RESUMO
Glutamic acid decarboxylase (GAD) is an intracellular enzyme found in the presynaptic end of nerve terminals that functions to synthesize ââgamma-aminobutyric acid (GABA) via decarboxylation. Autoantibodies to the GAD65 isoform have been found in high levels in neurological disorders including stiff person syndrome (SPS), autoimmune encephalitis, and refractory epilepsy. Low levels of anti-GAD65 have also been noted in type 1 diabetes mellitus. We present the unusual case of a woman with a longstanding history of focal seizures with impaired awareness and type 1 diabetes mellitus who was found to have extremely high titers of anti-GAD65 and clinical presentation suggestive of stiff person syndrome. This case highlights the increasing significance of autoimmune etiologies within neurologic disorders, as well as the importance of maintaining a high index of suspicion for rare anti-GAD65 syndromes. Although uncommon and with an unclear pathophysiology, we discuss the importance of establishing SPS diagnostic criteria to facilitate timely diagnosis and quickly direct patient management towards immunotherapy.
RESUMO
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by many diverse genetic etiologies. Although therapeutics that specifically target causal mutations may rescue individual types of ALS, such approaches cannot treat most patients since they have unknown genetic etiology. Thus, there is a critical need for therapeutic strategies that rescue multiple forms of ALS. Here, we combine phenotypic chemical screening on a diverse cohort of ALS patient-derived neurons with bioinformatic analysis of large chemical and genetic perturbational datasets to identify broadly effective genetic targets for ALS. We show that suppressing the gene-encoding, spliceosome-associated factor SYF2 alleviates TDP-43 aggregation and mislocalization, improves TDP-43 activity, and rescues C9ORF72 and causes sporadic ALS neuron survival. Moreover, Syf2 suppression ameliorates neurodegeneration, neuromuscular junction loss, and motor dysfunction in TDP-43 mice. Thus, suppression of spliceosome-associated factors such as SYF2 may be a broadly effective therapeutic approach for ALS.
Assuntos
Esclerose Lateral Amiotrófica , Doenças Neurodegenerativas , Camundongos , Animais , Esclerose Lateral Amiotrófica/genética , Neurônios Motores , Mutação , Proteínas de Ligação a DNA/genéticaRESUMO
BACKGROUND: Despite the significant impact of chronic symptoms on quality of life with cystic fibrosis (CF), the role of palliative care in management of this disease is not well defined. The coping, goal assessment, and relief from evolving CF symptoms (CF-CARES) model is a primary palliative care intervention designed to provide chronic symptom management at all stages of the disease. The goal of this pilot study was to estimate the effectiveness of the CF-CARES intervention on improving chronic symptoms and quality of life for people living with CF. METHODS: A structured assessment was used to guide referral to supportive services intended to address burdensome symptoms. Follow-up assessments were performed approximately 3 and 6 months later. Longitudinal regression analyses of changes in symptoms and quality of life were performed for all participants regardless of utilization of supportive services. Subgroup analyses were performed for subjects participating in mental health and alternative health services. RESULTS: Forty-one subjects completed assessment and referral processes. The mean number of CF-associated symptoms decreased over time, as did respiratory symptom-related distress and depressive symptoms. Subjects utilizing alternative health services reported less psychological distress at follow-up. Among subjects with severe disease, mental health, and quality of life improved, especially for those using mental health services. CONCLUSIONS: The CF-CARES model resulted in significant mental health and quality-of-life benefits, suggesting the value of integrating symptom management interventions into routine CF care. Moreover, mental health services can play a key role in CF-specific primary palliative care, especially for those with advanced disease.
Assuntos
Fibrose Cística/psicologia , Cuidados Paliativos , Atenção Primária à Saúde , Qualidade de Vida , Adaptação Psicológica , Adolescente , Adulto , Depressão , Feminino , Humanos , Masculino , Saúde Mental , Pessoa de Meia-Idade , Projetos Piloto , Adulto JovemRESUMO
BACKGROUND: Advance care planning (ACP) is recommended for people with cystic fibrosis (CF), yet guidance for optimal implementation is lacking. OBJECTIVE: To assess ACP-related thoughts, comfort level, and preferences among people with CF to guide evidence-based routine implementation of ACP in the CF clinic. DESIGN: A cross-sectional survey assessed ACP-related experiences and preferences. SUBJECTS: Thirty-eight adolescents and adults with CF from an urban CF center. RESULTS: Few subjects reported talking to their CF team about ACP care preferences (5%) or completing advance directives detailing desired medical treatments (11%). However, most participants worried about living with advanced disease (84%) and felt comfortable discussing ACP preferences with CF providers (92%). Subjects largely preferred that ACP conversations occur when they are generally healthy, in the outpatient setting, and with any familiar CF team member. Disease severity was not associated with frequency of worry about living with advanced disease, comfort level with ACP discussions, or ACP setting preferences. CONCLUSIONS: People with CF worry about advanced disease and feel comfortable discussing ACP, but need more guidance to understand and document ACP choices. CF patient experiences and preferences support implementation of an early, active approach to ACP for people with CF.
Assuntos
Planejamento Antecipado de Cuidados/estatística & dados numéricos , Diretivas Antecipadas/psicologia , Diretivas Antecipadas/estatística & dados numéricos , Fibrose Cística/psicologia , Preferência do Paciente/psicologia , Preferência do Paciente/estatística & dados numéricos , Assistência Terminal/psicologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: Current palliative care tools do not address distressing chronic symptoms that are most relevant to cystic fibrosis. METHODS: A CF-specific structured assessment based on a primary palliative care framework was administered to 41 adolescents and adults with CF. Descriptive and correlational analyses were conducted. RESULTS: Patients reported numerous physical and psychological symptoms (mean of 10 per patient), with psychological symptoms rated as more distressing. Anxiety (34%) and depression (44%) were prevalent and correlated with distress attributable to physical symptoms and difficulty with CF self-management, but did not correlate with disease severity. CONCLUSIONS: Individuals with CF, regardless of disease severity, face challenges managing symptom burden. Frequently reported symptoms are not consistently associated with distress, suggesting the importance of individualized evaluation. The CF-CARES (Coping, goal Assessment, and Relief from Evolving CF Symptoms) primary palliative care assessment model provides a framework for patients experiencing chronic symptoms to explore interventional options with their clinicians.