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BACKGROUND: Recently, Objective Structured Clinical Examinations (OSCE) became an official evaluation modality for 6-year medical students in France. Before, standard examination modalities were: written progressive clinical cases (PCC), written critical reading of scientific articles (CRA), and internship evaluation (IE). The aim of this study was to assess the performances of 6-year medical students in their final faculty tests by comparing OSCE-exams with standard examination modalities. METHODS: This was a prospective observational study. We included all 6-year medical students in our university from 2020 to 2021. The endpoints were the scores obtained at the following final faculty tests during the 6th year of medical studies: OSCE-training, OSCE-exams, written PCC, written CRA, and IE. All scores were compared in a paired-analysis. RESULTS: A total of 400 students were included in the study. No student was excluded in the final analysis. The mean scores obtained at the OSCE-exams were significantly different from those obtained at OSCE-training, PCC, CRA, and IE (12.6 ± 1.7, 11.7 ± 1.7, 13.4 ± 1.4, 13.2 ± 1.5, 14.7 ± 0.9, respectively; p < 0.001). OSCE-exams scores were moderately and significantly correlated with OSCE-training and PCC (Spearman rho coefficient = 0.4, p < 0.001); OSCE examination scores were lowly but significantly correlated with CRA and IE (Spearman rho coefficient = 0.3, p < 0.001). OSCE-scores significantly increased after an OSCE training session. CONCLUSION: In our faculty, 6-year medical students obtained lower scores at OSCE exams compared to other standard evaluation modalities. The correlation was weak to moderate but significant. These results suggest that OSCE are not redundant with the other evaluation modalities. Interestingly, a single OSCE training session led to an improvement in OSCE scores underlining the importance of a specific training.
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Avaliação Educacional , Estudantes de Medicina , Humanos , Avaliação Educacional/métodos , Competência Clínica , Exame Físico/métodos , RedaçãoRESUMO
Proinflammatory cytokines play an important role in the systemic and focal bone loss associated with chronic inflammatory diseases. Targeting these cytokines with biologics and small molecules has led to a major improvement of the bone health of patients with inflammatory arthritis. Cytokines from the IL-17 family have been shown to be involved in the pathogenesis of several diseases such as spondyloarthritis, psoriatic arthritis, or psoriasis. IL-17A has been the first described and the most studied. The recent development of targeted therapies against IL-17A or its receptor and their efficacy has confirmed the importance of this cytokine in the development of inflammatory diseases. The aim of this review was to describe the effects of the IL-17 family and more particularly of IL-17A on bone and cartilage tissues. At the cellular level, IL-17A is proosteoclastogenic whereas its effects on osteoblasts depend on the stage of differentiation of these cells. In vivo, IL-17A is not required for normal bone homeostasis but plays an important role in bone loss notably in an ovariectomized mouse model of osteoporosis. Preliminary data from clinical trials showed a stabilisation of bone density in patients treated with anti-IL-17A antibodies. IL-17A plays a central role in the cartilage damage through the induction of collagenases and by decreasing the expression of their inhibitors in synergy with the other proinflammatory cytokines. The prevention of structural damage by anti-IL-17A therapies has been demonstrated in several pivotal clinical trials. Overall, blocking the IL-17A pathway seems to have a positive effect on the bone and cartilage damage observed in inflammatory arthritis. Differences and specificity of these effects compared to those already described with other biologics such as anti-TNF therapies remain to be explored.
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Citocinas/metabolismo , Interleucina-17/uso terapêutico , Doenças Reumáticas/metabolismo , Animais , Humanos , Inflamação/imunologia , Inflamação/metabolismoRESUMO
Type 1 diabetes mellitus is associated with a high risk for bone fractures. Although bone mass is reduced, bone quality is also dramatically altered in this disorder. However, recent evidences suggest a beneficial effect of the glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) pathways on bone quality. The aims of the present study were to conduct a comprehensive investigation of bone strength at the organ and tissue level; and to ascertain whether enzyme resistant GIP or GLP-1 mimetic could be beneficial in preventing bone fragility in type 1 diabetes mellitus. Streptozotocin-treated mice were used as a model of type 1 diabetes mellitus. Control and streptozotocin-diabetic animals were treated for 21 days with an enzymatic-resistant GIP peptide ([D-Ala(2) ]GIP) or with liraglutide (each at 25 nmol/kg bw, ip). Bone quality was assessed at the organ and tissue level by microCT, qXRI, 3-point bending, qBEI, nanoindentation, and Fourier-transform infrared microspectroscopy. [D-Ala2]GIP and liraglutide treatment did prevent loss of whole bone strength and cortical microstructure in the STZ-injected mice. However, tissue material properties were significantly improved in STZ-injected animals following treatment with [D-Ala2]GIP or liraglutide. Treatment of STZ-diabetic mice with [D-Ala(2) ]GIP or liraglutide was capable of significantly preventing deterioration of the quality of the bone matrix. Further studies are required to further elucidate the molecular mechanisms involved and to validate whether these findings can be translated to human patients.
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Conservadores da Densidade Óssea/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Polipeptídeo Inibidor Gástrico/farmacologia , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Hipoglicemiantes/farmacologia , Incretinas/farmacologia , Tíbia/efeitos dos fármacos , Animais , Fenômenos Biomecânicos , Densidade Óssea/efeitos dos fármacos , Remodelação Óssea/efeitos dos fármacos , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/fisiopatologia , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Liraglutida , Masculino , Camundongos , Microespectrofotometria , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Espectroscopia de Infravermelho com Transformada de Fourier , Tíbia/diagnóstico por imagem , Tíbia/metabolismo , Tíbia/fisiopatologia , Fatores de Tempo , Microtomografia por Raio-XRESUMO
Interleukin-26 (IL-26), a member of the IL-10 cytokine family, induces the production of proinflammatory cytokines by epithelial cells. IL-26 has been also reported overexpressed in Crohn's disease, suggesting that it may be involved in the physiopathology of chronic inflammatory disorders. Here, we have analyzed the expression and role of IL-26 in rheumatoid arthritis (RA), a chronic inflammatory disorder characterized by joint synovial inflammation. We report that the concentrations of IL-26 are higher in the serums of RA patients than of healthy subjects and dramatically elevated in RA synovial fluids compared to RA serums. Immunohistochemistry reveals that synoviolin(+) fibroblast-like synoviocytes and CD68(+) macrophage-like synoviocytes are the main IL-26-producing cells in RA joints. Fibroblast-like synoviocytes from RA patients constitutively produce IL-26 and this production is upregulated by IL-1-beta and IL-17A. We have therefore investigated the role of IL-26 in the inflammatory process. Results show that IL-26 induces the production of the proinflammatory cytokines IL-1-beta, IL-6, and tumor necrosis factor (TNF)-alpha by human monocytes and also upregulates the expression of numerous chemokines (mainly CCL20). Interestingly, IL-26-stimulated monocytes selectively promote the generation of RORgamma t(+) Th17 cells, through IL-1-beta secretion by monocytes. More precisely, IL-26-stimulated monocytes switch non-Th17 committed (IL-23R(-) or CCR6(-) CD161(-)) CD4(+) memory T cells into Th17 cells. Finally, synovial fluids from RA patients also induce Th17 cell generation and this effect is reduced after IL-26 depletion. These findings show that IL-26 is constitutively produced by RA synoviocytes, induces proinflammatory cytokine secretion by myeloid cells, and favors Th17 cell generation. IL-26 thereby appears as a novel proinflammatory cytokine, located upstream of the proinflammatory cascade, that may constitute a promising target to treat RA and chronic inflammatory disorders.
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Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Citocinas/biossíntese , Mediadores da Inflamação/metabolismo , Interleucinas/metabolismo , Células Th17/imunologia , Artrite Reumatoide/sangue , Citocinas/metabolismo , Demografia , Feminino , Fibroblastos/imunologia , Fibroblastos/patologia , Humanos , Imuno-Histoquímica , Memória Imunológica , Interleucina-17/metabolismo , Interleucina-1beta/metabolismo , Interleucinas/sangue , Articulações/imunologia , Articulações/patologia , Masculino , Pessoa de Meia-Idade , Modelos Imunológicos , Monócitos/metabolismo , Células Mieloides/metabolismo , Líquido Sinovial/metabolismo , Membrana Sinovial/metabolismo , Membrana Sinovial/patologiaRESUMO
Bone resorption follows a circadian rhythm, with a marked reduction in circulating markers of resorption (such as carboxy-terminal telopeptide region of collagen type I in serum) in the postprandial period. Several gut hormones, including glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP1) and GLP2, have been linked to this effect in humans and rodent models. These hormones are secreted from enteroendocrine cells in the gastrointestinal tract in response to a variety of stimuli and effect a wide range of physiological processes within and outside the gut. Single GLP1, dual GLP1-GIP or GLP1-glucagon and triple GLP1-GIP-glucagon receptor agonists have been developed for the treatment of type 2 diabetes mellitus and obesity. In addition, single GIP, GLP1 and GLP2 analogues have been investigated in preclinical studies as novel therapeutics to improve bone strength in bone fragility disorders. Dual GIP-GLP2 analogues have been developed that show therapeutic promise for bone fragility in preclinical studies and seem to exert considerable activity at the bone material level. This Review summarizes the evidence of the action of gut hormones on bone homeostasis and physiology.
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Osso e Ossos , Polipeptídeo Inibidor Gástrico , Hormônios Gastrointestinais , Homeostase , Humanos , Homeostase/fisiologia , Osso e Ossos/metabolismo , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/fisiologia , Animais , Hormônios Gastrointestinais/fisiologia , Hormônios Gastrointestinais/metabolismo , Polipeptídeo Inibidor Gástrico/metabolismo , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/metabolismo , Peptídeo 2 Semelhante ao Glucagon/fisiologia , Peptídeo 2 Semelhante ao Glucagon/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismoRESUMO
Diabetes mellitus and obesity are rapidly growing worldwide. Aside from metabolic disturbances, these two disorders also affect bone with a higher prevalence of bone fractures. In the last decade, a growing body of evidence suggested that several gut hormones, including ghrelin, gastrin, glucose-dependent insulinotropic polypeptide (GIP), glucagon, and glucagon-like peptide-1 and 2 (GLP-1 and GLP-2, respectively) may affect bone physiology. Several gut hormone analogues have been developed for the treatment of type 2 diabetes and obesity, and could represent a new alternative in the therapeutic arsenal against bone fragility. In the present review, a summary of the physiological roles of these gut hormones and their analogues is presented at the cellular level but also in several preclinical models of bone fragility disorders including type 2 diabetes mellitus, especially on bone mineral density, microarchitecture and bone material properties. The present review also summarizes the impact of GLP-1 receptor agonists approved for the treatment of type 2 diabetes mellitus and the more recent dual or triple analogue on bone physiology and strength.
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Diabetes Mellitus Tipo 2 , Hormônios Gastrointestinais , Obesidade , Humanos , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/complicações , Animais , Hormônios Gastrointestinais/metabolismo , Densidade Óssea/efeitos dos fármacos , Osso e Ossos/metabolismo , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/patologia , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Polipeptídeo Inibidor Gástrico/metabolismo , Polipeptídeo Inibidor Gástrico/uso terapêuticoRESUMO
INTRODUCTION: Hypophosphatasia (HPP) is a rare genetic disease caused by loss-of-function mutations in the ALPL gene encoding the tissue non-specific alkaline phosphatase (ALP). Mild HPP is usually misdiagnosed in adult age. While an elevated serum ALP value draws more attention than a low value, low serum ALP should be better recognised and may lead to HPP detection. METHODS: Patients were selected from the records of the biochemistry department of six University Hospitals in France. Patients were hospitalised in the departments of rheumatology and internal medicine between 2007 and 2017. RESULTS: 56 321 hospitalised patients had at least 2 serum ALP dosages and 664 of these patients had at least 2 low serum ALP≤35 UI/L. Among these 664 patients, 482 (72.6%) had fluctuating low values (mean age 62.9 years; 60% of women) and 182 patients (27.4%) had persistent low values below 35 IU/L (mean age 53.4 years; 67% of women). Among patients with persistent hypophosphatasaemia treated with bisphosphonates, 70.8% never had ALP measurement before treatment and 20.8% were treated despite an abnormal decrease of ALP. Genetic testing was performed in 18 patients and was positive in 11. Genetic diagnosis of HPP was at least 6.0% in persistent hypophosphatasaemia and at least 15.9% in patients with at least three symptoms suggestive of HPP. CONCLUSION: In this 10-year retrospective study, 0.32% of adult patients hospitalised in the rheumatology and internal medicine departments had persistently low serum ALP, and among them, 6% had genetically proven HPP. Reported hypophosphatasaemia represented only 3.6% of hospitalised patients.
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Hipofosfatasia , Reumatologia , Adulto , Humanos , Feminino , Pessoa de Meia-Idade , Hipofosfatasia/diagnóstico , Hipofosfatasia/epidemiologia , Hipofosfatasia/genética , Fosfatase Alcalina/genética , Estudos Retrospectivos , MutaçãoAssuntos
Antirreumáticos/efeitos adversos , Artrite Reumatoide/tratamento farmacológico , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/genética , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Adulto , Idoso , Feminino , Predisposição Genética para Doença/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/genética , Polimorfismo de Nucleotídeo Único , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
OBJECTIVE: To determine the pattern of demyelinating disorders (DDs) occurring during anti-TNF-α therapy. METHODS: Between June 2005 and April 2008, 1800 French rheumatologists and internists were contacted to report cases of DDs occurring in patients treated with anti-TNF-α. RESULTS: After a median of 10.2 (1.5-39.9) months of treatment, 33 patients developed DDs: 22 had CNS and 11 peripheral nervous system (PNS) involvement. Underlying diseases were RA (n = 16), AS (n = 11), PsA (n = 4), JIA (n = 1) and PM (n = 1). Anti-TNF-α was infliximab (n = 15), etanercept (n = 12) or adalimumab (n = 6). CNS involvement was encephalic lesions (n = 16), transverse myelitis (n = 8) or retrobulbar optic neuritis (n = 5). Cerebrospinal fluid (CSF) analysis in 16 patients and MRI in 20 patients were abnormal. All patients discontinued anti-TNF-α. Fifteen patients required steroids. Twenty patients initially improved. Five patients developed multiple sclerosis. PNS involvement was chronic (n = 9) or acute inflammatory demyelinating polyneuropathy (n = 2). CSF analysis revealed an increased protein level in nine patients. Nerve conduction studies confirmed DD in all these patients. Anti-TNF-α was discontinued in 10 patients and 8 received i.v. immunoglobulins. Two patients relapsed after introduction of another anti-TNF-α. Overall, a causal relationship between anti-TNF-α and DD was considered as probable in 31 patients and definite in 2 who had positive rechallenge. CONCLUSION: Causal relationship between anti-TNF-α and induction of DD remains unclear, but in some cases the chronology of clinical events is suggestive. Nevertheless, DD might persist despite treatment discontinuation, suggesting that anti-TNF-α could trigger the demyelinating process, which further evolves independently.
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Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/epidemiologia , Fator de Necrose Tumoral alfa/efeitos adversos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adalimumab , Adolescente , Adulto , Distribuição por Idade , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/tratamento farmacológico , Estudos Transversais , Doenças Desmielinizantes/fisiopatologia , Relação Dose-Resposta a Droga , Etanercepte , Feminino , Seguimentos , França/epidemiologia , Humanos , Imunoglobulina G/administração & dosagem , Imunoglobulina G/efeitos adversos , Incidência , Infliximab , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/tratamento farmacológico , Receptores do Fator de Necrose Tumoral/administração & dosagem , Reumatologia/métodos , Medição de Risco , Distribuição por Sexo , Estatísticas não Paramétricas , Inquéritos e Questionários , Taxa de Sobrevida , Fator de Necrose Tumoral alfa/administração & dosagem , Adulto JovemRESUMO
Due to aging of the population, bone frailty is dramatically increasing worldwide. Although some therapeutic options exist, they do not fully protect or prevent against the occurrence of new fractures. All current drugs approved for the treatment of bone fragility target bone mass. However, bone resistance to fracture is not solely due to bone mass but relies also on bone extracellular matrix (ECM) material properties, i.e., the quality of the bone matrix component. Here, we introduce the first-in-class unimolecular dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-2 (GIP/GLP-2) analogue, GL-0001, that activates simultaneously the glucose-dependent insulinotropic polypeptide receptor (GIPr) and the glucagon-like peptide-2 receptor (GLP-2r). GL-0001 acts synergistically through a cyclic adenosine monophosphate-lysyl oxidase pathway to enhance collagen maturity. Furthermore, bilateral ovariectomy was performed in 32 BALB/c mice at 12 weeks of age prior to random allocation to either saline, dual GIP/GLP-2 analogues (GL-0001 or GL-0007) or zoledronic acid groups (n = 8/group). Treatment with dual GIP/GLP-2 analogues was initiated 4 weeks later for 8 weeks. At the organ level, GL-0001 modified biomechanical parameters by increasing ultimate load, postyield displacement, and energy-to-fracture of cortical bone. GL-0001 also prevented excess trabecular bone degradation at the appendicular skeleton and enhanced bone ECM material properties in cortical bone through a reduction of the mineral-to-matrix ratio and augmentation in enzymatic collagen cross-linking. These results demonstrate that targeting bone ECM material properties is a viable option to enhance bone strength and opens an innovative pathway for the treatment of patients suffering from bone fragility. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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Fraturas Ósseas , Peptídeo 1 Semelhante ao Glucagon , Animais , Camundongos , Osso e Ossos/metabolismo , Densidade Óssea , Fraturas Ósseas/tratamento farmacológico , Polipeptídeo Inibidor Gástrico/análogos & derivados , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismoRESUMO
Despite an increased availability of non-invasive procedures to assess bone mass, histological examination of undecalcified transiliac bone biopsies remains a very valuable tool in the diagnosis of metabolic or malignant bone disorders. Nonetheless, clinicians are sometimes reluctant to perform this "invasive" examination, arguing that it might be a painful procedure. The aim of our study was to evaluate pain and anxiety described by patients in the months following the biopsy and to characterize potential early or late side effects. A single interviewer conducted a phone survey (19 items questionnaire) in 117 patients in whom a bone biopsy had been performed by two experienced physicians, with the same material and similar anesthetic and technical procedure. The topics covered pain during or after the biopsy, anxiety, comparison of other potentially painful procedures, early or late side effects as well as global evaluation by the patients. Bone biopsy was judged as non-painful by almost 70% of patients; some discomfort was present in 25% in the following days. The procedure was described as similar as or less painful than bone marrow aspiration, venipuncture or tooth extraction. About 90% of the patients estimated that it was a quite bearable diagnostic procedure. Side effects were not serious. About 7% remembered a vasovagal episode, 47% of local bruising in the following days. There was no report of hematoma or infection. In experienced hands and adapted trephine, transiliac bone biopsy is a safe procedure that brings invaluable information in bone disorders.
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Biópsia/efeitos adversos , Osso e Ossos/patologia , Dor/etiologia , Feminino , Humanos , Ílio , MasculinoRESUMO
Epidemiologic studies have shown that 25% of osteoporotic fractures occur in men. Their prognosis is poor with one third of deaths in the year following the proximal femur fracture. Screening is based on the analysis of risk factors (prolonged corticosteroid therapy, anti androgen, smoking or alcohol abuse, liver disease or chronic inflammatory diseases), taking into account fracture history and bone density measurement. The prescription of bisphosphonates or teriparatide must be preceded by an etiologic investigation, a withdrawal of bone loss-induced drugs (tobacco, alcohol, steroids), a recovery of walking and a specific action on fall risk, especially after 70 years.
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Saúde do Homem , Osteoporose/diagnóstico , Osteoporose/terapia , Alcoolismo/complicações , Alcoolismo/diagnóstico , Conservadores da Densidade Óssea/uso terapêutico , Doença Crônica , Diagnóstico Diferencial , Fraturas Ósseas/diagnóstico , Fraturas Ósseas/etiologia , Humanos , Hipogonadismo/complicações , Hipogonadismo/diagnóstico , Masculino , Osteoporose/complicações , Osteoporose/etiologia , Fumar/efeitos adversos , Fraturas da Coluna Vertebral/diagnóstico , Fraturas da Coluna Vertebral/etiologiaRESUMO
INTRODUCTION: Using a network analysis, the present study investigated the extent to which physical activity (PA), objective fitness level, kinesiophobia, and health-related quality of life (HRQoL) interact in patients with rheumatic and musculoskeletal diseases. The objectives were twofold: 1) to clarify the direct and indirect relationships between these variables while controlling for the shared variance between them, and 2) to establish a potential ranking of influence among them. METHODS: This cross-sectional design study involved patients recruited from a rheumatology unit. One hundred and twenty patients completed self-reported measures of PA, the Tampa scale of kinesiophobia and the 36-item Short-Form Health Survey, and ninety-seven of those patients performed the six-minute walking test and the thirty-second sit-to-stand test. Network analyses were conducted using bootnet and qgraph packages. RESULTS: Weekly time spent on PA, as well as physical fitness measures, were directly linked to kinesiophobia and the HRQoL physical dimension, but indirectly linked to HRQoL mental dimension through the mediation of kinesiophobia. Specifically, weekly PA time had direct relationships to physical functioning, vitality, and role limitations due to physical and emotional problems. Fitness measures had direct relationships with physical functioning, bodily pain, and mental health. The analyses did not clearly highlight one variable as the most influential in the network. DISCUSSION: The study highlights the complexities of direct and indirect biopsychosocial relationships that are at the core of patients' daily functioning. Measurement of PA, use of a longitudinal design, and interventions are discussed.
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Bone tissue is organized at the molecular level to resist fracture with the minimum of bone material. This implies that several modifications of the extracellular matrix, including enzymatic collagen crosslinking, take place. We previously highlighted the role of several gut hormones in enhancing collagen maturity and bone strength. The present study investigated the effect of proglucagon-derived peptides on osteoblast-mediated collagen post-processing. Briefly, MC3T3-E1 murine osteoblasts were cultured in the presence of glucagon (GCG), [D-Ala²]-glucagon-like peptide-1 ([D-Ala²]-GLP-1), and [Gly²]-glucagon-like peptide-2 ([Gly²]-GLP-2). Gut hormone receptor expression at the mRNA and protein levels were investigated by qPCR and Western blot. Extent of collagen postprocessing was examined by Fourier transform infrared microspectroscopy. GCG and GLP-1 receptors were not evidenced in osteoblast cells at the mRNA and protein levels. However, it is not clear whether the known GLP-2 receptor is expressed. Nevertheless, administration of [Gly²]-GLP-2, but not GCG or [D-Ala²]-GLP-1, led to a dose-dependent increase in collagen maturity and an acceleration of collagen post-processing. This mechanism was dependent on adenylyl cyclase activation. In conclusion, the present study highlighted a direct effect of [Gly²]-GLP-2 to enhance collagen post-processing and crosslinking maturation in murine osteoblast cultures. Whether this effect is translatable to human osteoblasts remains to be elucidated.
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Colágeno/metabolismo , Peptídeo 2 Semelhante ao Glucagon/farmacologia , Osteoblastos/metabolismo , Animais , Células CHO , Células Cultivadas , Colágeno/efeitos dos fármacos , Cricetulus , Hormônios Gastrointestinais/genética , Hormônios Gastrointestinais/metabolismo , Expressão Gênica/efeitos dos fármacos , Glucagon/farmacologia , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Peptídeo 2 Semelhante ao Glucagon/química , Receptor do Peptídeo Semelhante ao Glucagon 2/genética , Receptor do Peptídeo Semelhante ao Glucagon 2/metabolismo , Camundongos , Osteoblastos/efeitos dos fármacos , Multimerização Proteica/efeitos dos fármacosRESUMO
The incidence of fragility fractures increases progressively with advance in age after 50 years, and the phenomenon of population ageing will lead to an increased proportion of the world population having osteoporosis and fractures. The consequences of fractures are more serious in older adults: all low-trauma fractures were associated with increased mortality risk and the risk of a second major osteoporotic fracture after a first one also increased with advance in age. Along with the decrease in bone mineral density, falls play an essential role in the occurrence of fragility fractures in older adults, and the assessment of the risk of falling is part of the fracture risk assessment. Despite advances in the diagnosis of osteoporosis, the assessment of fracture risk, and a wide range of effective anti-osteoporosis medications, with parenteral route which can improve observance, many data indicate that the therapeutic care gap is particularly wide in the elderly in whom the importance and impact of a treatment are high and even more in those living in institutions.
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Conservadores da Densidade Óssea , Osteoporose , Fraturas por Osteoporose , Acidentes por Quedas , Idoso , Densidade Óssea , Conservadores da Densidade Óssea/uso terapêutico , Humanos , Pessoa de Meia-Idade , Osteoporose/diagnóstico , Osteoporose/epidemiologia , Fraturas por Osteoporose/epidemiologia , Fraturas por Osteoporose/etiologia , Fatores de RiscoRESUMO
OBJECTIVES: The usual treatments for crystal-associated arthritis are sometimes contraindicated; thus, new therapies against interleukin-1beta (IL-1) have been developed. We evaluated the characteristics of patients who received biological treatment for crystal-associated arthritis. PATIENTS AND METHODS: We conducted a multicentric retrospective observational study in six rheumatology units in western France. Patients receiving a biological treatment for crystal-associated arthritis between 1 January 2010 and 31 December 2018 were included. Improvement was defined as at least a 50% decrease in the count of synovitis and C-reactive protein level. RESULTS: Forty-six patients were included: 31 (67.4%) were treated for gouty arthritis, and 15 (32.6%) for calcium pyrophosphate crystal deposition disease (CCPD). The first biotherapy used was anakinra for 14 patients (93.3%) with CCPD and 31 patients (100.0%) with gout. The first biotherapy course was more efficient in treating gout than in treating CCPD, with success in 28 patients (90.3%) and 5 patients (35.7%), respectively (p = 0.001). Six patients (42.9%) with CCPD stopped their first biotherapy course because of side effects. Among the patients with gout, urate-lowering therapy was more frequently used after (100%) than before the first biotherapy course (67.7%) (p = 0.002). CONCLUSION: Anakinra was prescribed for cases of refractory crystal-associated arthritis or cases with contraindications for usual treatments. The efficacy of anakinra in treating CCPD was not obvious. Patients with CCPD had more side effects. The biotherapy was introduced with a long-term objective, while anti-IL-1 therapies are approved for acute crises only.
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Whipple disease (WD) is a rare infectious systemic disease. Rheumatologists are at the frontline of WD diagnosis due to the early rheumatological manifestations. An early diagnosis is crucial, as usual anti-rheumatic drugs, especially TNF inhibitors, may worsen the disease course. We conducted a retrospective multicentre national study from January 2010 to April 2020 to better characterize the rheumatological features of WD. Classic WD (CWD) was defined by positive periodic acid-Schiff (PAS) staining of a small-bowel biopsy sample, and non-CWD (NCWD) was defined by negative PAS staining of a small-bowel biopsy sample but at least one positive Tropheryma whipplei (TW) polymerase chain reaction (PCR) for a digestive or extradigestive specimen. Sixty-eight patients were enrolled, including 11 CWD patients. Twenty patients (30%) received TNF inhibitors during the WD course, with inefficacy or symptom worsening. More digestive symptoms and systemic biological features were observed in CWD patients than in NCWD patients, but both patient groups had similar outcomes, especially concerning the response to antibiotics and relapse rate. Stool and saliva TW PCR sensitivity were both 100% for CWD and 75% for NCWD and 89% and 60% for small-bowel biopsy sample PCR, respectively. WD encountered in rheumatology units has many presentations, which might result from different pathophysiologies that are dependent on host immunity. Given the heterogeneous presentations and the presence of chronic carriage, multiple TW PCR tests on samples from specific rheumatological sites when possible should be performed, but samples from nonspecific digestive and extradigestive sites also have great value.
Assuntos
Doença de Whipple/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/uso terapêutico , Biomarcadores , Diagnóstico Diferencial , Diagnóstico por Imagem/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Doenças Reumáticas/diagnóstico , Avaliação de Sintomas , Resultado do Tratamento , Doença de Whipple/tratamento farmacológico , Doença de Whipple/microbiologiaRESUMO
INTRODUCTION: Preclinical, clinical, and population-based studies have provided evidence that anti-diabetic drugs affect bone metabolism and may affect the risk of fracture in diabetic patients. AREAS COVERED: An overview of the skeletal effects of anti-diabetic drugs used in type 2 diabetes is provided. Searches on AdisInsight, PubMed, and Medline databases were conducted up to 1st July 2020. The latest evidence from randomized clinical trials and population-based studies on the skeletal safety of the most recent drugs (DPP-4i, GLP-1RA, and SGLT-2i) is provided. EXPERT OPINION: Diabetic patients present with a higher risk of fracture for a given bone mineral density suggesting a role of bone quality in the etiology of diabetic fracture. Bone quality is difficult to assess in human clinical practice and the use of preclinical models provides valuable information on diabetic bone alterations. As several links have been established between bone and energy homeostasis, it is interesting to study the safety of anti-diabetic drugs on the skeleton. So far, evidence for the newest molecules suggests a neutral fracture risk, but further studies, especially in different types of patient populations (patients at risk or with history of cardiovascular disease, renal impairment, neuropathy) are required to fully appreciate this matter.
Assuntos
Osso e Ossos/efeitos dos fármacos , Fraturas Ósseas/etiologia , Hipoglicemiantes/administração & dosagem , Animais , Densidade Óssea/efeitos dos fármacos , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Complicações do Diabetes/patologia , Complicações do Diabetes/prevenção & controle , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/fisiopatologia , Fraturas Ósseas/prevenção & controle , Humanos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Fatores de RiscoRESUMO
The combined presence of two cancers in a single patient is rare. Usually, the second cancer is caused by immunosuppression resulting from treatment (chemotherapy, radiotherapy) of the first neoplasia. Multiple myeloma and kidney cancer share similar risk factors (obesity, smoking, hypertension), and several cases involving the combination of these two neoplasias have been described in the literature. We are reporting, for the first time, two clinical cases involving the combined presence of multiple myeloma and clear cell renal cell carcinoma discovered synchronously, with concomitant bone recurrence some time after the initial diagnosis. Pathophysiological mechanisms have been described that are common to renal carcinoma and multiple myeloma; in particular, the role of interleukin-6, which is produced by the renal cells and stimulates the proliferation of myeloma cells. Clinicians must be aware of the possibility of this disease combination and, in the event of an obvious recurrence of one of these two diseases, should search systematically for recurrence of the other disease.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Mieloma Múltiplo , Humanos , Rim , Neoplasias Renais/diagnóstico , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/terapia , Recidiva Local de NeoplasiaRESUMO
The involvement of a gut-bone axis in controlling bone physiology has been long suspected, although the exact mechanisms are unclear. We explored whether glucose-dependent insulinotropic polypeptide (GIP)-producing enteroendocrine K cells were involved in this process. The bone phenotype of transgenic mouse models lacking GIP secretion (GIP-GFP-KI) or enteroendocrine K cells (GIP-DT) was investigated. Mice deficient in GIP secretion exhibited lower bone strength, trabecular bone mass, trabecular number, and cortical thickness, notably due to higher bone resorption. Alterations of microstructure, modifications of bone compositional parameters, represented by lower collagen cross-linking, were also apparent. None of these alterations were observed in GIP-DT mice lacking enteroendocrine K cells, suggesting that another K-cell secretory product acts to counteract GIP action. To assess this, stable analogues of the known K-cell peptide hormones, xenin and GIP, were administered to mature NIH Swiss male mice. Both were capable of modulating bone strength mostly by altering bone microstructure, bone gene expression, and bone compositional parameters. However, the two molecules exhibited opposite actions on bone physiology, with evidence that xenin effects are mediated indirectly, possibly via neural networks. Our data highlight a previously unknown interaction between GIP and xenin, which both moderate gut-bone connectivity. © 2020 American Society for Bone and Mineral Research.