Displaying publications 1 - 20 of 27 in total

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  1. Routh J, Paramasivam SJ, Cockcroft P, Nadarajah VD, Jeevaratnam K
    Animals (Basel), 2021 Jun 18;11(6).
    PMID: 34207202 DOI: 10.3390/ani11061818
    The public health implications of the Covid-19 pandemic have caused unprecedented and unexpected challenges for veterinary schools worldwide. They are grappling with a wide range of issues to ensure that students can be trained and assessed appropriately, despite the international, national, and local restrictions placed on them. Moving the delivery of knowledge content largely online will have had a positive and/or negative impact on veterinary student learning gain which is yet to be clarified. Workplace learning is particularly problematic in the current climate, which is concerning for graduates who need to develop, and then demonstrate, practical core competences. Means to optimise the learning outcomes in a hybrid model of curriculum delivery are suggested. Specific approaches could include the use of video, group discussion, simulation and role play, peer to peer and interprofessional education.
  2. Ahmad S, Valli H, Chadda KR, Cranley J, Jeevaratnam K, Huang CL
    Mech Ageing Dev, 2018 Jul;173:92-103.
    PMID: 29763629 DOI: 10.1016/j.mad.2018.05.004
    INTRODUCTION: Ageing and age-related bioenergetic conditions including obesity, diabetes mellitus and heart failure constitute clinical ventricular arrhythmic risk factors.

    MATERIALS AND METHODS: Pro-arrhythmic properties in electrocardiographic and intracellular recordings were compared in young and aged, peroxisome proliferator-activated receptor-γ coactivator-1β knockout (Pgc-1β-/-) and wild type (WT), Langendorff-perfused murine hearts, during regular and programmed stimulation (PES), comparing results by two-way ANOVA.

    RESULTS AND DISCUSSION: Young and aged Pgc-1β-/- showed higher frequencies and durations of arrhythmic episodes through wider PES coupling-interval ranges than WT. Both young and old, regularly-paced, Pgc-1β-/- hearts showed slowed maximum action potential (AP) upstrokes, (dV/dt)max (∼157 vs. 120-130 V s-1), prolonged AP latencies (by ∼20%) and shortened refractory periods (∼58 vs. 51 ms) but similar AP durations (∼50 ms at 90% recovery) compared to WT. However, Pgc-1β-/- genotype and age each influenced extrasystolic AP latencies during PES. Young and aged WT ventricles displayed distinct, but Pgc-1β-/- ventricles displayed similar dependences of AP latency upon (dV/dt)max resembling aged WT. They also independently increased myocardial fibrosis. AP wavelengths combining activation and recovery terms paralleled contrasting arrhythmic incidences in Pgc-1β-/- and WT hearts. Mitochondrial dysfunction thus causes pro-arrhythmic Pgc-1β-/- phenotypes by altering AP conduction through reducing (dV/dt)max and causing age-dependent fibrotic change.

  3. Lee NY, Khoo WK, Adnan MA, Mahalingam TP, Fernandez AR, Jeevaratnam K
    J Pharm Pharmacol, 2016 Jun 10.
    PMID: 27283048 DOI: 10.1111/jphp.12565
    Phyllanthus niruri is a traditional shrub of the genus Phyllanthaceae with long-standing Ayurvedic, Chinese and Malay ethnomedical records. Preliminary studies from cell and animal model have provided valuable scientific evidence for its use.
  4. 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 
  5. 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.
  6. Pau A, Jeevaratnam K, Chen YS, Fall AA, Khoo C, Nadarajah VD
    Med Teach, 2013 Dec;35(12):1027-41.
    PMID: 24050709 DOI: 10.3109/0142159X.2013.829912
    The Multiple Mini-Interview (MMI) has been used increasingly for selection of students to health professions programmes.
  7. 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 

  8. Jeevaratnam K, Guzadhur L, Goh YM, Grace AA, Huang CL
    Acta Physiol (Oxf), 2016 Feb;216(2):186-202.
    PMID: 26284956 DOI: 10.1111/apha.12577
    Normal cardiac excitation involves orderly conduction of electrical activation and recovery dependent upon surface membrane, voltage-gated, sodium (Na(+) ) channel α-subunits (Nav 1.5). We summarize experimental studies of physiological and clinical consequences of loss-of-function Na(+) channel mutations. Of these conditions, Brugada syndrome (BrS) and progressive cardiac conduction defect (PCCD) are associated with sudden, often fatal, ventricular tachycardia (VT) or fibrillation. Mouse Scn5a(+/-) hearts replicate important clinical phenotypes modelling these human conditions. The arrhythmic phenotype is associated not only with the primary biophysical change but also with additional, anatomical abnormalities, in turn dependent upon age and sex, each themselves exerting arrhythmic effects. Available evidence suggests a unified binary scheme for the development of arrhythmia in both BrS and PCCD. Previous biophysical studies suggested that Nav 1.5 deficiency produces a background electrophysiological defect compromising conduction, thereby producing an arrhythmic substrate unmasked by flecainide or ajmaline challenge. More recent reports further suggest a progressive decline in conduction velocity and increase in its dispersion particularly in ageing male Nav 1.5 haploinsufficient compared to WT hearts. This appears to involve a selective appearance of slow conduction at the expense of rapidly conducting pathways with changes in their frequency distributions. These changes were related to increased cardiac fibrosis. It is thus the combination of the structural and biophysical changes both accentuating arrhythmic substrate that may produce arrhythmic tendency. This binary scheme explains the combined requirement for separate, biophysical and structural changes, particularly occurring in ageing Nav 1.5 haploinsufficient males in producing clinical arrhythmia.
  9. Chadda KR, Jeevaratnam K, Lei M, Huang CL
    Pflugers Arch., 2017 06;469(5-6):629-641.
    PMID: 28265756 DOI: 10.1007/s00424-017-1959-1
    Arrhythmias arise from breakdown of orderly action potential (AP) activation, propagation and recovery driven by interactive opening and closing of successive voltage-gated ion channels, in which one or more Na+ current components play critical parts. Early peak, Na+ currents (I Na) reflecting channel activation drive the AP upstroke central to cellular activation and its propagation. Sustained late Na+ currents (I Na-L) include contributions from a component with a delayed inactivation timecourse influencing AP duration (APD) and refractoriness, potentially causing pro-arrhythmic phenotypes. The magnitude of I Na-L can be analysed through overlaps or otherwise in the overall voltage dependences of the steady-state properties and kinetics of activation and inactivation of the Na+ conductance. This was useful in analysing repetitive firing associated with paramyotonia congenita in skeletal muscle. Similarly, genetic cardiac Na+ channel abnormalities increasing I Na-L are implicated in triggering phenomena of automaticity, early and delayed afterdepolarisations and arrhythmic substrate. This review illustrates a wide range of situations that may accentuate I Na-L. These include (1) overlaps between steady-state activation and inactivation increasing window current, (2) kinetic deficiencies in Na+ channel inactivation leading to bursting phenomena associated with repetitive channel openings and (3) non-equilibrium gating processes causing channel re-opening due to more rapid recoveries from inactivation. All these biophysical possibilities were identified in a selection of abnormal human SCN5A genotypes. The latter presented as a broad range of clinical arrhythmic phenotypes, for which effective therapeutic intervention would require specific identification and targeting of the diverse electrophysiological abnormalities underlying their increased I Na-L.
  10. Jeevaratnam K, Salvage SC, Li M, Huang CL
    Ann N Y Acad Sci, 2018 Dec;1433(1):18-28.
    PMID: 29846007 DOI: 10.1111/nyas.13861
    Alterations in cellular levels of the second messenger 3',5'-cyclic adenosine monophosphate ([cAMP]i ) regulate a wide range of physiologically important cellular signaling processes in numerous cell types. Osteoclasts are terminally differentiated, multinucleated cells specialized for bone resorption. Their systemic regulator, calcitonin, triggers morphometrically and pharmacologically distinct retraction (R) and quiescence (Q) effects on cell-spread area and protrusion-retraction motility, respectively, paralleling its inhibition of bone resorption. Q effects were reproduced by cholera toxin-mediated Gs -protein activation known to increase [cAMP]i , unaccompanied by the [Ca2+ ]i changes contrastingly associated with R effects. We explore a hypothesis implicating cAMP signaling involving guanine nucleotide-exchange activation of the small GTPase Ras-proximate-1 (Rap1) by exchange proteins directly activated by cAMP (Epac). Rap1 activates integrin clustering, cell adhesion to bone matrix, associated cytoskeletal modifications and signaling processes, and transmembrane transduction functions. Epac activation enhanced, whereas Epac inhibition or shRNA-mediated knockdown compromised, the appearance of markers for osteoclast differentiation and motility following stimulation by receptor activator of nuclear factor kappa-Β ligand (RANKL). Deficiencies in talin and Rap1 compromised in vivo bone resorption, producing osteopetrotic phenotypes in genetically modified murine models. Translational implications of an Epac-Rap1 signaling hypothesis in relationship to N-bisphosphonate actions on prenylation and membrane localization of small GTPases are discussed.
  11. Ahmad S, Valli H, Smyth R, Jiang AY, Jeevaratnam K, Matthews HR, et al.
    J Cell Physiol, 2019 Apr;234(4):3921-3932.
    PMID: 30146680 DOI: 10.1002/jcp.27183
    Peroxisome proliferator-activated receptor-γ coactivator-1 deficient (Pgc-1β-/- ) murine hearts model the increased, age-dependent, ventricular arrhythmic risks attributed to clinical conditions associated with mitochondrial energetic dysfunction. These were accompanied by compromised action potential (AP) upstroke rates and impaired conduction velocities potentially producing arrhythmic substrate. We tested a hypothesis implicating compromised Na+ current in these electrophysiological phenotypes by applying loose patch-clamp techniques in intact young and aged, wild-type (WT) and Pgc-1β-/- , ventricular cardiomyocyte preparations for the first time. This allowed conservation of their in vivo extracellular and intracellular conditions. Depolarising steps elicited typical voltage-dependent activating and inactivating inward Na+ currents with peak amplitudes increasing or decreasing with their respective activating or preceding inactivating voltage steps. Two-way analysis of variance associated Pgc-1β-/- genotype with independent reductions in maximum peak ventricular Na+ currents from -36.63 ± 2.14 (n = 20) and -35.43 ± 1.96 (n = 18; young and aged WT, respectively), to -29.06 ± 1.65 (n = 23) and -27.93 ± 1.63 (n = 20; young and aged Pgc-1β-/- , respectively) pA/μm2 (p k in plots of voltage dependences of both Na+ current activation and inactivation, and time constants for its postrepolarisation recovery from inactivation, remained indistinguishable through all experimental groups. So were the activation and rectification properties of delayed outward (K+ ) currents, demonstrated from tail currents reflecting current recoveries from respective varying or constant voltage steps. These current-voltage properties directly implicate decreases specifically in maximum available Na+ current with unchanged voltage dependences and unaltered K+ current properties, in proarrhythmic reductions in AP conduction velocity in Pgc-1β-/- ventricles.
  12. Valli H, Ahmad S, Fraser JA, Jeevaratnam K, Huang CL
    Exp Physiol, 2017 12 01;102(12):1619-1634.
    PMID: 28960529 DOI: 10.1113/EP086589
    NEW FINDINGS: What is the central question of this study? Can we experimentally replicate atrial pro-arrhythmic phenotypes associated with important chronic clinical conditions, including physical inactivity, obesity, diabetes mellitus and metabolic syndrome, compromising mitochondrial function, and clarify their electrophysiological basis? What is the main finding and its importance? Electrocardiographic and intracellular cardiomyocyte recording at progressively incremented pacing rates demonstrated age-dependent atrial arrhythmic phenotypes in Langendorff-perfused murine Pgc1β-/- hearts for the first time. We attributed these to compromised action potential conduction and excitation wavefronts, whilst excluding alterations in recovery properties or temporal electrophysiological instabilities, clarifying these pro-arrhythmic changes in chronic metabolic disease. Atrial arrhythmias, most commonly manifesting as atrial fibrillation, represent a major clinical problem. The incidence of atrial fibrillation increases with both age and conditions associated with energetic dysfunction. Atrial arrhythmic phenotypes were compared in young (12-16 week) and aged (>52 week) wild-type (WT) and peroxisome proliferative activated receptor, gamma, coactivator 1 beta (Ppargc1b)-deficient (Pgc1β-/- ) Langendorff-perfused hearts, previously used to model mitochondrial energetic disorder. Electrophysiological explorations were performed using simultaneous whole-heart ECG and intracellular atrial action potential (AP) recordings. Two stimulation protocols were used: an S1S2 protocol, which imposed extrasystolic stimuli at successively decremented intervals following regular pulse trains; and a regular pacing protocol at successively incremented frequencies. Aged Pgc1β-/- hearts showed greater atrial arrhythmogenicity, presenting as atrial tachycardia and ectopic activity. Maximal rates of AP depolarization (dV/dtmax ) were reduced in Pgc1β-/- hearts. Action potential latencies were increased by the Pgc1β-/- genotype, with an added interactive effect of age. In contrast, AP durations to 90% recovery (APD90 ) were shorter in Pgc1β-/- hearts despite similar atrial effective recovery periods amongst the different groups. These findings accompanied paradoxical decreases in the incidence and duration of alternans in the aged and Pgc1β-/- hearts. Limiting slopes of restitution curves of APD90 against diastolic interval were correspondingly reduced interactively by Pgc1β-/- genotype and age. In contrast, reduced AP wavelengths were associated with Pgc1β-/- genotype, both independently and interacting with age, through the basic cycle lengths explored, with the aged Pgc1β-/- hearts showing the shortest wavelengths. These findings thus implicate AP wavelength in possible mechanisms for the atrial arrhythmic changes reported here.
  13. Callwood A, Jeevaratnam K, Kotronoulas G, Schneider A, Lewis L, Nadarajah VD
    Nurse Educ Today, 2018 May;64:56-64.
    PMID: 29459193 DOI: 10.1016/j.nedt.2018.01.016
    OBJECTIVES: To examine the personal domains multiple mini interviews (MMIs) are being designed to assess, explore how they were determined and contextualise such domains in current and future healthcare student selection processes DESIGN: A systematic review of empirical research reporting on MMI model design was conducted from database inception to November 2017.

    DATA SOURCES: Twelve electronic bibliographic databases.

    REVIEW METHODS: Evidence was extracted from original studies, and integrated in a narrative synthesis guided by the PRISMA statement for reporting systematic reviews. Personal domains were clustered into themes using a modified Delphi technique.

    RESULTS: A total of 584 articles were screened. 65 unique studies (80 articles) matched our inclusion criteria of which seven were conducted within nursing/midwifery faculties. Six in 10 studies featured applicants to medical school. Across selection processes, we identified 32 personal domains assessed by MMIs, the most frequent being: communication skills (84%), teamwork/collaboration (70%), and ethical/moral judgement (65%). Domains capturing ability to cope with stressful situations (14%), make decisions (14%), and resolve conflict in the workplace (13%) featured in fewer than ten studies overall. Intra- and inter-disciplinary inconsistencies in domain profiles were noted, as well as differences by entry level. MMIs deployed in nursing and midwifery assessed compassion and decision-making more frequently than in all other disciplines. Own programme philosophy and professional body guidance were most frequently cited (~50%) as sources for personal domains; a blueprinting process was reported in only 8% of studies.

    CONCLUSIONS: Nursing, midwifery and allied healthcare professionals should develop their theoretical frameworks for MMIs to ensure they are evidence-based and fit-for-purpose. We suggest a re-evaluation of domain priorities to ensure that students who are selected, not only have the capacity to offer the highest standards of care provision, but are able to maintain these standards when facing clinical practice and organisational pressures.

  14. Jeevaratnam K, Nadarajah VD, Judson JP, Nalliah S, Abdullah MF
    PMID: 20920154 DOI: 10.1186/1471-2393-10-58
    Hypertensive disorders in pregnancy contributes to about 12% of maternal deaths in Malaysia and similarly worldwide. Early detection and adequate management are preventable strategies. Biochemical markers of abnormal angiogenesis would be more specific in early detection than routine blood pressure and proteinuria measurements. The aim of this study was to estimate maternal plasma PlGF and sFlt-1 levels in pregnant women with gestational hypertension at three intervals of pregnancy and correlate these biomarker levels with placental morphometry.
  15. Salvage SC, Chandrasekharan KH, Jeevaratnam K, Dulhunty AF, Thompson AJ, Jackson AP, et al.
    Br J Pharmacol, 2018 Apr;175(8):1260-1278.
    PMID: 28369767 DOI: 10.1111/bph.13807
    Flecainide suppresses cardiac tachyarrhythmias including paroxysmal atrial fibrillation, supraventricular tachycardia and arrhythmic long QT syndromes (LQTS), as well as the Ca2+ -mediated, catecholaminergic polymorphic ventricular tachycardia (CPVT). However, flecainide can also exert pro-arrhythmic effects most notably following myocardial infarction and when used to diagnose Brugada syndrome (BrS). These divergent actions result from its physiological and pharmacological actions at multiple, interacting levels of cellular organization. These were studied in murine genetic models with modified Nav channel or intracellular ryanodine receptor (RyR2)-Ca2+ channel function. Flecainide accesses its transmembrane Nav 1.5 channel binding site during activated, open, states producing a use-dependent antagonism. Closing either activation or inactivation gates traps flecainide within the pore. An early peak INa related to activation of Nav channels followed by rapid de-activation, drives action potential (AP) upstrokes and their propagation. This is diminished in pro-arrhythmic conditions reflecting loss of function of Nav 1.5 channels, such as BrS, accordingly exacerbated by flecainide challenge. Contrastingly, pro-arrhythmic effects attributed to prolonged AP recovery by abnormal late INaL following gain-of-function modifications of Nav 1.5 channels in LQTS3 are reduced by flecainide. Anti-arrhythmic effects of flecainide that reduce triggering in CPVT models mediated by sarcoplasmic reticular Ca2+ release could arise from its primary actions on Nav channels indirectly decreasing [Ca2+ ]i through a reduced [Na+ ]i and/or direct open-state RyR2-Ca2+ channel antagonism. The consequent [Ca2+ ]i alterations could also modify AP propagation velocity and therefore arrhythmic substrate through its actions on Nav 1.5 channel function. This is consistent with the paradoxical differences between flecainide actions upon Na+ currents, AP conduction and arrhythmogenesis under circumstances of normal and increased RyR2 function.

    LINKED ARTICLES: This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc.

  16. Jeevaratnam K, Chadda KR, Salvage SC, Valli H, Ahmad S, Grace AA, et al.
    Clin Exp Pharmacol Physiol, 2017 12;44 Suppl 1:38-45.
    PMID: 28024120 DOI: 10.1111/1440-1681.12721
    Ageing is associated with increased prevalences of both atrial and ventricular arrhythmias, reflecting disruption of the normal sequence of ion channel activation and inactivation generating the propagated cardiac action potential. Experimental models with specific ion channel genetic modifications have helped clarify the interacting functional roles of ion channels and how their dysregulation contributes to arrhythmogenic processes at the cellular and systems level. They have also investigated interactions between these ion channel abnormalities and age-related processes in producing arrhythmic tendency. Previous reviews have explored the relationships between age and loss-of-function Nav 1.5 mutations in producing arrhythmogenicity. The present review now explores complementary relationships arising from gain-of-function Nav 1.5 mutations associated with long QT3 (LQTS3). LQTS3 patients show increased risks of life-threatening ventricular arrhythmias, particularly after 40 years of age, consistent with such interactions between the ion channel abnormailities and ageing. In turn clinical evidence suggests that ageing is accompanied by structural, particularly fibrotic, as well as electrophysiological change. These abnormalities may result from biochemical changes producing low-grade inflammation resulting from increased production of reactive oxygen species and superoxide. Experimental studies offer further insights into the underlying mechanisms underlying these phenotypes. Thus, studies in genetically modified murine models for LQTS implicated action potential recovery processes in arrhythmogenesis resulting from functional ion channel abnormalities. In addition, ageing wild type (WT) murine models demonstrated both ion channel alterations and fibrotic changes with ageing. Murine models then suggested evidence for interactions between ageing and ion channel mutations and provided insights into potential arrhythmic mechanisms inviting future exploration.
  17. Valli H, Ahmad S, Sriharan S, Dean LD, Grace AA, Jeevaratnam K, et al.
    Clin Exp Pharmacol Physiol, 2018 03;45(3):278-292.
    PMID: 29027245 DOI: 10.1111/1440-1681.12870
    Acute RyR2 activation by exchange protein directly activated by cAMP (Epac) reversibly perturbs myocyte Ca2+ homeostasis, slows myocardial action potential conduction, and exerts pro-arrhythmic effects. Loose patch-clamp studies, preserving in vivo extracellular and intracellular conditions, investigated Na+ current in intact cardiomyocytes in murine atrial and ventricular preparations following Epac activation. Depolarising steps to varying test voltages activated typical voltage-dependent Na+ currents. Plots of peak current against depolarisation from resting potential gave pretreatment maximum atrial and ventricular currents of -20.23 ± 1.48 (17) and -29.8 ± 2.4 (10) pA/μm2 (mean ± SEM [n]). Challenge by 8-CPT (1 μmol/L) reduced these currents to -11.21 ± 0.91 (12) (P  .05). Assessment of the inactivation that followed by applying subsequent steps to a fixed voltage 100 mV positive to resting potential gave concordant results. Half-maximal inactivation voltages and steepness factors, and time constants for Na+ current recovery from inactivation in double-pulse experiments, were similar through all the pharmacological conditions. Intracellular sharp microelectrode membrane potential recordings in intact Langendorff-perfused preparations demonstrated concordant variations in maximum rates of atrial and ventricular action potential upstroke, (dV/dt)max . We thus demonstrate an acute, reversible, Na+ channel inhibition offering a possible mechanism for previously reported pro-arrhythmic slowing of AP propagation following modifications of Ca2+ homeostasis, complementing earlier findings from chronic alterations in Ca2+ homeostasis in genetically-modified RyR2-P2328S hearts.
  18. Ahmad S, Valli H, Edling CE, Grace AA, Jeevaratnam K, Huang CL
    Pflugers Arch., 2017 Dec;469(12):1579-1590.
    PMID: 28821956 DOI: 10.1007/s00424-017-2054-3
    A range of chronic clinical conditions accompany cardiomyocyte energetic dysfunction and constitute independent risk factors for cardiac arrhythmia. We investigated pro-arrhythmic and arrhythmic phenotypes in energetically deficient C57BL mice with genetic ablation of the mitochondrial promoter peroxisome proliferator-activated receptor-γ coactivator-1β (Pgc-1β), a known model of ventricular arrhythmia. Pro-arrhythmic and cellular action potential (AP) characteristics were compared in intact Langendorff-perfused hearts from young (12-16 week) and aged (> 52 week), wild-type (WT) and Pgc-1β -/- mice. Simultaneous electrocardiographic and intracellular microelectrode recordings were made through successive trains of 100 regular stimuli at progressively incremented heart rates. Aged Pgc-1β -/- hearts displayed an increased incidence of arrhythmia compared to other groups. Young and aged Pgc-1β -/- hearts showed higher incidences of alternans in both AP activation (maximum AP upshoot velocity (dV/dt)max and latency), recovery (action potential duration (APD90) and resting membrane potential (RMP) characteristics compared to WT hearts. This was particularly apparent at lower pacing frequencies. These findings accompanied reduced (dV/dt)max and increased AP latency values in the Pgc-1β -/- hearts. APs observed prior to termination of the protocol showed lower (dV/dt)max and longer AP latencies, but indistinguishable APD90 and RMPs in arrhythmic compared to those in non-arrhythmic hearts. APD restitution analysis showed that Pgc-1β -/- and WT hearts showed similar limiting gradients. However, Pgc-1β -/- hearts had shortened plateau AP wavelengths, particularly in aged Pgc-1β -/- hearts. Pgc-1β -/- hearts therefore show pro-arrhythmic instabilities attributable to altered AP conduction and activation rather than recovery characteristics.
  19. 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.

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