Molecular signatures of Calpain 10 isoforms sequences, envisage functional similarity and therapeutic potential

Calpain 10 plays a role in insulin secretion, action and susceptibility to type 2 diabetes. The mechanism through which it influences the insulin secretion and action is not completely defined. A structural bioinformatics approach is applied to envision its mechanism of action using available tools on NCBI (blastp and blastn), EMBL-EBI, Ensembl, Swiss Model Repository websites, I-TASSER, PROCHECK program and Discovery Studio software. Homology of domain I and II of calpain10 (isoform a) was established with super family cysteine proteinase domains (II a and II b, e=1.30e-77, 1.00e-20). Remaining sequences of domain III and T from (isoform a and c) indicated some similarity (Avg. e=1.94e-37) to calpain large subunit domain III (PF01067), the isoform g (139 AA) showed similarity with a part of catalytic domain of cysteine protease super family (e-value 1.00e-20). Swiss-model repository for 3D structures of protein, showed structural resemblance of 29% with 1QXP template of mu-calpain, 27% with 1KFX of m-calpain and 32% with 2P0R of calpain 9 in complex with leupeptin. Models prepared through I-TASSER confirmed through Ramachandran (RC) plots. The calpain 10 isoforms a, c and g show partial structural and functional resemblance to m, mu and calpain 9. This information is useful to find new drugs for disease management

The Pakistan risk of myocardial infarction study: A resource for the study of genetic, lifestyle and other determinants of myocardial infarction in south Asia

The burden of coronary heart disease (CHD) is increasing at a greater rate in South Asia than in any other region globally, but there is little direct evidence about its determinants. The Pakistan Risk of Myocardial Infarction Study (PROMIS) is an epidemiological resource to enable reliable study of genetic, lifestyle and other determinants of CHD in South Asia. By March 2009, PROMIS had recruited over 5,000 cases of first-ever confirmed acute myocardial infarction (MI) and over 5,000 matched controls aged 30-80 years. For each participant, information has been recorded on demographic factors, lifestyle, medical and family history, anthropometry, and a 12-lead electrocardiogram. A range of biological samples has been collected and stored, including DNA, plasma, serum and whole blood. During its next stage, the study aims to expand recruitment to achieve a total of about 20,000 cases and about 20,000 controls, and, in subsets of participants, to enrich the resource by collection of monocytes, establishment of lymphoblastoid cell lines, and by resurveying participants. Measurements in progress include profiling of candidate biochemical factors, assay of 45,000 variants in 2,100 candidate genes, and a genomewide association scan of over 650,000 genetic markers. We have established a large epidemiological resource for CHD in South Asia. In parallel with its further expansion and enrichment, the PROMIS resource will be systematically harvested to help identify and evaluate genetic and other determinants of MI in South Asia. Findings from this study should advance scientific understanding and inform regionally appropriate disease prevention and control strategies

Effect of SGLT2 inhibitors on stroke and atrial fibrillation in diabetic kidney disease: Results from the CREDENCE trial and meta-analysis

BACKGROUND AND PURPOSE: Chronic kidney disease with reduced estimated glomerular filtration rate or elevated albuminuria increases risk for ischemic and hemorrhagic stroke. This study assessed the effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) on stroke and atrial fibrillation/flutter (AF/AFL) from CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) and a meta-Analysis of large cardiovascular outcome trials (CVOTs) of SGLT2i in type 2 diabetes mellitus. METHODS: CREDENCE randomized 4401 participants with type 2 diabetes mellitus and chronic kidney disease to canagliflozin or placebo. Post hoc, we estimated effects on fatal or nonfatal stroke, stroke subtypes, and intermediate markers of stroke risk including AF/AFL. Stroke and AF/AFL data from 3 other completed large CVOTs and CREDENCE were pooled using random-effects meta-Analysis. RESULTS: In CREDENCE, 142 participants experienced a stroke during follow-up (10.9/1000 patient-years with canagliflozin, 14.2/1000 patient-years with placebo; hazard ratio [HR], 0.77 [95% CI, 0.55-1.08]). Effects by stroke subtypes were: ischemic (HR, 0.88 [95% CI, 0.61-1.28]; n=111), hemorrhagic (HR, 0.50 [95% CI, 0.19-1.32]; n=18), and undetermined (HR, 0.54 [95% CI, 0.20-1.46]; n=17). There was no clear effect on AF/AFL (HR, 0.76 [95% CI, 0.53-1.10]; n=115). The overall effects in the 4 CVOTs combined were: Total stroke (HRpooled, 0.96 [95% CI, 0.82-1.12]), ischemic stroke (HRpooled, 1.01 [95% CI, 0.89-1.14]), hemorrhagic stroke (HRpooled, 0.50 [95% CI, 0.30-0.83]), undetermined stroke (HRpooled, 0.86 [95% CI, 0.49-1.51]), and AF/AFL (HRpooled, 0.81 [95% CI, 0.71-0.93]). There was evidence that SGLT2i effects on total stroke varied by baseline estimated glomerular filtration rate (P=0.01), with protection in the lowest estimated glomerular filtration rate (45 mL/min/1.73 m2]) subgroup (HRpooled, 0.50 [95% CI, 0.31-0.79]). CONCLUSIONS: Although we found no clear effect of SGLT2i on total stroke in CREDENCE or across trials combined, there was some evidence of benefit in preventing hemorrhagic stroke and AF/AFL, as well as total stroke for those with lowest estimated glomerular filtration rate. Future research should focus on confirming these data and exploring potential mechanisms

Evaluation of appendicitis risk prediction models in adults with suspected appendicitis

Background Appendicitis is the most common general surgical emergency worldwide, but its diagnosis remains challenging. The aim of this study was to determine whether existing risk prediction models can reliably identify patients presenting to hospital in the UK with acute right iliac fossa (RIF) pain who are at low risk of appendicitis. Methods A systematic search was completed to identify all existing appendicitis risk prediction models. Models were validated using UK data from an international prospective cohort study that captured consecutive patients aged 16–45 years presenting to hospital with acute RIF in March to June 2017. The main outcome was best achievable model specificity (proportion of patients who did not have appendicitis correctly classified as low risk) whilst maintaining a failure rate below 5 per cent (proportion of patients identified as low risk who actually had appendicitis). Results Some 5345 patients across 154 UK hospitals were identified, of which two‐thirds (3613 of 5345, 67·6 per cent) were women. Women were more than twice as likely to undergo surgery with removal of a histologically normal appendix (272 of 964, 28·2 per cent) than men (120 of 993, 12·1 per cent) (relative risk 2·33, 95 per cent c.i. 1·92 to 2·84; P < 0·001). Of 15 validated risk prediction models, the Adult Appendicitis Score performed best (cut‐off score 8 or less, specificity 63·1 per cent, failure rate 3·7 per cent). The Appendicitis Inflammatory Response Score performed best for men (cut‐off score 2 or less, specificity 24·7 per cent, failure rate 2·4 per cent). Conclusion Women in the UK had a disproportionate risk of admission without surgical intervention and had high rates of normal appendicectomy. Risk prediction models to support shared decision‐making by identifying adults in the UK at low risk of appendicitis were identified

SWOT analysis of Community Midwifery Program in Pakistan

The community midwifery program was launched in 2006 by the Government of Pakistan as a major initiative to provide skill birth attendance to women living in rural areas of Pakistan. The main purpose of the program is to extend maternal and newborn services to the communities, through the selection and training of community midwives (CMWs) from rural areas, and to deliver services to their local communities. However, there is a substantial difference between the number of CMWs trained and those working at their birthing stations. Therefore, this paper uses a SWOT (Strengths, Weaknesses, Opportunities, Threats) analysis to evaluate the different aspects of the CMW program. To avoid potential bias in the analysis and results, all four investigators reviewed the content and the published literature. The results from the evaluation of the reviewed literature provided findings on the strengths, weaknesses, opportunities, and threats of the CMW program. Strengths of the Community Midwifery program include enrollment criterion of community midwives, extensive coverage of midwifery services, management and supervision of the program, healthcare delivery, and positive effect of the program on health indicators. Weaknesses include weak management of the program at district levels, problems in funding, job insecurities of community midwives, weak supplies and equipment provided to midwives, weak referral systems, poor quality care, and progress in meeting targets. Opportunities include the community’s acceptability, health system research, and support for the referral system. Threats include financial affordability, social and cultural norms, funding problems, political and socio-cultural environment, and non-acceptance by established medical professions. The strengthening of the Community Midwifery program requires more political commitment and proper integration into the existing health system of Pakistan

1st International Conference on Biomedical Sciences, Dow University of Health Sciences, Karachi Pakistan

Institute of Biomedical Sciences (IBMS) at Dow University of Health Sciences (DUHS), organised a two day’s conference on Biomedical Sciences. IBMS being the part of one of the largest public sector health universities of Pakistan, is now transforming the research trends to be effectively translated at the community level. Currently with a strong PhD faculty line in basic and clinical sciences, DUHS has a significant contribution in research output of the country. The scientific data however represents a small population per scientific study and the generalization of results may not be inferred. It must be extended through translational research for effectiveness. The conference was planned with a theme to bridge the gap between basic and translational research. The two day’s conference conducted in second week of March 2023 at Dow International Medical College Ojha Campus DUHS was able to attract more than 300 participants. The scientific sessions encompassed a vast variety of health issues and their proposed solutions including neurosciences, virtual biopsies, metabolomics, medical writings and incorporation of engineering and artificial intelligence to facilitate detection and prognosis of disease. The conference was able to conclude that the multidisciplinary research studies with collaboration of two or more institutes/organizations are the need of time. Young researchers need an effective platform to showcase their research and make collaborations. Moreover, the incorporation of artificial intelligence would enhance patient care within health systems. Keywords: Biomedical Sciences, basic research, Translational research, IBMS, DUHS

Protective Efficacy of N-(2-Hydroxyphenyl) Acetamide against Adjuvant-Induced Arthritis in Rats

Rheumatoid arthritis is a chronic inflammatory joint disease characterized by synovial proliferation and tissue destruction. Proinflammatory cytokines like interleukin-1beta (IL-1 ) and tumor necrosis factor-alpha (TNF-) play a key role in the disease process and elevate energy expenditure, which further increases the joint pain and stiffness. To explore the effects of N-(2-hydroxyphenyl) acetamide (NA-2) on the development of arthritis, clinical signs, histopathology of knee joints, nociception analysis, and the serum levels of IL-1 and TNF-were monitored. Arthritis was induced by intradermal administration of heatkilled adjuvant Mycobacterium tuberculosis H37Ra in rats. NA-2 and indomethacin treatments were started in their respective group on the same day when adjuvant was administered. Experiments were terminated when arthritic score of 4 was observed in arthritic control group. NA-2 (5 mg/kg) treatment significantly ameliorated the disease severity. Reduction in body weight and increase in paw oedema were significantly reversed in arthritic animal receiving NA-2. The nociceptive sensation was also inhibited in the NA-2 treated arthritic rats. Remission was associated with improved histology and significant decreased expression of serum proinflammatory cytokines ( &lt; 0.05 for IL-1 and TNF-). Based on our observations, it can be suggested that NA-2 possesses promising anti-arthritic property, and it can be used as a therapeutic agent for arthritis

Synonymous polymorphism rs201256011 in dopamine receptor type 2 gene is associated with schizophrenia and PANSS score in Pakistani population: A first report

Aim: Variations of dopamine receptor type 2 (DRD2) are among the key factors involved in the pathology of schizophrenia. Presence of certain SNPs in DRD2 gene also amend patients\u27 response to antipsychotics. Keeping in view the genetic diversity among populations and important role of DRD2 polymorphisms in schizophrenia we aimed to study two of its SNPs rs1801028 and rs6277 in patients with schizophrenia from Pakistan.Methods: A total of 100 schizophrenia cases and 100 healthy controls were recruited. DNA was extracted from whole blood followed by PCR, Sanger sequencing and genotyping of two SNPs i.e. rs1801028 and rs6277.Results: No association of rs1801028 and rs6277 was found with schizophrenia in Pakistani population (P\u3e0.05). Highlight of our study is the association of polymorphism rs201256011 with schizophrenia (P=0.001), which is being reported for the first time. Significant association of rs201256011 was also found with PANSS negative, cognitive and total score (P\u3c0.05).Conclusion: In conclusion, genetic variants rs1801028 and rs6277 of DRD2 are not associated with schizophrenia in Pakistani population. While, previously unreported polymorphism rs201256011 have shown significant association with schizophrenia and its severity. A large scale multicenter replication study is required to confirm the association of this SNP with schizophrenia

Relation of copeptin with diabetic and renal function markers among patients with diabetes mellitus progressing towards diabetic nephropathy

Background: Arginine vasopressin (AVP) plays an important role in the pathophysiology of Diabetes Mellitus (DM) and its related complications like diabetic nephropathy. Copeptin is considered as a reliable surrogate biomarker of AVP. If raised levels of copeptin in diabetic patients are detected earlier, prognosis of DM can be improved by timely modulating the treatment strategy.Aims of the study: The study is therefore planned to assess copeptin levels in different groups of DM and in healthy controls to suggest a better and reliable biomarker for progressive stages of DM.Methods: Subjects were recruited as controls, pre diabetes, DM without nephropathy and diabetic nephropathy. Serum copeptin levels were measured by ELISA. While, Blood Urea Nitrogen (BUN), creatinine, Glycosylated Hemoglobin (HbA1c) and spot urinary albumin creatinine ratio (UACR) were done using spectrophotometry. Statistical analysis was done using ANOVA and Pearson\u27s correlation tests on SPSS.Results: The average copeptin levels were 215.096 pg/mL. Copeptin levels were significantly elevated in subjects with positive family history of DM (p = 0.025), levels were also raised in pre diabetes kpatients (252.85 pg/mL) as compared to other groups. Copeptin levels were also correlated with HbA1c r = 0.171 (p = 0.101), BUN r = 0.244 (p = 0.007), creatinine r = 0.215 (p = 0.018), UACR r = 0.375 (p = \u3c0.001) and GFR r = 0.215 (p = \u3c0.019).Conclusion: The significant correlation of copeptin with diabetic and renal biomarkers, along with its positive association with family history of DM support its\u27 role as an early and reliable biomarker of DM and its associated nephropathy