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INTRODUCTION/AIMS: Disease progression in myotonic dystrophy (DM) is marked by milestone events when functional thresholds are crossed. DM type 2 (DM2) is considered less severe than DM type 1 (DM1), but it is unknown whether this applies uniformly to all features. We compared the age-dependent risk for milestone events in DM1 and DM2 and tested for associations with age of onset and sex. METHODS: We studied a large cohort of adult participants in a national registry of DM1 and DM2. Using annual surveys from participants, we ascertained milestone events for motor involvement (use of cane, walker, ankle brace, wheelchair, or ventilatory device), systemic involvement (diabetes, pacemaker, cancer), loss of employment due to DM, and death. RESULTS: Mean follow-up of registry participants (929 DM1 and 222 DM2 patients) was 7 years. Disability and motor milestones occurred at earlier ages in DM1 than in DM2. In contrast, the risk of diabetes was higher and tended to occur earlier in DM2 (hazard ratio [HR], 0.56; P ≤ .001). In DM1, the milestone events tended to occur earlier, and life expectancy was reduced, when symptoms began at younger ages. In DM1, men were at greater risk for disability (HR, 1.34; P ≤ .01), use of ankle braces (HR, 1.41; P = .02), and diabetes (HR, 2.2; P ≤ .0001), whereas women were at greater risk for needing walkers (HR, 0.68; P = .001) or malignancy (HR, 0.66; P ≤ .01). DISCUSSION: Milestone events recorded through registries can be used to assess long-term impact of DM in large cohorts. Except for diabetes, the age-related risk of milestone events is greater in DM1 than in DM2.
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Diabetes Mellitus Tipo 2 , Distrofia Miotônica , Adulto , Estudos de Coortes , Feminino , Humanos , Masculino , Distrofia Miotônica/diagnóstico , Sistema de RegistrosRESUMO
INTRODUCTION/AIMS: Myotonic dystrophy type 1 (DM1) is known to affect cognitive function, but the best methods to assess central nervous system involvement in multicenter studies have not been determined. In this study our primary aim was to evaluate the potential of computerized cognitive tests to assess cognition in DM1. METHODS: We conducted a prospective, longitudinal, observational study of 113 adults with DM1 at six sites. Psychomotor speed, attention, working memory, and executive functioning were assessed at baseline, 3 months, and 12 months using computerized cognitive tests. Results were compared with assessments of muscle function and patient reported outcomes (PROs), including the Myotonic Dystrophy Health Index (MDHI) and the 5-dimension EuroQol (EQ-5D-5L) questionnaire. RESULTS: Based on intraclass correlation coefficients, computerized cognitive tests had moderate to good reliability for psychomotor speed (0.76), attention (0.82), working memory speed (0.79), working memory accuracy (0.65), and executive functioning (0.87). Performance at baseline was lowest for working memory accuracy (P < .0001). Executive function performance improved from baseline to 3 months (P < .0001), without further changes over 1 year. There was a moderate correlation between poorer executive function and larger CTG repeat size (r = -0.433). There were some weak associations between PROs and cognitive performance. DISCUSSION: Computerized tests of cognition are feasible in multicenter studies of DM1. Poor performance was exhibited in working memory, which may be a useful variable in clinical trials. Learning effects may have contributed to the improvement in executive functioning. The relationship between PROs and cognitive impairment in DM1 requires further study.
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Distrofia Miotônica , Adulto , Cognição , Computadores , Humanos , Estudos Longitudinais , Distrofia Miotônica/complicações , Distrofia Miotônica/diagnóstico , Estudos Prospectivos , Reprodutibilidade dos TestesRESUMO
INTRODUCTION: The prevalence and impact of symptoms affecting individuals with pediatric forms of myotonic dystrophy type-1 (DM1) are not well understood. METHODS: Patients from the United States, Canada, and Sweden completed a survey that investigated 20 themes associated with pediatric-onset DM1. Participants reported the prevalence and importance of each theme affecting their lives. Surveys from participants were matched with surveys from their caregivers for additional analysis. RESULTS: The most prevalent symptomatic themes included problems with hands or fingers (79%) and gastrointestinal issues (75%). Problems with urinary/bowel control and gastrointestinal issues were reported to have the greatest impact on patients' lives. Responses from participants and their caregivers had varying levels of agreement among symptomatic themes. DISCUSSION: Many symptoms have meaningful impact on disease burden. The highest levels of agreement between caregivers and individuals with pediatric forms of myotonic dystrophy were found for physical activity themes.
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Distrofia Miotônica/fisiopatologia , Distrofia Miotônica/psicologia , Atividades Cotidianas , Adolescente , Adulto , Cuidadores , Criança , Pré-Escolar , Comunicação , Efeitos Psicossociais da Doença , Transtornos de Deglutição/etiologia , Transtornos de Deglutição/fisiopatologia , Feminino , Dedos/fisiopatologia , Gastroenteropatias/etiologia , Gastroenteropatias/fisiopatologia , Mãos/fisiopatologia , Humanos , Masculino , Limitação da Mobilidade , Debilidade Muscular/etiologia , Debilidade Muscular/fisiopatologia , Miotonia/etiologia , Miotonia/fisiopatologia , Distrofia Miotônica/complicações , Medidas de Resultados Relatados pelo Paciente , Adulto JovemRESUMO
Paroxetine and fluconazole have neuroprotective effects in an in vitro model of HIV protein-mediated neuronal injury. This study evaluated the safety, tolerability, and efficacy of both paroxetine and fluconazole for the treatment of HIV-associated neurocognitive disorder (HAND). A 24-week randomized double-blind, placebo-controlled 2 × 2 factorial design study was used. HIV+ individuals with cognitive impairment were enrolled in the 24-week trial. Participants were randomly assigned to one of four groups: (1) paroxetine 20 mg/day, (2) fluconazole 100 mg every 12 h, (3) paroxetine and fluconazole, or (4) placebo. Safety, tolerability, and efficacy were evaluated. Forty-five HIV+ individuals were enrolled. Medications were well tolerated. Compared to no paroxetine arms, HIV+ individuals receiving paroxetine showed improved NPZ8 summary scores, (mean change = 0.25 vs - 0.19, p = 0.049), CalCAP sequential test reaction time (mean change = 0.34 vs -0.23, p = 0.014), Trail Making Part B test performance (mean change = 0.49 vs - 0.33, p = 0.041), and FAS verbal fluency (mean change = 0.25 vs 0.02, p = 0.020) but a decline in the Letter number sequencing test (mean change = - 0.40 vs 0.26, p = 0.023). Biomarkers of cellular stress, inflammation, and neuronal damage were not affected by paroxetine. HIV+ individuals receiving fluconazole did not show a benefit in cognition and showed an increase in multiple markers of cellular stress compared to the no fluconazole arms. In conclusion, paroxetine was associated with improvement in a summary neuropsychological test measure and in several neuropsychological tests but worse performance in one neuropsychological test. Further studies of paroxetine for the treatment of HAND and to define its precise neuroprotective properties are warranted.
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Complexo AIDS Demência/tratamento farmacológico , Fármacos Anti-HIV/uso terapêutico , Fluconazol/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Paroxetina/uso terapêutico , Complexo AIDS Demência/fisiopatologia , Complexo AIDS Demência/psicologia , Complexo AIDS Demência/virologia , Adulto , Antidepressivos de Segunda Geração/uso terapêutico , Antifúngicos/uso terapêutico , Método Duplo-Cego , Esquema de Medicação , Reposicionamento de Medicamentos , Análise Fatorial , Feminino , HIV-1/patogenicidade , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Segurança do Paciente , Resultado do TratamentoRESUMO
INTRODUCTION: As the Duchenne muscular dystrophy (DMD) population ages, it is essential that we understand the late-stage health profile and provide the appropriate care for this emerging population. METHODS: We undertook a descriptive study to document the health profile of a cohort of adults with DMD using data from the Muscular Dystrophy Surveillance Tracking and Research network (MD STARnet). Data included information collected from Arizona, Colorado, Iowa, Georgia, and 12 counties in western New York on individuals born since January 1982 and followed through December 2012. RESULTS: In 208 adults with DMD, the number of individuals (N) and median ages (years) at which certain critical milestones were crossed and interventions initiated were as follows: development of cardiomyopathy, N = 145 (16.7); initiation of non-invasive ventilation, N = 99 (18.0); gastrostomy, N = 47 (19.0); and death, N = 59 (21.8). DISCUSSION: These population-based data provide critical information about late-stage health profiles among adults with DMD for developing appropriate models of care. Muscle Nerve 58: 219-223, 2018.
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Nível de Saúde , Distrofia Muscular de Duchenne/fisiopatologia , Adulto , Fatores Etários , Estudos de Coortes , Feminino , Necessidades e Demandas de Serviços de Saúde , Humanos , Masculino , Distrofia Muscular de Duchenne/complicações , Distrofia Muscular de Duchenne/terapia , Vigilância da População , Estudos Retrospectivos , Estados Unidos , Adulto JovemRESUMO
INTRODUCTION: When preparing for clinical trials in myotonic dystrophy type-1 (DM1), it is important that researchers develop and identify patient-reported outcome measures with good measurement properties. METHODS: Fifty-two DM1 patients enrolled in 2 clinical studies completed the Myotonic Dystrophy Health Index (MDHI), 36-Item Short Form Health Survey (version 2; SF-36v2), Individualized Neuromuscular Quality of Life questionnaire (INQoL), and a questionnaire comparing the relevance, usability, overall preference, and perceived responsiveness of each measure. The associations between instrument scores and physical function, genetic test results, and employment status were examined. RESULTS: The MDHI was preferred over the INQoL in 13 of 13 areas and was preferred over the SF-36v2 in 9 of 13 areas. The MDHI was the only score that was associated with participant employment status, CTG repeat length, and the 3 measurements of clinical function. DISCUSSION: The MDHI correlates well with physical function and is viewed favorably by participants in DM1 clinical studies. Muscle Nerve, 2018.
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The US National Institute of Neurological Disorders and Stroke convened major stakeholders in June 2012 to discuss how to improve the methodological reporting of animal studies in grant applications and publications. The main workshop recommendation is that at a minimum studies should report on sample-size estimation, whether and how animals were randomized, whether investigators were blind to the treatment, and the handling of data. We recognize that achieving a meaningful improvement in the quality of reporting will require a concerted effort by investigators, reviewers, funding agencies and journal editors. Requiring better reporting of animal studies will raise awareness of the importance of rigorous study design to accelerate scientific progress.
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Editoração/normas , Projetos de Pesquisa/normas , Animais , Editoração/tendências , Distribuição Aleatória , Tamanho da Amostra , Estatística como AssuntoRESUMO
INTRODUCTION: The Myotonic Dystrophy Health Index (MDHI) is a disease-specific patient-reported outcome measure. Here, we examine the associations between the MDHI and other measures of disease burden in a cohort of individuals with myotonic dystrophy type-1 (DM1). METHODS: We conducted a cross-sectional study of 70 patients with DM1. We examined the associations between MDHI total and subscale scores and scores from other clinical tests. Participants completed assessments of strength, myotonia, motor and respiratory function, ambulation, and body composition. Participants also provided blood samples, underwent physician evaluations, and completed other patient-reported outcome measures. RESULTS: MDHI total and subscale scores were strongly associated with muscle strength, myotonia, motor function, and other clinical measures. CONCLUSIONS: Patient-reported health status, as measured by the MDHI, is associated with alternative measures of clinical health. These results support the use of the MDHI as a valid tool to measure disease burden in DM1 patients.
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Distrofia Miotônica/diagnóstico , Distrofia Miotônica/fisiopatologia , Avaliação de Resultados em Cuidados de Saúde/métodos , Índice de Gravidade de Doença , Absorciometria de Fóton , Adulto , Idoso , Creatina Quinase/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Força Muscular/fisiologia , Exame Neurológico , Estatística como Assunto , Adulto JovemRESUMO
AIM: The frequency and impact of symptoms experienced by patients with congenital, childhood, and juvenile-onset myotonic dystrophy (CDM/ChDM/JDM) is not documented. This report identifies symptomatic areas with the greatest disease burden in an international population of patients with early-onset myotonic dystrophy type-1 (DM1). METHOD: We distributed surveys to parents of patients with CDM/ChDM/JDM. Patients with CDM/ChDM/JDM were members of the US National Registry of DM1 Patients and Family Members, the Canadian Neuromuscular Disease Registry, or the Swedish Health System. Surveys inquired about 325 symptoms and 20 themes associated with CDM/ChDM/JDM. Parents identified the importance of each symptom and theme to their affected child. The prevalence of each symptom and theme were compared across subgroups of patients. The statistical analysis was performed using Fisher's exact and Kruskal-Wallis tests. RESULTS: One hundred and fifty parents returned surveys. The most frequently reported symptomatic themes in children were issues involving communication (81.7%) and problems with hands or fingers (79.6%). Problems with communication and fatigue were the issues that were reported to have the greatest impact on childrens' lives, while 24.1% of children reported cardiac disorders and 15.8% had problems with anesthesia. INTERPRETATION: A range of symptoms contribute to the burden of disease faced by children with DM1. Many of these symptoms are under-recognized.
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Cooperação Internacional , Distrofia Miotônica/fisiopatologia , Distrofia Miotônica/psicologia , Pais/psicologia , Adolescente , Idade de Início , Criança , Transtornos da Comunicação/etiologia , Fadiga/etiologia , Feminino , Gastroenteropatias/etiologia , Inquéritos Epidemiológicos , Humanos , Masculino , Distrofia Miotônica/epidemiologia , Qualidade de Vida/psicologiaRESUMO
Myotonic dystrophy type 1 and type 2 (DM1 and DM2) are genetic diseases in which mutant transcripts containing expanded CUG or CCUG repeats cause cellular dysfunction by altering the processing or metabolism of specific mRNAs and miRNAs. The toxic effects of mutant RNA are mediated partly through effects on proteins that regulate alternative splicing. Here we show that alternative splicing of exon 29 (E29) of Ca(V)1.1, a calcium channel that controls skeletal muscle excitation-contraction coupling, is markedly repressed in DM1 and DM2. The extent of E29 skipping correlated with severity of weakness in tibialis anterior muscle of DM1 patients. Two splicing factors previously implicated in DM1, MBNL1 and CUGBP1, participated in the regulation of E29 splicing. In muscle fibers of wild-type mice, the Ca(V)1.1 channel conductance and voltage sensitivity were increased by splice-shifting oligonucleotides that induce E29 skipping. In contrast to human DM1, expression of CUG-expanded RNA caused only a modest increase in E29 skipping in mice. However, forced skipping of E29 in these mice, to levels approaching those observed in human DM1, aggravated the muscle pathology as evidenced by increased central nucleation. Together, these results indicate that DM-associated splicing defects alter Ca(V)1.1 function, with potential for exacerbation of myopathy.
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Processamento Alternativo , Canais de Cálcio Tipo L/fisiologia , Cálcio/metabolismo , Ativação do Canal Iônico/fisiologia , Debilidade Muscular/etiologia , Transtornos Miotônicos/fisiopatologia , Distrofia Miotônica/fisiopatologia , Animais , Proteínas CELF1 , Células Cultivadas , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Éxons/genética , Regulação da Expressão Gênica , Humanos , Immunoblotting , Camundongos , Camundongos Transgênicos , Morfolinos/farmacologia , Debilidade Muscular/metabolismo , Debilidade Muscular/patologia , Músculo Esquelético/citologia , Músculo Esquelético/metabolismo , Mioblastos/citologia , Mioblastos/metabolismo , Técnicas de Patch-Clamp , RNA Mensageiro/genética , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
We identified and measured proteins in the cerebral spinal fluid (CSF) involved in HIV-associated neurological disorders. Protein levels were determined by mass spectrometry (MS) in pooled CSF taken from three patient groups (human immunodeficiency virus (HIV)-1-infected patients that developed HIV-associated neurocognitive disorders (HANDs), HIV-1-infected patients without HAND, and healthy controls). Pools were generated from 10 patients each per group. CSF from individual patient groups were digested with trypsin and separately labeled using with isobaric tags for relative and absolute quantitation (iTRAQ). After combining all samples in one, peptides were extensively fractionated by offline two-dimensional separation and identified by tandem MS. One hundred and ninety three proteins were deemed to be interpretable for quantitation based on permutation tests with a 95 % confidence interval with a p value ≤ 0.05. Using a cutoff of 1.5-fold for upregulation and 0.6 for downregulation, 16 proteins were differentially expressed in HIV + HAND (reporter p value ≤0.05) with seven of them previously described as HIV-interacting proteins: endoplasmin, mitochondrial damage mediator-BH3-interacting domanin death agonist, orosomucoid, apolipoprotein E, metalloproteinase inhibitor 2, peroxiredoxin-2, and the nuclear protein, ruvB-like 2. Several previously unidentified proteins with possible neurological implication in HIV patients include forming-binding protein 1, C-reactive protein, leukocyte-associated immunoglobulin receptor 1, renin receptor, mediator of RNA polymerase II transcription subunit 14, multimerin-2, alpha-N-acetylglucosaminidase, caldesmon, and cadherin EGF LAG G-type receptor. Our results suggest that not only a few but possibly a combination of biomarkers that are highly correlated can predict neurocognitive status in HIV-infected patients and might be involved in monocyte or macrophage activation.
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Complexo AIDS Demência/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Complexo AIDS Demência/tratamento farmacológico , Adulto , Antirretrovirais/uso terapêutico , Cromatografia Líquida , Feminino , Humanos , Masculino , Espectrometria de Massas , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: To develop RNA splicing biomarkers of disease severity and therapeutic response in myotonic dystrophy type 1 (DM1) and type 2 (DM2). METHODS: In a discovery cohort, we used microarrays to perform global analysis of alternative splicing in DM1 and DM2. The newly identified splicing changes were combined with previous data to create a panel of 50 putative splicing defects. In a validation cohort of 50 DM1 subjects, we measured the strength of ankle dorsiflexion (ADF) and then obtained a needle biopsy of tibialis anterior (TA) to analyze splice events in muscle RNA. The specificity of DM-associated splicing defects was assessed in disease controls. The CTG expansion size in muscle tissue was determined by Southern blot. The reversibility of splicing defects was assessed in transgenic mice by using antisense oligonucleotides to reduce levels of toxic RNA. RESULTS: Forty-two splicing defects were confirmed in TA muscle in the validation cohort. Among these, 20 events showed graded changes that correlated with ADF weakness. Five other splice events were strongly affected in DM1 subjects with normal ADF strength. Comparison to disease controls and mouse models indicated that splicing changes were DM-specific, mainly attributable to MBNL1 sequestration, and reversible in mice by targeted knockdown of toxic RNA. Splicing defects and weakness were not correlated with CTG expansion size in muscle tissue. INTERPRETATION: Alternative splicing changes in skeletal muscle may serve as biomarkers of disease severity and therapeutic response in myotonic dystrophy.
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Processamento Alternativo , Distrofia Miotônica/genética , Adolescente , Adulto , Idoso , Animais , Biomarcadores , Estudos de Coortes , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Pessoa de Meia-Idade , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Transtornos Miotônicos/genética , Transtornos Miotônicos/patologia , Transtornos Miotônicos/fisiopatologia , Distrofia Miotônica/patologia , Distrofia Miotônica/fisiopatologia , Oligonucleotídeos Antissenso/genética , Proteínas de Ligação a RNA/genética , Índice de Gravidade de Doença , Adulto JovemRESUMO
INTRODUCTION: In preparation for clinical trials we examine the validity, reliability, and patient understanding of the Myotonic Dystrophy Health Index (MDHI). METHODS: Initially we partnered with 278 myotonic dystrophy type-1 (DM1) patients and identified the most relevant questions for the MDHI. Next, we used factor analysis, patient interviews, and test-retest reliability assessments to refine and evaluate the instrument. Lastly, we determined the capability of the MDHI to differentiate between known groups of DM1 participants. RESULTS: Questions in the final MDHI represent 17 areas of DM1 health. The internal consistency was acceptable in all subscales. The MDHI had a high test-retest reliability (ICC = 0.95) and differentiated between DM1 patient groups with different disease severities. CONCLUSIONS: Initial evaluation of the MDHI provides evidence that it is valid and reliable as an outcome measure for assessing patient-reported health. These results suggest that important aspects of DM1 health may be measured effectively using the MDHI.
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Avaliação da Deficiência , Distrofia Miotônica/diagnóstico , Avaliação de Resultados em Cuidados de Saúde/métodos , Avaliação de Resultados da Assistência ao Paciente , Índice de Gravidade de Doença , Adulto , Idoso , Efeitos Psicossociais da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Autorrelato/normas , Inquéritos e Questionários/normas , Estados UnidosRESUMO
Human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND) is present in 30-60 % of HIV-positive (HIV+) individuals and can be assessed by neuropsychological testing and level of functional impairment. HAND diagnosis therefore requires accurate assessment of functional impairment. The Computer Assessment of Mild Cognitive Impairment (CAMCI) is a computer-based screening tool that includes performance-based measures of functional impairment. We sought to evaluate the CAMCI as a functional assessment tool in HAND. One hundred fourteen HIV+ patients and 38 HIV-negative (HIV-) patients underwent neuropsychological and CAMCI testing. Cognitive status for HIV+ subjects was classified using the Frascati criteria. HIV+ subjects grouped together and classified by cognitive impairment performed worse than HIV- subjects on several of the CAMCI tasks, including following directions to the supermarket (p = 0.05, p = 0.03), recalling which items to purchase (p = 0.01, p = 0.02), and remembering to stop at a supermarket (p < 0.01, p = 0.01) and the post office (p < 0.01, p = 0.03). After controlling for hepatitis C status and depression symptomatology, the tasks "following directions to the supermarket" and the "recalling which items to purchase" were no longer significant. The "remembering to run two separate errands" tasks retained their significance (p < 0.01 for both tasks). A subset of the CAMCI tasks therefore successfully differentiated HIV+ patients from HIV- individuals. Differences in hepatitis C status and depression symptomatology could account for some of the function assessment differences in the CAMCI. These results suggest the CAMCI could be a useful objective performance-based functional assessment in patients with HIV.
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Disfunção Cognitiva/diagnóstico , Depressão/diagnóstico , Diagnóstico por Computador/estatística & dados numéricos , Infecções por HIV/diagnóstico , Hepatite C/diagnóstico , Testes Neuropsicológicos/estatística & dados numéricos , Adulto , Disfunção Cognitiva/complicações , Disfunção Cognitiva/psicologia , Depressão/complicações , Depressão/psicologia , Feminino , Infecções por HIV/complicações , Infecções por HIV/psicologia , Hepatite C/complicações , Hepatite C/psicologia , Humanos , Modelos Logísticos , Masculino , Memória de Curto Prazo/fisiologia , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Análise e Desempenho de TarefasRESUMO
BACKGROUND: Myotonic dystrophy type 1 results from an RNA gain-of-function mutation, in which DM1 protein kinase (DMPK) transcripts carrying expanded trinucleotide repeats exert deleterious effects. Antisense oligonucleotides (ASOs) provide a promising approach to treatment of myotonic dystrophy type 1 because they reduce toxic RNA levels. We aimed to investigate the safety of baliforsen (ISIS 598769), an ASO targeting DMPK mRNA. METHODS: In this dose-escalation phase 1/2a trial, adults aged 20-55 years with myotonic dystrophy type 1 were enrolled at seven tertiary referral centres in the USA and randomly assigned via an interactive web or phone response system to subcutaneous injections of baliforsen 100 mg, 200 mg, or 300 mg, or placebo (6:2 randomisation at each dose level), or to baliforsen 400 mg or 600 mg, or placebo (10:2 randomisation at each dose level), on days 1, 3, 5, 8, 15, 22, 29, and 36. Sponsor personnel directly involved with the trial, participants, and all study personnel were masked to treatment assignments. The primary outcome measure was safety in all participants who received at least one dose of study drug up to day 134. This trial is registered with ClinicalTrials.gov (NCT02312011), and is complete. FINDINGS: Between Dec 12, 2014, and Feb 22, 2016, 49 participants were enrolled and randomly assigned to baliforsen 100 mg (n=7, one patient not dosed), 200 mg (n=6), 300 mg (n=6), 400 mg (n=10), 600 mg (n=10), or placebo (n=10). The safety population comprised 48 participants who received at least one dose of study drug. Treatment-emergent adverse events were reported for 36 (95%) of 38 participants assigned to baliforsen and nine (90%) of ten participants assigned to placebo. Aside from injection-site reactions, common treatment-emergent adverse events were headache (baliforsen: ten [26%] of 38 participants; placebo: four [40%] of ten participants), contusion (baliforsen: seven [18%] of 38; placebo: one [10%] of ten), and nausea (baliforsen: six [16%] of 38; placebo: two [20%] of ten). Most adverse events (baliforsen: 425 [86%] of 494; placebo: 62 [85%] of 73) were mild in severity. One participant (baliforsen 600 mg) developed transient thrombocytopenia considered potentially treatment related. Baliforsen concentrations in skeletal muscle increased with dose. INTERPRETATION: Baliforsen was generally well tolerated. However, skeletal muscle drug concentrations were below levels predicted to achieve substantial target reduction. These results support the further investigation of ASOs as a therapeutic approach for myotonic dystrophy type 1, but suggest improved drug delivery to muscle is needed. FUNDING: Ionis Pharmaceuticals, Biogen.
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Distrofia Miotônica , Oligonucleotídeos Antissenso , Adulto , Humanos , Método Duplo-Cego , Distrofia Miotônica/tratamento farmacológico , Distrofia Miotônica/genética , Miotonina Proteína Quinase , Oligonucleotídeos Antissenso/farmacologia , Oligonucleotídeos Antissenso/uso terapêutico , RNA , RNA Mensageiro/metabolismo , Resultado do TratamentoRESUMO
The objectives of this study are to compare the results of newer performance-based functional assessments in the study of HIV-associated neurocognitive disorders (HAND) and to correlate these functional assessments with specific levels of severity of HAND. One hundred fourteen HIV+ subjects in an existing cohort were evaluated with a medical history, neurological exam, neuropsychological test battery as well as subjective and novel objective measures of functional abilities. Self-reported measures of functional performance included the Karnofsky Performance Scale, a questionnaire for instrumental activities of daily living, and a questionnaire for physical quality of life measures. The newer objective functional performance assessments included the Columbia Medication Management and the San Diego Finances tests. These newer performance-based measures of function were assessed for their ability to predict level of HAND. The two objective measures of functional performance, The Columbia Medication Management Scale and the San Diego Finances Test, were both associated with levels of severity of HAND. The Karnofsky Performance Scale and the questionnaires for role and physical quality of life were subjective measures that were also associated with specific levels of HAND. Newer measures of functional performance can be used to objectively evaluate functional impairment in HAND and validate different levels of HAND.
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Complexo AIDS Demência/psicologia , Transtornos Cognitivos/psicologia , Infecções por HIV/psicologia , Aptidão Física/psicologia , Psicometria/métodos , Complexo AIDS Demência/etiologia , Complexo AIDS Demência/fisiopatologia , Atividades Cotidianas/psicologia , Contagem de Linfócito CD4 , Estudos de Casos e Controles , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/fisiopatologia , Feminino , HIV/fisiologia , Infecções por HIV/complicações , Infecções por HIV/fisiopatologia , Humanos , Avaliação de Estado de Karnofsky , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Atividade Motora , Testes Neuropsicológicos , Inquéritos e Questionários , Carga ViralRESUMO
CONTEXT: Myotonic muscular dystrophy (MMD) is an autosomal-dominant multisystem neuromuscular disorder characterized by unstable nucleotide repeat expansions. Case reports have suggested that MMD patients may be at increased risk of malignancy, putative risks that have never been quantified. OBJECTIVE: To quantitatively evaluate cancer risk in patients with MMD, overall and by sex and age. DESIGN, SETTING, AND PARTICIPANTS: We identified 1658 patients with an MMD discharge diagnosis in the Swedish Hospital Discharge Register or Danish National Patient Registry between 1977 and 2008. We linked these patients to their corresponding cancer registry. Patients were followed up from date of first MMD-related inpatient or outpatient contact to first cancer diagnosis, death, emigration, or completion of cancer registration. MAIN OUTCOME MEASURES: Risks of all cancers combined and by anatomic site, stratified by sex and age. RESULTS: One hundred four patients with an inpatient or outpatient discharge diagnosis of MMD developed cancer during postdischarge follow-up. This corresponds to an observed cancer rate of 73.4 per 10,000 person-years in MMD vs an expected rate of 36.9 per 10,000 person-years in the general Swedish and Danish populations combined (standardized incidence ratio [SIR], 2.0; 95% CI, 1.6-2.4). Specifically, we observed significant excess risks of cancers of the endometrium (n = 11; observed rate, 16.1/10,000 person-years; SIR, 7.6; 95% CI, 4.0-13.2), brain (n = 7; observed rate, 4.9/10,000 person-years; SIR, 5.3; 95% CI, 2.3-10.4), ovary (n = 7; observed rate, 10.3/10,000 person-years; SIR, 5.2; 95% CI, 2.3-10.2), and colon (n = 10; observed rate, 7.1/10,000 person-years; SIR, 2.9; 95% CI, 1.5-5.1). Cancer risks were similar in women and men after excluding genital organ tumors (SIR, 1.9; 95% CI, 1.4-2.5, vs SIR, 1.8; 95% CI, 1.3-2.5, respectively; P = .81 for heterogeneity; observed rates, 64.5 and 47.7 per 10,000 person-years in women and men, respectively). The same pattern of cancer excess was observed first in the Swedish and then in the Danish cohorts, which were studied sequentially and initially analyzed independently. CONCLUSION: Patients with MMD identified from the Swedish and Danish patient registries were at increased risk of cancer both overall and for selected anatomic sites.
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Distrofia Miotônica/epidemiologia , Neoplasias/epidemiologia , Adolescente , Adulto , Fatores Etários , Idoso , Criança , Pré-Escolar , Comorbidade , Dinamarca/epidemiologia , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Alta do Paciente/estatística & dados numéricos , Sistema de Registros/estatística & dados numéricos , Risco , Fatores Sexuais , Suécia/epidemiologia , Adulto JovemRESUMO
OBJECTIVE: To assess mexiletine's long-term safety and effect on 6-minute walk distance in a well-defined cohort of patients with myotonic dystrophy type 1 (DM1). METHODS: We performed a randomized, double-blind, placebo-controlled trial of mexiletine (150 mg 3 times daily) to evaluate its efficacy and safety in a homogenous cohort of adult ambulatory patients with DM1. The primary outcome was change in 6-minute walk distance at 6 months. Secondary outcomes included changes in hand grip myotonia, strength, swallowing, forced vital capacity, lean muscle mass, Myotonic Dystrophy Health Index scores, and 24-hour Holter and ECG results at 3 and 6 months. RESULTS: Forty-two participants were randomized and 40 completed the 6-month follow-up (n = 20 in both groups). No significant effects of mexiletine were observed on 6-minute walk distance, but hand grip myotonia was improved with mexiletine treatment. There were no differences between the mexiletine and placebo groups with respect to the frequency or type of adverse events. Changes in PR, QRS, and QTc intervals were similar in mexiletine- and placebo-treated participants. CONCLUSIONS: There was no benefit of mexiletine on 6-minute walk distance at 6 months. Although mexiletine had a sustained positive effect on objectively measured hand grip myotonia, this was not seen in measures reflecting participants' perceptions of their myotonia. No effects of mexiletine on cardiac conduction measures were seen over the 6-month follow-up period. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for ambulatory patients with DM1, mexiletine does not significantly change 6-minute walk distance at 6 months.
Assuntos
Força da Mão/fisiologia , Mexiletina/uso terapêutico , Distrofia Miotônica/tratamento farmacológico , Distrofia Miotônica/fisiopatologia , Bloqueadores do Canal de Sódio Disparado por Voltagem/uso terapêutico , Teste de Caminhada/tendências , Adulto , Estudos de Coortes , Método Duplo-Cego , Eletrocardiografia/efeitos dos fármacos , Eletrocardiografia/tendências , Feminino , Humanos , Masculino , Mexiletina/farmacologia , Pessoa de Meia-Idade , Distrofia Miotônica/diagnóstico , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Teste de Caminhada/métodosRESUMO
It is unknown how evoked myotonia varies with stimulus frequency or train length, or how it compares to voluntary myotonia in myotonic dystrophy type 1 (DM1). First dorsal interosseous (FDI) tetanic contractions evoked by trains of 10-20 ulnar nerve stimuli at 10-50 HZ were recorded in 10 DM1 patients and 10 normals. For comparison, maximum voluntary handgrip contractions were also recorded. An automated computer program placed cursors along the declining (relaxation) phase of the force recordings at 90% and 5% of peak force (PF) and calculated relaxation times (RTs) between these points. For all stimulus frequencies and train lengths, evoked RTs were much shorter, and evoked PFs were much greater in normals than in DM1. In normals, evoked RT was independent of stimulus frequency and train length, while in DM1 RT was longer for train lengths of 20 stimuli (mean: 9 s in DM1; 0.20 in normals) than for 10 stimuli (mean: 3 s in DM1, 0.19 in normals), but it did not change with stimulus frequency. In both groups PF increased greatly as stimulus frequency rose from 10-50 HZ but only slightly as train length rose from 10-20 stimuli. Voluntary handgrip RT (mean: 1.9 s) was less than evoked FDI RT (mean: 9 s). In DM1, evoked RT can be "dialed up" by increasing stimulus train length. Evoked myotonia testing utilizing a stimulus paradigm of at least 20 stimuli at 30-50 HZ may be useful in antimyotonic drug trials, particularly when grip RT is normal or equivocal.
Assuntos
Contração Muscular/fisiologia , Músculo Esquelético/fisiopatologia , Miotonia/fisiopatologia , Distrofia Miotônica/fisiopatologia , Adulto , Estudos de Casos e Controles , Estimulação Elétrica , Feminino , Força da Mão/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Relaxamento Muscular/fisiologia , Miotonia/etiologia , Nervo Ulnar/fisiologiaRESUMO
Tumorigenesis is a multi-step process due to an accumulation of genetic mutations in multiple genes in diverse pathways which ultimately lead to loss of control over cell growth. It is well known that inheritance of rare germline mutations in genes involved in tumorigenesis pathways confer high lifetime risk of neoplasia in affected individuals. Furthermore, a substantial number of multiple malformation syndromes include cancer susceptibility in their phenotype. Studies of the mechanisms underlying these inherited syndromes have added to the understanding of both normal development and the pathophysiology of carcinogenesis. Myotonic dystrophy (DM) represents a group of autosomal dominant, multisystemic diseases that share the clinical features of myotonia, muscle weakness, and early-onset cataracts. Myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2) result from unstable nucleotide repeat expansions in their respective genes. There have been multiple reports of tumors in individuals with DM, most commonly benign calcifying cutaneous tumors known as pilomatricomas. We provide a summary of the tumors reported in DM and a hypothesis for a possible mechanism of tumorigenesis. We hope to stimulate further study into the potential role of DM genes in tumorigenesis, and help define DM pathogenesis, and facilitate developing novel treatment modalities.