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Fulltext Age-dependent atrial arrhythmic phenotype secondary to mitochondrial dysfunction in Pgc-1β deficient murine hearts

Valli H, Ahmad S, Chadda KR, Al-Hadithi ABAK, Grace AA, Jeevaratnam K, et al.

Mech Ageing Dev, 2017 Oct;167:30-45.
PMID: 28919427 DOI: 10.1016/j.mad.2017.09.002

INTRODUCTION: Ageing and several age-related chronic conditions including obesity, insulin resistance and hypertension are associated with mitochondrial dysfunction and represent independent risk factors for atrial fibrillation (AF).
MATERIALS AND METHODS: Atrial arrhythmogenesis was investigated in Langendorff-perfused young (3-4 month) and aged (>12 month), wild type (WT) and peroxisome proliferator activated receptor-γ coactivator-1β deficient (Pgc-1β-/-) murine hearts modeling age-dependent chronic mitochondrial dysfunction during regular pacing and programmed electrical stimulation (PES).
RESULTS AND DISCUSSION: The Pgc-1β-/- genotype was associated with a pro-arrhythmic phenotype progressing with age. Young and aged Pgc-1β-/- hearts showed compromised maximum action potential (AP) depolarization rates, (dV/dt)max, prolonged AP latencies reflecting slowed action potential (AP) conduction, similar effective refractory periods and baseline action potential durations (APD90) but shortened APD90 in APs in response to extrasystolic stimuli at short stimulation intervals. Electrical properties of APs triggering arrhythmia were similar in WT and Pgc-1β-/- hearts. Pgc-1β-/- hearts showed accelerated age-dependent fibrotic change relative to WT, with young Pgc-1β-/- hearts displaying similar fibrotic change as aged WT, and aged Pgc-1β-/- hearts the greatest fibrotic change. Mitochondrial deficits thus result in an arrhythmic substrate, through slowed AP conduction and altered repolarisation characteristics, arising from alterations in electrophysiological properties and accelerated structural change.
Fulltext Association of antimicrobial resistance and gut microbiota composition in human and non-human primates at an urban ecotourism site

Chong CW, Alkatheeri AHS, Ali N, Tay ZH, Lee YL, Paramasivam SJ, et al.

Gut Pathog, 2020;12:14.
PMID: 32175011 DOI: 10.1186/s13099-020-00352-x

Background: The rise of nature-based ecotourism in the past decade has introduced unprecedented challenges in managing the increasing interaction between humans and animals. The potential transmission of antibiotic resistant microbes between humans and non-human primate populations is a concern due to their genetic similarity. Malaysia is well known for hotspots of wildlife diversity where non-human primates like monkeys and orangutans have become popular tourist attractions. In this study, we assessed the prevalence of antimicrobial resistant Staphylococcus aureus, Enterococcus species, and other Enterobacteriaceae in the faeces of human (HS) and two non-human primates (NHP) in Malaysia, the Long-tailed macaque (Macaca fascicularis, MF) and Silvered leaf monkey (Trachypithecus cristatus, TC). In addition, the faecal bacterial composition was profiled to evaluate the potential association between antibiotic resistant profiles and composition of gut microbiota.
Results: We tested the isolated bacteria using a selection of antibiotics. The results showed that both the number of antibiotic resistant strains and resistance level were higher in humans than NHPs. Overall, the composition of gut microbiome and pattern of antibiotic resistance showed that there was higher similarity between MF and TC, the two NHPs, than with HS. In addition, samples with higher levels of antibiotic resistance showed lower bacterial richness. Homo sapiens had the lowest bacterial diversity and yet it had higher abundance of Bacteroides. In contrast, NHPs displayed higher bacterial richness and greater prevalence of Firmicutes such as Ruminococceae and Oscillospira.
Conclusion: Higher antibiotic susceptibility in NHPs is likely related to low direct exposure to antibiotics. The lack of resistance may also suggest limited antimicrobial resistance transmission between humans and NHP. Nonetheless, continued monitoring over a long period will help mitigate the risk of anthropozoonosis and zooanthroponosis.
Fulltext Ageing in Pgc-1β-/- mice modelling mitochondrial dysfunction induces differential expression of a range of genes regulating ventricular electrophysiology

Edling CE, Fazmin IT, Chadda KR, Ahmad S, Valli H, Grace AA, et al.

Biosci Rep, 2019 04 30;39(4).
PMID: 30914453 DOI: 10.1042/BSR20190127

Mice deficient in mitochondrial promoter peroxisome proliferator activated receptor-γ co-activator-1β (Pgc-1β-/- ) is a valuable model for metabolic diseases and has been found to present with several pathologies including ventricular arrhythmia. In the present study, our aim was to shed light on the molecular mechanisms behind the observed arrhythmic substrate by studying how the expression of selected genes critical for cardiac function differs in wild-type (WT) compared with Pgc-1β knockout mice and young compared with aged mice. We found that a clear majority of genes are down-regulated in the Pgc-1β-/- ventricular tissue compared with the WT. Although most individual genes are not significantly differentially expressed, a pattern is apparent when the genes are grouped according to their functional properties. Genes encoding proteins relating to ATPase activity, potassium ion channels relating to repolarisation and resting membrane potential, and genes encoding proteins in the cAMP pathway are found to be significantly down-regulated in the Pgc-1β deficient mice. On the contrary, the pacemaker channel genes Hcn3 and Hcn4 are up-regulated in subsets of the Pgc-1β deficient tissue. Furthermore, we found that with age, especially in the Pgc-1β-/- genotype, most genes are up-regulated including genes relating to the resting membrane potential, calcium homeostasis, the cAMP pathway, and most of the tested adrenoceptors. In conclusion, we here demonstrate how a complex pattern of many modest changes at gene level may explain major functional differences of the action potential related to ageing and mitochondrial dysfunction.
Fulltext Student preparedness characteristics important for clinical learning: perspectives of supervisors from medicine, pharmacy and nursing

Banneheke H, Nadarajah VD, Ramamurthy S, Sumera A, Ravindranath S, Jeevaratnam K, et al.

BMC Med Educ, 2017 Aug 08;17(1):130.
PMID: 28789645 DOI: 10.1186/s12909-017-0966-4

BACKGROUND: Student perspectives of clinical preparedness have been studied in the literature, but the viewpoint of supervisors is limited. Hence, the aim was to examine the perspective of supervisors on the characteristics of health professional students important for preparedness for clinical learning.
METHODS: This was a descriptive, questionnaire-based, cross-sectional study conducted at three higher education institutions in Malaysia. A previously published questionnaire with 62 characteristics was adopted with modifications after pre-testing. Descriptive analysis was completed for the demographic data. The sample was grouped based on health profession, clinical practice experience and teaching experience for further analysis. Non-parametric Kruskal-Wallis test was selected to evaluate differences in mean ranks to assess the null hypothesis that the medians are equal across the groups. Kruskal-Wallis post-hoc pair wise comparison was performed on samples with significant differences across samples.
RESULTS: The sample was comprised of 173 supervisors from medicine (55, 32%), pharmacy (84, 48%) and nursing (34, 20%). The majority (63%) of the supervisors were currently in professional practice. A high percentage (40%) of supervisors had less than 4 years of teaching experience. The highest theme ratings were for willingness (6.00) and professionalism (5.90). There was a significant difference (p
Fulltext The effects of ageing and adrenergic challenge on electrocardiographic phenotypes in a murine model of long QT syndrome type 3

Chadda KR, Ahmad S, Valli H, den Uijl I, Al-Hadithi AB, Salvage SC, et al.

Sci Rep, 2017 09 11;7(1):11070.
PMID: 28894151 DOI: 10.1038/s41598-017-11210-3

Long QT Syndrome 3 (LQTS3) arises from gain-of-function Nav1.5 mutations, prolonging action potential repolarisation and electrocardiographic (ECG) QT interval, associated with increased age-dependent risk for major arrhythmic events, and paradoxical responses to β-adrenergic agents. We investigated for independent and interacting effects of age and Scn5a+/ΔKPQ genotype in anaesthetised mice modelling LQTS3 on ECG phenotypes before and following β-agonist challenge, and upon fibrotic change. Prolonged ventricular recovery was independently associated with Scn5a+/ΔKPQ and age. Ventricular activation was prolonged in old Scn5a+/ΔKPQ mice (p = 0.03). We associated Scn5a+/ΔKPQ with increased atrial and ventricular fibrosis (both: p
Clinical supervisors' and students' perspectives on preparedness for veterinary workplace clinical training: An international study

Routh J, Paramasivam SJ, Cockcroft P, Wood S, Remnant J, Westermann C, et al.

Vet Rec, 2023 Nov 18;193(10):e3504.
PMID: 37955283 DOI: 10.1002/vetr.3504

BACKGROUND: The alignment of student and workplace supervisors' perspectives on student preparedness for veterinary workplace clinical training (WCT) is unknown, yet misalignment could negatively impact workplace learning. The aim of this study was to quantify the relative importance of WCT preparedness characteristics according to students and supervisors and to identify differences.
METHODS: A survey was completed by 657 veterinary students and 244 clinical supervisors from 25 veterinary schools, from which rankings of the preparedness characteristics were derived. Significant rank differences were assessed using confidence intervals and permutation tests.
RESULTS: 'Honesty, integrity and dependability' was the most important characteristic according to both groups. The three characteristics with the largest rank differences were: students' awareness of their own and others' mental wellbeing and the importance of self-care; being willing to try new practical skills with support (students ranked both of these higher); and having a clinical reasoning framework for common problems (supervisors ranked higher).
LIMITATIONS: Using pooled data from many schools means that the results are not necessarily representative of the perspectives at any one institution.
CONCLUSION: There are both similarities and differences in the perspectives of students and supervisors regarding which characteristics are more important for WCT. This provides insights that can be used by educators, curriculum developers and admissions tutors to improve student preparedness for workplace learning.
Fulltext The RyR2-P2328S mutation downregulates Nav1.5 producing arrhythmic substrate in murine ventricles

Ning F, Luo L, Ahmad S, Valli H, Jeevaratnam K, Wang T, et al.

Pflugers Arch., 2016 Apr;468(4):655-65.
PMID: 26545784 DOI: 10.1007/s00424-015-1750-0

Catecholaminergic polymorphic ventricular tachycardia (CPVT) predisposes to ventricular arrhythmia due to altered Ca(2+) homeostasis and can arise from ryanodine receptor (RyR2) mutations including RyR2-P2328S. Previous reports established that homozygotic murine RyR2-P2328S (RyR2 (S/S)) hearts show an atrial arrhythmic phenotype associated with reduced action potential (AP) conduction velocity and sodium channel (Nav1.5) expression. We now relate ventricular arrhythmogenicity and slowed AP conduction in RyR2 (S/S) hearts to connexin-43 (Cx43) and Nav1.5 expression and Na(+) current (I Na). Stimulation protocols applying extrasystolic S2 stimulation following 8 Hz S1 pacing at progressively decremented S1S2 intervals confirmed an arrhythmic tendency despite unchanged ventricular effective refractory periods (VERPs) in Langendorff-perfused RyR2 (S/S) hearts. Dynamic pacing imposing S1 stimuli then demonstrated that progressive reductions of basic cycle lengths (BCLs) produced greater reductions in conduction velocity at equivalent BCLs and diastolic intervals in RyR2 (S/S) than WT, but comparable changes in AP durations (APD90) and their alternans. Western blot analyses demonstrated that Cx43 protein expression in whole ventricles was similar, but Nav1.5 expression in both whole tissue and membrane fractions were significantly reduced in RyR2 (S/S) compared to wild-type (WT). Loose patch-clamp studies similarly demonstrated reduced I Na in RyR2 (S/S) ventricles. We thus attribute arrhythmogenesis in RyR2 (S/S) ventricles resulting from arrhythmic substrate produced by reduced conduction velocity to downregulated Nav1.5 reducing I Na, despite normal determinants of repolarization and passive conduction. The measured changes were quantitatively compatible with earlier predictions of linear relationships between conduction velocity and the peak I Na of the AP but nonlinear relationships between peak I Na and maximum Na(+) permeability.