Exploring the variability of sarcopenia prevalence in a research population using different disease definitions.

BACKGROUND: Sarcopenia is the progressive loss of muscle mass and function with age. A number of different sarcopenia definitions have been proposed and utilised in research. This study aimed to investigate how the prevalence of sarcopenia in a research cohort of older adults is influenced by the use of independent aspects of these different definitions. METHODS: Data from 255 research participants were compiled. Defining criteria by the European Working Group on Sarcopenia in Older People, the International Working Group on Sarcopenia (IWGS), and the Foundation for the National Institutes of Health were applied. RESULTS: Prevalence of sarcopenia using muscle mass ranged from 4 to 22%. Gait speed and handgrip strength criteria identified 4-34% and 4-16% of participants as sarcopenic, respectively. CONCLUSION: Prevalence of sarcopenia differs substantially depending on the criteria used. Work is required to address the impact of this for sarcopenia research to be usefully translated to inform on clinical practice.

Engagement in research during specialist geriatric medicine training: results of a national trainee survey.

INTRODUCTION: Meaningful ageing research across the UK is dependent on a network of engaged geriatricians. The research in geriatric specialty training (RGST) survey aimed to establish current research opportunities available to geriatric medicine specialty trainees in the UK. METHODS: The RGST survey was disseminated to UK higher specialist trainees in geriatric medicine in 2019 via the Geriatric Medicine Research Collaborative network. RESULTS: Among the 36.9% (192/521) of respondents, 44% (83/188) reported previous research involvement and 7% (n=8) held a PhD or MD. Of the respondents with no research experience to date, 59.0% (n=49) reported a desire to undertake a period of research. One-third (31%) of geriatric registrars surveyed felt that they had gained sufficient research experience during their training. Perceived encouragement and support to undertake research was low (30.7%). Enablers and barriers to research engagement were identified. CONCLUSION: Research opportunity and engagement in geriatric medicine training is lacking. This could jeopardise the future workforce of research-active geriatricians in the UK and limit patient access to emerging research and innovation. Interventions to promote research engagement among geriatric medicine trainees are needed to facilitate integration of research into routine clinical practice to improve the health and care of older people.

Progressive multifocal leukoencephalopathy masquerading as cerebellar infarction.

Progressive neurological signs and symptoms, in immunocompromised individuals, could be due to progressive multifocal leukoencephalopathy (PML). We report the case of a patient who present a stroke unit with symptoms that were consistent initially with a posterior circulation stroke. Prior chemotherapy with Rituximab, for a lymphoma, had predisposed the patient to infection with the JC virus. Physicians need to be aware of the condition, and patients need to aware of these risks of chemotherapy.

Mutations in Troponin that cause HCM, DCM AND RCM: what can we learn about thin filament function?

Troponin (Tn) is a critical regulator of muscle contraction in cardiac muscle. Mutations in Tn subunits are associated with hypertrophic, dilated and restrictive cardiomyopathies. Improved diagnosis of cardiomyopathies as well as intensive investigation of new mouse cardiomyopathy models has significantly enhanced this field of research. Recent investigations have showed that the physiological effects of Tn mutations associated with hypertrophic, dilated and restrictive cardiomyopathies are different. Impaired relaxation is a universal finding of most transgenic models of HCM, predicted directly from the significant changes in Ca(2+) sensitivity of force production. Mutations associated with HCM and RCM show increased Ca(2+) sensitivity of force production while mutations associated with DCM demonstrate decreased Ca(2+) sensitivity of force production. This review spotlights recent advances in our understanding on the role of Tn mutations on ATPase activity, maximal force development and heart function as well as the correlation between the locations of these Tn mutations within the thin filament and myofilament function.

Dilated cardiomyopathy mutations in three thin filament regulatory proteins result in a common functional phenotype.

Dilated cardiomyopathy (DCM), characterized by cardiac dilatation and contractile dysfunction, is a major cause of heart failure. Inherited DCM can result from mutations in the genes encoding cardiac troponin T, troponin C, and alpha-tropomyosin; different mutations in the same genes cause hypertrophic cardiomyopathy. To understand how certain mutations lead specifically to DCM, we have investigated their effect on contractile function by comparing wild-type and mutant recombinant proteins. Because initial studies on two troponin T mutations have generated conflicting findings, we analyzed all eight published DCM mutations in troponin T, troponin C, and alpha-tropomyosin in a range of in vitro assays. Thin filaments, reconstituted with a 1:1 ratio of mutant/wild-type proteins (the likely in vivo ratio), all showed reduced Ca(2+) sensitivity of activation in ATPase and motility assays, and except for one alpha-tropomyosin mutant showed lower maximum Ca(2+) activation. Incorporation of either of two troponin T mutants in skinned cardiac trabeculae also decreased Ca(2+) sensitivity of force generation. Structure/function considerations imply that the diverse thin filament DCM mutations affect different aspects of regulatory function yet change contractility in a consistent manner. The DCM mutations depress myofibrillar function, an effect fundamentally opposite to that of hypertrophic cardiomyopathy-causing thin filament mutations, suggesting that decreased contractility may trigger pathways that ultimately lead to the clinical phenotype.

Alterations in thin filament regulation induced by a human cardiac troponin T mutant that causes dilated cardiomyopathy are distinct from those induced by troponin T mutants that cause hypertrophic cardiomyopathy.

We have compared the in vitro regulatory properties of recombinant human cardiac troponin reconstituted using wild type troponin T with troponin containing the DeltaLys-210 troponin T mutant that causes dilated cardiomyopathy (DCM) and the R92Q troponin T known to cause hypertrophic cardiomyopathy (HCM). Troponin containing DeltaLys-210 troponin T inhibited actin-tropomyosin-activated myosin subfragment-1 ATPase activity to the same extent as wild type at pCa8.5 (>80%) but produced substantially less enhancement of ATPase at pCa4.5. The Ca(2+) sensitivity of ATPase activation was increased (DeltapCa(50) = +0.2 pCa units) and cooperativity of Ca(2+) activation was virtually abolished. Equimolar mixtures of wild type and DeltaLys-210 troponin T gave a lower Ca(2+) sensitivity than with wild type, while maintaining the diminished ATPase activation at pCa4.5 observed with 100% mutant. In contrast, R92Q troponin gave reduced inhibition at pCa8.5 but greater activation than wild type at pCa4.5; Ca(2+) sensitivity was increased but there was no change in cooperativity. In vitro motility assay of reconstituted thin filaments confirmed the ATPase results and moreover indicated that the predominant effect of the DeltaLys-210 mutation was a reduced sliding speed. The functional consequences of this DCM mutation are qualitatively different from the R92Q or any other studied HCM troponin T mutation, suggesting that DCM and HCM may be triggered by distinct primary stimuli.