RESUMEN
Low serum levels of 25-hydroxyvitamin D [25(OH)D] and low sunlight exposure are known risk factors for the development of multiple sclerosis. Add-on vitamin D supplementation trials in established multiple sclerosis have been inconclusive. The effects of vitamin D supplementation to prevent multiple sclerosis is unknown. We aimed to test the hypothesis that oral vitamin D3 supplementation in high-risk clinically isolated syndrome (abnormal MRI, at least three T2 brain and/or spinal cord lesions), delays time to conversion to definite multiple sclerosis, that the therapeutic effect is dose-dependent, and that all doses are safe and well tolerated. We conducted a double-blind trial in Australia and New Zealand. Eligible participants were randomized 1:1:1:1 to placebo, 1000, 5000 or 10 000 international units (IU) of oral vitamin D3 daily within each study centre (n = 23) and followed for up to 48 weeks. Between 2013 and 2021, we enrolled 204 participants. Brain MRI scans were performed at baseline, 24 and 48 weeks. The main study outcome was conversion to clinically definite multiple sclerosis based on the 2010 McDonald criteria defined as either a clinical relapse or new brain MRI T2 lesion development. We included 199 cases in the intention-to-treat analysis based on assigned dose. Of these, 116 converted to multiple sclerosis by 48 weeks (58%). Compared to placebo, the hazard ratios (95% confidence interval) for conversion were 1000 IU 0.87 (0.50, 1.50); 5000 IU 1.37 (0.82, 2.29); and 10 000 IU 1.28 (0.76, 2.14). In an adjusted model including age, sex, latitude, study centre and baseline symptom number, clinically isolated syndrome onset site, presence of infratentorial lesions and use of steroids, the hazard ratios (versus placebo) were 1000 IU 0.80 (0.45, 1.44); 5000 IU 1.36 (0.78, 2.38); and 10 000 IU 1.07 (0.62, 1.85). Vitamin D3 supplementation was safe and well tolerated. We did not demonstrate reduction in multiple sclerosis disease activity by vitamin D3 supplementation after a high-risk clinically isolated syndrome.
Asunto(s)
Enfermedades Desmielinizantes , Esclerosis Múltiple , Humanos , Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/tratamiento farmacológico , Vitamina D/uso terapéutico , Vitaminas/uso terapéutico , Colecalciferol/uso terapéutico , Colecalciferol/efectos adversos , Calcifediol , Enfermedades Desmielinizantes/diagnóstico por imagen , Enfermedades Desmielinizantes/tratamiento farmacológico , Método Doble CiegoRESUMEN
Objectives: The glucagon-like peptide-1 (GLP-1) receptor agonist, liraglutide, reduces human prostate cancer incidence, and similar GLP-1 receptor agonists reduce in vitro proliferation and in vivo growth of prostate cancer cell lines. Primary human prostate cancer expresses the GLP-1 receptor (GLP-1R) in vitro. Cancer evolves with stage, and whether advanced-stage human prostate cancer expresses GLP-1R is unknown. We hypothesised and aimed to prove that human metastatic castrate-resistant prostate cancer (mCRPC) expresses the GLP-1R in vivo. We hypothesised that mCRPC would thus be detectable by positron emission tomography/computed tomography (PET/CT) using a radiotracer bound to a GLP-1R ligand, as in exendin PET/CT. Materials and methods: Men with mCRPC, with more than one prostate-specific membrane antigen (PSMA)-avid lesion on PET/CT scanning (pathognomic in that setting for prostate cancer lesions), were approached to undergo PET/CT with gallium68-Dota-exendin-4. We documented PET/CT PSMA-avid lesions, which were also PET/CT exendin avid, as evidence of in vivo GLP-1R expression. Results: Out of the 24 men referred, three did not meet the inclusion criteria. Seventeen declined, largely because the study offered them no therapeutic benefit. Among the four men imaged, three had no exendin-avid lesions, while one had six osseous PSMA-avid lesions, three of which were also exendin avid. Conclusions: We demonstrated in vivo GLP-1R expression by human mCPRC, detecting PET/CT lesions avid for both PSMA and exendin, in one of four participants. GLP-1R expression may thus occur even in advanced-stage prostate cancer. Our data contribute to growing evidence supporting the testing of GLP-1 receptor agonists for therapeutic benefit in prostate cancer.
RESUMEN
OBJECTIVE: Latent autoimmune diabetes in adults (LADA) is defined as adult-onset diabetes with circulating islet antibodies but not requiring insulin therapy initially. Diagnosing LADA has treatment implications because of the high risk of progression to insulin dependency. Currently, there are no recommendations for islet antibody testing in adult-onset diabetes. In this study, we aimed to develop a clinical screening tool to identify adults at high risk of LADA who require islet antibody testing. RESEARCH DESIGN AND METHODS: Subjects with LADA (n = 102, GAD antibody [GADA]+) and type 2 diabetes (n = 111, GADA-) (aged 30-75 years) were interviewed retrospectively. The clinical features documented were age of onset, acute symptoms of hyperglycemia, BMI, and personal and family history of autoimmune disease. Any clinical feature that was significantly more frequent in LADA was designated as a distinguishing clinical feature. In each subject, a "LADA clinical risk score," based on the total number of distinguishing features, was calculated. A prospective study of adults with newly diagnosed diabetes (n = 130) was used to determine whether the LADA clinical risk score could identify LADA. RESULTS: In the retrospective study, five clinical features were more frequent in LADA compared with type 2 diabetes at diagnosis: 1) age of onset <50 years (P < 0.0001), 2) acute symptoms (P < 0.0001), 3) BMI <25 kg/m2 (P = 0.0004), 4) personal history of autoimmune disease (P = 0.011), and 5) family history of autoimmune disease (P = 0.024). In the prospective study, the presence of at least two of these distinguishing clinical features (LADA clinical risk score > or =2) had a 90% sensitivity and 71% specificity for identifying LADA and a negative predictive value for a LADA clinical risk score < or =1 of 99%. CONCLUSIONS: At least two distinguishing clinical features are found in a majority of patients with LADA at diagnosis and can be used to identify adults with diabetes at higher risk for LADA.
Asunto(s)
Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 2/diagnóstico , Adulto , Factores de Edad , Anciano , Índice de Masa Corporal , Diagnóstico Diferencial , Humanos , Persona de Mediana Edad , Estudios Retrospectivos , Medición de RiesgoRESUMEN
OBJECTIVES: To determine whether vitamin D supplementation can reduce the incidence of falls and fractures in older people in residential care who are not classically vitamin D deficient. DESIGN: Randomized, placebo-controlled double-blind, trial of 2 years' duration. SETTING: Multicenter study in 60 hostels (assisted living facilities) and 89 nursing homes across Australia. PARTICIPANTS: Six hundred twenty-five residents (mean age 83.4) with serum 25-hydroxyvitamin D levels between 25 and 90 nmol/L. INTERVENTION: Vitamin D supplementation (ergocalciferol, initially 10,000 IU given once weekly and then 1,000 IU daily) or placebo for 2 years. All subjects received 600 mg of elemental calcium daily as calcium carbonate. MEASUREMENTS: Falls and fractures recorded prospectively in study diaries by care staff. RESULTS: The vitamin D and placebo groups had similar baseline characteristics. In intention-to-treat analysis, the incident rate ratio for falling was 0.73 (95% confidence interval (CI)=0.57-0.95). The odds ratio for ever falling was 0.82 (95% CI=0.59-1.12) and for ever fracturing was 0.69 (95% CI=0.40-1.18). An a priori subgroup analysis of subjects who took at least half the prescribed capsules (n=540), demonstrated an incident rate ratio for falls of 0.63 (95% CI=0.48-0.82), an odds ratio (OR) for ever falling of 0.70 (95% CI=0.50-0.99), and an OR for ever fracturing of 0.68 (95% CI=0.38-1.22). CONCLUSION: Older people in residential care can reduce their incidence of falls if they take a vitamin D supplement for 2 years even if they are not initially classically vitamin D deficient.
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Accidentes por Caídas/prevención & control , Ergocalciferoles/administración & dosificación , Anciano Frágil , Hogares para Ancianos , Casas de Salud , Instituciones Residenciales , Anciano , Anciano de 80 o más Años , Carbonato de Calcio/administración & dosificación , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Estudios de Seguimiento , Fracturas Óseas/prevención & control , Evaluación Geriátrica , Humanos , Masculino , Oportunidad Relativa , Cooperación del Paciente , Estudios Prospectivos , VictoriaRESUMEN
The review provides an evaluation of the therapeutic potential of vitamin D analogues in the context of the current understanding of vitamin D biochemistry, molecular biology and physiology. Vitamin D activity results from several circulating and intracellular physiological metabolites acting simultaneously through at least three receptors. Common analogues are reviewed. Although most vitamin D analogues have traditionally been analogues of 1,25-dihydroxyvitamin D, it may be better to deliver high doses of base vitamin or (analogues) of 25-hydroxyvitamin D. This would permit physiological endocrine, paracrine and autocrine vitamin D metabolism. Agonists or antagonists of tissue-specific vitamin D metabolic pathways could be coadministered. The importance of measuring endogenous vitamin D metabolites during in vivo studies and the pitfalls of extending data across species and time are emphasised. Human vitamin D analogue trials should include direct comparison against the related endogenous metabolite.
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Vitamina D/análogos & derivados , Vitamina D/uso terapéutico , Ensayos Clínicos como Asunto , Humanos , Receptores de Calcitriol/metabolismo , Relación Estructura-Actividad , Vitamina D/metabolismoRESUMEN
OBJECTIVES: To determine the prevalence of vitamin D deficiency in older people in residential care and the influence that the level of vitamin D may have on their incidence of falls. DESIGN: Prospective cohort. SETTING: Residential care facilities for older people in several states of Australia. PARTICIPANTS: Six hundred sixty-seven women in low-level care and 952 women in high-level care, mean age 83.7 years. MEASUREMENTS: Serum 25-hydroxyvitamin D (25D) levels and recognized risk factors for falls including current medication use, a history of previous fractures, weight, tibial length (as a surrogate for height), cognitive function, walking ability, and frequency of going outdoors were determined. The women in low-level care and high-level care were followed for an average of 145 and 168 days, respectively. Falls were recorded prospectively in diaries completed monthly by residential care staff. RESULTS: Vitamin D deficiency (defined as a serum 25D level below 25 nmol/L) was present in 144 (22%) women in low-level care and 428 (45%) in high-level care. After excluding 358 bed-bound residents and adjusting for weight, cognitive status, psychotropic drug use, previous Colles fracture, and the presence of wandering behavior, log serum 25D level remained independently associated with time to first fall. The adjusted hazards ratio was 0.74 (95% confidence interval=0.59-0.94; P=.01), implying a 20% reduction in the risk of falling with a doubling of the vitamin D level. CONCLUSION: Vitamin D deficiency is common in residential care in Australia. A low level of serum vitamin D is an independent predictor of incident falls.
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Accidentes por Caídas/estadística & datos numéricos , Deficiencia de Vitamina D/sangre , Vitamina D/sangre , Anciano , Anciano de 80 o más Años , Australia/epidemiología , Estudios de Cohortes , Femenino , Fracturas Óseas/epidemiología , Fracturas Óseas/prevención & control , Humanos , Análisis Multivariante , Estudios Prospectivos , Instituciones Residenciales , Análisis de Supervivencia , Deficiencia de Vitamina D/epidemiologíaRESUMEN
Poor vitamin D nutrition is linked with dementia, but vitamin D has not been tested in a randomized controlled trial (RCT) in Alzheimer's disease (AD). Nasal insulin acutely improves cognition and vitamin D upregulates insulin receptor expression and enhances insulin action. In an RCT we examined the effect of high-dose vitamin D followed by nasal insulin on memory and disability in mild-moderate AD. 63 community-dwelling individuals aged > 60 were recruited; 32 with mild-moderate disease (Folstein Mini-Mental State Examination [MMSE] score 12-24) met entry criteria and were randomized. All took low-dose vitamin D (1000 IU/day) throughout. After run-in (8 weeks), they were randomized to additional high-dose D/placebo for 8 weeks, followed immediately by randomization to nasal insulin (60 IU qid)/placebo for 48 h. Primary outcome measures were Alzheimer's disease assessment scale-cognitive subscale (ADAS-cog) and Disability Assessment in Dementia (after high-dose D) and ADAS-cog and Wechsler Memory Scale-Revised Logical memory (WMS-R LM) for immediate and delayed recall (after nasal insulin). Baseline median (interquartile range, IR) age, MMSE, and ADAS-cog were 77.5 (69-80), 19.5 (17-22), and 25.5 (20-31), respectively. Median 25OHD increased from 49 to 60 nM (p < 0.01) after run-in and was 187 nM after high-dose vitamin D and 72 nM after placebo (p < 0.001). Neither cognition nor disability changed significantly after high-dose D. ADAS-cog improved by a median (IR) of 9 (1-11) with nasal insulin after placebo high-dose vitamin D (p = 0.02), but may represent regression to the mean as WLS-R LM did not change. We conclude that high-dose vitamin D provides no benefit for cognition or disability over low-dose vitamin D in mild-moderate AD.
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Enfermedad de Alzheimer/tratamiento farmacológico , Ergocalciferoles/uso terapéutico , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Vitaminas/uso terapéutico , Administración Intranasal , Anciano de 80 o más Años , Enfermedad de Alzheimer/psicología , Cognición/efectos de los fármacos , Depresión/etiología , Depresión/psicología , Suplementos Dietéticos , Método Doble Ciego , Estudios de Factibilidad , Femenino , Humanos , Hipoglucemiantes/administración & dosificación , Insulina/administración & dosificación , Modelos Lineales , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Proyectos Piloto , Resultado del Tratamiento , Deficiencia de Vitamina D/complicaciones , Escalas de WechslerRESUMEN
Utilitarianism is more convincing than resource egalitarianism or welfare egalitarianism as a theory of how resources should be distributed between disabled people and nondisabled people. Unlike resource egalitarianism, utilitarianism can redistribute resources to the disabled when they would benefit more from those resources than nondisabled people. Unlike welfare egalitarianism, utilitarianism can halt redistribution when the disabled would no longer benefit more than the nondisabled from additional resources. The author considers one objection to this view: it has been argued, by Sen and others, that there are circumstances under which utilitarianism would unfairly distribute fewer resources to the physically disabled than to nondisabled people, on the ground that the disabled would derive less benefit from those resources. In response, the author claims that critics of utilitarianism have fallaciously exaggerated the circumstances under which the disabled would benefit less than the nondisabled from additional resources. In those limited circumstances in which the disabled really would benefit less from resources, the author argues, it does not seem unfair to distribute fewer resources to them.