Genetic variation and pesticide exposure influence blood DNA methylation signatures in females with early-stage Parkinson's disease.

Although sex, genetics, and exposures can individually influence risk for sporadic Parkinson's disease (PD), the joint contributions of these factors to the epigenetic etiology of PD have not been comprehensively assessed. Here, we profiled sex-stratified genome-wide blood DNAm patterns, SNP genotype, and pesticide exposure in agricultural workers (71 early-stage PD cases, 147 controls) and explored replication in three independent samples of varying demographics (n = 218, 222, and 872). Using a region-based approach, we found more associations of blood DNAm with PD in females (69 regions) than in males (2 regions, Δßadj| ≥0.03, padj ≤ 0.05). For 48 regions in females, models including genotype or genotype and pesticide exposure substantially improved in explaining interindividual variation in DNAm (padj ≤ 0.05), and accounting for these variables decreased the estimated effect of PD on DNAm. The results suggested that genotype, and to a lesser degree, genotype-exposure interactions contributed to variation in PD-associated DNAm. Our findings should be further explored in larger study populations and in experimental systems, preferably with precise measures of exposure.

The Characteristics, Reliability and Validity of the Persian Version of Simplified Nutritional Appetite Questionnaire (SNAQ).

BACKGROUND/AIMS: Using a reliable and valid instrument to measure appetite is highly important in clinical practice and research. We aimed to evaluate characteristics, reliability and validity of the Persian version of simplified nutritional appetite questionnaire (SNAQ). MATERIAL AND METHODS: After face and content validation of the SNAQ by a panel of experts, the reliability and validity of the Persian form of this questionnaire were assessed among 213 weight-reduction seeking women referring to a nutrition clinic. Furthermore, the factor analysis was performed by varimax rotation method. RESULTS: Confirmatory factor analysis shows that all items of the questionnaire are unified and loaded on one factor of "appetite". Internal consistency of the test was approved by Cronbach's alpha coefficient of 0.7. The test-retest reliability of the questionnaire was performed within a two weeks interval. The Pearson correlation showed a consistency of 0.85 between the two administrations (p<0.0001). Concurrent Validity of SNAQ with other eating questionnaires and visual analogue rating scale for appetite (r=0.7, p<0.001)) shows strong correlation. The SNAQ was positively correlated with total dietary calorie intake (r=0.23, p=0.018) Also convergent validity with body composition measurements shows positive weak correlation with body weight, waist circumference, and total body fat percentage, and negative correlation with muscle mass (divergent validity). CONCLUSION: The current study provides sufficient supports in favor of the reliability and validity of the Persian version of the SNAQ. This questionnaire is a simple and valid instrument to assess the patient's increased appetite in practice and research.

Efficacy and safety of oral insulin compared to subcutaneous insulin: a systematic review and meta-analysis.

INTRODUCTION: A systematic review and meta-analysis of interventional studies was conducted to compare the efficacy and safety of oral insulin versus subcutaneous (SC) insulin in diabetic patients. METHODS: Medline, Scopus, ISI Web of Knowledge and Cochrane Central Register of Controlled Trials were searched. Two independent reviewers evaluated studies for eligibility and quality and extracted the data. The primary outcomes were fasting blood glucose (FBG), 1h and 2h postprandial blood glucose, HbA1c, AUC of insulin, C max and T max of insulin, and T max of glucose infusion rate. Secondary outcomes were adverse events. RESULTS: Eleven studies (n = 373) met the inclusion criteria. Meta-analyses showed that there is no significant difference between oral and SC insulin in controlling HbA1c, FBG, 1 and 2 h postprandial blood glucose and producing C max of insulin (P > 0.05); however oral insulin had faster action as indicated by the shorter T max, compared to SC insulin (P < 0.05). The most included studies were varied in their methodological quality. CONCLUSION: This systematic review and meta-analysis showed that oral insulin is comparable to SC insulin with regard to glycemic efficacy and safety. However, is necessary to conduct additional studies in which oral insulin administered to large number of patients for long enough periods of time.

Seroprevalence of hepatitis A in Iranian adolescents: is it time to introduce a vaccine?

Universal vaccination of children for hepatitis A virus (HAV) has emerged as a cost-effective strategy to prevent this infection in regions with high incidence of symptomatic disease. Age-specific seroprevalence surveys are practical and reliable methods to estimate the rate of susceptibility in populations, and to help the implementation of vaccination policies. We surveyed the age-specific HAV seroprevalence in a nationally representative sample of Iranian adolescent students aged 10-18 years. Serum samples (n = 2494) were tested by enzyme immunoassay for total anti-HAV antibody. The overall rate of HAV seropositivity was 64% [95% confidence interval (CI), 62-66), which increased sharply from 14·8% (95% CI 7-23) at age 10 years to 72·9% (95% CI 68-78) at age 13 years, without a significant increase up to age 18 years. No significant difference in HAV seroprevalence was observed between males and females (63% vs. 65·1%), or urban and rural areas (63·4% vs. 65·2%); the seropositivity rate was similar in four different socioeconomic regions of Iran. We conclude that the seroconversion rate of HAV is high in Iranian adolescents and therefore mass vaccination of children may be necessary and should be considered by national health authorities.

Design and development of intraocular polymeric implant systems for long-term controlled-release of clindamycin phosphate for toxoplasmic retinochoroiditis.

BACKGROUND: The release of the anti-toxoplasmosis drug, clindamycin phosphate, from intraocular implants of the biodegradable polymers poly (D, L-lactic acid) (PLA) and poly (D, L-lactide-co-glycolide) (PLGA) has been studied in vitro. MATERIALS AND METHODS: The preparation of the implants was performed by a melt-extrusion method. The developed extrudates were characterized and compared in in-vitro release profiles for elucidating the drug release mechanism. The formulations containing up to 40% w/w of drug were prepared. Release data in phosphate buffer (pH 7.4) were analyzed by high performance liquid chromatography. The release kinetics were fitted to the zero-order, Higuchi's square-root, first order and the Korsmeyer-Peppas empirical equations for the estimation of various parameters of the drug release curves. Degradation of implants was also investigated morphologically with time (Scanning Electron Microscopy). RESULTS: It was observed that, the release profiles for the formulations exhibit a typical biphasic profile for bulk-eroding systems, characterized by a first phase of burst release (in first 24 hrs), followed by a phase of slower release. The duration of the secondary phase was found to be proportional to the molecular weight and monomer ratio of copolymers and also polymer-to-drug ratios. It was confirmed that Higuchi and first-order kinetics were the predominant release mechanisms than zero order kinetic. The Korsmeyer-Peppas exponent (n) ranged between 0.10 and 0.96. This value, confirmed fickian as the dominant mechanism for PLA formulations (n ≤ 0.45) and the anomalous mechanism, for PLGAs (0.45 < n < 0.90). CONCLUSION: The implant of PLA (I.V. 0.2) containing 20% w/w of clindamycin, was identified as the optimum formulation in providing continuous efficient in-vitro release of clindamycin for about 5 weeks.

Reduction of stroke assessment time for visually guided reaching task on KINARM exoskeleton robot.

Robotic technologies provide objective, highly reliable tools for assessment of brain function following stroke. KINARM is an exoskeleton device that quantifies sensorimotor brain function using a visually guided reaching task among many other behavioral tasks. As further tasks are developed to more broadly assess different aspects of behavior using the robot, techniques and approaches are required to reduce the time it takes to complete each task. The present study investigates how the value of robot-measured parameters changes under alternative schemes that significantly reduce assessment time compared to the current assessment protocol for the visually guided reaching task. Results of the study are validated by addressing an important diagnostic question using an SVM classifier, showing that the alternative schemes provide nearly identical performance in terms of classification sensitivity, specificity and accuracy.

Type I interferon signaling genes in recurrent major depression: increased expression detected by whole-blood RNA sequencing.

A study of genome-wide gene expression in major depressive disorder (MDD) was undertaken in a large population-based sample to determine whether altered expression levels of genes and pathways could provide insights into biological mechanisms that are relevant to this disorder. Gene expression studies have the potential to detect changes that may be because of differences in common or rare genomic sequence variation, environmental factors or their interaction. We recruited a European ancestry sample of 463 individuals with recurrent MDD and 459 controls, obtained self-report and semi-structured interview data about psychiatric and medical history and other environmental variables, sequenced RNA from whole blood and genotyped a genome-wide panel of common single-nucleotide polymorphisms. We used analytical methods to identify MDD-related genes and pathways using all of these sources of information. In analyses of association between MDD and expression levels of 13 857 single autosomal genes, accounting for multiple technical, physiological and environmental covariates, a significant excess of low P-values was observed, but there was no significant single-gene association after genome-wide correction. Pathway-based analyses of expression data detected significant association of MDD with increased expression of genes in the interferon α/ß signaling pathway. This finding could not be explained by potentially confounding diseases and medications (including antidepressants) or by computationally estimated proportions of white blood cell types. Although cause-effect relationships cannot be determined from these data, the results support the hypothesis that altered immune signaling has a role in the pathogenesis, manifestation, and/or the persistence and progression of MDD.

Biotransformation of methyl tert-butyl ether by human cytochrome P450 2A6.

Methyl tert-butyl ether (MTBE) is widely used as gasoline oxygenate and octane number enhancer for more complete combustion in order to reduce the air pollution caused by motor vehicle exhaust. The possible adverse effects of MTBE on human health are of major public concern. However, information on the metabolism of MTBE in human tissues is scarce. The present study demonstrates that human cytochrome P450 2A6 is able to metabolize MTBE to tert-butyl alcohol (TBA), a major circulating metabolite and marker for exposure to MTBE. As CYP2A6 is known to be constitutively expressed in human livers, we infer that it may play a significant role in metabolism of gasoline ethers in liver tissue.

Niosome as a drug carrier for topical delivery of N-acetyl glucosamine.

Niosomes are non-ionic surfactant vesicles that have potential applications in the delivery of hydrophilic and hydrophobic drugs. The topical form of N-acetyl glucosamine (NAG) recently has been considered in the treatment of hyperpigmentation disorders due to its inhibitory effect on thyrosinase enzymes in melanocytes. To improve NAG penetration into the skin we formulated the drug in niosomes and investigated its flux across excised rat skin using Franz diffusion cells. The drug assay was performed by a novel and specific high performance liquid chromatography method. Niosomal vesicles were further characterized by optical and scanning electron microscopy and particle size analysis. Niosomes prepared with Span 40 produced a drug encapsulation of about 50%. The vesicle size was markedly dependent on the composition of the niosome formulations and was in range of 500-4500 nm (Span 80 < Span 60 < Span 40 niosomes). Span 40-niosomes provided a higher NAG flux across the skin than Span 60- and Span 80-nisomes. All formulations significantly improved the extent of drug assessed to be localized in the skin (P< 0.05), as compared to NAG hydroalcoholic (HA) solution. Our study demonstrated the potential of niosomes for improved NAG localization in the skin, as needed in hyperpigmentation disorders.

A neural network based approach for inference and verification of transcriptional regulatory interactions.

In this paper, we present a comprehensive neural network based modeling and validation framework for reverse engineering gene regulatory interactions. We employ two approaches, Gene Set Stochastic Sampling and Sensitivity Analysis, to infer these interactions. We first apply these methods to a simulated artificial dataset to ensure their correctness and accuracy. True biological interactions are then modeled by analyzing a rat hippocampus development dataset. Finally, we present a thorough computational methodology to test the validity and robustness of the inferred regulations through novel assemblies of relevant testing datasets.

High-resolution CT in chronic pulmonary changes after mustard gas exposure.

PURPOSE: To identify the findings of high-resolution CT (HRCT) of the lung in patients with previous sulfur mustard gas exposure, and to correlate these findings with clinical and chest X-ray (CXR) results. MATERIAL AND METHODS: 50 consecutive patients were studied prospectively. The clinical data were recorded. Standard p.a. CXR and HRCT of the lung and spirometry were performed. The findings of CXR, HRCT and clinical and spirometry results were scored between 0 and 3 according to the severity of the findings. RESULTS: HRCT abnormality was detected in all 50 patients (100%), while CXR was abnormal in 40 patients (80%). The most common HRCT findings was airway abnormalities (bronchial wall thickening in 100% of cases). Other important findings were suggestive of interstitial lung disease (ILD) (80%), bronchiectasis (26%), and emphysema (24%). A statistically significant correlation was found between the severity of clinical presentation and that of the HCTR scores in patients with bronchiectasis, bronchitis and ILD (p< 0.05), but not with severity scores of HRCT in patients with emphysema. No significant correlation was found between severity scores of CXR findings. HRCT evidence of bronchial wall thickening and with a lower frequency ILD were present despite normal CXR in 20% of the patients. CONCLUSION: The results of this study suggest that bronchial wall thickening, ILD and emphysema are common chronic pulmonary sequelae of sulfur mustard injury. HRCT of the chest should be considered as the imaging modality of choice in chemical war injury.

Influence of cimetidine co-administration on the pharmacokinetics of acebutolol enantiomers and its metabolite diacetolol in a rat model: the effect of gastric pH on double-peak phenomena.

Acebutolol (AC) is a chiral beta-adrenergic receptor-blocking agent, which has been shown to be clinically effective in hypertension. The plasma concentration-time profiles of AC exhibit two peaks following oral administration of racemate for both R- and S-enantiomers. In the present study, the absorption of AC after a single dose was studied as a function of gastric pH in male Sprague-Dawley rats. Furthermore, the effect of cimetidine (CIM) on pharmacokinetic parameters of AC and its metabolite diacetolol (DC) was evaluated. CIM (50 mg kg(-1)) was administered via jugular vein 30 min prior to AC administration to elevate the intragastric pH. AC (50 mg kg(-1)) was administered orally by gavage and serial blood samples were collected before and for 8h after AC administration. Plasma samples were assayed for AC and DC, pharmacokinetic parameters were estimated and compared with those of control. The concentration-time profiles and the pharmacokinetics of AC were unchanged after co-administration of CIM. The oral absorption of AC, as assessed by the area under the plasma concentration-time curve (AUC) and the amount of unchanged drug recovered in the urine were not affected by CIM. The amount of metabolite recovered in the urine and the rate of absorption, however, were significantly altered. These are unlikely to be of clinically importance as we have found that the extent of absorption was not changed. We, therefore, concluded that intragastric elevation of pH has no effect either on generation of multiple peaking or on pharmacokinetic parameters of AC.

Antihypertensive and antihyperlipidemic effects of Achillea wilhelmsii.

Achillea wilhelmsii C. Koch (Asteraceae) is widely found in different parts of Iran. This plant is full of flavonoids and sesquiterpene lactones, which have been shown to be effective in lowering blood lipids and hypertension. We conducted a double-blind placebo controlled clinical trial to study the antihyperlipidemic and antihypertensive effects of Achillea drops. We randomly selected 120 men and women, aged 40-60 years, and divided them in two distinct groups of moderate hyperlipidemic and primary hypertensive subjects. They were treated either with hydroalcoholic extract or with placebo in the form of 15-20 drops twice daily for more than 6 months. Blood pressure and serum lipids (total cholesterol, triglyceride, low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol) were measured in the groups for 3 periods of 2 months each. The mean and standard deviation of alternations in these variables between the group taking placebo and that taking drugs was calculated by Student's t-test. The results showed a significant decrease in triglycerides after of 2 months while decreases in triglycerides, total cholesterol and LDL-cholesterol were significant after 4 months. Levels of HDL-cholesterol were significantly increased after 6 months' treatment. A significant decrease was observed in diastolic and systolic blood pressure after 2 and 6 months, respectively (p < 0.05).

Pharmacokinetics of metoprolol enantiomers following single and multiple administration of racemate in rat.

The chiral beta-adrenergic blocking agent metoprolol (MET), which is marketed as a racemate, is a highly extracted drug with rapid absorption. The enantiomeric disposition of MET is reported following racemic administration as a single and as multiple oral dosing four times per day for four days in male Sprague-Dawley rats (n=6 in each group). Plasma was collected and enantiomeric concentrations of MET were determined using a stereospecific HPLC assay. The R/S ratio for AUC is not statistically different from unity either after single or after multiple administration of racemate. The oral clearance after single dose was 1.99+/-0.87 and 2. 26+/-0.85 ml min(-1) kg(-1) for R- and S-MET, respectively. These values were decreased to 0.59+/-0.21 and 0.64+/-0.26 ml min(-1) kg(-1) after multiple administration of racemate. The corresponding values for the elimination half-lives were approximately 35 and 33 min after single and multiple dose administration for both enantiomers, respectively. These results may suggest a saturable first pass metabolism of MET as its enantiomers are accumulated in plasma following multiple dosing in the rat model.

Influence of acebutolol and metoprolol on cardiac output and regional blood flow in rats.

Beta-adrenoceptor blocking drugs are widely used as effective antihypertensive and antianginal agents. We have determined the effect of beta-blockade in the rat to ascertain whether there are differences between metoprolol (MET) and acebutolol (AC) with respect to regional blood flow (RBF). Both AC and MET were administered as a single or multiple intravenous (iv) doses in Sprague-Dawley rats. Microspheres labelled with (85)Sr and (141)Ce were used to measure cardiac output (CO) and RBF before and after drug administration. CO and RBF were measured 1 and 10 min after the i.v. administration of AC (30 mg/kg) and MET (10 mg/kg). After acute administration of MET, CO decreased by 65% and 31% after 1 and 10 min measurements, respectively. These values were 54% and 28% for AC as compared with baseline values. After chronic administration of either AC or MET, however, there were no significant reductions in CO as compared with saline. Both MET and AC significantly reduced RBF in most organs either after 1 or 10 min measurements when compared with the baseline values. It is concluded that both AC and MET reduced CO and RBF after acute administration. The CO and RBF however, returned to normal after chronic administration.

Prevalence of hypertension and associated risk factors in Isfahan, Islamic Republic of Iran.

A population-based cross-sectional survey was conducted to determine the mean levels of blood pressure and prevalence rates of hypertension and to identify differences in the prevalence of other risk factors in hypertensive and nonhypertensive people. A total of 8624 men and women > or = 19 years were randomly selected. Overall, 18.0% (16.8% males and 19.4% females) had systemic hypertension. The mean levels of systolic and diastolic blood pressure and the prevalence of hypertension increased with age, but no significant differences were found between the sexes when adjusted for body mass index. There was a high prevalence of obesity, hyperlipidaemia and diabetes mellitus among hypertensive people compared with nonhypertensive. Our study suggests that the prevalence of hypertension in Isfahan is greater than supposed.

Secular trends in cardiovascular mortality in Iran, with special reference to Isfahan.

OBJECTIVE: There has been a general decline in mortality from cardiovascular diseases (CVDs) in most of the developed countries since the beginning of the 1970s. Still, in recent years developing countries have seen an increasing frequency in CVD mortality. However, mortality rate studies in these populations are scarce. Here we report all-cause and CVD mortality rates for men and women aged 25-74 years over a 16-year period in 24 cities in Iran with special reference to the city of Isfahan. METHODS AND RESULTS: The study was based on national death records using the ninth international classification of diseases and age standardization was performed using the total population of Iran in 1985 as a standard. Due to limitations in available data, mortality rates for the specific categories of CVD for the whole country could not be provided. The in-hospital death rates following myocardial infarction in coronary care units (CCUs) and cardiology departments in Isfahan hospitals were also assessed. The completed medical records from hospitals or the relatives of decedents were reviewed by physicians certified in internal medicine, cardiology and neurology to assess the reliability of death certificate data regarding CVD by determining the sensitivity and specificity of the death certificates against the standard of the reviewers. The official circulatory diseases proportional mortality ratio continues to rise since 1981 with a steep increase since 1987, constituting 26.6% and 47.3% of all deaths in 1981 and 1995, respectively. Age-adjusted all-cause and CVD mortality data were decreasing since 1981 and increasing since 1990. During those years age-adjusted CVD, stroke and other CVD mortality rates were decreasing in Isfahan with a slight increase in ischaemic heart disease (IHD) death rates in both sexes. Mortality rates based on sex showed a 38% and 24.8% decline in all-cause and CVD mortality in men between 1981 to 1995, and a 35% and 34.9% decline for female mortality rates for the same period, respectively. The in-hospital death rate following myocardial infarction in Isfahan was increasing between 1993 and 1995 with a slight decrease thereafter. The results of death certification assessment showed a specificity of 0.89 and a sensitivity of 0.43 with the positive and negative predictive values of 0.82 and 0.57, respectively. CONCLUSION: These data indicate that circulatory diseases remain a serious public health threat in Iran. It suggests the ongoing need for more regular, systematic and innovative surveillance data to improve the capability of measuring, explaining and predicting the disease trend on which the national public health policy depends.

Prevalence of hypertension and associated risk factors in Isfahan, Islamic Republic of Iran

A population-based cross-sectional survey was conducted to determine the mean levels of blood pressure and prevalence rates of hypertension and to identify differences in the prevalence of other risk factors in hypertensive and nonhypertensive people. A total of 8624 men and women > or = 19 years were randomly selected. Overall, 18.0% [16.8% males and 19.4% females] had systemic hypertension. The mean levels of systolic and diastolic blood pressure and the prevalence of hypertension increased with age, but no significant differences were found between the sexes when adjusted for body mass index. There was a high prevalence of obesity, hyperlipidaemia and diabetes mellitus among hypertensive people compared with nonhypertensive. Our study suggests that the prevalence of hypertension in Isfahan is greater than supposed

Pharmacokinetics of single oral and multiple intravenous and oral administration of acebutolol enantiomers in a rat model.

Acebutolol (AC), is a chiral, beta-adrenergic blocking agent which possesses partial agonist activity and is metabolized to an equipotent chiral metabolite, diacetolol (DC). The enantiomeric disposition of AC is reported following racemic administration as a single oral (p.o., 50 mg kg(-1)) or as a multiple thrice daily intravenous (i.v.) or p.o. dosing for four days in male Sprague-Dawley rats (n = 6). Enantiomeric concentrations of AC and DC in plasma and urine were determined using a stereospecific HPLC assay. The bioavailabilities of R- and S-enantiomer were 0.40 and 0.39 after single dose administration of AC respectively. These values were increased to 0.51 and 0.53 after multiple dosing. Although no significant differences were found in AUC0-infinity after single i.v. as compared with AUC0-tau after multiple i.v. dosing of AC, the 39 and 45% increase in mean AUC0-tau were found after multiple p.o. dosing over the corresponding AUC0-infinity, for the single p.o. dose of AC for R- and S-enantiomer, respectively. The disposition of DC as well as the urinary excretion of metabolite was stereoselective in favor of R-enantiomer after oral administration of AC. These results indicate that AC enantiomers have low availability and moderate extraction through the first-pass metabolism in a rat model. The higher AUC values after p.o. multiple dosing may suggest a saturable first-pass metabolism of AC.

Pharmacokinetics of acebutolol enantiomers after intravenous administration of racemate in a rat model: a dosing range comparison.

Acebutolol (AC) is a chiral beta-adrenergic blocking drug, possessing intrinsic sympathomimetic activity (ISA), and is useful clinically as the racemate in treating hypertension. Utilizing a stereospecific high-performance liquid chromatographic (HPLC) assay, the enantiomeric disposition of AC and its major metabolite diacetolol (DC) are reported after intravenous administration of single 5, 15, 30, and 50 mg kg-1 doses of racemate to male Sprague-Dawley rats. The mean area under the plasma concentration versus time curve (AUC) values display a linear relationship with respect to the administered dose. No statistical differences are observed in apparent volume of distribution (Vd), terminal elimination half-life (t1/2), total body clearance (Clt), or renal clearance (Clr) with respect to dose administered. Generally, R-S ratios for AUC following AC administration are statistically different from unity (p < 0.05). However, for the 50 mg kg-1 doses the R-S ratio for AUC is not statistically different from one. For DC, the plasma disposition is nonstereoselective in plasma. The amount of R-DC recovered in urine, however, was greater than that of the antipode (R:S = 1.92 +/- 0.29). This study suggests that the enantiomeric disposition of intravenous AC is linear within the investigated range of 5-50 mg kg-1 racemate in rats.