Differential Use of Glycoprotein IIb/IIIa Inhibitors with Bivalirudin in Patients with STEMI Undergoing PCI: A Systematic Review and Meta-Analysis.

AIM: The efficacy and safety of bivalirudin when used concurrently with glycoprotein IIb/IIIa inhibitors (GPI) is uncertain. In this systematic review and meta-analysis, we aimed to evaluate the efficacy and safety of bivalirudin versus heparin in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI) and to explore the impact of differential use (greater and balanced) of GPI. METHODS: Online databases were queried from inception to March 2023 to identify eight randomized controlled trials (n = 22,483) for inclusion. The primary outcomes included all-cause mortality, major bleeding, major adverse cardiovascular events (MACE), and net adverse clinical events (NACE). Secondary efficacy endpoints included cardiac death, reinfarction, stent thrombosis (ST), and stroke. Data were pooled using a random-effects model to derive risk ratios (RRs) and 95% confidence intervals (CIs). RESULTS: When compared to heparin, bivalirudin was associated with a significant reduction in all-cause mortality (RR 0.83; 95% CI 0.72-0.97; P = 0.02), major bleeding (RR 0.73; 95% CI 0.57-0.93; P = 0.01), cardiac death (RR 0.79; 95% CI 0.66-0.94; P = 0.01), and NACE (RR 0.80; 95% CI 0.72-0.89; P < 0.0001). However, while the bivalirudin arm showed an increased likelihood of ST in the greater GPI subgroup (RR 1.70; 95% CI 1.13-2.56; P = 0.01), it was associated with a decreased likelihood of ST in the balanced GPI subgroup (RR 0.40; 95% CI 0.24-0.65; P = 0.0003). CONCLUSION: Overall, our findings suggest that bivalirudin may be a more efficacious intervention than heparin for reducing certain adverse events in patients with STEMI undergoing primary PCI.

Comparative Safety and Efficacy of Low/Moderate-Intensity Statin plus Ezetimibe Combination Therapy vs. High-Intensity Statin Monotherapy in Patients with Atherosclerotic Cardiovascular Disease: An Updated Meta-Analysis.

AIM: Statin therapy is considered the gold standard for treating hypercholesterolemia. This updated meta-analysis aims to compare the efficacy and safety of a low/moderate-intensity statin in combination with ezetimibe compared with high-intensity statin monotherapy in patients with atherosclerotic cardiovascular disease (ASCVD). METHODS: A systematic search of two databases (PubMed and Cochrane CENTRAL) was conducted from inception to January 2023 and a total of 21 randomized clinical trials (RCTs) were identified and included in the analysis. Data were pooled using Hedges's g and a Mantel-Haenszel random-effects model to derive standard mean differences (SMDs) and 95% confidence intervals (Cis). The primary outcome studied was the effect of these treatments on lipid parameters and safety events. RESULTS: The results revealed that combination therapy was more effective in reducing low-density lipoprotein cholesterol (LDL-C) levels (SMD= - 0.41; CI - 0.63 to - 0.19; P = 0.0002). There was no significant change in the levels of high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), triglyceride (TG), high-sensitivity C-reactive protein (hs-CRP), Apo A1, or Apo B. The safety of these treatments was assessed by the following markers alanine aminotransferase (ALT), aspartate aminotransferase (AST), and creatine phosphokinase (CK), and a significant difference was only observed in CK (SMD: - 0.81; CI - 1.52 to - 0.10; P = 0.02). CONCLUSION: This meta-analysis demonstrated that the use of low/moderate-intensity statin combination therapy significantly reduced LDL-C levels compared with high-intensity statin monotherapy, making it preferable for patients with related risks. However, further trials are encouraged to evaluate potential adverse effects associated with combined therapy.

Effect of Coca-Cola on the Dissolution of Persimmon-Related Phytobezoar in a Tertiary Care Hospital.

Introduction Bezoars, masses of indigestible foreign bodies formed in the gastrointestinal tract, pose challenges in their management. Phytobezoars are particularly problematic due to their difficult diagnosis and resilience towards treatment. Recently, Coca-Cola has emerged as a potential solution due to its acidic composition and mucolytic properties. However, existing evidence is limited, highlighting the need for comprehensive studies. This research explores the efficacy of Coca-Cola in dissolving persimmon-related phytobezoars, aiming to contribute valuable insights to non-invasive treatment options. Material and methods Conducted as a descriptive case series, this study employed gastric cola lavage using non-probability purposive sampling. Patients aged 18-70 with persimmon-related phytobezoars were included. Two nasogastric tubes were inserted for cola lavage over 12 hours, utilizing three liters of cola until the disappearance of symptoms. When the bezoar disappeared, it was considered as complete success to the treatment. Results Out of 31 patients, 45.2% were male and 54.8% were female, with a mean age of 56.77 ± 9.01 years. Efficacy was noted in 54.8% of cases. Age less than 50 and no history of diabetes mellitus were associated with higher chances of treatment success (p-value ≤0.05). Conclusion Ingestion of Coca-Cola was highly effective, safe, and reliable for the dissolution of persimmon-related phytobezoars, as the frequency of efficacy was high in our study. Coca-Cola ingestion is a non-invasive and cost-effective mode of phytobezoar dissolution that should be taken as a first-line initial treatment option to attain desired outcomes.

Enabling local provision of assistive products in rural South India: an organisational survey of needs, barriers, and facilitators.

Objective: Access to assistive products (APs) is essential to maximising function, participation, and inclusion of persons with disabilities. Challenges to AP access in low- and middle-income countries include stigma, costs, supply, and rehabilitation capacity gaps. This study aimed to examine AT access in the context of a low-resource setting in rural South India. Objectives were to examine rehabilitation professionals' perceptions of AP needs, barriers and facilitators of AP provision, and AT knowledge.Methods: A descriptive study design with a 2-part online survey methodology was utilized. This study was conducted in April-September 2020 at a non-governmental organization (NGO) serving children and adults with disabilities in 3 districts of rural South India. Purposive sampling of NGO's multidisciplinary rehabilitation professionals (N=62) was used. The survey was developed based on WHO's Assistive Products List (APL). Barriers and facilitators were classified according to the principles of AT access. Analyses revealed acceptability, affordability, and availability as the top three barrier themes across disciplines, including poor acceptance by clients/families due to stigma, high AP costs, and a long waitlist for government-provided devices. Acceptability, affordability, and accessibility were the top three facilitator themes, including community awareness, availability of AP funding, client/family education, and AT service provision training.Impact: Our study identified key enabling strategies for AT access, aimed at reducing reported barriers. Enabling AP provision was determined to be multi-factorial, aimed at users/ families, service providers, organizations, communities, and policymakers. Local stakeholder groups are crucial to understanding challenges and opportunities to AP provision within a low-resource context.

Identified barriers to assistive product (AP) provision in rural South India include poor acceptance by clients/families due to stigma, high AP costs, limited AP availability, and rehabilitation capacity gaps.Suggested facilitators to AP provision in rural South India include improving AP acceptability, affordability, and accessibility through community awareness, client/family education, AP funding and supply, and assistive technology (AT) service provision capacity building.An organisational-level survey based on the WHO's Priority Assistive Products List and the Principles of AT Access can identify local needs, barriers and facilitators.An AT access strategies in resource-limited areas may be developed based on barriers and facilitators identified by local/regional rehabilitation professionals.

Gain-of-function and loss-of-function variants in GRIA3 lead to distinct neurodevelopmental phenotypes.

AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors (AMPARs) mediate fast excitatory neurotransmission in the brain. AMPARs form by homo- or heteromeric assembly of subunits encoded by the GRIA1-GRIA4 genes, of which only GRIA3 is X-chromosomal. Increasing numbers of GRIA3 missense variants are reported in patients with neurodevelopmental disorders (NDD), but only a few have been examined functionally. Here, we evaluated the impact on AMPAR function of one frameshift and 43 rare missense GRIA3 variants identified in patients with NDD by electrophysiological assays. Thirty-one variants alter receptor function and show loss-of-function (LoF) or gain-of-function (GoF) properties, whereas 13 appeared neutral. We collected detailed clinical data from 25 patients (from 23 families) harbouring 17 of these variants. All patients had global developmental impairment, mostly moderate (9/25) or severe (12/25). Twelve patients had seizures, including focal motor (6/12), unknown onset motor (4/12), focal impaired awareness (1/12), (atypical) absence (2/12), myoclonic (5/12), and generalized tonic-clonic (1/12) or atonic (1/12) seizures. The epilepsy syndrome was classified as developmental and epileptic encephalopathy in eight patients, developmental encephalopathy without seizures in 13 patients, and intellectual disability with epilepsy in four patients. Limb muscular hypotonia was reported in 13/25, and hypertonia in 10/25. Movement disorders were reported in 14/25, with hyperekplexia or non-epileptic erratic myoclonus being the most prevalent feature (8/25). Correlating receptor functional phenotype with clinical features revealed clinical features for GRIA3-associated NDDs and distinct NDD phenotypes for LoF and GoF variants. GoF variants were associated with more severe outcomes: patients were younger at the time of seizure onset (median age one month), hypertonic, and more often had movement disorders, including hyperekplexia. Patients with LoF variants were older at the time of seizure onset (median age 16 months), hypotonic, and had sleeping disturbances. LoF and GoF variants were disease-causing in both sexes but affected males often carried de novo or hemizygous LoF variants inherited from healthy mothers, whereas all but one affected females had de novo heterozygous GoF variants.

Exploring the Cardiovascular Benefits of Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors: Expanding Horizons Beyond Diabetes Management.

Globally, cardiovascular disease (CVD) continues to be the primary cause of morbidity and mortality. The risk of cardiovascular disease is markedly increased in individuals with type 2 diabetes mellitus (T2DM), making managing cardiovascular health a top priority. Initially developed for their glucose-lowering properties, sodium-glucose cotransporter 2 (SGLT2) inhibitors have emerged as a transformative class of pharmaceuticals with profound cardiovascular benefits that extend far beyond glycemic control. One of the most striking findings is the substantial reduction in major adverse cardiovascular events (MACE), including myocardial infarction, stroke, and cardiovascular mortality, observed in clinical trials evaluating SGLT2 inhibitors. These extraordinary cardioprotective effects are demonstrated by landmark trials such as EMPA-REG OUTCOME, CANVAS, and DECLARE-TIMI 58, which are discussed in detail. In addition, SGLT2 inhibitors have demonstrated positive outcomes in heart failure (HF) with reduced ejection fraction, which has led to their incorporation into HF treatment guidelines. SGLT2 inhibitors offer renoprotection by delaying the progression of diabetic kidney disease, reducing albuminuria, preserving glomerular filtration rates, and their immediate cardiovascular benefits. We investigate the potential mechanisms underlying these renal benefits, focusing on the role of hemodynamic alterations and intraglomerular pressure reduction. In addition, SGLT2 inhibitors have a distinct diuretic effect that can contribute to volume reduction and symptom alleviation in patients with heart failure (HF). This diuretic action, distinct from conventional diuretics, warrants additional research to optimize their use in T2DM and HF patients. The risk of euglycemic diabetic ketoacidosis, genital mycobacterial infections, and bone fractures are also discussed. Understanding these issues is essential for making educated clinical decisions. In conclusion, SGLT2 inhibitors have transcended their initial function as anti-diabetic agents to become essential components of cardiovascular and renal protection strategies in T2DM patients. Their diverse benefits, which include cardioprotection, renoprotection, and the potential for HF management, highlight their potential to transform cardiovascular medicine. Optimizing the use of SGLT2 inhibitors in clinical practice bears the promise of improved cardiovascular outcomes for patients with T2DM and beyond as we navigate this changing landscape.

A new acyl derivative of sulfadimethoxine inhibits phagocyte oxidative burst and ameliorates inflammation in a mice model of zymosan-induced generalised inflammation.

Chronic inflammation and oxidative stress play a pivotal role in the pathophysiology of most challenging illnesses, including cancer, Alzheimer's, cardiovascular and autoimmune diseases. The present study aimed to investigate the anti-inflammatory potential of a new sulfadimethoxine derivative N-(4-(N-(2,6-dimethoxypyrimidin-4-yl) sulfamoyl) phenyl) dodecanamide (MHH-II-32). The compound was characterised by applying 1H-, 13C-NMR, EI-MS and HRFAB-MS spectroscopic techniques. The compound inhibited zymosan-induced oxidative bursts from whole blood phagocytes and isolated polymorphonuclear cells with an IC50 value of (2.5 ± 0.4 and 3.4 ± 0.3 µg/mL), respectively. Furthermore, the inhibition of nitric oxide with an IC50 (3.6 ± 2.2 µg/mL) from lipopolysaccharide-induced J774.2 macrophages indicates its in vitro anti-inflammatory efficacy. The compound did not show toxicity towards normal fibroblast cells. The observational findings, gross anatomical analysis of visceral organs and serological tests revealed the non-toxicity of the compound at the highest tested intraperitoneal (IP) dose of 100 mg/kg in acute toxicological studies in Balb/c mice. The compound treatment (100 mg/kg) (SC) significantly (P < 0.001) downregulated the mRNA expression of inflammatory markers TNF-α, IL-1ß, IL-2, IL-13, and NF-κB, which were elevated in zymosan-induced generalised inflammation (IP) in Balb/c mice while upregulated the expression of anti-inflammatory cytokine IL-10, which was reduced in zymosan-treated mice. No suppressive effect was observed at the dose of 25 mg/kg. Ibuprofen was taken as a standard drug. The results revealed that the new acyl derivative of sulfadimethoxine has an immunomodulatory effect against generalised inflammatory response with non-toxicity both in vitro and in vivo, and has therapeutic potential for various chronic inflammatory illnesses.

Unlocking the Potential of Immunotherapy in Cardiovascular Disease: A Comprehensive Review of Applications and Future Directions.

Immunotherapy has emerged as a pioneering therapeutic approach that harnesses the immune system's abilities to combat diseases, particularly in the field of oncology where it has led to significant advancements. However, despite its significant impact in the field of oncology, the potential of immunotherapy in the context of cardiovascular disease (CVD) has not been thoroughly investigated. The purpose of this narrative review is to address the existing knowledge and potential uses of immunotherapy in the field of cardiovascular disease (CVD), with the intention of filling the existing gap in understanding. Furthermore, the review thoroughly examines the future prospects of this swiftly advancing field, providing insights into the aspects that necessitate further investigation and addressing the forthcoming challenges. The review is organized into four distinct sections to enhance comprehension. The first section introduces immunotherapy, presenting the fundamental concepts and principles. The second section explores the immunomodulatory mechanisms in cardiovascular disease (CVD), with a specific focus on the intricate interplay between the immune system and the development of cardiovascular pathogenesis. The utilization of immunotherapy in specific cardiovascular conditions will be examined, investigating the application of immunotherapy in the context of different cardiovascular diseases. The future prospects and challenges in immunotherapy for cardiovascular diseases will be discussed, highlighting the potential areas for future research and addressing the barriers that must be overcome to effectively implement immunotherapeutic interventions in the management of cardiovascular diseases.

Exploring the Complex Connection Between Diabetes and Cardiovascular Disease: Analyzing Approaches to Mitigate Cardiovascular Risk in Patients With Diabetes.

Cardiovascular disease (CVD) is the primary cause of morbidity and mortality in individuals diagnosed with diabetes mellitus. This narrative review offers a comprehensive examination of the complex correlation between diabetes and cardiovascular complications. The objective of this review is to analyze the most recent evidence on preventive measures and treatment options for mitigating cardiovascular risk in patients with diabetes, by synthesizing existing literature. Insulin resistance plays a crucial role in connecting diabetes and CVD, leading to the development of dyslipidemia and atherogenesis. As a result, the risk of cardiovascular events in individuals with diabetes is significantly elevated. Moreover, the presence of hyperglycemia-induced oxidative stress and inflammation serves to intensify endothelial dysfunction and vascular damage, thereby exacerbating the risk of cardiovascular complications. The interaction between diabetes and CVD frequently speeds up the development of atherosclerotic plaque, making the plaque more prone to rupture. This can lead to severe cardiovascular events such as myocardial infarction and stroke. It is crucial to comprehend the intricate relationship between diabetes and CVD in order to formulate effective strategies aimed at enhancing patient outcomes and mitigating the burden associated with these interconnected chronic conditions. Healthcare practitioners can enhance the quality of life and reduce mortality rates associated with CVD in diabetic patients by thoroughly examining evidence-based preventive measures and treatment options. This approach allows them to make informed decisions when managing cardiovascular risk. In summary, this narrative review provides a valuable resource for healthcare professionals and researchers, presenting a comprehensive analysis of the complex relationship between diabetes and CVD. By providing a comprehensive analysis of the latest evidence and elucidating the underlying mechanisms, this review seeks to establish a foundation for the development of innovative strategies in diabetes management. These strategies have the potential to significantly improve cardiovascular outcomes and enhance overall patient care.

Is endovascular treatment alone as effective and safe as that with preceding intravenous thrombolysis for acute ischemic stroke? A meta-analysis of randomized controlled trials.

INTRODUCTION: This meta-analysis aimed to evaluate the safety and efficacy of direct endovascular therapy (EVT) and bridging therapy (EVT with preceding intravenous thrombolysis i.e. IVT), in acute anterior circulation, large vessel occlusion stroke. EVIDENCE ACQUISITION: Following the PRISMA guidelines, a systematic literature review of the English language literature was conducted using PubMed, Cochrane CENTRAL, SCOPUS and ClinicalTrials.gov. Outcomes of interest were measured by the modified Rankin Scale (mRS), and included: no disability (mRS0), no significant disability despite some symptoms (mRS1), slight disability (mRS2), moderate disability (mRS3), moderately severe disability (mRS4), severe disability (mRS5), mortality (mRS6). Additionally, we inspected patients having excellent outcome, functional independence outcome, and poor outcome, along with successful reperfusion and intracranial hemorrhage. We calculated pooled risk ratios (RRs) and their corresponding 95% confidence intervals (CI). EVIDENCE SYNTHESIS: A total of seven RCTs involving 2,392 patients were finally included. The chances of achieving successful reperfusion were significantly more with IVT+EVT as compared to EVT alone (RR: 0.97; 95% CI: 0.94, 1.00; P=0.03) (I2=0%). There was no significant difference in the number of patients having outcomes ranging from mRS0 to mRS6, excellent outcome, functional independence, poor outcome or incidence of intracranial hemorrhage, who underwent either EVT alone or IVT+EVT. CONCLUSIONS: Additional trials are needed to determine if the absence of significant differences is due to insufficient sample size or if the combination therapy is truly not beneficial.

Comparison of the Efficacy and Safety of Aspirin and Low-Molecular-Weight Heparin in Patients With a Fracture: A Meta-Analysis.

The aim of this study is to compare the efficacy and safety of aspirin and low-molecular-weight heparin (LMWH) in preventing thromboembolic events in patients with fractures. The present meta-analysis was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We searched EMBASE, PubMed, and EBSCO to find articles comparing aspirin and LMWH in patients with orthopedic trauma from inception to April 15, 2023. Limits were set to studies published in the English language only. Outcomes assessed in this meta-analysis included VTE and all-cause mortality. VTE can manifest as deep venous thrombosis (DVT) and pulmonary embolism. For safety analysis, rates of wound complication, infection, and bleeding complications were compared between the two study groups. A total of three studies were included in this meta-analysis enrolling 12884 patients. The study found no significant difference between the two groups in the risk of DVT and pulmonary embolism, and aspirin was non-inferior to LMWH for the prevention of all-cause mortality in patients. Additionally, no significant safety risk was associated with aspirin thromboprophylaxis. These findings suggest that inexpensive over-the-counter aspirin is as effective as LMWH in terms of safety and efficacy profile, making it a feasible option to consider in clinical practice.

Racial Disparity in Outcomes of Out-of-Hospital Cardiac Arrest (OHCA): A Systematic Review and Meta-Analysis.

Out-of-hospital Cardiac Arrest (OHCA) is the abrupt cessation of cardiac function outside of a hospital setting. With limited research into the presence of racial disparities among outcomes of OHCA patients, this systematic review and meta-analysis was conducted. PubMed, Cochrane, and Scopus were searched from inception to March 2023. This analysis includes a total of 53,507 black patients, and 185,173 white patients, resulting in the pooling of 238,680 patients in this meta-analysis. It was observed that the black population was associated with significantly worsened survival to hospital discharge (OR: 0.81; 95% CI: 0.68, 0.96, P = 0.01), return of spontaneous circulation (OR: 0.79; 95% CI: 0.69, 0.89, P = 0.0002), and neurological outcomes (OR: 0.80; 95% CI: 0.68, 0.93; P = 0.003) when compared to their white counterparts. However, there were no differences found with respect to mortality. To the best of our knowledge, this is the most comprehensive meta-analysis assessing racial disparities in OHCA outcomes that have never been explored before. Increased awareness programs, and greater racial inclusivity in the field of cardiovascular medicine is encouraged. Further studies are needed in order to arrive at a robust conclusion.

Mesenchymal stem cells and its translation into clinical orthodontics: current trends and future perspectives.

Oral mesenchymal stem cell populations in humans have been discovered in close vicinity to oral mucosal tissues and both primary (deciduous) and secondary (permanent) teeth. All these different kinds of stem cells have the ability to divide and replenish themselves, however they vary in their gene expression profiles and their capacity to give rise to distinct cell lineages. They all have multipotentiality i.e. chondrogenic, osteogenic, adipogenic, and neurogenic. Due to their relative accessibility, these cell types may form a source of stem cells with substantial potential for application in tissue regeneration. In this review, discoveries outlining stem cell potential are discussed on various aspects as, are their various applications in orthodontics i.e. orthodontic tooth movement, fixing external root resorption, correcting craniofacial anomalies, accelerating craniofacial distraction osteogenesis, recreating the TMJ, and ensuring a stable maxillary expansion.

In-vitro inhibition of NLRP3 inflammasome by 3,6-dihydroxyflavone (3,6-DHF): a therapeutic strategy for the treatment of chronic inflammatory and autoimmune diseases.

Nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome complex has an important role in immune system and its abnormal activation is associated with the pathogenesis of various inflammatory and auto-immune diseases. The study reveals the anti-inflammatory effects of 3,6-dihydroxyflavone (3,6-DHF). Here, we aimed to determine the inhibitory effects of 3,6-DHF on NLRP3 inflammasome and its associated components, thereby determining the signaling pathways involved in the inhibition. Reactive oxygen species (ROS) and nitric oxide (NO) were quantified by chemiluminescence and Griess methods, respectively. Inflammatory cell model was induced in human leukemic monocytes (THP-1). mRNA levels were estimated through real-time RT-PCR, protein expressions were evaluated by protein slot blot and immunocytochemistry, MTT and alamar blue assays were employed for toxicity studies. The compound 3,6-DHF was found to be the potent inhibitor of NLRP3 inflammasome by targeting the molecules involve in its activation pathway. Anti-inflammatory effects were revealed by inhibition of ROS and NO, reduction in the transcription of caspase-1, ASC, IL-1ß and TLR-4 was observed along with the marked inhibition of NLRP3, IL-18, NF-κB and pNF-κB at translational level. 3,6-DHF was non-toxic on normal human fibroblast (BJ) and THP-1 cells and, could be a potential therapeutic agent in NLRP3 inflammasome driven diseases.

miRNAs in Regulation of Tumor Microenvironment, Chemotherapy Resistance, Immunotherapy Modulation and miRNA Therapeutics in Cancer.

miRNAs are 20-22 long nucleotide non-coding ribonucleic acid molecules critical to the modulation of molecular pathways. Immune evasion and the establishment of a suitable tumor microenvironment are two major contributors that support tumor invasion and metastasis. Tumorigenic miRNAs support these two hallmarks by desensitizing important tumor-sensitive regulatory cells such as dendritic cells, M1 macrophages, and T helper cells towards tumors while supporting infiltration and proliferation of immune cells like Treg cells, tumor-associated M2 macrophages that promote self-tolerance and chronic inflammation. miRNAs have a significant role in enhancing the efficacies of immunotherapy treatments like checkpoint blockade therapy, adoptive T cell therapy, and oncolytic virotherapy in cancer. A clear understanding of the role of miRNA can help scientists to formulate better-targeted treatment modalities. miRNA therapeutics have emerged as diverse class of nucleic acid-based molecules that can suppress oncogenic miRNAs and promote the expression of tumor suppressor miRNAs.

Association of CTLA-4 and IL-4 polymorphisms in viral induced liver cancer.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most prevalent types of cancer and is responsible for close to one million annual deaths globally. In Pakistan, HCC accounts for 10.7% of cancer incidence. Prior studies indicated an association between interleukin 4 (IL-4) and cytotoxic T lymphocyte protein 4 (CTLA-4) gene polymorphisms in many types of cancers, including HCC that are either hepatitis B virus (HBV)- or hepatitis C Virus (HCV)-induced. The association of IL-4 and CTLA-4 genetic polymorphisms with HCV-induced HCC is not yet determined in the Pakistani population. Therefore, this research is designed to investigate the implication of IL-4 and CTLA-4 gene polymorphisms by determining the association of IL-4 -590 C/T (rs2243250) and CTLA-4 + 49 A/G (rs231775) with HCC in Pakistan. METHODS: Different bioinformatics tools were employed to determine the pathogenicity of these polymorphisms. Samples were collected from HCV-induced HCC patients, followed by DNA extraction and ARMS-PCR analysis. RESULTS: The SNP analysis results indicated a positive association of IL-4 -590C/T and CTLA-4 + 49A/G gene polymorphisms with HCV-induced HCC in Pakistan. The CTLA-4 polymorphism might enhance therapeutic efficiency of HCC chemotherapy medicines. The IL-4 polymorphism might introduce new transcription factor binding site in IL-4 promoter region. CONCLUSION: This study delineated risk factor alleles in CTLA-4 and IL-4 genes associated with HCV-mediated HCC among Pakistani patients that may have application to serve as genetic markers for pre- and early diagnosis and prognosis of HCC in HCV patients.

Evaluation of In Vitro Models for Assessment of Human Intestinal Metabolism in Drug Discovery.

Although intestinal metabolism plays an important role in drug disposition, early predictions of human outcomes are challenging, in part because of limitations of available in vitro models. To address this, we have evaluated three in vitro models of human intestine (microsomes, permeabilized enterocytes, and cryopreserved intestinal mucosal epithelium) as tools to assess intestinal metabolism and estimate the fraction escaping gut metabolism (f g) in drug discovery. The models were tested with a chemically diverse set of 32 compounds, including substrates for oxidoreductive, hydrolytic, and conjugative enzymes. Liquid chromatography-high-resolution mass spectrometry was used to quantify substrate disappearance [intrinsic clearance (CLint)] and qualify metabolite formation (quantitative-qualitative bioanalysis). Fraction unbound in the incubation (f u,inc) was determined by rapid equilibrium dialysis. Measured in vitro results (CLint and f u,inc) were supplemented with literature data [passive Caco-2 apical to basolateral permeability, enterocyte blood flow, and intestinal surface area (A)] and combined using a midazolam-calibrated Q gut model to predict human f g values. All three models showed reliable CYP and UDP-glucuronosyltransferase activities, but enterocytes and mucosa may offer advantages for low-clearance compounds and alternative pathways (e.g., sulfation, hydrolases, and flavin-containing monooxigenases). Early predictions of human f g values were acceptable for the high-f g compounds (arbitrarily f g > 0.7). However, predictions of low- and moderate-f g values (arbitrarily f g < 0.7) remain challenging, indicating that further evaluation is needed (e.g., saturation effects and impact of transporters) but not immediate compound avoidance. Results suggest that tested models offer an additional value in drug discovery, especially for drug design and chemotype evaluation. SIGNIFICANCE STATEMENT: We found that cellular models of the human gut (permeabilized enterocytes and cryopreserved intestinal mucosa) offer an alternative to and potential advantage over intestinal microsomes in studies of drug metabolism, particularly for low-clearance compounds and alternative pathways (e.g., sulfation, hydrolases, and flavin-containing monooxigenases). The predictivity of human fraction escaping gut metabolism for common CYP and UDP-glucuronosyltransferase substrates based on the Q gut model is still limited, however, and appropriate further evaluation is recommended.

5-Azacytidine upregulates melatonin MT1 receptor expression in rat C6 glioma cells: oncostatic implications.

The multiple physiological effects of the indoleamine melatonin, are mediated primarily by its two G protein-coupled MT1 and MT2 receptors. Treatment with histone deacetylase (HDAC) inhibitors, including valproic acid (VPA) and trichostatin A, upregulates melatonin receptors in cultured cells and the rat brain. VPA increases histone H3 acetylation of the MT1 gene promoter in rat C6 glioma cells, indicating that this epigenetic mechanism is involved in upregulation of MT1 expression. Since HDAC inhibitors can alter DNA methylation, the possible involvement of this other epigenetic mechanism, in the regulation of MT1 expression, was examined. RT-qPCR and western blotting studies confirmed that treatment with the DNA demethylating agent, 5-azacytidine (AZA; 10 or 20 µM) for 24 or 48 h, suppressed DNA methyltransferase 1 mRNA and protein expression in C6 cells. Subsequent treatment with AZA (1-25 µM) for 24 h, revealed a significant concentration-dependent upregulation of MT1 mRNA expression. Moreover, a combination of 5 µM AZA plus 3 mM VPA caused a synergistic upregulation of the MT1 receptor, which exceeded the sum of the independent effects of these drugs. These results show that DNA methylation plays a role in the regulation of the MT1 receptor, consistent with the established effects of this major epigenetic mechanism on gene transcription. Combinatorial epigenetic regulation of melatonin receptor expression could provide novel strategies for enhancing the oncostatic, neuroprotective and other therapeutic benefits of this pleiotropic indoleamine and its receptor agonists.

Progress Of Khyber Pakhtunkhwa (Pakistan) Towards Universal Health Coverage.

BACKGROUND: Khyber Pakhtunkhwa (KP) launched its flagship Social health protection initiative (SHPI), named Sehat Sahulat Program (SSP). SSP envisions to improve access to healthcare for poorest of the poor and contribute towards achieving Universal Health Coverage (UHC). Current study was undertaken to analyze SSP in context of UHC framework i.e. to see as to (i) who is covered, (ii) what services are covered, and (iii) what extent of financial protection is conferred. METHODS: We conducted thorough archival research. Official documents studied were concept paper(s), approved planning commission documents (PC-1 forms) and signed agreement(s) between government of KP and the insurance firm. RESULTS: SSP enrolled poorest 51% of province' population i.e. 14.4 million people. It covers for all secondary and limited tertiary services. Maximum expenditure limit per family per year is Rs.540, 000/-. Government pays a premium of Rs.1549/- per year per household to 3rd party (insurance firm) which ensures services through a mix of public-private providers. CONCLUSIONS: The breadth, depth and height of SSP are significant. It is a phenomenal progress towards achieving UHC.