Analysis of carbapenemases genes of carbapenem-resistant Klebsiella pneumoniae isolated from Tehran heart center.

Background and Objectives: Emerging of carbapenem-resistant Klebsiella pneumoniae (CRKP) is one of the major concerns among healthcare systems. This study aimed to investigate the antibiotic susceptibility pattern and carbapenemase genes of carbapenemase-producing K. pneumoniae isolates obtained from Iranian hospitalized patients. Materials and Methods: This study was performed on 71 CRKP strains isolated from different clinical specimens collected in Tehran Heart Center (Tehran, Iran). A Modified Hodge test (MHT) was done for the detection of carbapenemase-producing K. pneumoniae. The presence of bla KPC, bla VIM, bla IMP, bla NDM, and bla OXA-48 -type carbapenemases was evaluated by the PCR method. Results: We identified 8.82% (71/805) of K. pneumoniae isolates as CRKP by MHT test. The antibiotic susceptibility indicated that all isolates were resistant to imipenem, meropenem, cefotaxime, ceftazidime, cefepime, ceftriaxone, cephalothin, ciprofloxacin, and augmentin, and then mostly resistant to aztreonam, cefoxitin, gentamicin, and trimethoprim/sulfamethoxazole with 98.6%, 98.6%, 97.2%, and 94.4%, respectively. The lowest resistance was related to amikacin with 46.5% (33/71 isolates). The level of imipenem MIC for all carbapenem-resistant isolates was estimated ≥32 µg/mL. Among positive isolates for carbapenemase genes, the most frequent gene was bla OXA-48. It was found in 48 (67.6%) isolates followed by bla VIM in 28 (39.4%) isolates. bla IMP, bla NDM, and bla KPC genes were identified in 19 (26.8%), 13 (18.3%) and 5 (7.0%) isolates, respectively. These genes were not detected in nine isolates. Conclusion: The relatively high frequency of some carbapenemase genes suggests major concern about the emergence of isolates containing carbapenem resistance genes as a potential health threat.

Association between rs3088440 (G > A) polymorphism at 9p21.3 locus with the occurrence and severity of coronary artery disease in an Iranian population.

BACKGROUND: Several genome-wide association studies showed that a series of genetic variants located at the chromosome 9p21 locus are strongly associated with coronary artery disease (CAD). RATIONALE AND PURPOSE OF THE STUDY: In the present study, the relationship of rs3088440 (G > A) in cyclin-dependent kinase inhibitor 2A (CDKN2A) gene site with the presence of coronary artery disease (CAD) and its severity was evaluated in an Iranian population. METHODS AND RESULTS: The presence of rs3088440 (G > A) genotypes was assessed by polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) technique in 324 CAD patients and 148 normal controls. rs3088440 (G > A) polymorphism was associated with increased risk of CAD in the total population (adjusted OR = 1.76, 95% CI = 1.10-2.82; p-value = 0.017) or in women (adjusted OR = 2.96, 95% CI = 1.34-6.55; p-value = 0.007), but not in the men (adjusted OR = 1.35, 95% CI = 0.70-2.6; p-value = 0.368). CONCLUSIONS: Our findings suggest that the presence of rs3088440 (G > A) is potentially linked with the risk of CAD and its severity in whole study subjects or in women only, independent of CAD risk factors.

Predictive Inflammation-related microRNAs for Cardiovascular Events Following Early-Onset Coronary Artery Disease.

BACKGROUND: Early-onset coronary artery disease (EOCAD) increases the risk of major cardiac adverse events (MACE) at the level of safety/effectiveness-related events. Since adverse events affect the quality of life of young patients with EOCAD, MACE prediction is of great importance for improving medical decision-making. AIMS OF THE STUDY: We sought to determine whether the most important inflammation-related microRNAs in atherogenesis could predict MACE among patients with EOCAD. METHODS: This nested case-control study recruited 143 young patients (males ≤45 and females ≤55 years old), selected from a cohort of patients with premature coronary atherosclerosis at a median follow-up period of 64.1 months. Total RNAs were extracted from their peripheral blood mononuclear cells. The expression levels of 18 miRNAs, which are involved in inflammation and atherogenesis, were analyzed via quantitative reverse transcription PCR. RESULTS: A scoring model based on the upregulation of miR-146a_1 and miR-342_1, along with a history of myocardial infarction and the chronic usage of antithrombotic drugs, was able to predict MI/death at the level of safety-related events (higher vs lower risk scores: sHR: 4.61, 95% CI: 1.57-13.57, and p = 0.005). Another prediction model based on the downregulation of miR-145_1, age, and a history of unstable angina was also able to predict revascularization at the level of effectiveness-related events (higher vs lower risk scores: sHR: 2.90, 95% CI: 1.49-5.66, and p = 0.002). CONCLUSIONS: Our results highlighted the role of miRNAs in adverse cardiac events and suggest that miR-146a_1, miR-342_1, and miR-145_1 may be useful biomarkers in predictive and preventive cardiology.

Association of Preoperative Hemoglobin A1c with In-hospital Mortality Following Valvular Heart Surgery.

OBJECTIVE: To determine the association between the preoperative level of hemoglobin A1c (HbA1c) and in-hospital mortality in patients who underwent valvular heart surgery in our center in a retrospective cohort. METHODS: In this retrospective consecutive cohort study, patients with type 2 diabetes mellitus who were referred to our center for elective valvular surgery were enrolled and followed up. The endpoint of this study was in-hospital mortality. Based on the level of HbA1c, patients were dichotomized around a level of 7% into two groups: exposed patients with HbA1c ≥ 7% and unexposed patients with HbA1c < 7%. Then, the study variables were compared between the two groups. RESULTS: Two hundred twenty-four diabetic patients who were candidates for valvular surgery were enrolled; 106 patients (47.3%) had HbA1c < 7%, and 118 patients (52.6%) had HbA1c ≥ 7%. The duration of diabetes was higher in patients with HbA1c ≥ 7% (P=0.007). Thirteen (5.8%) patients died during hospital admission, of which nine patients were in the high HbA1c group. There was no significant difference between the groups regarding in-hospital mortality (P=0.899). Both the unadjusted and adjusted logistic regression models showed that HbA1c was not a predictor for in-hospital mortality (P=0.227 and P=0.388, respectively). CONCLUSION: This study showed no association between preoperative HbA1c levels and in-hospital mortality in candidates for valvular heart surgery.

Association of preoperative hemoglobin a1c with in-hospital mortality following valvular heart surgery

Abstract Objective: To determine the association between the preoperative level of hemoglobin A1c (HbA1c) and in-hospital mortality in patients who underwent valvular heart surgery in our center in a retrospective cohort. Methods: In this retrospective consecutive cohort study, patients with type 2 diabetes mellitus who were referred to our center for elective valvular surgery were enrolled and followed up. The endpoint of this study was in-hospital mortality. Based on the level of HbA1c, patients were dichotomized around a level of 7% into two groups: exposed patients with HbA1c ≥ 7% and unexposed patients with HbA1c < 7%. Then, the study variables were compared between the two groups. Results: Two hundred twenty-four diabetic patients who were candidates for valvular surgery were enrolled; 106 patients (47.3%) had HbA1c < 7%, and 118 patients (52.6%) had HbA1c ≥ 7%. The duration of diabetes was higher in patients with HbA1c ≥ 7% (P=0.007). Thirteen (5.8%) patients died during hospital admission, of which nine patients were in the high HbA1c group. There was no significant difference between the groups regarding in-hospital mortality (P=0.899). Both the unadjusted and adjusted logistic regression models showed that HbA1c was not a predictor for in-hospital mortality (P=0.227 and P=0.388, respectively) Conclusion: This study showed no association between preoperative HbA1c levels and in-hospital mortality in candidates for valvular heart surgery.

The association between CYBA gene C242T variant and risk of metabolic syndrome.

BACKGROUND: Both inflammation and oxidative stress may contribute to pathogenesis of metabolic syndrome (MetS). The C242T polymorphism (rs4673) in the CYBA gene, as the main components of NAD (P) H oxidase, causes inter-individual variability in the enzyme activity. We aimed to investigate the association between this polymorphism with MetS and its components. METHODS: Two hundred nine patients with MetS and 232 controls were included in this study. MetS was defined based on NCEP ATP-III A criteria with some modifications. The C242T polymorphism within CYBA gene was determined by using PCR-based restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: After applying a multiple logistic regression model with adjusting for potential confounders of MetS including, age, sex, body mass index, hypertension, used medications, and diabetes mellitus, C242T polymorphism was found to be associated with the presence of MetS in men but not in the total population or in women. T allele as compared to C allele was associated with decreased odds of MetS in men (adjusted OR = 0.42, 95% CI = 0.24-0.74; P = .003), but not in women (adjusted OR = 1.03, 95% CI = 0.07-1.61; P = .890), or in the total population (adjusted OR = 0.72, 95% CI = 0.51-1.02; P = .063). CONCLUSION: This study shows that T allele of C242T polymorphism in CYBA gene is protective against MetS in Iranian men but not in women. Further cohort studies with larger sample size in subgroups of men and women are required to confirm such association in other racial or ethnic group.

Association between polymorphisms in microRNA seed region and warfarin stable dose.

BACKGROUND: The optimal dose of anticoagulant warfarin varies among patients to achieve the target international normalised ratio. Although genetic variations related to warfarin pharmacokinetics and vitamin K cycle are important factors associated with warfarin dose requirements, these variations do not completely explain the large interindividual variability observed in the most populations, suggesting that additional factors may contribute to this variability. microRNAs have recently been introduced as regulators of drug function genes, and therefore, may be involved in drug responses. In this study, we aimed to evaluate the possible association between variants in the seed region of microRNAs, which target the genes involved in the action of warfarin and warfarin dose requirement. METHODS: 526 samples were collected from Iranian patients. Four selected polymorphisms in the seed region of microRNAs (rs2910164, rs66683138, rs12416605 and rs35770269 in miR-146a, miR-3622a, miR-938 and miR-449c, respectively) were genotyped by PCR-restriction fragment length polymorphism method. RESULTS: rs2910164 C/G in the seed region of miR-146a was associated with warfarin dose requirement (p<0.001); the patients with GG genotype had the higher mean dose of warfarin (40.6 mg/week, compared with 33.9 and 31.8 mg/week for GC and CC genotypes, respectively). The association of other polymorphisms with warfarin dose requirement was not statistically significant. CONCLUSION: rs2910164 C/G in the seed region of miR-146a is associated with warfarin maintenance dose, likely by disrupting interaction between miR-146a and ATP-binding cassette subfamily B member 1 gene, ABCB1. Therefore, this polymorphism may possibly be a potential factor for assessment of warfarin dose requirements.

Association between four microRNA binding site-related polymorphisms and the risk of warfarin-induced bleeding complications.

Bleeding is the most serious complication of warfarin anticoagulation therapy and is known to occur even at patients with therapeutic international normalized ratio (INR) range. Recently, it has been shown that microRNAs play a significant role in pharmacogenetics by regulating genes that are critical for drug function. Interaction between microRNAs and these target genes could be affected by single-nucleotide polymorphisms (SNPs) located in microRNA-binding sites. This study focused on 3'-untranslated region (3'-UTR) SNPs of the genes involved in the warfarin action and the occurrence of bleeding complications in an Iranian population receiving warfarin. A total of 526 patients under warfarin anticoagulation therapy with responding to the therapeutic dose and maintenance of the INR in the range of 2.0-3.5 in three consecutive blood tests were included in the study. Four selected 3'-UTR SNPs (rs12458, rs7294, rs1868774 and rs34669593 located in GATA4, VKORC1, CALU and GGCX genes, respectively) with the potential to disrupt/eliminate or enhance/create microRNA-binding site were genotyped using a simple PCR-based restriction fragment length polymorphism (PCR-RFLP) method. Patients with the rs12458 AT or TT genotypes of the GATA4 gene had a lower risk of bleeding compared to patients with the AA genotype (adjusted OR: 0.478, 95% CI: 0.285-0.802, P= 0.005, OR: 0.416, 95% CI: 0.192-0.902, P= 0.026, respectively). 3'-UTR polymorphisms in other genes were not significantly associated with the risk of bleeding complications. In conclusion, the SNP rs12458A>T in the 3'UTR region of GATA4 is associated with the incidence of warfarin-related bleeding at target range of INR, likely by altering microRNA binding and warfarin metabolism. Further genetics association studies are needed to validate these findings before they can be implemented in clinical settings.

Prothrombin Gene G20210A Variant in Angiographically Documented Patients with Coronary Artery Stenosis.

Background: Studies on the association between the prothrombin G20210A variant and coronary artery disease (CAD) risk are inconclusive. This study aimed to investigate the possible association between the G20210A variant in the prothrombin gene and documented CAD and its severity. Methods: This study enrolled 1460 patients who were consecutively admitted for elective coronary angiography. Via the standard angiographic techniques, coronary angiographies were done and the presence and severity of CAD were determined through the clinical vessel score and the Gensini score. Prothrombin G20210A genotypes were identified using PCR-RFLP. Results: This cross-sectional study was performed on 953 men and 507 women at a mean age of 58.21±10.33 years. The median and the interquartile range for the Gensini score were not statistically significantly different between the wild (GG) and mutant (AA+GA) genotypes (P=0.440). The association between the G20210A polymorphism and the severity of CAD with respect to the vessel score also showed no significant linear trend of higher numbers of diseased vessels (P= 0.765 for the Mantel-Haenszel test of linear trend) in the AA+GA genotype as compared with the GG genotype. Conclusion: Our data failed to confirm the hypothesis that the G20210A variant mutation may be a significant determinant of CAD risk or its severity.

Oxidative stress in opium users after using lead-adulterated opium: The role of genetic polymorphism.

Use of lead-adulterated opium has become one of the major sources of lead poisoning in Iran. This study was designed to assess clinical effects and oxidative stress and its association with GSTM1, GSTT1, NQO1, and ALAD genes polymorphisms and blood lead level (BLL) in lead-adulterated opium users. The oxidative stress status in 192 opium users with lead poisoning symptoms measured and compared with 102 healthy individuals. Gluthatione S-transferase (GST)-M1 and -T1 genes deletion, NQO1 rs1800566, and δ-aminolevulinic acid dehydratase (ALAD) rs1800435 polymorphisms were determined using PCR and PCR-RFLP. The relation between the polymorphisms, BLL, and oxidative stress parameters were analysed using multivariate linear regressions. The common symptoms of lead toxicity were gastrointestinal and neurologic complications. Oxidative stress was significantly higher in opium addicts and lipid peroxidation significantly correlated with BLL. There was significant association between ALAD rs1800435 and BLL, and the BLL was significantly lower in the patients with ALAD 1-2 genotype. Use of lead-adulterated opium causes high frequency of lead toxicity symptoms, hematological and biochemical abnormalities, and oxidative stress which are associated with BLL. Route of opioid use and the polymorphism of rs1800435 in ALAD gene are the major determinants of BLL in lead-adulterated opium users.

Hematological Abnormality, Oxidative Stress, and Genotoxicity Induction in the Greenhouse Pesticide Sprayers; Investigating the Role of NQO1 Gene Polymorphism.

The widespread use of pesticides in agriculture represents a threat to the human populations exposed to them. In this cross-sectional study, the hematological and biochemical parameters, plasma cholinesterase (PChE) activity, oxidative stress, genotoxicity, and NAD(P)H: quinone oxidoreductase 1 (NQO1) C609T polymorphism were measured in 100 greenhouse workers occupationally exposed to pesticide mixture and 104 normal healthy controls. There was a decrease in erythrocytes (5.45%, p = 0.026) and hemoglobin (3.26%, p = 0.025), and an increase in mean corpuscular hemoglobin (3.54%, p = 0.013) in the exposed workers. Sprayers showed a reduction in PChE (23%) and GSH (50%) levels, and an increase in lipid peroxidation (LPO) (55%), protein carbonyl (145%), Superoxide dismutase activity (61%), and total antioxidant capacity (35%) (p < 0.001 for all parameters but LPO: p = 0.009). Genotoxicity parameters were significantly high in the exposed cases (for all parameters: p < 0.001 but tail length: p = 0.002). There was a significant correlation between oxidative stress and genotoxicity parameters, and also between these biomarkers and PChE activity. The NQO1 C609T polymorphism was not significantly associated with studied biomarkers. The findings indicate that occupational exposure to a mixture of pesticides can induce hematotoxicity, oxidative stress, and genotoxicity in greenhouse workers.

Pirfenidone protects against paraquat-induced lung injury and fibrosis in mice by modulation of inflammation, oxidative stress, and gene expression.

In this study we investigated the protective effects and possible mechanisms of pirfenidone (PF) in paraquat (PQ)-induced lung injury and fibrosis in mice. Lung injury was induced by injection of PQ (20 mg/kg). Thereafter, mice orally received water and PF (100 and 200 mg/kg) for four weeks. After 28 days, the inflammation and fibrosis were determined in the lungs by analysis of histopathology, bronchoalveolar lavage fluid (BALF) cell count, lung wet/dry weight ratio, hydroxyproline content, and oxidative stress biomarkers. Expression of several genes involved in fibrogenesis and modulation of reactive oxygen species (ROS) production, such as TGF-ß1, α-SMA, collagen Iα and IV, NOX1, NOX4, iNOS, and GPX1 were determined using RT-qPCR. PF significantly decreased the lung fibrosis and edema, inflammatory cells infiltration, TGF-ß1 concentration, and amount of hydroxyproline in the lung tissue. PF dose-dependently improved the expression level of the studied genes to the near normal. Decreasing of lung lipid peroxidation and catalase activity, and increasing of SOD activity in the treated mice were significant compared to the control group. Pirfenidone ameliorate paraquat induced lung injury and fibrosis partly through inhibition of inflammation and oxidative stress, and downregulation of genes encoding for profibrotic cytokines and enzymatic systems for ROS production.

Association between the Hepatic Lipase Promoter Region Polymorphism (-514 C/T) and the Presence and Severity of Premature Coronary Artery Disease.

Background: Hepatic lipase (HL) plays a crucial role in lipid metabolism, but there is debate about whether HL acts in a more pro- or more anti-atherogenic fashion. We aimed to examine the relationship between the -514 C/T polymorphism within the HL gene (LIPC) and the risk of angiographically determined premature coronary artery disease (CAD). Methods: Four hundred seventy-one patients with newly diagnosed angiographically documented (≥ 50% luminal stenosis of any coronary vessel) premature CAD were compared to 503 controls (subjects with no luminal stenosis in coronary arteries). A real-time polymerase chain reaction and high-resolution melting analysis was used to distinguish between the genotypes. Results: There was no significant difference in the distribution of -514 C/T genotypes between the 2 groups in the whole population or in the men, but the examined polymorphism was found to be associated with the presence of CAD in the women (p value = 0.029). After the application of a multiple logistic regression model, the minor T allele of the LIPC gene was not found to be independently associated with the presence of CAD either in the total population (adjusted OR = 0.97, 95% CI = 0.75-1.25; p value = 0.807) or in the women (adjusted OR = 0.91, 95% CI = 0.59-1.40; p value = 0.650) and in the men (adjusted OR = 1.15, 95% CI = 0.81-1.64; p value = 0.437) separately. Conclusion: Our findings suggest that there is no relationship between the LIPC -514 C/T and the risk of premature CAD or its severity in patients undergoing coronary angiography.

Analysis of virulence genes and accessory gene regulator (agr) types among methicillin-resistant Staphylococcus aureus strains in Iran.

OBJECTIVES: Methicillin-resistant Staphylococcus aureus (MRSA) strains are a major cause of hospital-acquired infections and are considered a serious public health concern. MRSA isolates have abundant virulence factors that are the basis for their pathogenicity. The accessory gene regulator (agr) locus co-ordinates the expression of these genes. The aim of this study was to determine the presence and frequency of various virulence genes encoding enterotoxins and adhesins as well as to identify agr specificity groups in MRSA isolates. METHODS: This descriptive study included a total of 296 MRSA strains isolated from clinical samples collected in Tehran Heart Center (Tehran, Iran) between October 2004 and March 2013. Following DNA extraction, PCR-based assays were used to evaluate the presence of various virulence genes. IBM SPSS Statistics for Windows v.21.0 was used for statistical analysis. RESULTS: The results indicated that the most frequent toxin genes were see (120/296; 40.5%), followed by sea (79/296; 26.7%); the other genes were encoded less frequently. The presence of seb and seh was not found in any of the isolates. Furthermore, the most frequent adhesin genes were clfA, spa, cna, map/eap and bbp, found in 281 (94.9%), 275 (92.9%), 267 (90.2%), 265 (89.5%) and 264 (89.2%) isolates, respectively. The majority of isolates belonged to agr group I (53.0%), followed by agr group III (1.4%). None of the isolates belonged to agr group II. CONCLUSIONS: The relatively high frequency of various virulence genes suggests the emergence and pathogenic potential of MRSA isolates containing these genes in the study area.

Association between herpes simplex virus Types 1 and 2 with cardiac myxoma.

Most cases of atrial myxoma are sporadic, and the exact etiology is unknown. We examined if herpes simplex virus (HSV)-1 and HSV-2 antigens and/or DNA could be detected in a cohort of Iranian patients with cardiac myxomas. From July 2004 to June 2014, among a total of 36,703 patients undergoing open heart surgeries, consecutive patients with cardiac myxoma who were treated by surgical excision at our center included in this study. Of 73 patients studied, 56% were female with a mean age of 54 years (ranging from 23 to 77 years). Seventy-four myxomas were surgically removed from 73 patients, since one patient had two myxomas which were located on both the right atrium and right ventricle. The materials for this analysis were retrospectively gathered from extracted tumors that stored in a pathology bank of tissue paraffin blocks. The formalin fixed paraffin embedded tissue samples were investigated for HSV genomic DNA by both immunohistochemistry (IHC) and polymerase chain reaction (PCR) analysis. In all 74 cases there was no presence of HSV 1 and HSV 2 infection. This suggests that HSV may not play a role in sporadic cardiac myxomas; however, evidence for such association is currently lacking, and further studies are required to determine such a role.

The impact of vascular endothelial growth factor +405 C/G polymorphism on long-term outcome and severity of coronary artery disease.

BACKGROUND: The association between genetic variations of vascular endothelial growth factor (VEGF) gene and the risk for atherosclerosis has been hypothesized. We aimed to assess the relationship between rs2010963 (+405 C/G) polymorphism and presence, severity, and outcome of coronary artery disease (CAD) in an Iranian cohort. METHODS: Genotyping of VEGF rs2010963 polymorphism was performed on 520 individuals, comprising 347 patients with documented coronary artery disease based on angiography report and 173 individuals with normal coronary arteries, using the TaqMan real-time PCR method. In final, 484 subjects were followed up over a 5-year period for cardiovascular-related outcomes. RESULTS: C allele of VEGF rs2010963 polymorphism was related to increase risk for CAD and also slightly to 5-year cardiovascular mortality. The 5-year survival in C and G allele subgroups were 92.3% and 94.3% in CAD group and 95.7% and 98.0% in non-CAD group, respectively. CONCLUSIONS: Vascular endothelial growth factor rs2010963 polymorphism may be associated with the presence of CAD and its long-term survival, but not with its severity. To the best of our knowledge, this is the first report of genetic association between rs2010963 SNP and CAD-related death. It can be thus suggested that rs2010963 VEGF gene can be considered as a genetic risk predictor for CAD and its outcomes.

NQO1 C609T Polymorphism is Associated with Coronary Artery Disease in a Gender-Dependent Manner.

Findings on the association of NQO1 C609T polymorphism in the NQO1 gene and cardiovascular disease susceptibility are controversial. The objective of the current study was to examine the relationship between this polymorphism and the presence and severity of angiographically determined coronary artery disease (CAD). One-hundred and forty-five patients with newly diagnosed angiographically documented CAD (≥50 % luminal stenosis of any coronary vessel) as case group were compared to 139 controls (subjects with no luminal stenosis at coronary arteries). The presence of C609T polymorphism was analyzed using polymerase chain reaction-based restriction fragment length polymorphism. Among total population, those with combined CT/TT (T allele carrier) genotype showed a trend toward lower odds of CAD compared to those with CC (wild type) genotype, but it did not reach a statistically significant level (p = 0.061). When data were analyzed separately for men or women, CT + TT group as compared to CC genotype was associated with decreased odds of CAD in women (adjusted OR 0.4, 95 % CI 0.2-0.9; p = 0.043), but not in men (adjusted OR 0.8, 95 % CI 0.3-1.9; p = 0.612). The C609T polymorphism within NQO1 is independently associated with CAD in women, but no association was observed in whole study population or in men.

Gene polymorphisms and the risk of warfarin-induced bleeding complications at therapeutic international normalized ratio (INR).

BACKGROUND: Bleeding episodes commonly occur in patients on warfarin treatment even in those within therapeutic range of international normalized ratio (INR). The objective of this study was to investigate the effects of the 8 examined polymorphisms on the risk of bleeding complications in a sample of Iranian patients. METHODS: A total of 552 warfarin treated patients who maintained on a target INR level of 2.0-3.5 for at least three consecutive intervals were enrolled from those attended our anticoagulation clinics. Ninety-two bleeding events were observed in 87 patients. The presences of the examined polymorphisms were analyzed using polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP). RESULTS: Patients with the T allele in NQO1*2 (CT or TT genotypes) had a higher risk of bleeding than patients with the CC genotype (adjusted OR: 2.25, 95% CI: 1.37 to 3.70, P=0.001). Those who were carriers of CYP2C9 one-variant haplotypes (*1/*2 or *1/*3) were also found to be associated with the higher risk of bleeding events. Compared to reference group (*1/*1), the odds of bleeding increased for carriers of one variant allele (*1/*2 or *1/*3) (adjusted OR: 1.75, 95% CI: 1.03 to 2.97, P=0.039). Variant VKORC1, Factor VII, and EPHX1 genotypes were not significantly associated with the risk of bleeding events. CONCLUSION: The SNP C609T within NQO1 and haplotypes of CYP2C9 (1*2 or 1*3) are independently associated to bleeding complications of warfarin at normal INR. Further studies are required to confirm such associations in diverse racial and ethnic populations.

Thymoquinone effectively alleviates lung fibrosis induced by paraquat herbicide through down-regulation of pro-fibrotic genes and inhibition of oxidative stress.

The potential preventive and therapeutic effects of thymoquinone (TQ) and its molecular mechanism were evaluated in paraquat (PQ)-induced pulmonary fibrosis in mice. TQ was administered orally at the doses of 20 and 40mg/kg during the course and after development of fibrosis. Pathological changes, expressions of genes involved in fibrogenesis, hydroxyproline (HP) and oxidative stress parameters were determined in the lung tissues. TQ dose-dependently recovered the pathological changes induced by PQ. TQ decreased hydroxyproline content, lipid peroxidation and restored the antioxidant enzymes to the normal values. In molecular level, expressions of TGF-ß1, α-SMA, collagen 1a1 and collagen 4a1 genes were also returned to the control level by TQ. This study indicated that TQ has the preventive and therapeutic potentials for the treatment of lung fibrosis by inhibition of oxidative stress and down-regulation of profibrotic genes.

Association between the atrial natriuretic peptide rs5065 gene polymorphism and the presence and severity of coronary artery disease in an Iranian population.

OBJECTIVE: The atrial natriuretic peptide (ANP) gene expression and some of its related single-nucleotide polymorphisms have been well established as a characterized biomarker of cardiovascular diseases. In the present study, we aimed to evaluate the potential association between one of the introduced ANP gene polymorphisms of 2238 T/C (rs5065) with coronary artery disease (CAD) in an Iranian population. BASIC METHODS: A total of 573 patients with CAD according to angiography reports and 293 controls without any evidence of CAD were enrolled. Allelic discrimination of the single-nucleotide polymorphism rs5065 in both groups was performed using a High Resolution Melt technique in real-time PCR analysis. MAIN RESULTS: With respect to the prevalence of different genotypes of rs5065 polymorphism, the frequency of the T allele in the CAD group was significantly lower in CAD than that in the non-CAD group (59.7 vs. 65.1%, P=0.032). A significant inverse association was also found between the frequency of T allele and severity of CAD assessed by the Gensini score; the average of this score in T-allele carriers was 38.6±41.6 and that in C-allele carriers was 57.7±46.3 (P≤0.0001). Using multivariable linear regression modeling with the presence of baseline variables, the presence of the rs5065 ANP T allele could predict decreased severity of CAD assessed by the Gensini score in our population. PRINCIPAL CONCLUSION: The presence of the rs5065 ANP polymorphism is potentially associated with a reduced risk of CAD as well as with reduced severity of CAD independent of the general risk factors of CAD.