised with heightened protein levels of cyclin D1 (CCND1) and hyperphosphorylation of retinoblastoma 1 (RB1). A FLCN interactome screen uncovered FLCN binding to DNA-dependent protein kinase (DNA-PK). This novel interaction was reversed in an irradiation-responsive manner. Knockdown of FLCN in HK2 cells caused a marked elevation of γH2AX and RB1 phosphorylation. Both CCND1 and RB1 phosphorylation remained raised during DNA damage, showing an association with defective cell cycle control with FLCN knockdown. Furthermore, Flcn-knockdown C. elegans were defective in cell cycle arrest by DNA damage. This work implicates that long-term FLCN loss and associated cell cycle defects in BHD patients could contribute to their increased risk of cancer., Competing Interests: The authors declare no competing financial interests. While this study is part-funded by Health and Care Research Wales, the views expressed are those of the author/s and not necessarily those of Health and Care Research Wales or Welsh Government.

The association between personal habits and metabolic syndrome (MetS) remains controversial. This study aimed to assess the prevalence of MetS among youths and its association with cigarette, tobacco, opium, and alcohol consumption in the Rafsanjan Youth Cohort Study (RYCS). The current cross-sectional study was based on data from RYCS, as part of the Rafsanjan Cohort Study (RCS). RCS is a branch of the prospective epidemiological research studies in Iran (PERSIAN). In the present study, 2843 youths aged 15-35 were included. MetS was diagnosed using the international diabetes federation (International IDF), National Cholesterol Education Panel- Adult Treatment Panel III (NCEP-ATPIII), and Iranian criteria (IDF Iranian). Binary logistic regression models were performed to estimate odds ratios (ORs) and confidence intervals (CIs). The prevalence of MetS was 7.67%, 7.14%, and 10.13% based on NCEP-ATPIII, IDF Iranian, and International IDF criteria respectively. The odds of MetS according to international IDF and Iranian IDF in the alcohol-drinking group in the last 12 months (OR: 1.51, 95%CI 1.02-2.21, OR: 1.66, 95%CI 1.11-2.48 respectively) were greater compared with the non-drinking group. The odds of having high TG in the alcohol-drinking group in the last 12 months was 1.53 times higher than the control group (OR = 1.53, 95% CI: 1.20-1.94). Furthermore, the odds of having high waist circumference (WC) according to IDF International was significantly higher in the tobacco-smoking group in the last 12 months and in the tobacco-smoking group in the last 12 months daily (OR: 1.23, 95%CI 1.01-1.49 and OR: 1.41, 95%CI 1.01-1.98 respectively) compared to the control groups. The prevalence of MetS was 7.67%, 7.14%, and 10.13% based on NCEP-ATPIII, IDF Iranian, and International IDF criteria respectively. The odds of MetS and high TG were greater in the alcohol-drinking group in the last 12 months compared with the non-drinking group. The odds of high WC in the last 12 months, were greater in the tobacco-smoking group compared with the non-smoking group. However, more longitudinal studies are needed to verify the associations observed in the current study., (© 2024. The Author(s).)

Hypothyroidism has been linked to reduced mortality rate and increased lifespan and health span. Telomere shortening, enhanced oxidative stress, and reduced cellular mitochondrial content are important hallmarks of aging shown to be related to age-associated diseases. It was proposed that the status of these markers in early life can be predictive of lifespan and the predisposition to certain age-associated disease in adulthood. Animal studies indicated that prenatal injection of thyroid hormones affects postnatal telomere length. Here, we sought to determine whether thyroid hormones TSH and fT4 are related to the telomere length, mitochondrial DNA copy number (mtDNAcn), and oxidative stress resistance marker GPX in the cord blood of newborns. In this study, we analyzed 70 mothers (18-42 years) and neonate dyads born in 2022 at the Nik Nafs maternity Hospital in Rafsanjan. The relative telomere length (RTL) and mtDNAcn were measured in the genomic DNA of cord blood leukocytes using real-time PCR. GPX enzyme activity was measured in the serum using colorimetric assays. In this study the correlation between these markers and the cord blood TSH and fT4 hormones were assessed using regression models. We found a reverse relationship between TSH levels and RTL in the cord blood of neonates. Additionally, our results displayed increased TSH levels associated with enhanced GPX activity. Regarding the mitochondrial DNA copy number, we found an indirect relationship between fT4 level and mtDNAcn only in male newborns. Future analyses of various oxidative stress markers, mitochondrial biogenesis status, telomerase activity, and the level of DNA damage are warranted to demonstrate the underlying mechanism of our observations., (© 2024. The Author(s).)

Background: Gastric cancer (GC) is known as the fourth leading cause of cancer-related death and the fifth major cancer in the world, and this is a serious threat to general health all over the world. The lack of early detection markers results in a belated diagnosis, i.e. the final stages, which could be associated with the ineffectiveness of the treatment strategies, and naturally, it leads to poor prognosis. Even though a variety of treatments have been developed, there is a trend of studying traditional medicinal plants, due to the worrying side effect of drugs available in the market., Methods: In this study, pharmacophore generation and 3D-QSAR model were created using 50 compounds with anti-gastric cancer activity (with IC 50 had been reported in the previous studies)., Results: Based on three of the best pharmacophoric hypotheses, virtual screening was performed to discover the top anti-gastric cancer compounds from a database of 183,885 compounds. The selected compounds were used for molecular docking with three protein receptors 7BKG, 4F5B, and 4ZT1 to investigate the intermolecular interactions between these ligands and receptors. Finally, 21 lead compounds with the highest amount of docking score ranging from - 13.366 to -6.404 kcal/mol were selected, and then the ADME/Tox properties of these compounds were calculated. All these compounds have a fitness score above 1.8, a molecular weight of less than 500 g/mol, hydrogen bond donors up to 3, hydrogen bond acceptors up to 8.50, and logP of 1.013 to 4.174. Finally, molecular dynamic simulations for top-scoring ligand-receptor complexes were investigated., Conclusion: These selected lead compounds have the most anti-gastric cancer effects among the 183,885 compounds in the database. Therefore, lead compounds might be considered for gastric cancer therapy in future studies., (© 2023. The Author(s), under exclusive licence to Tehran University of Medical Sciences.)

Oral health status can be affected by some factors including drug abuse, systemic conditions and environmental pollutants. The present study was designed to investigate the most important and prevalent dental and oral conditions in adult population of Rafsanjan with the age of 35-70 years. Dental and oral health cohort center as part of the Rafsanjan Cohort Study (RCS) included in the prospective epidemiological research studies in IrAN was established in 2015. Of 9991 subjects enrolled in the RCS, 8682 people participated in the Oral Health Branch of Rafsanjan Cohort Study (OHBRCS). The OHBRCS included 4021 men and 4661 women with the mean age of 49.94 ± 9.51. The most prevalent of oral lesion in total population was candidiasis and the least was aphthous lesion. The prevalence of candidiasis, white and red lesions, periodontal pocket, dental calculus, CAL and the mean of DMFT were higher in the male group than that of female group (p < 0.05). Candidiasis, herpes, oral cancer, white and red lesions were more prevalent in the older age groups (p < 0.05). The mean of DMFT index in total population was 21.30 and was higher among opium users, men and older age (p < 0.05). Also, the opium users had a higher rate of CAL, periodontal pocket, red and white lesions, and candidiasis but a lower rate of BOP (p < 0.05). Younger people had more decayed and filling teeth compared to other age groups, whereas older people had more missing teeth and a higher DMFT index (p < 0.001)., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Interleukin 27 has both pro-inflammatory and anti-inflammatory properties in autoimmunity. The anti-inflammatory effects of IL-27 are linked with inhibition of Th17 differentiation but the IL-27 effect on myeloid cells is less studied. Herein we demonstrate that IL-27 inhibits IL-23-induced inflammation associated not only with Th17 cells but also with myeloid cell infiltration in the joints and splenic myeloid populations of CD11b + GR1 + and CD3 - CD11b + CD11c - GR1 - cells. The IL-27 anti-inflammatory response was associated with reduced levels of myeloid cells in the spleen and bone marrow. Overall, our data demonstrate that IL-27 has an immunosuppressive role that affects IL-23-dependent myelopoiesis in the bone marrow and its progression to inflammatory arthritis and plays a crucial role in controlling IL-23 driven joint inflammation by negatively regulating the expansion of myeloid cell subsets., Competing Interests: Declaration of Competing Interest The authors have no financial conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Chronic administration of d-galactose (d-gal) in rodents reproduces the overproduction of reactive oxygen species of physiological aging. The present research shows for the first time distinct signatures on d-gal-induced aging (500 mg/kg, 6 weeks) and the preventive and protective potential of two vitamin D (50 IU) supplementation regimens (pre-induction and simultaneous, respectively) in two vital organs (heart and brain). d-gal-induced notorious alterations in working memory, a strong increase in brain malondialdehyde (MDA) oxidative levels, and strong downregulation of sirtuin 1 (SIRT1) in the heart and hippocampus and of calstabin2 in the heart. Cardiac and brain superoxide dismutase (SOD) and glutathione peroxidase (GPx) enzymatic antioxidant capacities were damaged, brain calstabin2 was downregulated, and neuropathology was observed. Heart damage also included a moderate increase in MDA levels, serologic lactate dehydrogenase (LDH), total creatine kinase (CK) activities, and histopathological alterations. The used dose of vitamin D was enough to prevent cognitive impairment, avoid muscular damage, hamper cardiac and cerebral oxidative stress, and SIRT1 and calstabin2 downregulation. Most importantly, the potencies of the two preventive schedules depended on the tissue and level of study. The pre-induction schedule prevented d-gal-induced aging by 1 order of magnitude higher than simultaneous administration in all the variables studied except for SIRT1, whose strong downregulation induced by d-gal was equally prevented by both schedules. The benefits of vitamin D for oxidative stress were stronger in the brain than in the heart. Brain MDA levels were more sensitive to damage, while SOD and GPx antioxidant enzymatic activities were in the heart. In this order, the magnitude of SOD, MDA, and GPx oxidative stress markers was sensitive to prevention. In summary, the results unveiled distinct aging induction, preventive signatures, and sensitivity of markers depending on different levels of study and tissues, which are relevant from a mechanistic view and in the design of targeted interventions., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors. Food Science & Nutrition published by Wiley Periodicals LLC.)

Background: Obesity has become a major health issue in both high and middle-income countries, increasing the risk of cardiovascular diseases and all-cause mortality. Risk of obesity is related to both unchangeable factors such as genetics and gender, and modifiable lifestyle factors. Most importantly, finding the major modifiable lifestyle factors which contribute to obesity may provide valuable benefits to every society. This study aimed to determine the association of demographic and lifestyle parameters with overweight/obesity and abdominal obesity in a population of Iranian adults., Methods: In this cross-sectional study, adult participants of Rafsanjan Cohort Study (RCS) (as one of the district areas of the PERSIAN cohort (Prospective Epidemiological Research Studies in IrAN) included the study population. RCS is a population-based prospective cohort of men and women aged 35-70 years, launched in August 2015. Individuals were recruited from four urban and suburban areas of Rafsanjan, south-eastern of Iran. Trained experts interviewed each participant and completed the related questionnaires about his/her socioeconomic status, demography, anthropometric features, personal habits, physical activity and medical history. Multinomial logistic regression models were used to examine the relationships between overweight/obesity/abdominal obesity and associated factors., Results: From 9980 participants, 1974 (42.42%) males and 2115 (39.70%) females were overweight, 784 (16.85%) males, 2223 (41.73%) females were obese and 1895 (40.73%) males and 989 (18.57%) females were normal weight. Also, 832 (17.9%) males and 4548 (85.4%) females had abdominal obesity and 3819 (82.1%) males and 778 (14.6%) females didn't have abdominal obesity. Based on the adjusted multiple logistic regression, overweight/obesity (BMI > 25) was associated with age > 45, female gender, education ≥ 13 years, heavy physical activity, wealth status index (WSI), alcohol consumption, current cigarette smoking and opium consumption compared to reference group. Also, odds of abdominal obesity displayed a significant association with age > 45, female gender, education > 5 years, physical activity, WSI, current cigarette smoking, alcohol and opium consumption compared to reference group., Conclusions: Our results recommend local public health strategies that promote training the society on the health benefits of avoiding alcohol, getting more physical exercise and gaining more personal education on the health-threatening lifestyle., (© 2023. The Author(s).)

Hyperglycemia during the first trimester leads to an increased risk of innate malformations as well as death at times close to delivery dates. The methylated genes include those from paternal H19 and PEG3 and those from maternal MEST and MEG3 that are necessary for the growth and regulation of the human fetus and its placenta. The aim of this study was to evaluate and compare the expression of these genes in the cord blood of healthy infants born to mothers with gestational diabetes mellitus (GDM) and healthy mothers.This case-control study was conducted on the cord blood of 40 infants born to mothers with GDM and 35 infants born to healthy mothers. Mothers were identified by measuring oral glucose tolerance in the 24th-26th week of pregnancy. Cord blood was obtained post-delivery, and cord blood mononuclear cells were immediately extracted, using Ficoll solution. Then, RNA extraction and cDNA synthesis were performed, and gene expression of MEG3, PEG3, H19, and MEST was assessed through quantitative real-time PCR.Findings show that the expression levels of MEG3, PEG3, H19, and MEST genes were significantly decreased in mononuclear cord blood cells of infants born to mothers with GDM when compared to those of the healthy control group.These findings reveal that the reduction of imprinted genes in mothers with GDM is most likely due to changes in their methylation by an epigenetic process. Considering the importance of GDM due to its high prevalence and its side effects both for mother and fetus, recognizing their exact mechanisms is of high importance. This has to be studied more widely.

Both short sleep duration (SSD) and long sleep duration (LSD) are associated with an increased risk of morbidity and mortality. Here, we aimed to assess the prevalence of sleep duration disturbances among adults in association with demographic, medication use, personal habits, and chronic diseases, while also considering the impact of hypnotic drug use. We performed a cross-sectional study of 9991 adult participants of the Rafsanjan Cohort Study (RCS), as part of the Prospective epidemiological research studies in Iran (PERSIAN). Multivariate logistic regression analyses were conducted to assess the association between short (< 6 h) and long (> 9 h) sleep duration with demographic and lifestyle parameters and common non-communicable diseases. Additionally, we performed stratified analysis to investigate the association of sleep duration with the abovementioned factors and diseases, in groups with and without hypnotic drug use. We found higher odds of SSD significantly associated with age (P < 0.001), BMI (P < 0.001), physical activity (P < 0.001), and depression (P = 0.023). LSD displayed a positive association with the female sex (P < 0.001), opium consumption (P < 0.001), and history of MI (P = 0.045), and a reverse connection with education (P = 0.007), physical activity (P < 0.001) and alcohol consumption (P = 0.027). Stratifying for the hypnotic drug use, our sensitivity analyses indicated that in hypnotic drug users, education (P = 0.034) and physical activity (P < 0.001) were associated with LSD, in this group, significantly increased odds ratio of LSD were associated with opium consumption (P = 0.046) and thyroid dysfunction (P = 0.037). Our findings demonstrated the demographic and lifestyle factors and diseases associated with long and short sleep duration in the population of the RCS. Additionally, after stratifying for hypnotic drug use, our results indicated that some diseases are only associated with abnormal sleep duration upon using hypnotic drugs., (© 2023. The Author(s).)

The Pineal gland (PG) is the site of production of melatonin as an important central hormone in the body. It is not known yet whether PG calcification (PGC) is an age-associated physiological process or a pathologic condition caused by lifestyle-factors and metabolic-dysregulations.Here, we performed a cross-sectional analysis on 586 patients referred to have Computed Tomographic (CT) scans (above 15 years old), in the Ali Ebne Abi Taleb hospital radiology center in 2017-2018. Based on the CT-scans of the brain, the presence of PGC was recorded and a score of scale 0 to 6 (PGC&#95;score) was calculated for its intensity based on the volume and the Hounsfield units of the calcified pineal. Logistic and ordered logistic regression tests were employed to determine potential risk factor of PGC and higher PGC&#95;score, respectively, testing the factors age, sex, history of cardiovascular and metabolic diseases, smoking and opioid use. We found male sex (OR: 2.30 (95% CI:1.39-3.82) and smoking cigarettes (OR: 4.47 (95% CI:1.01-19.78)) as the main potential risk factors for the pineal gland calcification. For PGC&#95;score, we found age to be dose-dependently associated with PGC&#95;score only in patients aged below 63 (p-trend < 0.001). Stratifying for age, in patients < 63 years old, we found age, male sex (positive association) and dyslipidemia (negative association) as the main significantly associated factors of PGC&#95;score. On the contrary, in patients aged >  = 63, cigarette smoking was the only significantly associated factor of higher PGC&#95;score.In conclusion, our results indicate that at ages below 63, age, male sex and blood lipid are the main associated factors of higher PGC, but at ages above that, the lifestyle factor smoking is significantly associated with higher pineal gland calcification., (© 2023. The Author(s).)

Objectives: High-risk behaviors (HRBs) represent significant health threats for adolescents and significantly affect adolescents' mental health. Adolescents often engage in risky behaviors. The present study was conducted to investigate the relationship between high-risk behaviors (HRBs) and mental health in adolescents in Rabor., Content: The present study was a cross-sectional analytical study that was performed on 334 girl and boy students aged 12-18 years in Rabor city in 2021. In this study, adolescents answered high risk behaviors and mental health questionnaires. Data were analyzed using SPSS-26 software and the spearman correlation coefficient and linear regression analysis (univariate and multivariate analysis) were used to analyze the data., Summary and Outlook: In this study, the mean age was 15.25 ± 1.78. The findings indicate that smoking and hookah use were higher in boys than girls. Among the demographic variables, age and level of education had a positive and significant relationship with HRBs and mental health (p<0.05). The mean score of total mental health for all subjects was 12.83 ± 10.82. The variables of age, sex, marital status of parents, the number of children in the family, educational level, smoking, hookah, and alcohol have been determined as influential and facilitating factors in HRBs of adolescents. Father's literacy was considered as a facilitator and age variables, alcohol consumption and parents' marital status were considered as deterrents to mental health. The present study showed that the male gender is one of the risk factors for alcohol, smoking and other substances, the tendency to high-risk sexual behaviors, depression, and suicide in adolescents. Among the determinants of the tendency to HRBs in adolescents, psychological variables are of particular importance at the individual, social, and family levels. Good mental health can improve quality of life, while poor mental health can make it worse., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

Opiate use is related to neuropathological disorders, stroke and stroke attributable risk factors. However, secondary exposure to opiate in relation to the above-mentioned complications is studied only in animal models and remains to be evaluated in human populations. We tested whether passive exposure to opiate is associated with stroke and the known stroke predictive factors. We carried out a cross-sectional study of 1541 never smoker women who participated in the Rafsanjan Cohort Study (RCS) with their husbands (2015-2017 recruitment phase). RCS is one of the 19 geographic districts of the Prospective Epidemiological Research Studies in Iran (PERSIAN cohort study). Unadjusted and adjusted multiple logistic regression analyses were performed to evaluate the relationship between second-hand opiate exposure (husband opiate smoking after marriage) and the odds ratio of stroke and the following stroke risk factors and predictive parameters: overweight/obesity (BMI > 25), cholesterol (chol) > 200 mg/dl, fasting blood sugar (FBS) > 125 mg/dl, low density lipoprotein (LDL) > 100 mg/dl, triglyceride (TG) >  = 150 mg/dl, hypertension, diabetes, and chronic headache. We observed a significant increased adjusted odds ratio (OR) of stroke (OR = 3.43, 95% CI:1.33-8.82) and its risk factors LDL > 100 mg/dl (OR = 1.37, 95% CI:1.01-1.87) and FBS > 125 mg/dl (OR = 1.58, 95% CI:1.08-2.30) in women associated with husbands' opiate smoking. This relationship was observed after adjusting for the confounding parameters including age, education years, and first-degree family history of the relevant diseases. The increased odds ratio for stroke and high LDL displayed a dose-sensitive trend with years of husband's opiate smoking after marriage (respective p-trends: 0.02 & 0.01). We did not observe a significant association between passive opiate smoking and high TG, high Chol or the diseases diabetes, hypertension and chronic headache. However, 89% increased odds ratio of chronic headache was observed to be associated with passive opiate smoking for more than 10 years (OR = 1.89, 95% CI:1.02-3.50). We found an increased risk of stroke and high LDL and FBS in women associated with passive opiate smoking. Furthermore, a dose-sensitive connection was found between the risks of stroke, high LDL and chronic headache with the years of passive opiate exposure. Our results point to the necessity of the future analyses, which further assess whether passive opiate exposure could be considered as an independent risk factor for stroke and metabolic diseases., (© 2022. The Author(s).)

Objectives: Age of menarche is a determinant factor of cardiometabolic risk, adiposity and stature at adulthood. However, little is known about the transgenerational effects of age of menarche, especially beyond childhood of any offspring, and the studies remain limited to anthropometric outcomes in children at birth or before adolescence. In the present study, we aim to investigate the relationship of maternal age at menarche (MAM) with anthropometric and metabolic parameters in the young adult offspring (aged 15-35 years) in a Persian population., Design, Patients and Measurements: In this cohort-based cross-sectional study, we recruited 1139 mother-young adult dyads enroled in Rafsanjan Cohort Study (RCS) at adult RCS (aged 35-70 years) and youth RCS (aged 15-35 years) as part of the comprehensive PERSIAN (Prospective Epidemiological Research Studies in IrAN). In this study, MAM was categorized to early (MAM < 12 years), normal (12 ≤ MAM ≤ 14) and late menarche (MAM > 14 years). For these analyses, bivariate and multiple logistic regression models were used to investigate the relationships between late or early MAM and offspring anthropometric and metabolic parameters., Results: Early MAM displayed a significant association with an increased odds ratio (OR) of tall stature adjusting for sex, age, socioeconomic status index, maternal age at birth and maternal height (as genetically determined factor). Sensitivity analysis by sex indicated this relationship to be specific to male offspring only (adjusted OR: 1.84 95% CI: 1.13-3.00, p value: .014). In addition, late MAM displayed a significant association with reduced OR of overweight/obesity and abdominal obesity in daughters only (obesity adjusted OR: 0.49, 95% CI: 0.27-0.88, p value: .018, abdominal obesity adjusted OR: 0.44, 95% CI: 0.23-0.82, p value: .010). dose-response analysis by categorization of MAM, further supported our results. On the contrary, our analyses do not support a significant relationship between MAM and youth metabolic indices, that is, metabolic syndrome, fasting blood sugar (FBS), high-density lipoprotein (HDL) and triglyceride (TG)., Conclusions: The results of the present study indicate an association of maternal age of menarche with anthropometric measures of offspring in young adulthood in a sex differential manner. The data does not support a significant relationship between the metabolic indices FBS, TG and HDL in offspring with MAM. Overall, this study provides evidence for the intergenerational effects of age at menarche in the development of anthropometric measures in offspring in young adulthood (15-35), which is the first study of this kind in this age range., (© 2021 John Wiley & Sons Ltd.)

Objective: This study was undertaken to identify the mechanistic role of γδ T cells in the pathogenesis of experimental psoriatic arthritis (PsA)., Methods: In this study, we performed interleukin-23 (IL-23) gene transfer in wild-type (WT) and T cell receptor δ-deficient (TCRδ -/- ) mice and conducted tissue phenotyping in the joint, skin, and nails to characterize the inflammatory infiltrate. We further performed detailed flow cytometry, immunofluorescence staining, RNA sequencing, T cell repertoire analysis, and in vitro T cell polarization assays to identify regulatory mechanisms of γδ T cells., Results: We demonstrated that γδ T cells support systemic granulopoiesis, which is critical for murine PsA-like pathology. Briefly, γδ T cell ablation inhibited the expression of neutrophil chemokines CXCL1 and CXCL2 and neutrophil CD11b+Ly6G+ accumulation in the aforementioned PsA-related tissues. Although significantly reduced expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-17A was detected systemically in TCRδ -/- mice, no GM-CSF+/IL-17A+ γδ T cells were detected locally in the inflamed skin or bone marrow in WT mice. Our data showed that nonresident γδ T cells regulate the expansion of an CD11b+Ly6G+ neutrophil population and their recruitment to joint and skin tissues, where they develop hallmark pathologic features of human PsA., Conclusion: Our findings do not support the notion that tissue-resident γδ T cells initiate the disease but demonstrate a novel role of γδ T cells in neutrophil regulation that can be exploited therapeutically in PsA patients., (© 2022 American College of Rheumatology.)

Nitrate, as a major pollutant of drinking water, is associated with colorectal cancer (CRC) and serves as an environmental health concern, especially in the districts with unregulated agriculture. In this case study in northwestern Iran, we used two databases of nitrate concentration (1999-2013) and age-standardized incidence rate (ASR) for CRC (2002-2012) from 19 counties of East Azerbaijan province. The trend and correlation between nitrate and ASR was investigated. Inverse distance weighted technique was used to spatially interpolate the maps. Expectedly, drinking water nitrate has increased throughout the province (8-20.5 mg/L) as well as the ASR for CRC of men (from 2.07 to 18.05 mg/L) and women (from 1.57 to 10.94 mg/L). While ASR for CRC of men was positively correlated to nitrate (Pearson's r = 0.624, p -value = 0.040), no statistically significant correlation was found between nitrate and ASR for women's CRC (Pearson's r = 0.289, p -value = 0.351). According to our findings, the incidence of CRC was not higher for those residing in the regions with higher nitrate, suggesting that risk factors such as genetic predisposition and diet that were not taken into account could be determinants of this pattern. However, even a small increase in CRC rate due to water nitrate could translate into a large public health concern. The incremental pattern observed in nitrate levels of different counties over the years gives the health policymakers a better perspective of the problem and how the control of water nitrate level as a CRC risk factor might contribute to the prevention of CRC.

Aim: Human Papillomavirus is one of the most crucial infectious disease in gynecology disease. To assess the efficacy of supplemental zinc treatment in clearance of HPV infection., Methods: Eighty zinc-sufficient women between 21-55 years, with positive HPV DNA testing, and abnormal cervical cytology in Pap test (ASCUS or LISL) were randomly divided to case (n=40) and control group (n=40). Case group received oral tablets of zinc sulfate twice a day for 3 months while control group received no placebo. During follow-up patients underwent repeat HPV DNA test and PAP test and were evaluated for clearance/persistence of HPV infection and regression/progression in the lesion grading., Results: As far as demographics, serum zinc levels and the relevant risk factors for persistence of HPV were concerned, there was no significant difference between two groups, except for the frequency distribution of HR-HPV which was significantly higher in case  group. Zinc treatment for 3 months reduced the risk of persistence of HPV infection and progression from baseline cytology (OR = 0.130) (CI 95% 0.04-0.381; p <0.001) and 0.301 (95% CI 0.777-0.116; p = 0.012), respectively. Age, initial cytology, HPV type, and contraceptive method were not related to persistence of HPV. Serum zinc levels increased in the casr group as a result of oral zinc consumption for 3-month period, though without any statistical significance (p = 0.407)., Conclusion: The results of the following study suggested that oral intake of zinc sulfate supplement for 3 months increases the rates of HPV clearance and resolution of pre-existing cervical lesion.

Purpose: To compare the efficacy and safety of up to two-time administration of 85% TCA, as a promising alternative therapy to conservative and surgical management of grade one to three CINs., Methods: In this two-armed randomized clinical trial, a total of 53 patients with biopsy-proven CIN lesions were allocated to two groups of TCA treatment. The first group (n=26) received a single dose of local therapy with 85% TCA while the second group (n=27) was treated on two separate occasions with a two-week interval. Two participants (one in each group) were lost to follow-up. At the two-month follow-up after TCA application, a colposcopy-guided biopsy was performed for all patients and the pathological specimens were studied by a single experienced pathologist to determine the post-intervention grading of CIN., Results: Two groups were comparable in terms of age and base-line lesion grading, as CIN 1 lesions comprised the majority of cases (54%), followed by CIN 2(37%). While our sample was a poor representative of CIN3 lesions (7%), no significant difference was noticed between the single and twice TCA treated groups with a response rate of 52% and 54% respectively (either complete remission to normal histology or regression to any low-grade lesion). Either separate analysis (with respect to the base-line grading within each treatment group) or combined analysis (regardless of CIN sub-group) could not generate any statistical significance. The second dose of TCA did not increase the frequency of reported adverse events., Conclusion: The second dose of topical 85% TCA does not seem to increase the CIN response rate more so than its single dose. However, further controlled clinical trials with larger samples are warranted to verify current findings. The use of TCA was not limited by any major side effect, therefore, the potential to achieve an increased efficacy with more frequent TCA applications is appealing.

Objectives: The breast cancer stigma affects Health-related quality of life (HRQoL), while general resilience resources (GRRs), namely, sense of coherence (SOC), social support, and coping skills, are thought to alleviate this effect. The study aimed to explore the mediating/moderation role of GRRs in the relationship between stigma and HRQoL and its dimensions in Iranian patients with breast cancer., Methods: In this cross-sectional study, Stigma Scale for Chronic Illness 8-item version (SSCI-8), SOC-13, Medical Outcome Survey- Social Support Scale (MOS-SSS), Brief COPE, and Functional Assessment of Cancer Therapy-Breast (FACT-B) were investigated in a convenience sample of Iranian women with confirmed non-metastatic breast cancer. Following the establishment of correlations using Pearson's correlation, single and parallel mediation analysis and moderation analysis were conducted to determine the extent to which each GRR might be impacted by stigma or decrease the adverse impact of stigma on HRQoL., Results: An analysis of 221 women (response rate of 87.5%) with the mean age of 47.14 (9.13) showed that stigma was negatively correlated to all HRQoL's dimensions ( r = -0.27∼0.51, p < 0.05), SOC ( r = -0.26∼0.35, p < 0.01), social support ( r = -0.23∼0.30, p < 0.01), and the bulk of coping skills. In the single mediation analysis, stigma affected all facets of SOC, all subscales of social support, and positive reframing, which partially reduced breast cancer HRQoL. Stigma affects general HRQoL through damaging meaningfulness, social support (except for tangible), and positive reframing. Meaningfulness was marked as the most impacted GRR in terms of all domains of HRQoL. In parallel mediation, reduced meaningfulness, total social support, and positive reframing were highlighted as the pathways of diminished breast cancer HRQoL. Moderation analysis indicated the higher levels of humor, behavioral disengagement, and use of instrumental support behaviors to be functional in protecting different dimensions of HRQoL, while the results were mixed for venting, especially in patients with mastectomy surgery., Conclusion: While GRRs may be impacted by stigma, they exert a relatively small protective effect against the impact of stigma on HRQoL. This study provides some novel findings, but longitudinal studies are needed to further verify these before any causal conclusion or recommendations for health policy can be drawn., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zamanian, Amini-Tehrani, Jalali, Daryaafzoon, Ramezani, Malek, Adabimohazab, Hozouri and Rafiei Taghanaky.)

Opioid use accelerates normal aging in adults that raises a question on whether it may trans-generationally affect aging and aging biomarkers in the offspring of users as well? In the present research, we investigated the relative telomere length in umbilical cord blood of newborns born to opioid consuming mothers compared to normal controls. Telomere length shortening is a known biomarker of aging and aging related diseases. Its measure at birth or early in life is considered as a predictor of individual health in adulthood. Here, we performed a case-control study to investigate whether maternal opioid use affects newborns relative telomere length (RTL). 57 mother-newborn dyads were included in this study, 30 neonates with opioid using mothers (OM), and 27 with not-opioid using mothers (NOM)). RTL was measured in leukocyte cells genomic DNA using real-time PCR. The correlation of maternal opioid use with neonates telomer length was assessed using logistic regression analysis. The results displayed a significant association between odds ratio of long RTL and maternal opioid use when sensitivity analysis was performed by neonate sex; where the data indicates significantly increased odds ratio of long leukocyte RTL in association with maternal opioid use in male neonates only. Further work is necessary to assess this association in larger samples and test the potential underlying mechanisms for this observation., Competing Interests: The authors have declared that no competing interests exist.

Proprotein convertases subtilisin kexins are serine endoproteases, playing critical roles in the biological functions, including lipid, glucose, and bile acid metabolism, as well as cell proliferation, migration, and metastasis. Experimental studies have demonstrated the physiological functions of PCSKs and their association with diseases; however, studies on the evolutionary history and diversification of these proteins are missing. In the present research, a bioinformatics study was conducted on the molecular evolution of several PCSKs family members and gene loss events across placental mammalian. In order to detect evolutionary constraints and positive selection, the CodeML program of the PAML package was used. The results showed the positive selection to occur in PCSK1, PCSK3, PCSK5, and PCSK7. A decelerated rate of evolution was observed in PCSK7, PCSK3, and MBTPS1 in Carnivores compared to the rest of phylogeny, and an accelerated evolution of PCSK1, PCSK7, and MBTPS1 in Muridae family of rodents was found. Additionally, our results indicated pcsk9 gene loss in 12 species comprising Carnivores and bats (Chiroptera). Future studies are required to evaluate the functional relevance and selective evolutionary advantages associated with these modifications in PCSK proteins during evolution., Competing Interests: The authors declare no conflict of interest with respect to the present manuscript.

Aims: To investigate the roles of total stigma, enacted stigma, and internalized stigma in the prediction of psychological distress among breast cancer patients, and to evaluate the mediating effect of body image in this process., Design: Cross-sectional., Methods: Between Oct-2014 to May-2015, a cross-sectional study was conducted with participation of 223 patients from three cancer centres located in Tehran, Iran. The study variables were assessed using the stigma scale for chronic illnesses 8-item version (SSCI-8), body image scale (BIS), and depression anxiety stress scale (DASS-21). Structural equation modelling using MLR estimator was employed based on the two-step procedure to validate both the full measurement models and the structural models. Five models were tested to determine predictability of all stigma constructs for psychological distress, including stress, anxiety, and depression, through the mediation of body image. Three equivalent models were further examined to re-evaluate the direction of the relationships., Results: Psychological distress and body image were largely predicted by total stigma, enacted stigma, and internalized stigma. The effect of stigma on psychological distress was mediated through body image. In a serial mediation model, the significance of the pathway of enacted stigma > internalized stigma > body image > psychological distress was confirmed. The serial model in which internalized stigma precedes body image was also supported by the equivalent models., Conclusion: Stigma has been identified as a major source of psychological distress among women with breast cancer. Enacted stigma not only psychologically disturbs the patients but also triggers a chain of other identity transformations (i.e. internalization of stigma and distortion of body image), their ultimate result being a full-blown psychological distress., Impact: Both enacted and internalized stigma distorts breast cancer patients' perception of their body image, which in turn renders them psychologically distressed. The serial process of enacted stigma, internalized stigma, and body image plays an important role in perpetuating distress in these patients. To break this chain of psychological consequences and for interventions to have a greater impact on overall well-being of patients, the effect of enacted stigma on distress via the sequence of two mediators needs to be specifically targeted at each stage., (© 2021 John Wiley & Sons Ltd.)

A growing body of evidence suggests that opioid use may affect consumer's offspring by second-hand passive smoke exposure, as well as by transgenerational impacts mediated by genetic and epigenetic alterations of paternal gametes. In human studies, these effects are limited to investigating the neural, behavioral and cognitive characteristics of offspring. Only animal studies have investigated the metabolic parameters influenced by passive opium smoke exposure. Here, we conducted population-based analyses aimed to estimate the association of paternal opioid consumption, started before or after child birth, with BMI status and plasma lipid profile of young adult offspring. The present study includes 840 parents-offspring trios (offspring aged 15-35, parents aged 35-70) who participated in the prospective Rafsanjan Cohort Study (RCS)-a city in the south-east of Iran-as one of the district areas of the PERSIAN cohort (Prospective Epidemiological Research Studies in IrAN). All procedures for interviews, anthropometric measurements and physical examinations, biological sample collection and laboratory tests for blood biochemical parameters were conducted according to the PERSIAN cohort protocol, and in the well-established RCS setting. Crude and adjusted multiple logistic regression analysis were conducted to assess the relationship of paternal regular opioid use with offspring's BMI status, and plasma lipid factors. The prevalence of fathers who use opioids regularly among the studied trios was 42.8% (360/840). Our regression analyses demonstrated that paternal opioid use started pre-fatherhood is associated with 76% higher adjusted odds ratio (OR) of overweight/obesity in young offspring (adjusted OR 1.76 (95% CI 1.15-2.71)), adjusting for sex, age, parental BMIs, paternal smoking status and socioeconomic status index (WSI). This relationship persisted when fathers who used opioid by routes other than inhaling (oral) were excluded from logistic analysis (adjusted OR 1.73 (95% CI 1.12-2.68)). Interestingly, sex stratified analysis displayed a 201% increased odds ratio of overweight/obesity in sons of fathers who use opioid regularly, started after child birth (Adjusted OR 3.01 (95% CI 1.68-5.39), while no significant association was found in daughters (adjusted OR 0.74 (95% CI 0.35-1.54)). Additionally, increasing exposure-response relationships were observed between odds ratios of overweight/obesity and the number of years of paternal opioid use after birth (p-trend = 0.0008). Paternal regular opioid use started pre-fatherhood was associated with 54% lowered risk of underweight [adjusted OR 0.46 (95% CI 0.24-0.86)]. Finally, paternal opioid consumption started either before or after child birth did not show a significant association with the high level of the three parameters of plasma lipid factors (triglyceride, cholesterol and HDL-cholesterol) in offspring. Our results suggest that the environmental impacts of paternal regular opioid use may be sufficient to make an effect on male offspring metabolism independent of genetic and epigenetic impact on gametes.

Smoking, heavy alcohol drinking and drug abuse are detrimental lifestyle factors leading to loss of million years of healthy life annually. One of the major health complications caused by these substances is the development of cardiovascular diseases (CVD), which accounts for a significant proportion of substance-induced death. Smoking and excessive alcohol consumption are related to the higher risk of acute myocardial infarction. Similarly, opioid addiction, as one of the most commonly used substances worldwide, is associated with cardiac events such as ischemia and myocardial infarction (MI). As supported by many studies, coronary artery disease (CAD) is considered as a major cause for substance-induced cardiac events. Nonetheless, over the last three decades, a growing body of evidence indicates that a significant proportion of substance-induced cardiac ischemia or MI cases, do not manifest any signs of CAD. In the absence of CAD, the coronary microvascular dysfunction is believed to be the main underlying reason for CVD. To date, comprehensive literature reviews have been published on the clinicopathology of CAD caused by smoking and opioids, as well as macrovascular pathological features of the alcoholic cardiomyopathy. However, to the best of our knowledge there is no review article about the impact of these substances on the coronary microvascular network. Therefore, the present review will focus on the current understanding of the pathophysiological alterations in the coronary microcirculation triggered by smoking, alcohol and opioids.

Background: Caudal block is one of the methods of pain management performed following lower abdominal surgery, though having its own limitations., Objectives: In the present study, the effects and side effects of adding dexmedetomidine to ropivacaine in the caudal epidural block were investigated in children after lower abdominal surgery., Methods: In this randomized, double-blinded clinical trial, 46 children aged three to six years were divided into two groups to perform a caudal block following lower abdominal surgery under general anesthesia. The injectable solution contained ropivacaine in the R group (1 mL/kg ropivacaine 0.2%), as the control group, and dexmedetomidine (2 µg/kg) and ropivacaine 0.2% (1 mL/kg) in the DR group. The pain score (modified CHEOPS score), duration of analgesia, amount of analgesia consumed (i.v. paracetamol), hemodynamic changes, and possible adverse effects were assessed at one, two, and six hours in both groups., Results: The pain score at one and two hours showed no significant difference between the two study groups (P > 0.05). In the DR group, however, the pain score at the sixth hour was significantly lower, and the duration of analgesia was longer (P = 0.001). The amount of analgesic consumption was also lower in the DR group (P = 0.001). However, there was no significant difference in systolic blood pressure and heart rate (P < 0.05), in the case of diastolic blood pressure, a significant difference (P < 0.05) was seen (DR group lower than the R group). There was no statistically significant difference between the study groups in the duration of surgery, recovery time, and side effects (P < 0.05)., Conclusions: In the present study, the addition of dexmedetomidine to ropivacaine in the caudal epidural blockade improved postoperative analgesia without significant adverse effects in pediatric patients., Competing Interests: Conflict of Interests: The authors have no conflict of interest., (Copyright © 2021, Author(s).)

Owning the largest human-made jungle of pistachio, the second largest copper mine, and being located on the trade route of opium transit, distinguish Rafsanjan from many other cities in Iran. The environmental exposures and lifestyle factors associated with these characteristics of Rafsanjan, have raised concern about possible health outcomes for individuals living in and around this city. Thus, local health authorities initiated the Rafsanjan Cohort Study (RCS), as part of the prospective epidemiological research studies in IrAN (PERSIAN). RCS is a population-based prospective cohort of men and women aged 35-70 years, launched in August 2015. Individuals from diverse socioeconomic levels and lifestyles were recruited from four urban and suburban areas of Rafsanjan (participation rate 67.42%). Questionnaire-based interviews regarding demographics, dietary and environmental exposures, medical and occupational history, as well as anthropometric measurements were completed for all participants. Additionally, bio-specimens (blood, urine, hair, and nail) were collected, and dental and eye examinations were performed. The enrollment phase ended in December 2017, and a 15-year follow-up is planned. A total of 9990 individuals were enrolled in RCS (53.41% females). About 26% of men are pistachio farmers. The baseline prevalence of major non-communicable disease (NCD) risk factors such as cigarette smoking, alcohol consumption and opium use were 25.45%, 10.02%, and 23.81%, respectively. The mean ± SD of other common risk factors are as follows: body mass index (27.83 ± 4.89 mm Hg), systolic blood pressure (107.18 ± 17.56 mm Hg) diastolic blood pressure (71.13 ± 10.83), fasting blood sugar (113.27 ± 39.11 mg/dL) and plasma cholesterol (198.78 ± 41.89 mg/dL). These results indicate a concerning prevalence of NCD risk factors in Rafsanjan city, warranting further detailed investigations, particularly regarding the association of NDC with agricultural/industrial pollutants and drug abuse.

Purpose: Depression and anxiety are now considered as common adverse reactions to cancer. Prior research has shown that social support and functional coping strategies alleviate depressive and anxious symptoms of cancer patients but the exact relationship between social support and coping strategies in amelioration of the symptoms is yet to be elaborated., Methods: The current study examined the relationship between social support, coping strategies and depressive-anxious symptomatology and explored the possible role of coping strategies in mediating the relationship between social support, depression and anxiety in Iranian breast cancer patients (N = 221). Anxiety and depressive symptoms were measured using the Depression-Anxiety-Stress (DASS-21) scale, social support was measured using the Medical Outcome Survey, Social Support Scale (MOSS-SSS), and coping strategies were measured using the brief COPE., Results: All of the social support subscales were negatively correlated with depression and anxiety. Most of the coping strategies were negatively correlated with depressive-anxious symptoms. When controlling for covariates, mediation analysis revealed that active coping, positive reframing and acceptance partially mediated the association of social support of different types with depression. Positive reframing also partially mediated the relationship of the total social support and positive social interactions with anxiety., Conclusions: High levels of social support may relieve depressive and anxious symptoms of breast cancer patients through functional coping. The management of breast cancer patients should also focus on providing patients with social support and educating them on the practice of functional coping strategies., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Aim: To assess the role of ascites calprotectin in early detection of SBP in patients with cirrhosis and to investigate its prognostic value in determination of the 6-month outcome. Methods and material: In this cross-sectional study, patients with liver cirrhosis who were consecutively referred to Imam Reza hospital, tertiary referral center in the northwest of Iran, underwent abdominal paracentesis. The samples were collected for measurement of calprotectin, albumin, total protein, WBCs, and PMNs., Results: The mean age of a total of 87 included patients was 56.86 (SD 16.05) years old with over half of the subjects (55.2%) being female. About 28.7% of performed paracenteses tested positive for SBP. Ascitic calprotectin was positively correlated to the PMN counts. Patients with SBP were found to have higher levels of ascites albumin, total protein, and calprotectin. Only 51 individuals survived the 6-month follow-up period and mortality outcomes were significantly related to the levels of aforementioned biochemical markers ( p -value <.05)., Conclusion: Alongside with standard PMN counts, calprotectin measurement in the ascitic fluid could be used as an available test for early diagnosis of SBP. Calprotectin can also serve as a valuable prognostic marker in the evaluation of cirrhotic patients.

Autophagy is the cellular process of removal of misfolded or damaged macromolecules and organelles. Experimental studies have demonstrated autophagy as a major mechanism of lifespan extension in long-lived mammals such as bats and mole rat rodents. Moreover, the role of this biological process has been well documented in protection against age-associated diseases and viral infection. However, studies on the molecular adaptive changes of autophagy factors during evolution are scarce. Here, we conducted a bioinformatics study of the molecular evolution of the Lysosomal Associated Membrane Protein 2 (LAMP2), as a rate-limiting factor in the lysosomal degradation stage of autophagy (the communal step of two of autophagy types: macroautophagy and chaperone-mediated). Analyzing LAMP2 across placental mammals, our phylogenetic-based maximum likelihood analyses indicate that the majority of the coding sites undergo purifying selection. However, around 27% of sites display a relaxation of purifying constraints (average ω = 0.42128), among which, 14 particular sites undergo positive selection (ω > 1). These sites are mostly located in the first luminal domain of LAMP2 (N-domain), with a hotspot region in the 135-144 codons interval. Therefore, the N-domain may account for the functional diversity and regulation of LAMP2. In addition, the identified positive selection sites could act as key regulatory sites in the LAMP2 function. On the other hand, testing the rate of evolution in LAMP2 along different clades of placental mammals revealed a relatively relaxed evolution in LAMP2 along megabats' clade. It is not clear yet whether an expedited evolution of LAMP2 in megabats has contributed to their reported up-regulation of autophagy. Finally, our data indicate positive selection sites along the ancestral branch of the clades of rodents, mouse-related rodents, and mole-rats; and suggest the potentially important regulatory role of these sites in LAMP2. Identifying the residues under positive selection, our findings pave the way for future experimental investigations to define how these selective substitutions have functionally affected autophagy., (Copyright © 2019 Elsevier B.V. All rights reserved.)

BACKGROUND Myonecrosis is an uncommon complication of poorly controlled diabetes, predominantly involving the lower limbs. It is an atypical presentation in the upper limbs. Here, we report a rare case with atypical involvement of the upper limbs. CASE REPORT A 53-year-old diabetic woman presented with left arm pain for the past week. She was not compliant with her medications. The patient denied any history of trauma or injection. Physical examination revealed a warm, tender, and erythematous swelling on the medial side of the left arm and was otherwise unremarkable. Her glycemic control was poor, with Hb A1C of 9.6%. Duplex ultrasonography demonstrated no evidence of fluid collection or thrombosis. An initial MRI (without contrast) report was misleadingly suggestive of polymyositis. Orthopedic consultant urged the patient to transfer to the operating room for aspiration of a probable infectious nidus, which resulted in a dry tap. Despite confusing radiological clues, ischemic myonecrosis was suspected, and second MRI studies (with contrast) reported necrosis. Tissue biopsy (the criterion standard) was withheld to avoid the risk of delayed healing or superimposed infection. Meanwhile, the patient received supportive treatment and achieved full recovery within 1 month. CONCLUSIONS Diabetic myonecrosis should be suspected in any poorly controlled diabetic patient presenting with otherwise unexplained muscle pain without any evidence of infection. Diagnosis can be made by MRI, leaving very few indications for invasive procedures. Analgesics and glycemic control are the mainstays of treatment.

Dens invaginatus is one of the most common anomalies of tooth structure. It is caused by the invagination of the crown surface during odontogenesis that enters the pulp chamber of the affected tooth. Depending on the complexity of invagination, the tooth might present with pulp necrosis, open apex and a complicated root canal system. This case report presents an Oehlers' type 2 dens-invaginatus in a mandibular premolar with chronic apical abscess. In most cases, dens invaginatus is removed during treatment. However, in this case report, based on cone-beam computed tomography (CBCT) evaluation, non-surgical treatment and maintenance of the invaginated segment was chosen in order to prevent compromising the tooth structure and its susceptibility to future root fracture. This is a new treatment approach and has not been performed in previous reports. Calcium-enriched mixture (CEM) cement was used as an apical plug followed by gutta-percha in warm vertical compaction for root canal obturation. The case was followed up for 36 months after treatment. This report highlights the importance of selecting the appropriate treatment approach based on CBCT evaluation., Competing Interests: ‘None declared’.

Because of antimicrobial, antioxidant, and anticancer potential, Salvia chorassanica Bunge (Lamiaceae) has been considered as a popular herb in Iranian traditional medicine. Previous studies have shown remarkable cytotoxic properties of the methanol, n-hexane and dichloromethane extract of S. chorassanica on human cervical cancer cells. To seek the therapeutic potentials of S. chorassanica, this study was undertaken to evaluate the cytotoxic activities of various extracts of this plant on human breast MCF-7 and prostate cancer DU 145 cells. The DU 145 cells were exposed to different concentrations of plant extracts (1-200 μg/ml). Cytotoxic activities were examined using alamarBlue(®) assay and apoptosis was assessed by acridine orange/propodium iodide double staining and evaluation of DNA fragmentation by flow cytometry. Our findings indicated that n-hexane and dichloromethane extracts had more cytotoxic activities against DU 145 and MCF-7 cell lines compared with other extracts (P<0.05). The acridine orange/propodium iodide staining showed apoptogenic properties of n-hexane and dichloromethane extracts which was consequently confirmed by flow cytometric histogram that exhibited an increase in sub-G1 peak in treated cells as compared with untreated cancer cell lines. Taken together, these observations demonstrated cytotoxic effects of S. chorassanica extracts on MCF-7 and DU 145 cell lines which is most likely exerted via apoptosis cell death. Therefore, further investigations on S. chorassanica extracts as potential chemotherapeutic agents are warranted.

The Warburg effect is a tumorigenic metabolic adaptation process characterized by augmented aerobic glycolysis, which enhances cellular bioenergetics. In normal cells, energy homeostasis is controlled by AMPK; however, its role in cancer is not understood, as both AMPK-dependent tumor-promoting and -inhibiting functions were reported. Upon stress, energy levels are maintained by increased mitochondrial biogenesis and glycolysis, controlled by transcriptional coactivator PGC-1α and HIF, respectively. In normoxia, AMPK induces PGC-1α, but how HIF is activated is unclear. Germline mutations in the gene encoding the tumor suppressor folliculin (FLCN) lead to Birt-Hogg-Dubé (BHD) syndrome, which is associated with an increased cancer risk. FLCN was identified as an AMPK binding partner, and we evaluated its role with respect to AMPK-dependent energy functions. We revealed that loss of FLCN constitutively activates AMPK, resulting in PGC-1α-mediated mitochondrial biogenesis and increased ROS production. ROS induced HIF transcriptional activity and drove Warburg metabolic reprogramming, coupling AMPK-dependent mitochondrial biogenesis to HIF-dependent metabolic changes. This reprogramming stimulated cellular bioenergetics and conferred a HIF-dependent tumorigenic advantage in FLCN-negative cancer cells. Moreover, this pathway is conserved in a BHD-derived tumor. These results indicate that FLCN inhibits tumorigenesis by preventing AMPK-dependent HIF activation and the subsequent Warburg metabolic transformation.

Dysregulation of AMPK signaling has been implicated in many human diseases, which emphasizes the importance of characterizing AMPK regulators. The tumor suppressor FLCN, responsible for the Birt-Hogg Dubé renal neoplasia syndrome (BHD), is an AMPK-binding partner but the genetic and functional links between FLCN and AMPK have not been established. Strikingly, the majority of naturally occurring FLCN mutations predisposing to BHD are predicted to produce truncated proteins unable to bind AMPK, pointing to the critical role of this interaction in the tumor suppression mechanism. Here, we demonstrate that FLCN is an evolutionarily conserved negative regulator of AMPK. Using Caenorhabditis elegans and mammalian cells, we show that loss of FLCN results in constitutive activation of AMPK which induces autophagy, inhibits apoptosis, improves cellular bioenergetics, and confers resistance to energy-depleting stresses including oxidative stress, heat, anoxia, and serum deprivation. We further show that AMPK activation conferred by FLCN loss is independent of the cellular energy state suggesting that FLCN controls the AMPK energy sensing ability. Together, our data suggest that FLCN is an evolutionarily conserved regulator of AMPK signaling that may act as a tumor suppressor by negatively regulating AMPK function.

Hepatitis C virus (HCV) causes chronic hepatitis, cirrhosis, and liver cancer. cis-acting RNA elements of the HCV genome are critical for translation initiation and replication of the viral genome. We hypothesized that the coding regions of nonstructural proteins harbor enhancer and essential cis-acting replication elements (CRE). In order to experimentally identify new cis RNA elements, we utilized an unbiased approach to introduce synonymous substitutions. The HCV genome coding for nonstructural proteins (nucleotide positions 3872 to 9097) was divided into 17 contiguous segments. The wobble nucleotide positions of each codon were replaced, resulting in 33% to 41% nucleotide changes. The HCV genome containing one of each of 17 mutant segments (S1 to S17) was tested for genome replication and infectivity. We observed that silent mutations in segment 13 (S13) (nucleotides [nt] 7457 to 7786), S14 (nt 7787 to 8113), S15 (nt 8114 to 8440), S16 (nt 8441 to 8767), and S17 (nt 8768 to 9097) resulted in impaired genome replication, suggesting CRE structures are enriched in the NS5B region. Subsequent high-resolution mutational analysis of NS5B (nt 7787 to 9289) using approximately 51-nucleotide contiguous subsegment mutant viruses having synonymous mutations revealed that subsegments SS8195-8245, SS8654-8704, and SS9011-9061 were required for efficient viral growth, suggesting that these regions act as enhancer elements. Covariant nucleotide substitution analysis of a stem-loop, JFH-SL9098, revealed the formation of an extended stem structure, which we designated JFH-SL9074. We have identified new enhancer RNA elements and an extended stem-loop in the NS5B coding region. Genetic modification of enhancer RNA elements can be utilized for designing attenuated HCV vaccine candidates.

Purpose: To assess the effect of homatropine eye drops on pain after photorefractive keratectomy (PRK)., Methods: This randomized, double masked, interventional study included 15 patients (30 eyes) who underwent bilateral PRK. After operation, patients received homatropine eye drops, 4 times daily in only one eye (homatropine eye). The level of pain was evaluated using visual analogue scale (VAS), verbal rating scale (VRS) and pain rating index (PRI) at 0.5, 24 and 48 h after operation., Results: The level of pain was statistically similar between the two eyes half an hour after operation, however, homatropine eyes had significantly less pain 24 h after operation compared to fellow eyes (2.5 ± 1.9 vs 5.3 ± 2.5, P = 0.004 for VAS, 2.0 ± 1.2 vs 3.2 ± 0.9, P = 0.023 for VRS, and 9.4 ± 5.7 vs 16.0 ± 9.0, P = 0.031 for PRI). Also, 48 h after surgery, the pain scales were less in the homatropine eyes (2.3 ± 1.7 vs 4.0 ± 2.1, P = 0.014 for VAS, 1.6 ± 1.0 vs 2.5 ± 1.0, P = 0.038 for VRS, and 6.8 ± 5.7 vs 12.0 ± 8.9, P = 0.005 for PRI). No delayed epithelial healing was observed., Conclusion: Homatropine eye drops may be useful for reducing pain after Photorefractive keratectomy.

With effective treatment of HIV-1, hepatitis C virus (HCV) has become increasingly recognized as a major cause of morbidity and mortality in this population. Rapid progression of liver disease and cirrhosis has been documented in HIV/HCV co-infected individuals, particularly with lower CD4-counts (< 200/μL). Therefore, HCV treatment has become a priority for many clinicians, despite the presence of many. An important issue among HIV/HCV co-infected patients is the selection of antiretroviral therapy (ART) during treatment with pegylated interferon, ribavirin (RBV), plus new HCV protease inhibitors. Extensive drug-drug interactions (DDI) and overlapping drug-associated adverse events can impact the outcome of HCV therapy. In this review, we focus on the important data and studies regarding optimizing antiretroviral regimens before starting HCV treatment in HIV/HCV co-infected patients to increase the chance of sustained virologic response (SVR).

Metformin is a dimethyl biguanide oral anti-hyperglycemic agent. Lactic acidosis due to metformin is a fatal metabolic condition that limits its use in patients in poor clinical condition, consequently reducing the number of patients who benefit from this medication. In a double blind randomized clinical trial, we investigated 200 type 2 diabetic patients after coronary artery bypass surgery in the open heart ICU of the Mazandaran Heart Center, and randomly assigned them to equal intervention and control groups. The intervention group received regular insulin infusion along with 2 metformin 500 mg tablets every twelve hours, while the control group received only intravenous insulin with 2 placebo tablets every twelve hours. Lactate level, pH, base excess, blood glucose and serum creatinine were measured over five 12 h periods, with data averaged for each period. The primary outcome in this study was high lactate levels. Comparison between the 2 groups was made by independent Student's t-test. To compare changes in multiple measures in each group and analysis of group interaction, a repeated measurement ANOVA test was used.There was no significant difference between the 2 groups regarding pH, base excess, or bicarbonate intake (P>0.05). No patient showed lactic acidosis in either group. Lactate levels were 23.0 vs 23.4 in the insulin-metformin and insulin only groups when the study was started, respectively. At the end of the study, those levels were 18.7 vs 18.9, respectively. In addition, the ANOVA repeated measurement test did not show a significant difference in terms of changes in the amount of lactate level between the 2 groups during the five measurement tests of the study period (P>0.05).High-dose metformin (1,000 mg twice daily with insulin) does not cause lactic acidosis in type 2 diabetic patients after coronary artery bypass surgery.

Background: Thoracic endovascular aortic repair is a promising treatment modality. The advantages in the short term include shorter hospital stay, avoidance of lengthy invasive procedures, and decreased anesthesia time. It has made possible the treatment of elderly patients with coexisting comorbidities who otherwise would be difficult candidates for open surgery., Objective: Although the technical aspects of thoracic endovascular procedures have been described in the literature, the adjunct pharmacology has not been discussed. The aim of this study is therefore to review the clinical pharmacology necessary for procedural details in repair of patients with aortic aneurysms and aortic dissection., Methods: A literature search was performed using PUBMED by combining relevant Medical Subject Heading key words. The query was subsequently limited to English language, and involving "human". The articles were assessed for their validity, importance, and applicability. The publications were analyzed and clinically important data were collected and incorporated., Results/conclusion: Thoracic endovascular aortic repair is a complex procedure on a morbid cohort of patients with aortic pathologies. The pharmacotherapy is a crucial component of the procedure: It is aimed at facilitating the endovascular procedure and improving outcomes.

The current adenosine diphosphate inhibitors, ticlopidine and clopidogrel, are thienopyridine compounds that inhibit adenosine diphosphate mediated platelet aggregation. They interfere with platelet activation by selectively and irreversibly blocking P2Y12 sub-unit of the adenosine diphosphate receptor on the surface of platelets. This provides an antiplatelet effect that is additive to the inhibition of the thromboxane A2 pathway by aspirin. Dual antiplatelet therapy is extensively used in cardiovascular medicine. Randomized controlled trials have substantiated the fact that thrombotic complications after percutaneous coronary intervention procedures can be decreased by using dual antiplatelet therapy. However, there is a concern of bleeding due to enhanced and irreversible platelet inhibition in patients who will require any operation including coronary artery bypass grafting while on adenosine diphosphate inhibitors. This applies to a large population of patients requiring either coronary artery bypass grafting after angiographic definition of their coronary anatomy, or patients requiring semi-elective or urgent operation while under dual antiplatelet therapy. This concern is more present in era of drug-eluting stents, where long-term use of dual antiplatelet therapy is encouraged, and the incidence of late thrombosis after late cessation of adenosine diphosphate inhibitors is increasingly surfacing in the literature. The goal this review is to provide the medical chemistry of most commonly used adenosine diphosphate inhibitors, examine the literature on the effect of adenosine diphosphate inhibitors in hemorrhagic-related complications after surgical intervention, and provide the ramifications and alternatives in modern clinical practice.

Daptomycin is a novel bactericidal agent active against Gram-positive pathogens including meticillin-resistant Staphylococcus aureus (MRSA). Our case is unique in the description of an MRSA USA 300 isolate that developed decreased susceptibility to daptomycin during daptomycin and vancomycin therapy. Directed sequencing detected a previously reported mutation in mprF, resulting in a T345A substitution, associated with non-susceptibility to daptomycin.

The pharmacology characteristics of dihydropyridine calcium channel blockers (CCB) make them an attractive antihypertensive medication for use in the perioperative setting of coronary artery bypass graft (CABG) surgery. They lack the negative inotropic, negative chronotropic, and negative bathmotropic effects of phenylalkylamine and benzothiazepine CCB that limit the use in patients with heart failure or patients with bradyarrythmias. With the aging population and significant rise in the prevalence of heart failure, the use of dihydropyridine CCB as antihypertensive medication after CABG surgery has become more common. Furthermore, intravenous dihydropyridine CCB are being used in the perioperative setting as vasodilatory agents after radial artery harvesting for total arterial coronary revascularization. We review the pharmacological effects of intravenous dihydropyridine CCB, analyze the literature, and comment on the consequences in modern clinical practice.