The Detrimental Effect of Pre-Treatment with Ivermectin on Myocardial Ischemia.

INTRODUCTION: Ivermectin (IVM) is a broad-spectrum anti-parasitic agent with potential antibacterial, antiviral, and anti-cancer effects. There are limited studies on the effects of IVM on cardiovascular diseases, so the present study sought to determine the effects of pre-treatment with IVM on myocardial ischemia in both ex vivo and in vivo. METHODS: In the ex vivo part, two groups of control and treated rats with IVM (0.2 mg/kg) were examined for cardiac function and arrhythmias by isolated heart perfusion. In the in vivo part, four groups, namely, control, IVM, Iso (MI), and Iso + IVM 0.2 mg/kg were used. Subcutaneous injection of isoproterenol (100 mg/kg/day) for 2 consecutive days was used for the induction of myocardial infarction (MI) in male Wistar rats. Then electrocardiogram, hemodynamic factors, cardiac hypertrophy, and malondialdehyde (MDA) levels were investigated. RESULTS: The ex vivo results showed that administration of IVM induces cardiac arrhythmia and decreases the left ventricular maximal rate of pressure increase (contractility) and maximal rate of pressure decline (relaxation). The isoproterenol-induced MI model used as an in vivo model showed that cardiac hypertrophy were increased with no improvement in the hemodynamic and electrocardiogram pattern in the IVM-treated group in comparison to MI (Iso) group. However, the MDA level was lower in the IVM-treated group. CONCLUSION: IVM pre-treatment demonstrates detrimental effects in cardiac ischemia through exacerbation of cardiac arrhythmia, myocardial dysfunction, and increased cardiac hypertrophy. Therefore, the use of IVM in ischemic heart patients should be done with great caution.

Evaluation of a warfarin dosing algorithm including CYP2C9, VKORC1, and CYP4F2 polymorphisms and non-genetic determinants for the Iranian population.

BACKGROUND: The response to warfarin, as an oral anticoagulant agent, varies widely among patients from different ethnic groups. In this study, we tried to ascertain and determine the relationship between non-genetic factors and genetic polymorphisms with warfarin therapy; we then proposed a new warfarin dosing prediction algorithm for the estimation of drug sensitivity and resistance in the Iranian population. METHODS: Overall, 200 warfarin-treated patients with stable doses were recruited, the demographic and clinical characteristics were documented, and genotyping was done using a sequencing assay. RESULTS: The outcomes of our investigation showed that the genetic polymorphisms of VKORC1(-1639 G > A), CYP2C9*3, CYP2C9*2, amiodarone use, and increasing age were found to be related to a significantly lower mean daily warfarin dose. In contrast, the CYP4F2*3 variant and increased body surface area were linked with an increased dose of warfarin in the Iranians. Our descriptive model could describe 56.5% of the variability in response to warfarin. This population-specific dosing model performed slightly better than other previously published warfarin algorithms for our patient's series. Furthermore, our findings provided the suggestion that incorporating the CYP4F2*3 variant into the dosing algorithm could result in a more precise calculation of warfarin dose requirements in the Iranian population. CONCLUSIONS: We proposed and validated a population-specific dosing algorithm based on genetic and non-genetic determinants for Iranian patients and evaluated its performance. Accordingly, by using this newly developed algorithm, prescribers could make more informed decisions regarding the treatment of Iranian patients with warfarin.

A Novel ARMC5 Germline Variant in Primary Macronodular Adrenal Hyperplasia Using Whole-Exome Sequencing.

Background: Primary macronodular adrenocortical hyperplasia (PMAH) is a rare form of adrenal Cushing's syndrome with incomplete penetrance which may be sporadic or autosomal dominant. The inactivation of the ARMC5 gene, a potential tumor suppressor gene, is one of the associated causes of PMAH. This study aimed to identify the variant responsible for Iranian familial PMAH. Methods: The proband, a 44-year-old woman, was directed to whole-exome sequencing (WES) of the blood sample to discover a germline variant. In addition, the identified causative variant was confirmed and segregated in other and available unaffected family members. Results: The novel germline heterozygous missense variant, c.2105C>A in the ARMC5 gene, was found, and the same germline variant as the proband was confirmed in two affected sisters. This variant was detected in the brother of the proband with an asymptomatic condition and this considered because of incomplete penetrance and age-dependent appearance. The function of the ARMC5 protein would be damaged by the identified variant, according to in silico and computer analyses that followed. Conclusion: The new germline ARMC5 variation (c.2105C>A, (p. Ala702Glu)) was interpreted as a likely pathogenic variant based on ACMG and Sherloc standards. PMAH may be diagnosed early using genetic testing that shows inherited autosomal dominant mutations in the ARMC5 gene.

The association of umbilical coiling and angiogenesis markers: Impact assessment of gestational diabetes.

INTRODUCTION: The purpose of this study was to determine the association between the postnatal umbilical coiling index (pUCI) and vascular endothelial growth factor A (VEGFA) and its receptor (VEGFR2) in parturients with and without gestational diabetes mellitus (GDM). METHODS: Within 24 h following birth, the umbilical cord and pUCI of 29 newborns with GDM and 28 neonates with non-GDM parturients were prospectively examined. Real-time PCR tests were used to determine the expression levels of the VEGFA and VEGFR2 genes, measured from the umbilical cord. The Mann-Whitney and Chi-squared tests were used to compare continuous and discrete variables with and without GDM. RESULTS: The median (IQR) of maternal age was 30 (26-34) years. There were no differences in demographic features between GDM and non-GDM parturients. While there was a marginal difference in VEGFA expression levels between the GDM and non-GDM groups (P-values = 0.07), no difference was detected for VEGFR2 (P-values = 0.75). Comparing hyper- and hypocoiling cords revealed a small difference in VEGFA levels (P-values = 0.05), but no change in VEGFR2 (P-values = 0.50). Furthermore, in both GDM and non-GDM parturients, down-regulated VEGFA was the general rule among abnormal pUCIs. DISCUSSION: The GDM and coiling state both are associated with the amount of VEGFA expression, but neither is related to VEGFR2. Furthermore, regardless of whether the patient has GDM or not, the abnormal coiling pattern appears to be related to the VEGFA down-regulation.

A systematic review of molecular alterations in invasive non-functioning pituitary adenoma.

PURPOSE: Invasive non-functional pituitary adenomas (NFPAs) constitute 35% of NFPAs. Despite a relatively large body of molecular investigations on the invasiveness of NFPA, the underlying molecular mechanisms of invasiveness are yet to be determined. Herein, we aimed to provide an overview of gene/microRNA(miRNAs) expression alterations in invasive NFPA. METHODS: This article describes a systematic literature review of articles published up to March 23, 2021, on the transcriptional alterations of invasive NFPA. Five digital libraries were searched, and 42 articles in total fulfilled the eligibility criteria. Pathway enrichment was conducted, and protein interactions among the identified deregulated genes were inferred. RESULTS: In total 133 gene/protein transcriptional alterations, comprising 87 increased and 46 decreased expressions, were detected in a collective number of 1001 invasive compared with 1007 non-invasive patients with NFPA. Deregulation of CDH1, PTTG1, CCNB1, SNAI1, SLUG, EZR, and PRKACB, which are associated with epidermal-mesenchymal transition (EMT), was identified. Moreover, six members of the angiogenesis pathway, i.e., VEGFA, FLT1, CCND1, CTNNB1, MYC(c-MYC), and PTTG1, were detected. SLC2A1, FLT1, and VEGFA were also recognized in the hypoxia pathway. Physical interactions of CTNNB1 with FLT1, CCND1, and EZR as well as its indirect interactions with VEGFA, MYC, CCNB1, and PCNA indicate the tight interplay between EMT, angiogenesis, and hypoxia pathways in invasive NFPAs. In addition, Hippo, JAK-STAT, MAPK, Wnt, PI3K-Akt, Ras, TGF-b, VEGF, and ErbB were identified as interwoven signaling pathways. CONCLUSION: In conclusion, invasive NFPA shares very common deregulated signaling pathways with invasive cancers. A large amount of heterogeneity in the reported deregulations in different studies necessitates the validation of the expressional changes of the suggested biomarkers in a large number of patients with invasive NFPA.

The PTRHD1 Mutation in Intellectual Disability.

BACKGROUND: Intellectual disability (ID) is a heterogonous disorder with complex etiology. The frequency of autosomal recessive inheritance defects was elevated in a consanguineous family. METHODS: In this study, high-throughput DNA sequencing was performed in an Iranian consanguineous family with two affected individuals to find potential causative variants. Whole-exome sequencing was carried out on the proband and Sanger sequencing was implemented for validation of the likely causative variant in the family members. RESULTS: A novel homozygous missense mutation (p.Arg122Trp) was detected in the PTRHD1 gene. CONCLUSION: PTRHD1 has been recently introduced as a candidate ID and Parkinsonism causing gene. Our findings are in agreement with the clinical spectrum of PTRHD1 mutations; however, our affected individuals suffer from ID manifestations.

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.

A novel PTC mutation in the BTB domain of KLHL7 gene in two patients with Bohring-Opitz syndrome-like features.

The bric-a-brac, tramtrack and broad complex (BTB) superfamily of conserved proteins are involved in ubiquitin-proteasome system that contains the Kelch-like (KLHL) gene family. Kelch-like family member 7 (KLHL7), one of the KLHL gene family, consists of one BTB/POZ domain, one BACK domain and five or six Kelch motifs. Numerous variants in KLHL7 gene domains have been reported with Crisponi syndrome/cold-induced sweating syndrome type 1 (CS/CISS1)-like features and retinitis pigmentosa 42, and have recently been identified as causing Bohring-Opitz syndrome (BOS)-like features. We report two siblings with BOS-like phenotype with healthy parents and living in Qazvin province (Central Iran). We performed whole-exome sequencing (WES) on the older patient and Sanger sequencing was carried out for validation of potential causative variants in the close family. A novel homozygous frameshift mutation, p.(Phe83Leufs*3), was identified in the BTB domain of KLHL7 that caused a premature translation-termination codon (PTC) in the two siblings with severe developmental delay, microcephaly, facial dysmorphism, peripheral retinal and optic disc atrophy and cardiac septal defects. Our findings are in agreement with the clinical spectrum of KLHL7 mutations, which are associated with BOS-like features that reports for first time in our population.

C1019T Polymorphism in the Connexin 37 Gene and Myocardial Infarction Risk in Premature Coronary Artery Disease.

Background: The C1019T polymorphism of the connexin-37 (GJA4) gene is a single-nucleotide polymorphisms involved in atherosclerotic plaque rupture and atherosclerosis predisposition. We examined the association between the C1019T polymorphism of the GJA4 gene and the occurrence of myocardial infarction (MI) in patients with premature coronary artery disease (CAD). Methods: Our study recruited 1000 patients with the final diagnosis of premature CAD and classified them into 2 groups: with a history of MI (n = 461) and without it (n = 539). The polymorphism variants were determined via the PCR-RFLP, and then genotyping was conducted through the high-resolution melting method. From a total of 1000 patients, 554 patients, who had been previously followed-up with a median follow-up time of 45.74 months vis-à-vis long-term major adverse cardiac events, were enrolled in this retrospective cohort phase. Results: The frequencies of the wild, heterozygous, and mutant genotypes of the C1019T polymorphism were 54.0%, 40.6%, and 5.4% in the MI group and 49.2%, 43.2%, and 7.6% in the non-MI group (p value = 0.187). After adjustment for the baseline covariates, no difference was found between the MI and non-MI groups apropos the frequency of the heterozygous genotype (p value = 0.625) and the mutant genotype (p value = 0.452). Regarding the level of human connexin-37, the serum level of this marker was not different between the MI and non-MI groups. Conclusion: The C1019T polymorphism of the GJA4 gene may not be useful for predicting the occurrence of MI in patients with premature CAD. The presence of this polymorphism in such patients may also have a low value for predicting long-term CAD complications.

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.

The Kalirin Gene rs9289231 Polymorphism as a Novel Predisposing Marker for Coronary Artery Disease.

BACKGROUND: Atherosclerosis is the leading cause of death and disability worldwide. Genetic variations play a major role in the process of atherosclerosis. Recently, rs9289231 genetic variations of the Kalirin gene (KALRN) on chromosome 3q21.2 have been introduced as potential genetic markers for coronary artery disease (CAD). OBJECTIVE: In this case-control study, we investigated the association between genetic susceptibility to CAD and rs9289231 G/T polymorphism, located on the KALRN gene, in an Iranian population. METHODS: Our cohort consisted of 1486 individuals undergoing coronary angiography. Of these, we considered the 1007 patients with CAD to be case individuals and the 479 individuals with normal coronary conditions to be control individuals. We performed single-nucleotide polymorphism (SNP) genotyping via the high resolution melting (HRM) technique. RESULTS: Our data showed that the minor allele (G) frequency of rs9289231 SNP was higher in our CAD group than that in our control group (odds ratio, 1:37; confidence interval, 1.07-1.74; P = .01). The results of our data analysis highlighted a genetic association between rs9289231 polymorphism and severity and development of CAD. CONCLUSIONS: We consider the GG genotype and the G allele of rs9289231 polymorphism of KALRN to be genetic risk factors for CAD in an Iranian population, especially in early-stage atherosclerotic vascular disease.

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.

Association between R353Q polymorphism for coagulative factor VII and severity of coronary artery disease in Iranian population.

BACKGROUND: Recent research has supported the central role of coagulative factors in advancing atherosclerosis and causing coronary artery disease (CAD). The present study, for the first time, aimed to clarify the relationship between R353Q polymorphism for factor VII and the occurrence and severity of CAD in a large sample of Iranian population. METHODS: Nine hundred and nineteen consecutive patients with suspected CAD, who candidated for coronary angiography in the Tehran Heart Center between January 2006 and March 2007, were examined. The number of diseased coronary vessels was determined, and the severity of CAD was assessed by the Gensini score. Genotyping was done via the PCR-RFLP method. RESULTS: The frequency of Q and R alleles was 74.1% and 25.9% in the patients with CADand 75.2% and 24.8% in those without CAD, with an insignificant difference (p = 0.625). The frequency of Q allele in the patients with single-vessel, two-vessel, and three-vessel diseases was 72.8%, 71.5%, and 76.4%, respectively; the difference was also insignificant (p = 0.379). No relationship was observed between the distribution of the genotypes and the number of the involved coronary vessels. The average of the Gensini score was 43.39 ± 46.18 in the patients with QQ genotype, 38.87 ± 42.89 in those with QR genotype, and 55.61 ± 53.80 in the ones with RR genotype, with the difference not constituting any statistical significance (p = 0.084). CONCLUSIONS: The results suggest no association between R353Q polymorphism for factor VII and the presence or progression of CAD in the Iranian population.