Dense-core granules: a specific hallmark of the neuronal/neurosecretory cell phenotype.

Expression of dense-core granules, a typical exocytic organelle, is widely believed to be controlled by coordinate gene expression mechanisms specific to neurones and neurosecretory cells. Recent studies in PC12 cells, however, have suggested the number of granules/cells depends on the levels of only one of their cargo proteins, chromogranin A, regulating the metabolism of the other proteins, and thus the composition of the organelles, by an on/off switch mechanism. In addition, transfection of chromogranin A was reported to induce appearance of dense-core granules in the non-neurosecretory fibroblasts of the CV-1 line. Here the role of chromogranin A has been reinvestigated using not the heterogeneous PC12 line but several clones isolated therefrom. In these clones, investigated as such or after transfection with chromogranin A antisense sequences, the ratio between chromogranin A and its secretory protein mate, chromogranin B, was not constant but highly and apparently randomly variable. Variability of the chromogranin A/chromogranin B ratio was seen by confocal immunofluorescence also among the cells of single clones and subclones and among the granules of single cells. Moreover, stable and transient transfections of chromogranin A in a PC12 clone characterised by a low number of dense-core granules (one fifth of the reference clone) failed to modify significantly the number of the organelles, despite the several-fold increase of the granin. Finally, in three types of non-neurosecretory cells (CV-1, adenocarcinoma TS/A and a clone of PC12 incompetent for secretion) the transfected chromogranin A accumulated mostly in the Golgi/transGolgi area and was released rapidly from resting cells (constitutive secretion) as revealed by both immunofluorescence during cycloheximide treatment and pulse-chase experiments. Only a minor fraction was sorted to discrete organelles that were not dense-core granules, but primarily lysosomes because they contained no chromogranin B, and were largely positive for the late endosomal-lysosomal markers, lamp1 and lamp3. Dense-core granules are therefore true hallmarks of neurones and neurosecretory cells. Their number/cell appears independent of chromogranin A and their composition does not appear to be constant; in particular, they exhibit considerable, and so far unexplained variability in the chromogranin A/chromogranin B ratio

An Approach to Support the Performance Management of Public Health Authorities using an IT based Modeling Method

In this paper we describe a modeling method for supportingperformance management by building upon the currentchallenges of public health authorities. Through focusingon the performance management requirements of nationalcompetent authorities (NCA) that fulll several duties inregard to the marketing authorization of medicinal products,we derive a modeling language, an according modeling procedureand mechanisms and algorithms. Thereby, particularrequirements in regard to the compliance to legal regulations,the competition of NCAs within the European Union, theallocation of resources under uncertainty, and the specichuman resource requirements of NCAs have to be taken intoaccount. The modeling language is formally described usinga meta model based approach and implemented on a metamodeling platform. For the evaluation, the modeling methodhas been applied in a scientic study with the Austriannational competent authority AGES PharmMed

Correction to: Is There Enough Evidence for Osteosarcopenic Obesity as a Distinct Entity? A Critical Literature Review

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The authors reply: Letter on: 'Pitfalls in the measurement of muscle mass: a need for a reference standard' by Clark et al.

However, semantics aside, we think that DXA can indeed serve as a reference standard for measuring muscle mass. Obviously, CT and MRI are advanced techniques that can and have been used to obtain important information such as muscle size/volume and more recently amount and distribution of intra- and intermuscular adipose tissue. Also individual muscles can be assessed separately. However, with respect to muscle mass, the comparison of DXA with CT/MRI is rather difficult because DXA and QCT/MRI measure different physical parameters

A Need to Meet Patient Expectations

Funding Information: Open access funding provided by Università degli Studi di Palermo within the Nicola Veronese reports personal fees from IBSA, Mylan, and Fidia outside of the submitted work. Cyrus Cooper reports personal fees from Alliance for Better Bone Health, Amgen, Eli Lilly, GSK, Medtronic, Merck, Novartis, Pfizer, Roche, Servier, Takeda, and UCB outside of the submitted work. Jean-Yves Reginster reports CRUI-CARE Agreement. Funding Information:grants from IBSA-Genevrier, Mylan, CNIEL, and Radius Health (through his institution); consulting fees from IBSA-Genevrier, Mylan, CNIEL, Radius Health, and Pierre Fabre; fees for participation in review activities from IBSA-Genevrier, Mylan, CNIEL, Radius Health, and Teva; and payment for lectures from Ag-Novos, CERIN, CNIEL, Dairy Research Council (DRC), Echolight, IBSA-Genevrier, Mylan, Pfizer Consumer Health, Teva, and Theramex outside of the submitted work. Olivier Bruyère reports grants or lecture fees from Amgen, Aptissen, Biophytis, IBSA, MEDA, Mylan, Novartis, Sanofi, Servier, SMB, TRB Chemedica, UCB, and Viatris outside of the submitted work. Ali Mobasheri declares personal fees from Abbott, Abbvie, Achē Laboratórios Farmacêuticos, Galapagos, GSK Consumer Healthcare, Kolon TissueGene, Laboratoires Expansciences, Merck, Pacira Biosciences, Pfizer, Sanofi, and Servier. François Rannou reports grants or lecture fees from Pierre Fabre, Mylan, MSD, Thuasne, IBSA, Pfizer, Genévrier, Expanscience, Scarcell, Skindermic, and Peptinov. Ida K. Haugen reports grants from Pfizer and is a consultant for Novartis outside of the submitted work. Elaine M. Dennison declares grants/fees from Pfizer, Lilly, UCB, and Viatris. Philip G. Conaghan is supported in part by the National Institute for Health and Care Research (NIHR) Leeds Biomedical Research Centre (the views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health), and reports consultancies or lecture fees from AbbVie, Amgen, AstraZeneca, Eli Lilly, Galapagos, GSK, Grunenthal, Pfizer, Novartis, and UCB. Nasser M. Al-Daaghri, Antonella Fioravanti, Sara Cheleschi, Jean-Pierre Pelletier, Maarten de Wit, Etienne Cavalier, Radmila Matijevic, Germain Honvo, Régis Pierre Radermecker, René Rizzoli, Jaime Branco, Andrea Laslop, María Concepción Prieto Yerro, Alberto Migliore, Gabriel Herrero-Beaumont, and Nicholas R. Fuggle declare that they have no conflicts of interest. Publisher Copyright: © 2022, The Author(s).Knee osteoarthritis (OA) is one of the most common and disabling medical conditions. In the case of moderate to severe pain, a single intervention may not be sufficient to allay symptoms and improve quality of life. Examples include first-line, background therapy with symptomatic slow-acting drugs for OA (SYSADOAs) or non-steroidal anti-inflammatory drugs (NSAIDs). Therefore, the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) performed a review of a multimodal/multicomponent approach for knee OA therapy. This strategy is a particularly appropriate solution for the management of patients affected by knee OA, including those with pain and dysfunction reaching various thresholds at the different joints. The multimodal/multicomponent approach should be based, firstly, on different combinations of non-pharmacological and pharmacological interventions. Potential pharmacological combinations include SYSADOAs and NSAIDs, NSAIDs and weak opioids, and intra-articular treatments with SYSADOAs/NSAIDs. Based on the available evidence, most combined treatments provide benefit beyond single agents for the improvement of pain and other symptoms typical of knee OA, although further high-quality studies are required. In this work, we have therefore provided new, patient-centered perspectives for the management of knee OA, based on the concept that a multimodal, multicomponent, multidisciplinary approach, applied not only to non-pharmacological treatments but also to a combination of the currently available pharmacological options, will better meet the needs and expectations of patients with knee OA, who may present with various phenotypes and trajectories.publishersversionpublishe

Role of vitamin D supplementation in the management of musculoskeletal diseases: update from an European Society of Clinical and Economical Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) working group.

Vitamin D is a key component for optimal growth and for calcium-phosphate homeostasis. Skin photosynthesis is the main source of vitamin D. Limited sun exposure and insufficient dietary vitamin D supply justify vitamin D supplementation in certain age groups. In older adults, recommended doses for vitamin D supplementation vary between 200 and 2000 IU/day, to achieve a goal of circulating 25-hydroxyvitamin D (calcifediol) of at least 50 nmol/L. The target level depends on the population being supplemented, the assessed system, and the outcome. Several recent large randomized trials with oral vitamin D regimens varying between 2000 and 100,000 IU/month and mostly conducted in vitamin D-replete and healthy individuals have failed to detect any efficacy of these approaches for the prevention of fracture and falls. Considering the well-recognized major musculoskeletal disorders associated with severe vitamin D deficiency and taking into account a possible biphasic effects of vitamin D on fracture and fall risks, an European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) working group convened, carefully reviewed, and analyzed the meta-analyses of randomized controlled trials on the effects of vitamin D on fracture risk, falls or osteoarthritis, and came to the conclusion that 1000 IU daily should be recommended in patients at increased risk of vitamin D deficiency. The group also addressed the identification of patients possibly benefitting from a vitamin D loading dose to achieve early 25-hydroxyvitamin D therapeutic level or from calcifediol administration

Quality of Life in Sarcopenia and Frailty

The reduced muscle mass and impaired muscle performance that define sarcopenia in older individuals are associated with increased risk of physical limitation and a variety of chronic diseases. They may also contribute to clinical frailty. A gradual erosion of quality of life (QoL) has been evidenced in these individuals, although much of this research has been done using generic QoL instruments, particularly the SF-36, which may not be ideal in older populations with significant comorbidities. This review and report of an expert meeting presents the current definitions of these geriatric syndromes (sarcopenia and frailty). It then briefly summarizes QoL concepts and specificities in older populations and examines the relevant domains of QoL and what is known concerning QoL decline with these conditions. It calls for a clearer definition of the construct of disability, argues that a disease-specific QoL instrument for sarcopenia/frailty would be an asset for future research, and discusses whether there are available and validated components that could be used to this end and whether the psychometric properties of these instruments are sufficiently tested. It calls also for an approach using utility weighting to provide some cost estimates and suggests that a time trade-off study could be appropriat

Algorithm for the use of biochemical markers of bone turnover in the diagnosis, assessment and follow-up of treatment for osteoporosis

Introduction Increased biochemical bone turnover markers (BTMs) measured in serum are associated with bone loss, increased fracture risk and poor treatment adherence, but their role in clinical practice is presently unclear. The aim of this consensus group report is to provide guidance to clinicians on how to use BTMs in patient evaluation in postmenopausal osteoporosis, in fracture risk prediction and in the monitoring of treatment efficacy and adherence to osteoporosis medication. Methods A working group with clinical scientists and osteoporosis specialists was invited by the Scientific Advisory Board of European Society on Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO). Results Serum bone formation marker PINP and resorption marker βCTX-I are the preferred markers for evaluating bone turnover in the clinical setting due to their specificity to bone, performance in clinical studies, wide use and relatively low analytical variability. BTMs cannot be used to diagnose osteoporosis because of low sensitivity and specificity, but can be of value in patient evaluation where high values may indicate the need to investigate some causes of secondary osteoporosis. Assessing serum levels of βCTX-I and PINP can improve fracture prediction slightly, with a gradient of risk of about 1.2 per SD increase in the bone marker in addition to clinical risk factors and bone mineral density. For an individual patient, BTMs are not useful in projecting bone loss or treatment efficacy, but it is recommended that serum PINP and βCTX-I be used to monitor adherence to oral bisphosphonate treatment. Suppression of the BTMs greater than the least significant change or to levels in the lower half of the reference interval in young and healthy premenopausal women is closely related to treatment adherence. Conclusion In conclusion, the currently available evidence indicates that the principal clinical utility of BTMs is for monitoring oral bisphosphonate therapy