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INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is an idiopathic neurodegenerative disease usually fatal in less than three years. Even if standard guidelines are available to diagnose ALS, the mean diagnosis delay is more than one year. In this context, biomarker discovery is a priority. Research has to focus on new diagnostic tools, based on combined explorations. AREAS COVERED: In this review, we specifically focus on biology and imaging markers. We detail the innovative field of 'omics' approach and imaging and explain their limits to be useful in routine practice. We describe the most relevant biomarkers and suggest some perspectives for biomarker research. Expert commentary: The successive failures of clinical trials in ALS underline the need for new strategy based on innovative tools to stratify patients and to evaluate their responses to treatment. Biomarker data may be useful to improve the designs of clinical trials. Biomarkers are also needed to better investigate disease pathophysiology, to identify new therapeutic targets, and to improve the performance of clinical assessments for diagnosis and prognosis in the clinical setting. A consensus on the best management of neuroimaging and 'omics' methods is necessary and a systematic independent validation of findings may add robustness to future studies.
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Esclerose Lateral Amiotrófica/diagnóstico por imagem , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Biomarcadores , Pesquisa Biomédica , Estudo de Associação Genômica Ampla , Genômica/métodos , Humanos , Metabolômica/métodos , Imagem Multimodal , Neuroimagem/métodos , Proteômica/métodosRESUMO
INTRODUCTION: Amyotrophic lateral sclerosis (ALS), one in a family of age-related neurodegenerative disorders, is marked by predominantly cryptogenic causes, partially elucidated pathophysiology, and elusive treatments. The challenges of ALS are illustrated by two decades of negative drug trials. AREAS COVERED: In this article, we lay out the current understanding of disease genesis and physiology in relation to drug development in ALS, stressing important accomplishments and gaps in knowledge. We briefly consider clinical ALS, the ongoing search for biomarkers, and the latest in trial design, highlighting major recent and ongoing clinical trials; and we discuss, in a concluding section on future directions, the prion-protein hypothesis of neurodegeneration and what steps can be taken to end the drought that has characterized drug discovery in ALS. EXPERT OPINION: Age-related neurodegenerative disorders are fast becoming major public health problems for the world's aging populations. Several agents offer promise in the near-term, but drug development is hampered by an interrelated cycle of obstacles surrounding etiological, physiological, and biomarkers discovery. It is time for the type of government-funded, public-supported offensive on neurodegenerative disease that has been effective in other fields.
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Esclerose Lateral Amiotrófica/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Esclerose Lateral Amiotrófica/diagnóstico , Esclerose Lateral Amiotrófica/genética , Biomarcadores/metabolismo , Ensaios Clínicos como Assunto , Demência Frontotemporal/diagnóstico , Demência Frontotemporal/tratamento farmacológico , Demência Frontotemporal/genética , Humanos , Hidroxilaminas/uso terapêutico , Memantina/uso terapêutico , Riluzol/uso terapêutico , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Vitamina B 12/análogos & derivados , Vitamina B 12/uso terapêuticoRESUMO
Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease. Alongside identification of aetiologies, development of biomarkers is a foremost research priority. Metabolomics is one promising approach that is being utilized in the search for diagnosis and prognosis markers. Our aim is to provide an overview of the principal research in metabolomics applied to ALS. References were identified using PubMed with the terms 'metabolomics' or 'metabolomic' and 'ALS' or 'amyotrophic lateral sclerosis' or 'MND' or 'motor neuron disorders'. To date, nine articles have reported metabolomics research in patients and a few additional studies examined disease physiology and drug effects in patients or models. Metabolomics contribute to a better understanding of ALS pathophysiology but, to date, no biomarker has been validated for diagnosis, principally due to the heterogeneity of the disease and the absence of applied standardized methodology for biomarker discovery. A consensus on best metabolomics methodology as well as systematic independent validation will be an important accomplishment on the path to identifying the long-awaited biomarkers for ALS and to improve clinical trial designs.
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Esclerose Lateral Amiotrófica/metabolismo , Metabolômica/métodos , Humanos , Metabolômica/normasRESUMO
BACKGROUND AND PURPOSE: The objectives of this study were to define the metabolomic profile of cerebrospinal fluid in amyotrophic lateral sclerosis (ALS) patients, to model outcome through combined clinical and metabolomic parameters and independently to validate predictive models. METHODS: In all, 74 consecutive newly diagnosed patients were enrolled into training (Tr, n = 49) and test (Te, n = 25) cohorts. Investigators recorded clinical data and the metabalomic profile of cerebrospinal fluid at baseline was analyzed with (1)H nuclear magnetic resonance spectroscopy. Markers of disease progression, collected in 1-year prospective follow-up, included change in ALS Functional Rating Scale (var_ALSFRS), change in weight (var_weight) and survival time. Stepwise multiple regression selected from metabolomic and clinical parameters to model rate of progression in the Tr cohort. Best fit models were validated independently in the Te cohort. RESULTS: The best-fit statistical models, using both metabolomic and clinical covariates, predicted outcome with 70.8% (var_weight), 72% (var_ALSFRS) and 76% (survival) accuracy in the Te cohort. Models that used metabolomics or clinical data alone predicted outcome less well. Highlighted metabolites are involved in pathophysiological pathways previously described in ALS. CONCLUSION: Cerebrospinal fluid metabolomics can aid in predicting the clinical course of ALS and tap into pathophysiological processes. The precision of predictive models, independently reproduced in this study, is enhanced through inclusion of both metabolomic and clinical parameters. The findings bring the field closer to a clinically meaningful disease marker.
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Esclerose Lateral Amiotrófica/líquido cefalorraquidiano , Progressão da Doença , Metaboloma/fisiologia , Idoso , Biomarcadores/líquido cefalorraquidiano , Seguimentos , Humanos , Metabolômica , Pessoa de Meia-Idade , Prognóstico , Espectroscopia de Prótons por Ressonância MagnéticaRESUMO
Amyotrophic lateral sclerosis (ALS) is an age-related neurodegenerative disorder that is believed to have complex genetic and environmental influences in the pathogenesis, but etiologies are unidentified for most patients. Until the major causes are better defined, drug development is directed at downstream pathophysiological mechanisms, themselves incompletely understood. For nearly 30 years, glutamate-induced excitotoxicity has lain at the core of theories behind the spiraling events, including mitochondrial dysfunction, oxidative stress, and protein aggregation, that lead to neurodegenerative cell death. One drug, riluzole, which possesses anti-glutamatergic properties, is approved as neuroprotective for ALS. Following the achievement of the riluzole trials, numerous other agents with similar mechanisms have been tested without success. This article provides an overview of excitotoxicity in ALS, focusing on the events that contribute to excess glutamate, how the excess might damage nerve cells, and how this information is being harnessed in the development of potential new neuroprotective agents. The work highlights clinical trials of drugs that have targeted the glutamate system, comments on the potential role of glutamate as a biomarker and concludes with a section on future directions for the field. As research uncovers elusive etiologies and brings clarity to pathophysiological mechanisms, the success of new interventions will increasingly depend on the design of agents that target particular mechanisms for specific individuals. The heady future of personalized drug regimens for ALS rests with medicinal chemists, the scientists whose ideas and work produce these designer drugs.
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Esclerose Lateral Amiotrófica/patologia , Ácido Glutâmico/metabolismo , Sistema X-AG de Transporte de Aminoácidos/antagonistas & inibidores , Sistema X-AG de Transporte de Aminoácidos/genética , Sistema X-AG de Transporte de Aminoácidos/metabolismo , Esclerose Lateral Amiotrófica/tratamento farmacológico , Ácido Glutâmico/toxicidade , Humanos , Neurônios Motores/efeitos dos fármacos , Neurônios Motores/metabolismo , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Receptores de Glutamato/química , Receptores de Glutamato/genética , Receptores de Glutamato/metabolismo , Riluzol/química , Riluzol/farmacologia , Riluzol/uso terapêuticoRESUMO
Amyotrophic lateral sclerosis (ALS), the most common adult-onset motor neuron disorder, is fatal for most patients less than 3 years from when the first symptoms appear. The aetiologies for sporadic and most familial forms of ALS are unknown, but genetic factors are increasingly recognized as causal in a subset of patients. Studies of disease physiology suggest roles for oxidative stress, glutamate-mediated excitotoxicity or protein aggregation; how these pathways interact in the complex pathophysiology of ALS awaits elucidation. Cellular models are being used to examine disease mechanisms. Recent advances include the availability of expanded cell types, from neuronal or glial cell culture to motoneuron-astrocyte co-culture genetically or environmentally modified. Cell culture experiments confirmed the central role of glial cells in ALS. The recent adaptation of induced pluripotent stem cells (iPSC) for ALS modeling could allow a broader perspective and is expected to generate new hypotheses, related particularly to mechanisms underlying genetic factors. Cellular models have provided meaningful advances in the understanding of ALS, but, to date, complete characterization of in vitro models is only partially described. Consensus on methodological approaches, strategies for validation and techniques that allow rapid adaptation to new genetic or environmental influences is needed. In this article, we review the principal cellular models being employed in ALS and highlight their contribution to the understanding of disease mechanisms. We conclude with recommendations on means to enhance the robustness and generalizability of the different concepts for experimental ALS.
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Esclerose Lateral Amiotrófica/patologia , Esclerose Lateral Amiotrófica/fisiopatologia , Astrócitos/patologia , Neurônios/patologia , Esclerose Lateral Amiotrófica/metabolismo , Animais , Astrócitos/metabolismo , Técnicas de Cultura de Células , Linhagem Celular , Técnicas de Cocultura , Humanos , Neuroglia/metabolismo , Neuroglia/patologia , Neurônios/metabolismo , Estresse Oxidativo/fisiologiaRESUMO
The optineurin (OPTN) gene, known to be implicated in primary open-angle glaucoma (POAG), is the more recent genetic factor linked to ALS. We report the case of a 75year-old man who developed ALS and whose medical history was dominated by a familial POAG. The absence of OPTN gene mutation in a patient who suffered from two conditions linked to mutations of this gene does not support involvement of OPTN in ALS.
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Esclerose Lateral Amiotrófica/diagnóstico , Esclerose Lateral Amiotrófica/genética , Inativação Gênica , Glaucoma de Ângulo Aberto/diagnóstico , Glaucoma de Ângulo Aberto/genética , Mutação , Fator de Transcrição TFIIIA/genética , Idoso , Esclerose Lateral Amiotrófica/complicações , Proteínas de Ciclo Celular , Glaucoma de Ângulo Aberto/complicações , Humanos , Masculino , Proteínas de Membrana Transportadoras , Mutação/genéticaRESUMO
OBJECTIVE: Several association studies have identified possible susceptibility factors for sporadic amyotrophic lateral sclerosis (SALS). Studies on the APOE gene provided conflicting results, especially about the effect on bulbar onset. We assessed the possible role of APOE gene in a large cohort of patients with ALS and matched controls. METHODS: The APOE alleles were determined in 1482 patients with SALS and 955 controls and analysed by univariate and multivariate statistics, taking into account gender, site-of-onset and age-at-onset. RESULTS: Patients with bulbar onset were more likely to be women [odds ratio (OR)=2.17; 95% CI: 1.74-2.72] and to be older (OR=3.47; 95% CI: 2.58-4.67). The ε4-carriers were more frequent in the bulbar-onset group than in the limb-onset group (OR=1.39 bulbar onset versus limb onset; 95% CI: 1.08-1.80) but this association was observed amongst men (OR=1.78; 95% CI: 1.25-2.53) and not women (OR=1.09; 95% CI: 0.75-1.59). CONCLUSION: Our study provides evidence for a contribution of the ε4 allele in the occurrence of bulbar-onset ALS amongst men. We propose that men are normally protected by androgens against bulbar onset and that the ε4 allele inhibits this protection, perhaps by interfering with the androgen pathway.
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Esclerose Lateral Amiotrófica/epidemiologia , Esclerose Lateral Amiotrófica/genética , Apolipoproteína E4/genética , Paralisia Bulbar Progressiva/epidemiologia , Paralisia Bulbar Progressiva/genética , Predisposição Genética para Doença/genética , Idoso , Androgênios/deficiência , Androgênios/genética , Androgênios/fisiologia , Estudos de Casos e Controles , Estudos de Coortes , Citoproteção/genética , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença/epidemiologia , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Fatores Sexuais , Transdução de Sinais/genéticaRESUMO
Familial amyotrophic lateral sclerosis (FALS) cases linked to SOD1 mutations may sometimes present with unusual clinical features such as pure lower motor neuron involvement or sensory signs. The authors describe a FALS pedigree with the L144F SOD1 mutation in which all cases had respiratory involvement as a first symptom. Although atypical clinical features are not rare in ALS families, this is the first pedigree with respiratory-onset in three affected members. This unusual presentation led to delayed diagnosis in the proband and highlights the fact that respiratory-onset can occur in familial ALS cases carrying SOD1 mutation.
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Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/fisiopatologia , Doenças Respiratórias/etiologia , Doenças Respiratórias/genética , Superóxido Dismutase/genética , Adulto , Idoso , DNA/genética , Análise Mutacional de DNA , Dispneia/etiologia , Fadiga/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Mutação de Sentido Incorreto/genética , Linhagem , Músculos Respiratórios/fisiopatologia , Superóxido Dismutase-1 , Adulto JovemRESUMO
Colorectal carcinoma is the second most common cause of death in Canada. Because there is a precursor lesion (that is, the polyp), screening is critically important to prevent the disease through polyp removal-and failing that, to detect colorectal carcinoma at an early stage, when it can be cured. Several screening modalities are available, but colonoscopy is considered the best. People should avail themselves of such examinations, and physicians should encourage them to do so.
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BACKGROUND: Amyotrophic lateral sclerosis (ALS) patients report both fatigue and depression. It is not clear how frequently each occurs, to what extent they occur together, how each relates to ALS disease status, or their stability over time. OBJECTIVE: To assess frequency and persistence of fatigue and depression, and relationship to ALS disease status, for patients attending an ALS interdisciplinary centre for routine 3-month visits. METHOD: Measures included the Fatigue Severity Scale, Patient Health Questionnaire-9. ALS Functional Rating Scale -- Revised and forced vital capacity, rate of disease progression, and bulbar/nonbulbar disease onset. RESULTS: 223 patients completed the ratings once; of these, 113 completed them twice, and 65 on three visits. At baseline, 44% (99/223) had clinically significant fatigue, including 34 patients who also had a depressive disorder; 7% (16/223) had major or minor depression only, and 48% (108/223) had neither condition. Fatigue was associated with greater ALS severity, but depression was not. Among the 113 patients seen 3 months later, 75% (33/44) who were fatigued at Time 1 remained fatigued, while 48% (10/21) remained depressed. New-onset fatigue was reported by 22% (25/113), and new-onset depression by 6% (7/113). For the 65 patients seen a third time, rates remained nearly the same. CONCLUSION: Fatigue was more prevalent and persistent than depression, although 15% (34/223) of patients had both conditions. Fatigue but not depression was associated with ALS severity. The two conditions appear to be independent, although sometimes co-occurring, and both warrant consideration in evaluating patient functioning and treatment.
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Esclerose Lateral Amiotrófica/psicologia , Transtorno Depressivo/epidemiologia , Fadiga/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Esclerose Lateral Amiotrófica/complicações , Esclerose Lateral Amiotrófica/fisiopatologia , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de Risco , Índice de Gravidade de Doença , Capacidade VitalRESUMO
Localized giant pseudopolyposis of the colon (pseudopolyp larger than 1.5 cm in size) is a rare complication of inflammatory bowel disease. There is one report of an occult carcinoma within such a lesion, and no reports of sole dysplasia. A case of a 42-year-old man with longstanding Crohn's colitis who underwent a colonoscopy revealing a large, multilobulated mass at the splenic flexure that was not amenable to endoscopic removal, is described. Multiple biopsies showed no dysplasia and histology was consistent with an inflammatory pseudopolyp. Computed tomographic colonography demonstrated a mass resembling a large villous tumour. A decision for surgery was made. The surgical specimen was a complex anastomosing inflammatory pseudopolyp 5 cm x 4 cm x 3 cm in size, with a focus of low-grade dysplasia in an area free of inflammation. The present case is the first reported occult dysplasia in a giant pseudopolyp. Occult dysplasia without superficial dysplasia may exist in these lesions and further studies are needed to examine risk factors that make a giant pseudopolyp more likely to harbour dysplasia and/or carcinoma.
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Pólipos do Colo/diagnóstico , Pólipos do Colo/etiologia , Doença de Crohn/complicações , Doença de Crohn/patologia , Adulto , Pólipos do Colo/cirurgia , Doença de Crohn/cirurgia , Humanos , MasculinoRESUMO
OBJECTIVE: To determine how clinical features at the first evaluation and in follow-up can be used to suggest a diagnostic outcome for patients with only upper motor neuron (UMN) signs at disease onset. METHODS: We reviewed the records of 34 patients (9 primary lateral sclerosis [PLS], 15 UMN-dominant amyotrophic lateral sclerosis [ALS], and 10 randomly selected control patients with ALS) seen in 1984-2007. Analysis of variance F tests for continuous variables and chi2 tests for categorical variables analyzed differences in baseline data among the diagnostic categories. Linear and generalized mixed effects models assessed the relation between examination data and diagnostic group over time. RESULTS: At first examination, the lowest score of the weakest muscle (p < 0.001), the site of onset (p = 0.041), and time to evaluation (p = 0.05) discriminated between eventual diagnostic group; patients with PLS were stronger, slower in progressing, and more likely to have limb onset than the other groups. Strength < or = 4 on any muscle was associated with the diagnosis of ALS (p = 0.0001), but not PLS. Across all visits, muscle strength (p = 0.003), ALS Functional Rating Scale score (p = 0.009), and vital capacity (p = 0.026) predicted group assignment. UMN-dominant and ALS groups had more weight loss (p = 0.004), even when controlled for dysphagia (p = 0.021) and muscle atrophy (p = 0.009), and patients with ALS were more likely to have hyporeflexia (p = 0.001). CONCLUSIONS: Features at baseline most suggestive of eventual lower motor neuron signs were focal muscle weakness or bulbar onset. Later, weight loss, reduced forced vital capacity, and limb weakness predicted lower motor neuron dysfunction. We suggest that patients with only upper motor neuron signs have periodic evaluations of strength, weight, forced vital capacity, Amyotrophic Lateral Sclerosis Functional Rating Scale score, and EMG, because a change in any can signal the imminent development of lower motor neuron signs.
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Esclerose Lateral Amiotrófica/diagnóstico , Doença dos Neurônios Motores/diagnóstico , Debilidade Muscular/diagnóstico , Adulto , Esclerose Lateral Amiotrófica/fisiopatologia , Biomarcadores/análise , Biomarcadores/metabolismo , Encéfalo/fisiopatologia , Paralisia Bulbar Progressiva/diagnóstico , Paralisia Bulbar Progressiva/fisiopatologia , Diagnóstico Diferencial , Progressão da Doença , Vias Eferentes/fisiopatologia , Humanos , Pessoa de Meia-Idade , Doença dos Neurônios Motores/fisiopatologia , Neurônios Motores/fisiologia , Força Muscular/fisiologia , Debilidade Muscular/etiologia , Debilidade Muscular/fisiopatologia , Músculo Esquelético/inervação , Músculo Esquelético/fisiopatologia , Exame Neurológico , Valor Preditivo dos Testes , Paralisia Respiratória/diagnóstico , Paralisia Respiratória/etiologia , Paralisia Respiratória/fisiopatologia , Estudos Retrospectivos , Medula Espinal/fisiopatologia , Capacidade Vital/fisiologiaRESUMO
Venous and arterial thromboembolism is a significant cause of morbidity and mortality in patients with ulcerative colitis (UC). Arterial thrombosis of the splanchnic region is a rare event with a very high mortality rate. Furthermore, it represents a challenging complication since it tends to be overlooked and misinterpreted as a clinical exacerbation of UC. We present the case of a 62-year-old female with pancolonic UC complicated by an extensive arterial thrombosis involving the aorta, the celiac trunk, the hepatic, gastric and splenic arteries and the superior mesenteric artery. A thrombosis of the splenic vein extending into the proximal portal vein was also present. The patient was successfully treated by a combined interventional-radiological and surgical treatment. We discuss the rationale behind our management of this case and review the literature on splanchnic arterial thrombosis associated with UC.
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Anticoagulantes/administração & dosagem , Colite Ulcerativa/complicações , Oclusão Vascular Mesentérica/tratamento farmacológico , Oclusão Vascular Mesentérica/etiologia , Ativador de Plasminogênio Tecidual/administração & dosagem , Trombose Venosa , Feminino , Humanos , Infusões Intravenosas , Artéria Mesentérica Superior/patologia , Pessoa de Meia-Idade , Veia Porta/patologia , Artéria Esplênica/patologia , Trombose Venosa/complicações , Trombose Venosa/tratamento farmacológico , Trombose Venosa/etiologiaRESUMO
OBJECTIVE: To investigate the value of objective biomarkers for upper (UMN) and lower (LMN) motor neuron involvement in ALS. METHODS: We prospectively studied 64 patients with ALS and its subsets using clinical measures, proton MR spectroscopic imaging ((1)H MRSI), diffusion tensor imaging, transcranial magnetic stimulation, and the motor unit number estimation (MUNE) at baseline and every 3 months for 15 months and compared them with control subjects. RESULTS: (1)H MRSI measures of the primary motor cortex N-acetyl-aspartate (NAA) concentration were markedly reduced in ALS (p = 0.009) and all UMN syndromes combined (ALS, familial ALS [fALS], and primary lateral sclerosis; p = 0.03) vs control values. Central motor conduction time to the tibialis anterior was prolonged in ALS (p < 0.0005) and combined UMN syndromes (p = 0.001). MUNE was lower in ALS (p < 0.0005) and all LMN syndromes combined (ALS, fALS, and progressive muscular atrophy; p = 0.001) vs controls. All objective markers correlated well with the ALS Functional Rating Scale-Revised, finger and foot tapping, and strength testing, suggesting these markers related to disease activity. Regarding changes over time, MUNE changed rapidly, whereas neuroimaging markers changed more slowly and did not significantly differ from baseline. CONCLUSIONS: (1)H MR spectroscopic imaging measures of the primary motor cortex N-acetyl-aspartate (NAA) concentration and ratio of NAA to creatine, central motor conduction time to the tibialis anterior, and motor unit number estimation significantly differed between ALS, its subsets, and control subjects, suggesting they have potential to provide insight into the pathobiology of these disorders.
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Esclerose Lateral Amiotrófica/patologia , Ácido Aspártico/análogos & derivados , Creatina/análise , Córtex Motor/química , Doença dos Neurônios Motores/patologia , Neurônios Motores/fisiologia , Atrofia Muscular Espinal/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Esclerose Lateral Amiotrófica/classificação , Esclerose Lateral Amiotrófica/fisiopatologia , Ácido Aspártico/análise , Biomarcadores , Imagem de Difusão por Ressonância Magnética , Feminino , Seguimentos , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Doença dos Neurônios Motores/fisiopatologia , Atrofia Muscular Espinal/fisiopatologia , Condução Nervosa , Estudos Prospectivos , Estimulação Magnética TranscranianaRESUMO
We evaluated the reliability and sensitivity to change over time of a newly developed self-administered version of the ALS functional rating scale-revised (ALSFRS-R) in 60 consecutive patients from an ALS clinic. The self-administered ALSFRS-R showed excellent reliability (intraclass correlation = 0.93, 95% CI: 088 to 0.96) and similar sensitivity to change over time vs the standard evaluator-administered ALSFRS-R.
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Atividades Cotidianas , Esclerose Lateral Amiotrófica/classificação , Esclerose Lateral Amiotrófica/diagnóstico , Indicadores Básicos de Saúde , Inquéritos e Questionários , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Distribuição Aleatória , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
The authors conducted a randomized controlled trial to test the safety and immunology of glatiramer acetate in ALS. Twenty treated patients were randomly assigned to daily or biweekly injections. Ten control patients were selected from another trial and followed up concurrently. Injection reactions were the only common adverse event (p = 0.01). Treated patients showed enhanced lymphocyte proliferation (p = 0.02). The safety profile and immune effects support conducting larger trials of dose selection and efficacy.
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Imunossupressores/uso terapêutico , Doença dos Neurônios Motores/tratamento farmacológico , Peptídeos/uso terapêutico , Esquema de Medicação , Acetato de Glatiramer , Humanos , Imunossupressores/toxicidade , Injeções/efeitos adversos , Ativação Linfocitária , Doença dos Neurônios Motores/imunologia , Peptídeos/administração & dosagem , Peptídeos/toxicidade , Linfócitos T/imunologiaRESUMO
OBJECTIVE: To define the syndrome of primary lateral sclerosis (PLS) and disorders that contain features of both ALS and PLS, to determine the time beyond which PLS is less likely to become ALS clinically, and to determine the outcome of people with PLS and those who develop lower motor neuron (LMN) signs. METHODS: The authors reviewed the records of all 39 patients initially diagnosed with PLS in 1984 to 2004. Diagnostic subgroups were defined based on clinical features. The authors used Kaplan-Meier methods to estimate the time to diagnosis, linear regression analyses to assess function, and a Cox proportional hazard model to assess survival in subgroups. RESULTS: Of the 39 patients, 29 had only upper motor neuron (UMN) signs on initial evaluation. Thirteen of the 29 were later classified as having UMN-dominant ALS (UMN-D) because they acquired evidence of denervation by EMG (3.17 years) or examination (3.67 years). Sixteen of the 29 patients, classified as clinically pure PLS, retained only UMN signs and a normal EMG (mean follow-up 8.7 years). Ten patients who met criteria for ALS at the initial visit were used as controls. The UMN-dominant ALS group had lower functional scores (p = 0.033) than the PLS group, and similar scores to those with ALS. Survival was longer in both the PLS group (p = 0.027) and the UMN-D group (p = 0.067) than the ALS group. CONCLUSIONS: Clinically pure PLS can be defined by isolated UMN signs 4 years after symptom onset, and is a syndrome of slow progression with high levels of function. Prior to the fourth year, the diagnosis of PLS cannot be made with certainty because many patients develop LMN signs. UMN-dominant ALS, defined by predominantly UMN disease with minor LMN signs, has disability similar to ALS, but slower progression.
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Doença dos Neurônios Motores/fisiopatologia , Adulto , Idoso , Esclerose Lateral Amiotrófica/mortalidade , Esclerose Lateral Amiotrófica/fisiopatologia , Progressão da Doença , Eletromiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença dos Neurônios Motores/classificação , Doença dos Neurônios Motores/mortalidade , Estudos Retrospectivos , Análise de SobrevidaRESUMO
BACKGROUND: A 3 bp deletion located at the 5' end of exon 3 of MLH1, resulting in deletion of exon 3 from RNA, was recently identified. HYPOTHESIS: That this mutation disrupts an exon splicing enhancer (ESE) because it occurs in a purine-rich sequence previously identified as an ESE in other genes, and ESEs are often found in exons with splice signals that deviate from the consensus signals, as does the 3' splice signal in exon 3 of MLH1. DESIGN: The 3 bp deletion and several other mutations were created by polymerase chain reaction mutagenesis and tested using an in vitro splicing assay. Both mutant and wild type exon 3 sequences were cloned into an exon trapping vector and transiently expressed in Cos-1 cells. RESULTS: Analysis of the RNA indicates that the 3 bp deletion c.213_215delAGA (gi:28559089, NM_000249.2), a silent mutation c.216T-->C, a missense mutation c.214G-->C, and a nonsense mutation c.214G-->T all cause varying degrees of exon skipping, suggesting the presence of an ESE at the 5' end of exon 3. These mutations are situated in a GAAGAT sequence 3 bp downstream from the start of exon 3. CONCLUSIONS: The results of the splicing assay suggest that inclusion of exon 3 in the mRNA is ESE dependent. The exon 3 ESE is not recognised by all available motif scoring matrices, highlighting the importance of RNA analysis in the detection of ESE disrupting mutations.
Assuntos
Proteínas de Transporte/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Éxons/genética , Proteínas Nucleares/genética , Mutação Puntual/genética , Splicing de RNA/genética , Sequências Reguladoras de Ácido Ribonucleico/genética , Proteínas Adaptadoras de Transdução de Sinal , Animais , Células COS , Chlorocebus aethiops , Humanos , Proteína 1 Homóloga a MutL , Quebeque , Sítios de Splice de RNA/genéticaRESUMO
BACKGROUND: Repetitive tasks in the workplace are one cause of injury. This study aimed to identify injuries specific to physicians routinely performing colonoscopy, and to identify prevention strategies. METHODS: A survey was sent to all 2,173 worldwide members of the American Society for Colon and Rectal Surgery to investigate injuries or disabilities that resulted from performing colonoscopy and the methods used to prevent and alleviate symptoms related to the procedure. RESULTS: The response rate was 28%. Of the respondents, 96% performed colonoscopy. At least one injury or pain believed to result from performing colonoscopy was reported by 39% of the respondents. The most frequently reported injuries were to hands and fingers (n = 257), neck (n = 65), and back (n = 52). The methods adopted to alleviate injury included changing the height of the stretcher or video monitor, changing from a standing to a sitting position, minimizing torque on the colonoscope, having an assistant perform the torque maneuver, and resting or taking time off from colonoscopy. Two respondents also created devices to make the instrument more ergonomic. CONCLUSION: The number of colorectal surgeons encountering injury from colonoscopy highlights the need for preventive strategies. The study results suggest that it may be necessary to improve the design of colonoscopes to make them more ergonomic. Appropriate positioning of the endoscopist, patient, and monitors may diminish some of the injuries encountered.