Delving the vitamin D receptor variation and expression profiles in the context of type 2 diabetes among families.

BACKGROUND: Vitamin D is essential for insulin secretion and sensitivity. Consequently, its inadequacy is linked to higher insulin resistance and Type 2 Diabetes (T2D). The Vitamin D receptor (VDR) gene is one potential candidate for T2D, and multiple polymorphisms in VDR have been examined in various populations, but no conclusive answers have been provided. OBJECTIVES: This study was designed to evaluate the susceptibility of VDR gene polymorphism and its expression in diabetic families in Pakistan. METHODOLOGY: In this family-based study, twenty diabetic families with a positive family history of T2D and at least three T2D patients were recruited from outpatient clinics and public hospitals. The current study comprised 143 individuals with 55 affected and 88 unaffected individuals. Blood samples of the selected families were collected. DNA was extracted from the collected samples and the PCR-RFLP method was followed to identify the genotyping and RT-qPCR for expression. Phenotypic and genotypic pedigrees of the families were developed by the progeny online tool. The association values of SNPs were determined by TDT and DFAM analysis implemented on Plink software. RESULTS: The results explained a significant familial aggregation among phenotypic characters including Age, Gender, BMI (body mass index), age of disease diagnosis, disease duration, and blood pressure in the probands, affected FDRs (First Degree Relatives) and affected SDRs (Second Degree Relatives). A significant association of rs731236 C/T (OR = 1.522), rs2228570 C/T (OR = 1.327) with p < 0.05. Whereas, for rs1544410 G/A (OR = 0.9706) and rs7975232 T/G (OR = 0.7368) no considerable association evidence was seen (p > 0.05) in families. The mRNA expression of VDR increased threefold (p = 0.0204) in patients compared to controls. Variation-based expression analysis exhibited that the rs2228570 genotype influences the expression. CONCLUSION: A linkage was found among the FDRs with probands. Variation in the gene VDR at loci rs731236 and rs2228570 was associated with familial T2D. However further research is required to explore more genetic factors that could influence T2D risks in families.

Prediagnostic selenium status, selenoprotein gene variants and association with breast cancer risk in a European cohort study.

Selenium (Se) may help prevent breast cancer (BC) development. Owing to limited observational evidence, we investigated whether prediagnostic Se status and/or variants in the selenoprotein genes are associated with BC risk in a large European cohort. Se status was assessed by plasma measures of Se and its major circulating proteins, selenoprotein P (SELENOP) and glutathione peroxidase 3 (GPX3), in matched BC case-control pairs (2208 for SELENOP; 1785 for GPX3 and Se) nested within the European Prospective Investigation into Cancer and Nutrition (EPIC). Single nucleotide polymorphisms (SNPs, n = 452) in 55 selenoprotein and Se metabolic pathway genes and an additional 18 variants previously associated with Se concentrations were extracted from existing genotyping data within EPIC for 1564 case-control pairs. Multivariable-adjusted logistic regression models were used to calculate the odds ratios (ORs) and 95 % confidence intervals (CIs) of the association between Se status markers, SNP variants and BC risk. Overall, there was no statistically significant association of Se status with BC risk. However, higher GPX3 activity was associated with lower risk of premenopausal BC (4th versus 1st quartile, OR = 0.54, 95 % CI: 0.30-0.98, Ptrend = 0.013). While none of the genetic variant associations (P ≤ 0.05) retained significance after multiple testing correction, rs1004243 in the SELENOM selenoprotein gene and two SNPs in the related antioxidant TXN2 gene (rs4821494 and rs5750261) were associated with respective lower and higher risks of BC at a significance threshold of P ≤ 0.01. Fourteen SNPs in twelve Se pathway genes (P ≤ 0.01) in interaction with Se status were also associated with BC risk. Higher Se status does not appear to be associated with BC risk, although activity of the selenoenzyme GPX3 may be inversely associated with premenopausal BC risk, and SNPs in the Se pathway alone or in combination with suboptimal Se status may influence BC risk.

Mechanisms of stress management in mitochondrial protein import.

Mitochondria are vital to the functions of eukaryotic cells. Most mitochondrial proteins are transported into the organelle following their synthesis by cytoplasmic ribosomes. However, precise protein targeting is complex because the two diverse lipid membranes encase mitochondria. Efficient protein translocation across membranes and accurate sorting to specific sub-compartments require the cooperation of multiple factors. Any failure in mitochondrial protein import can disrupt organelle fitness. Proteins intended for mitochondria make up a significant portion of all proteins produced in the cytosol. Therefore, import defects causing their mislocalization can significantly stress cellular protein homeostasis. Recognition of this phenomenon has increased interest in molecular mechanisms that respond to import-related stress and restore proteostasis, which is the focus of this review. Significantly, disruptions in protein homeostasis link strongly to the pathology of several degenerative disorders highly relevant in ageing societies. A comprehensive understanding of protein import quality control will allow harnessing this machinery in therapeutic approaches.

GABRG2 C588T Polymorphism Is Associated with Idiopathic Generalized Epilepsy but Not with Antiepileptic Drug Resistance in Pakistani Cohort.

Idiopathic generalized epilepsy (IGE) is the most prevalent type of epilepsy with genetic origin. Mutations in ion channel genes have been identified as a common cause of IGE. Several studies have reported various epilepsy risk variants of GABRG2 (gamma-aminobutyric acid type A receptor subunit gamma2 subunit) gene in different ethnic groups, but the results are inconsistent. The purpose of this case-control research is to determine if GABRG2 polymorphisms contribute to IGE susceptibility and antiepileptic drug resistance in Pakistani population. For this purpose, we genotyped exon2, exon5 (C540T and C588T), exon7 (T813C), exon8 (K289M), and exon9 of GABRG2 gene by restriction fragment length polymorphism and Sanger's sequencing in 87 drug-responsive idiopathic generalized epilepsy patients, 55 drug-resistant epilepsy patients, and 83 healthy controls. Restriction fragment length polymorphism (RFLP) and sequencing results indicated only C588T polymorphism in the studied subjects. The comparison of genotypic and allelic frequencies showed significant differences between IGE patients and control groups (P = 0.008 and odds ratio = 4.2) and nonsignificant association of C588T polymorphism in antiseizure medication-resistant patients (P = 0.9). Our findings showed that C588T polymorphism of GABRG2 is a risk variant for IGE in Pakistani population. Further studies are required to validate the results.

TLR-8, TNF-α, and ESR-1α Gene Polymorphism Susceptibility in Onset of Arthritis.

Arthritis is a genetic disorder characterized by bones and joint degradation assisted by severe pain and inflammation. It is evident by the studies that 0 candidate genes variations play vital role in its development and progression. Therefore, we investigated the genetic variation of TLR-8, TNF, and ESR-1α genes in the Pakistani population. A case-control study comprising 300 RA, 316 OA, and 412 control subjects was conducted. PCR-RFLP and direct sequencing methods were used for determining genetic variations. Analysis was performed by using PLINK and MEGA 6.0 software. Allelic and genetic frequencies of polymorphisms identified on rs3764879 (TLR-8), rs3764880 (TLR-8), rs5744080 (TLR-8), rs1800629 (TNF), rs2228480 (ESR-1α), and rs1451501590 (ESR-1α) were significantly varied among RA, OA, and controls. Novel functional mutations SCV000844945 and SCV000844946 on TLR-8 as well as a non-functional SCV000804801 and functional variation SCV000804802 on ESR-1α were also identified and reported for the first time in the studied population. Multiple site analyses indicated that polymorphisms on TLR-8 and ESR-1α genes were significant risk factors in disease onset to the next generation. In conclusion, TLR-08 and ESR-1α were significant in the onset of arthritis whereas the TNF was not found as a significant risk factor in the onset of RA and OA.

The Associations of Selenoprotein Genetic Variants with the Risks of Colorectal Adenoma and Colorectal Cancer: Case-Control Studies in Irish and Czech Populations.

BACKGROUND: Selenium manifests its biological effects through its incorporation into selenoproteins, which play several roles in countering oxidative and inflammatory responses implicated in colorectal carcinogenesis. Selenoprotein genetic variants may contribute to colorectal cancer (CRC) development, as we previously observed for SNP variants in a large European prospective study and a Czech case-control cohort. METHODS: We tested if significantly associated selenoprotein gene SNPs from these studies were also associated with CRC risk in case-control studies from Ireland (colorectal neoplasia, i.e., cancer and adenoma cases: 450, controls: 461) and the Czech Republic (CRC cases: 718, controls: 646). Genotyping of 23 SNPs (20 in the Irish and 13 in the Czechs) was performed by competitive specific allele-specific PCR (KASPar). Multivariable adjusted logistic regression was used to assess the associations with CRC development. RESULTS: We found significant associations with an increased CRC risk for rs5859 (SELENOF) and rs2972994 (SELENOP) in the Irish cohort but only with rs4802034 (SELENOV) in the Czechs. Significant associations were observed for rs5859 (SELENOF), rs4659382 (SELENON), rs2972994 (SELENOP), rs34713741 (SELENOS), and the related Se metabolism gene variant rs2275129 (SEPHS1) with advanced colorectal neoplasia development. However, none of these findings retained significance after multiple testing corrections. CONCLUSIONS: Several SNPs previously associated with CRC risk were also associated with CRC or colorectal neoplasia development in either the Irish or Czech cohorts. Selenoprotein gene variation may modify CRC risk across diverse European populations, although the specific variants may differ.

Corrigendum to "Outcomes of open mitral valve replacement versus Transcatheter mitral valve repair; insight from the National Inpatient Sample Database" [IJC Heart Vasculat. 28 (2020) 100540].

[This corrects the article DOI: 10.1016/j.ijcha.2020.100540.].

Novel functional polymorphism on PADI-4 gene and its association with arthritis onset.

BACKGROUND: Citrullinated proteins formed by peptidyl arginine deiminases (PADIs) deimination of arginine residues in proteins are of particular interest in arthritis pathogenesis. Polymorphisms on the PADI-4 gene lead to the malfunctioning of PADIs leading to the onset of arthritis. OBJECTIVE: The present study was conducted to determine the polymorphisms on the PADI-4 gene and their association with rheumatoid arthritis (RA) as well as Osteoarthritis (OA). METHODOLOGY: To achieve the above-mentioned objective a case-control study was conducted. Blood samples were collected from RA, OA, and control subjects. DNA was extracted from each blood sample by modified organic method and was quantified as well as qualified by DNA gel electrophoresis and Nanodrop. Patients were tested for rs874881, rs11203366, rs11203367, rs2240336, rs2240337, rs2240339, rs1748033 and rs2240340 polymorphic sites by amplifying targeted regions through PCR with site-specific primers. Genotyping was performed by Restriction Fragment Length Polymorphism and direct sequencing method. Mutations were identified by analyzing sequences on BioEdit software. Allelic, genetic, and multiple site analysis were performed by SHEsis and PLINK software. Change in the amino acid sequence was identified by MEGA 6.0 software. RESULTS: Polymorphisms were identified on all targeted polymorphic sites except rs2240337 in both RA and OA individuals. In addition, two novel mutations were also identified in exon 4 identified i-e SCV000804840: c.218T > C and SCV000807675: c.241G > T. All the SNPs except rs11203366 were found to be significantly associated with RA at an allelic level whereas all SNP's have been significant risk factors in the onset of OA. At genotypic level rs874881, rs11203366, rs2240339, SCV000804840 and SCV000807675 were significantly associated to RA development whereas rs874881, rs11203366, rs11203367, rs2240339, SCV000804840 and SCV000807675 were genetic risk factors in OA onset. Haplotype analysis indicated that GACCACGCC and GACCACGCT were highly significant in disease development. Polymorphisms identified altered the functioning of PADIs by altering their amino acid sequence. CONCLUSION: In conclusion, it was found that PADI-4 gene polymorphism was not only involved in the onset of RA but was also found to be a significant risk factor in OA onset.

High-fat diet intake ameliorates the expression of hedgehog signaling pathway in adult rat liver.

BACKGROUND: Disproportionate fatty diet intake provokes hepatic lipid accumulation that causes non-alcoholic fatty liver disease, triggering the embryonically conserved Hedgehog (Hh) pathway in the adult liver. The present study incorporates exploring the impact of chronically administered unsaturated (D-1) and saturated (D-2) fat-enriched diets on hematological parameters, liver functioning, and lipid profile in the rat model. Besides, hepatohistology and real time gene expression analysis of Hh signaling pathway genes i.e., Shh, Ihh, Hhip, Ptch1, Smo, Gli1, Gli2, and Gli3 were carried out. METHODS AND RESULTS: Fifteen Rattus norvegicus (♂) of 200 ± 25 g weight were grouped into control, D-1, and D-2. Animals were fed on their respective diets for 16 weeks. Fatty diet intake resulted in neutropenia, lymphocytosis, monocytosis, polycythemia, and macrocytosis in both experimental groups. Altered liver injury biomarkers, hypertriglyceridemia, and significantly increased very-low-density lipoprotein VLDL were also noted in both high-fat diet (HFD) groups as compared to control. Hepatohistological examination showed disrupted microarchitecture, infiltration of inflammatory cells, cellular necrosis, widened sinusoidal spaces, and microvesicular steatotic hepatocytes in D-1 and D-2. Collagen deposition in both HFD groups marks the extent of fibrosis. Significant upregulation of hedgehog pathway genes was found in fatty diet groups. In comparison with the control group, Shh Ihh, Hhip, Ptch1, Smo, Gli1, Gli2, and Gli3 were upregulated in D-1. In D-2 Shh, Hhip, and Smo expressions were upregulated, Ihh exhibited downregulation as compared to control. CONCLUSION: Excess fat deposits in liver due to chronic consumption of high-fat diet results in anomalous architecture and functioning. High-fat diet induced significant variations in Hh pathway genes expression; especially Shh, Ihh, Hhip, Ptch1, Smo, Gli1, Gli2, and Gli3 were upregulated. Infiltration of inflammatory cells ( ), widened sinusoidal spaces (▲), cellular necrosis, and micro vesicular steatotic hepatocytes (*) were shown in the liver. Significant collagen deposition in both HFD groups i.e. D-1 and D-2 confirmed liver fibrosis. Excessive intake of dietary fats impaired normal liver functioning and liver inflammation triggered Hh signaling in adult rats.

Angiographic-only or intravascular ultrasound-guided approach for left-main coronary artery intervention: a systematic review and meta-analysis.

INTRODUCTION: The use of intravascular ultrasound (IVUS) in percutaneous revascularization of left-main coronary artery disease (LMCAD) warrants further exploration. We aimed to collate all available data on the merits of IVUS in LMCAD to help decision-making. METHODS: The MEDLINE, Embase, and Cochrane databases were queried for relevant randomized controlled trials (RCTs) and observational cohort studies (OCS). The data were analyzed using random-effects model to calculate unadjusted odds ratio (OR) between IVUS-guided and angiography-only LMCA revascularization. RESULTS: A total of 14 studies (2 RCTs and 12 OCS), comprising 18944 patients, were included. The pooled odds of all-cause mortality (OR 0.57, 95%CI 0.46-0.70, p = <0.00001), cardiovascular mortality (OR 0.37, 95%CI 0.26-0.54, p = <0.00001), left-main revascularization (OR 0.63, 95%CI 0.45-0.89, p = 0.009) and myocardial infarction (OR 0.80, 95% CI 0.66-0.97, p = 0.02) were significantly lower with IVUS-guidance. There was no difference observed in the odds of the stent thrombosis (OR 0.57, 95% CI 0.31-1.05, p = 0.07) and stroke (OR 1.7, 95%CI 0.56-5.14, p = 0.35) between the two groups. A subgroup analysis based on the study design and follow-up duration mirrored the pooled estimates. CONCLUSION: IVUS-guided LMCA intervention is associated with overall improved cardiovascular outcomes than the angiography-only approach. This needs to be tested in a large randomized controlled trial.

Polymorphism in drug transporter gene ABCB1 is associated with drug resistance in Pakistani epilepsy patients.

Despite the best possible medication and treatment protocols, one-third of epilepsy patients have drug resistance which is associated with an elevated risk of mortality and debilitating psychological consequences. P-glycogen encoded by ABCB1 is major drug transporter for a wide variety of AED. To evaluate the complex haplotypic association, genetic and allelic frequency distribution of rs1128503, rs1045642, and rs2032582 polymorphisms of ABCB1 gene with drug resistance in Pakistani pediatric epilepsy patients, we performed this study. A total of 337 individuals including 100 healthy control, 110 drug-resistant patients, and 127 drug-responsive patients were enrolled and genotyped for three polymorphisms. PCR and direct sequencing of DNA were done for genotyping. All the studied SNPs showed a statistically significant association with drug-resistant epilepsy at p < 0.01. In addition, we identified a novel variant at c 0.2678C > A (SCV001712095) position. The haplotype analysis indicated strong linkage disequilibrium between three SNPs. The in-silico analysis indicated that rs2032582 polymorphism at c 0.2677T > A is benign while c 0.2677T > G and c 0.2678C > A are possibly damaging. Our findings showed that pharmacogenetic variants play a key role in disease. Our findings shed light on the pharmacogenomic association of ABCB1 with epilepsy which might facilitate study on pharmacokinetics concerning ethnology.

Predictors of Permanent Pacemaker Implantation in Patients Undergoing Transcatheter Aortic Valve Replacement - A Systematic Review and Meta-Analysis.

Background As transcatheter aortic valve replacement (TAVR) technology expands to healthy and lower-risk populations, the burden and predictors of procedure-related complications including the need for permanent pacemaker (PPM) implantation needs to be identified. Methods and Results Digital databases were systematically searched to identify studies reporting the incidence of PPM implantation after TAVR. A random- and fixed-effects model was used to calculate unadjusted odds ratios (OR) for all predictors. A total of 78 studies, recruiting 31 261 patients were included in the final analysis. Overall, 6212 patients required a PPM, with a mean of 18.9% PPM per study and net rate ranging from 0.16% to 51%. The pooled estimates on a random-effects model indicated significantly higher odds of post-TAVR PPM implantation for men (OR, 1.16; 95% CI, 1.04-1.28); for patients with baseline mobitz type-1 second-degree atrioventricular block (OR, 3.13; 95% CI, 1.64-5.93), left anterior hemiblock (OR, 1.43; 95% CI, 1.09-1.86), bifascicular block (OR, 2.59; 95% CI, 1.52-4.42), right bundle-branch block (OR, 2.48; 95% CI, 2.17-2.83), and for periprocedural atriorventricular block (OR, 4.17; 95% CI, 2.69-6.46). The mechanically expandable valves had 1.44 (95% CI, 1.18-1.76), while self-expandable valves had 1.93 (95% CI, 1.42-2.63) fold higher odds of PPM requirement compared with self-expandable and balloon-expandable valves, respectively. Conclusions Male sex, baseline atrioventricular conduction delays, intraprocedural atrioventricular block, and use of mechanically expandable and self-expanding prosthesis served as positive predictors of PPM implantation in patients undergoing TAVR.

Comparative safety of percutaneous ventricular assist device and intra-aortic balloon pump in acute myocardial infarction-induced cardiogenic shock.

BACKGROUND: The relative safety of percutaneous left ventricular assist device (pVAD) and intra-aortic balloon pump (IABP) in patients with cardiogenic shock after acute myocardial infarction remain unknown. METHODS: Multiple databases were searched to identify articles comparing pVAD and IABP. An unadjusted OR was used to calculate hard clinical outcomes and mortality differences on a random effect model. RESULTS: Seven studies comprising 26 726 patients (1110 in the pVAD group and 25 616 in the IABP group) were included. The odds of all-cause mortality (OR 0.57, 95% CI 0.47 to 0.68, p=<0.00001) and need for revascularisation (OR 0.16, 95% CI, 0.07 to 0.38, p=<0.0001) were significantly reduced in patients receiving pVAD compared with IABP. The odds of stroke (OR 1.12, 95% CI 0.14 to 9.17, p=0.91), acute limb ischaemia (OR=2.48, 95% CI 0.39 to 15.66, p=0.33) and major bleeding (OR 0.36, 95% CI 0.01 to 25.39, p=0.64) were not significantly different between the two groups. A sensitivity analysis based on the exclusion of the study with the largest weight showed no difference in the mortality difference between the two mechanical circulatory support devices. CONCLUSIONS: In patients with acute myocardial infarction complicated by cardiogenic shock, there is no significant difference in the adjusted risk of all-cause mortality, major bleeding, stroke and limb ischaemia between the devices. Randomised trials are warranted to investigate further the safety and efficacy of these devices in patients with cardiogenic shock.

Mutational Analysis of Myoclonin1 Gene in Pakistani Juvenile Myoclonic Epilepsy Patients.

Juvenile myoclonic epilepsy (JME) is the most prevalent and genetically heterogeneous form of epilepsy and accounts for 10-30% of all the cases worldwide. Ef-hand domain- (c-terminal-) containing protein 1 (EFHC1) encodes for a nonion channel protein and mutations in this gene have been extensively reported in different populations to play a causative role in JME. Linkage between JME and 6p11-12 locus has already been confirmed in Mexican and Dutch families. A case-control study was conducted on Pakistani JME patients for the first time, aimed at finding out EFHC1 mutations that have been reported in different populations. For this purpose, 66 clinically diagnosed JME patients and 108 control subjects were included in the study. Blood samples were collected from all the participants, and DNA was isolated from the lymphocytes by the modified organic method. Total 3 exons of EFHC1, harboring extensively reported mutations, were selected for genotypic analysis. We identified three heterozygous variants, R159W, V460A, P436P, and one insertion in the current study. V460A, an uncommon variant identified herein, has recently been reported in public databases in an unphenotyped American individual. This missense variant was found in 3 Pakistani JME patients from 2 unrelated families. However, in silico analysis showed that V460A may possibly be a neutral variant. While the absence of a majority of previously reported mutations in our population suggests that most of the mutations of EFHC1 are confined to particular ethnicities and are not evenly distributed across the world. However, to imply the causation, the whole gene and larger number of JME patients should be screened in this understudied population.

Clinical outcomes of patients with diabetes mellitus and acute ST-elevation myocardial infarction following fibrinolytic therapy: a nationwide inpatient sample (NIS) database analysis.

The impact of diabetes mellitus (DM) on clinical outcomes of acute ST-segment elevation myocardial infarction (STEMI) following fibrinolytic therapy remains uncertain. We queried the National Inpatient Sample (NIS) for STEMI patients who received fibrinolytic therapy. Categorical and continuous variables were compared using the unadjusted odds ratio (uOR) and t-test analysis, respectively. A binary logistic regression model was used to control the outcomes for patient demographics, procedural characteristics, and baseline comorbidities. A total of 111,155 (no-DM 84,146, DM 27,009) were included. The unadjusted odds of in-hospital mortality (8.4% vs. 6.8%, uOR 1.25, 95% CI 1.19-1.31, P = <0.0001) and cardiogenic shock (7.7% vs. 6.2%, uOR 1.26, 95% CI 1.20-1.33, P = <0.0001) were significantly higher in patients with DM compared to those with no DM, respectively. The odds for major bleeding and cardiopulmonary arrest were significantly lower for in diabetes. The adjusted pooled estimates mirrored the unadjusted findings. Diabetic patients receiving fibrinolytic therapy for STEMI might have higher odds of all-cause mortality and cardiogenic shock compared to non-diabetic patients.

Clinical outcomes of renal and liver transplant patients undergoing transcatheter aortic valve replacement: analysis of national inpatient sample database.

Background: The transcatheter aortic valve replacement (TAVR) has recently gained traction as a viable alternative to surgical aortic valve replacement (SAVR), but data on its safety and clinical outcomes in transplant patients are limited.Methods: We retrieved relevant demographic and clinical outcome data from the U.S. National Inpatient Sample (NIS) for the year 2012-2015. The clinical outcomes of TAVR in renal transplant (RT) and liver transplant (LT) were ascertained using an adjusted odds ratio (aOR) with a 95% confidence interval (CI) on Mantzel-Hensel test.Results: A total of 62,399 TAVR patients were identified; 62,180 (99.6%) with no history of transplant, 219 (0.4%) with RT and 85 (0.1%) with LT. There was no significant difference in odds of in-hospital mortality (OR 0.61, 95% CI 0.25-1.5, p = 0.37), major cardiovascular, respiratory or neurological complications in patients with and without RT. Similarly, the odds of cardiac complications, renal and neurological complications between patients with and without LT were identical.Conclusion: Compared to non-transplant patients, TAVR appears to be associated with similar odds of major systemic complications or mortality in patients with a history of kidney or liver transplant.

Association of interleukin-17 gene polymorphisms with the onset of Rheumatoid Arthritis.

Rheumatoid Arthritis (RA) is an autoimmune disorder where multiple cytokines including IL-17A and IL-17F produced by T helper cell 17 (Th17), contribute to its pathogenesis. By initiating inflammatory responses in joints Th17 act as pathogenic driver leading to bone and cartilage destruction in RA patients. Hence, the planned study was aimed to estimate IL-17 gene polymorphism association with RA susceptibility in Pakistani population. The present study included 100 subjects (50 RA patients and 50 healthy controls). Blood samples were taken and DNA was isolated for genotyping purpose. Chi square and Logistic regression analysis was performed to check the association of selected SNPs with RA. For rs2397084 and rs763780 polymorphism T allele acted as significant risk factor as compared to the reference C allele. TT vs. CC comparison in rs2397084 showed that T allele is a risk factor (OR 5.538; 95%Cl 1.757-17.458) in RA susceptibility. In case of rs763780 heterozygous CT (OR 10.80; 95% Cl 3.736-31.218) and homozygous mutant TT (OR 7.50; 95% Cl 2.360-23.831) genotypes proved to be a potential risk for RA patients. The significant differences in allelic and genotypic frequencies were observed for both SNPs. While for rs2275913 significantly varied frequency was observed only for dominant model of inheritance and non significant differences were seen at allelic level. Variation at all these three polymorphic sites substituted mutant amino acids leading to further functional changes in protein structure. Three polymorphic sites rs2275913, rs763780 and rs2397084 positioned on IL-17 gene were significantly strong factors in RA incidence among Pakistani population as they alter normal function of inflammatory cytokine IL-17.

High-Fat Diet Induced Hedgehog Signaling Modifications during Chronic Kidney Damage.

Excessive consumption of dietary fats leads to the deposition of unnecessary metabolites and multiple organ damage. Lipids, important key regulators of Hedgehog signaling, are involved in triggering fibrotic chronic kidney disease. The present study encompasses the assessment of renal morphofunctional modifications and alteration of lipid metabolism influencing the changes in gene expression of hedgehog signaling pathway genes. Fifteen male Rattus norvegicus of 200 ± 25 grams weight were equally divided into three groups: control (standard rat chow), D-1 (unsaturated high-fat diet) and D-2 (saturated high-fat diet). Animals were provided with respective diets and were followed for 16 weeks. Both HFD-fed groups did not show overall body weight gain as compared to the control. While significant downregulation of hedgehog pathway genes was found in fatty diet groups. In comparison with the control group, Shh, Gli1, Gli2, and Gli3 were downregulated after the consumption of both unsaturated and saturated fatty diets. Ihh and Smo exhibit a similar downregulation in the D-1 group, but an upregulation was detected in the D-2 group. D-2 group also had an increased serum urea concentration as compared to the control (P = 0.0023). Furthermore, renal histopathology revealed tubular necrosis, glomerular edema, glomerular shrinkage, and hypocellularity. Collagen deposition in both HFD groups marks the extent of fibrosis summary figure. Extravagant intake of dietary fats impaired normal kidney functioning and morphofunctionally anomalous kidney triggers on Hh signaling in adult rats. These anomalies can be linked to an escalated risk of chronic kidney disease in adults strongly recommending the reduced uptake of fatty diets to prevent impaired metabolism and renal lipotoxicity.

Safety and efficacy of soluble guanylate cyclase stimulators in patients with heart failure: A systematic review and meta-analysis.

BACKGROUND: The utility of novel oral soluble guanylate cyclase (sGC) stimulators (vericiguat and riociguat), in patients with reduced or preserved ejection fraction heart failure (HFrEF/HFpEF) is currently unclear. AIM: To determine the efficacy and safety of sGC stimulators in HF patients. METHODS: Multiple databases were searched to identify relevant randomized controlled trials (RCTs). Data on the safety and efficacy of sGC stimulators were compared using relative risk ratio (RR) on a random effect model. RESULTS: Six RCTs, comprising 5604 patients (2801 in sGC stimulator group and 2803 placebo group) were included. The primary endpoint (a composite of cardiovascular mortality and first HF-related hospitalization) was significantly reduced in patients receiving sGC stimulators compared to placebo [RR 0.92, 95% confidence interval (CI): 0.85-0.99, P = 0.02]. The incidence of total HF-related hospitalizations were also lower in sGC group (RR 0.91, 95%CI: 0.86-0.96, P = 0.0009), however, sGC stimulators had no impact on all-cause mortality (RR 0.96, 95%CI: 0.86-1.07, P = 0.45) or cardiovascular mortality (RR 0.94, 95%CI: 0.83-1.06, P = 0.29). The overall safety endpoint (a composite of hypotension and syncope) was also similar between the two groups (RR 1.50, 95%CI: 0.93-2.42, P = 0.10). By contrast, a stratified subgroup analysis adjusted by type of sGC stimulator and HF (vericiguat vs riociguat and HFrEF vs HFpEF) showed near identical rates for all safety and efficacy endpoints between the two groups at a mean follow-up of 19 wk. For the primary composite endpoint, the number needed to treat was 35, the number needed to harm was 44. CONCLUSION: The use of vericiguat and riociguat in conjunction with standard HF therapy, shows no benefit in terms of decreasing HF-related hospitalizations or mortality.

Percutaneous Intervention or Bypass Graft for Left Main Coronary Artery Disease? A Systematic Review and Meta-Analysis.

BACKGROUND: The safety and efficacy of percutaneous coronary intervention (PCI) versus coronary artery bypass grafting (CABG) for stable left main coronary artery disease (LMCAD) remains controversial. METHODS: Digital databases were searched to compare the major adverse cardiovascular and cerebrovascular events (MACCE) and its components. A random effect model was used to compute an unadjusted odds ratio (OR). RESULTS: A total of 43 studies (37 observational and 6 RCTs) consisting of 29,187 patients (PCI 13,709 and CABG 15,478) were identified. The 30-day rate of MACCE (OR, 0.56; 95% CI, 0.42-0.76; p = 0.0002) and all-cause mortality (OR, 0.52; 95% CI, 0.30-0.91; p = 0.02) was significantly lower in the PCI group. There was no significant difference in the rate of myocardial infarction (MI) (p = 0.17) and revascularization (p = 0.12). At 5 years, CABG was favored due to a significantly lower rate of MACCE (OR, 1.67; 95% CI, 1.18-2.36; p = <0.04), MI (OR, 1.67; 95% CI, 1.35-2.06; p = <0.00001), and revascularization (OR, 2.80; 95% CI, 2.18-3.60; p = <0.00001), respectively. PCI was associated with a lower overall rate of a stroke, while the risk of all-cause mortality was not significantly different between the two groups at 1- (p = 0.75), 5- (p = 0.72), and 10-years (p = 0.20). The Kaplan-Meier curve reconstruction revealed substantial variations over time; the 5-year incidence of MACCE was 38% with CABG, significantly lower than 45% with PCI (p = <0.00001). CONCLUSION: PCI might offer early safety advantages, while CABG provides greater durability in terms of lower long-term risk of ischemic events. There appears to be an equivalent risk for all-cause mortality.