A non-functional galanin receptor-2 in a multiple sclerosis patient.

Multiple Sclerosis (MS) is an inflammatory neurodegenerative disease that affects approximately 2.5 million people globally. Even though the etiology of MS remains unknown, it is accepted that it involves a combination of genetic alterations and environmental factors. Here, after performing whole exome sequencing, we found a MS patient harboring a rare and homozygous single nucleotide variant (SNV; rs61745847) of the G-protein coupled receptor (GPCR) galanin-receptor 2 (GALR2) that alters an important amino acid in the TM6 molecular toggle switch region (W249L). Nuclear magnetic resonance imaging showed that the hypothalamus (an area rich in GALR2) of this patient exhibited an important volumetric reduction leading to an enlarged third ventricle. Ex vivo experiments with patient-derived blood cells (AKT phosphorylation), as well as studies in recombinant cell lines expressing the human GALR2 (calcium mobilization and NFAT mediated gene transcription), showed that galanin (GAL) was unable to stimulate cell signaling in cells expressing the variant GALR2 allele. Live cell confocal microscopy showed that the GALR2 mutant receptor was primarily localized to intracellular endosomes. We conclude that the W249L SNV is likely to abrogate GAL-mediated signaling through GALR2 due to the spontaneous internalization of this receptor in this patient. Although this homozygous SNV was rare in our MS cohort (1:262 cases), our findings raise the potential importance of impaired neuroregenerative pathways in the pathogenesis of MS, warrant future studies into the relevance of the GAL/GALR2 axis in MS and further suggest the activation of GALR2 as a potential therapeutic route for this disease.

Effects of Short-Term Calcium Supplementation in Children and Adolescents with Phenylketonuria.

Reduction of bone mineral density and the risk of osteopenia have been reported to occur in phenylketonuria (PKU) patients. This study aimed to evaluate the short-term effects of calcium supplementation in phenylketonuric children and adolescents. The study included 18 patients with PKU aged 5-18 yr (61% male) under clinical and nutritional treatment. Evaluation of food intake, anthropometry, and biochemical and phalangeal quantitative ultrasound were performed before (phase 1) and after (phase 2) calcium supplementation (1000 mg/d) for 34 d. Statistical analysis was performed using t test for paired samples, Wilcoxon's test, and McNemar's test (p <0.05). There was an inadequate intake of phosphorus and vitamin D, the same occurring with serum concentrations of these nutrients. About 50% of the patients had an accumulation of adipose tissue measures, with a negative correlation between Z-score, body mass index, and phalangeal quantitative ultrasound (amplitude-dependent speed of sound [AD-SoS]). There was a significant difference in urinary phosphorus excretion with higher values before supplementation. Comparison of the two phases revealed significantly higher AD-SoS values after the supplementation (p = 0.017). The reduction in phosphorus excretion associated with increased AD-SoS between the two phases suggested increased bone formation, and showed no negative effects in relation to short-term calcium supplementation in children and in adolescents with PKU.

Immunological correlates of favorable long-term clinical outcome in multiple sclerosis patients after autologous hematopoietic stem cell transplantation.

High dose immunosuppression followed by autologous hematopoietic stem cell transplantation (AHSCT) induces prolonged clinical remission in multiple sclerosis (MS) patients. However, how patient immune profiles are associated with clinical outcomes has not yet been completely elucidated. In this study, 37 MS patients were assessed for neurological outcomes, thymic function and long-term immune reconstitution after AHSCT. Patients were followed for a mean (SD) of 68.5 (13.9) months post-transplantation and were retrospectively clustered into progression- and non-progression groups, based on Expanded Disease Status Scale (EDSS) outcomes at last visit. After AHSCT, both patient groups presented increased regulatory T-cell subset counts, early expansion of central- and effector-memory CD8(+)T-cells and late thymic reactivation. However, the non-progression group presented early expansion of PD-1(+)CD8(+)T-cells and of PD-1-expressing CD19(+) B-cells. Here, we suggest that along with increased numbers of regulatory T-cell subsets, PD-1 inhibitory signaling is one possible immunoregulatory mechanism by which AHSCT restores immune tolerance in MS patients.

Cross-cultural Adaptation, Reliability, and Validity of the BICAMS in Brazil.

OBJECTIVE: To investigate the reliability and validity of a Brazilian-Portuguese adaptation of the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS). METHOD: A Brazilian sample of 58 multiple sclerosis (MS) patients and 58 healthy controls (HC) were administered the Brazilian-Portuguese BICAMS test battery, comprising the Symbol Digit Modalities Test (SDMT), California Verbal Learning Test Second Edition (CVLT2), and the Brief Visuospatial Memory Test Revised (BVMTR). Mean differences between groups on BICAMS tests were assessed using analysis of covariance (ANCOVA), controlling for age, gender, education, anxiety, and depression. Test-retest data were obtained from 49 of the MS patients, two weeks after the initial assessment. RESULTS: The MS patient group scored significantly lower on all BICAMS tests (CVLT2 F1,110 = 28.99, p < .001; BVMTR F1,110 = 7.77, p < .01; SDMT F1,110 = 21.09, p < .001). Mixed-factor ANCOVAs tested differences in learning curves across trials for CVLT2 and BVMTR. HCs had significantly steeper learning curves on both CVLT2 (F1,111 = 10.82, p < .01) and BVMTR (F1,110 = 7.816, p < .01). These findings support diagnostic validity of the Brazilian-Portuguese adaptation. Test-retest reliability was satisfactory for SDMT, CVLT2, and BVMTR (.86, .84, and .77, respectively). CONCLUSION: The results suggest that this Brazilian version of the BICAMS will be a valid and reliable measure once complete normative data become available.

Modified constraint-induced movement therapy and modified forced-use therapy for stroke patients are both effective to promote balance and gait improvements / Terapia de constrição com indução do movimento e terapia de uso forçado modificadas em pacientes pós-acidente vascular encefálico são eficientes em promover melhora do equilíbrio e da marcha

BACKGROUND: Previous studies show that chronic hemiparetic patients after stroke, presents inabilities to perform movements in paretic hemibody. This inability is induced by positive reinforcement of unsuccessful attempts, a concept called learned non-use. Forced use therapy (FUT) and constraint induced movement therapy (CIMT) were developed with the goal of reversing the learned non-use. These approaches have been proposed for the rehabilitation of the paretic upper limb (PUL). It is unknown what would be the possible effects of these approaches in the rehabilitation of gait and balance. OBJECTIVES: To evaluate the effect of Modified FUT (mFUT) and Modified CIMT (mCIMT) on the gait and balance during four weeks of treatment and 3 months follow-up. METHODS: This study included thirty-seven hemiparetic post-stroke subjects that were randomly allocated into two groups based on the treatment protocol. The non-paretic UL was immobilized for a period of 23 hours per day, five days a week. Participants were evaluated at Baseline, 1st, 2nd, 3rd and 4th weeks, and three months after randomization. For the evaluation we used: The Stroke Impact Scale (SIS), Berg Balance Scale (BBS) and Fugl-Meyer Motor Assessment (FM). Gait was analyzed by the 10-meter walk test (T10) and Timed Up & Go test (TUG). RESULTS: Both groups revealed a better health status (SIS), better balance, better use of lower limb (BBS and FM) and greater speed in gait (T10 and TUG), during the weeks of treatment and months of follow-up, compared to the baseline. CONCLUSION: The results show mFUT and mCIMT are effective in the rehabilitation of balance and gait.

CONTEXTUALIZAÇÃO: Pacientes hemiparéticos crônicos, após acidente vascular encefálico (AVE), apresentam incapacidade para executar movimentos no hemicorpo parético. Essa incapacidade é reforçada positivamente por tentativas fracassadas de movimento, conceito chamado desuso aprendido. A terapia de uso forçado (FUT) e a terapia de constrição com indução do movimento (CIMT) foram desenvolvidas objetivando a reversão do desuso aprendido do membro superior parético. Não se encontrou na literatura quais seriam os possíveis efeitos dessas técnicas na reabilitação da marcha e do equilíbrio. OBJETIVOS: Avaliar o efeito da FUT e da CIMT modificadas (mFUT e mCIMT) na marcha e no equilíbrio durante quatro semanas de tratamento e três meses de seguimento. MÉTODOS: Este estudo incluiu 37 sujeitos hemiparéticos pós-AVE, divididos em dois grupos com base no protocolo de tratamento. A imobilização do membro superior não-parético foi feita por 23 horas ao dia, cinco dias por semana. Os sujeitos foram avaliados no início, durante quatro semanas de tratamento e três meses de acompanhamento. Para a avaliação, utilizou-se a Escala de Impacto do AVE (SIS), Berg Balance Scale (BBS) e Fugl-Meyer Motor Assesment (FM). Para a marcha, utilizou-se o teste de caminhada de 10 metros (T10) e Timed Up & Go test (TUG). RESULTADOS: Ambos os grupos revelaram um melhor estado de saúde (SIS), melhor equilíbrio, com melhor utilização dos membros inferiores (BBS e FM) e maior velocidade na marcha (T10 e TUG) durante tratamento e seguimento em comparação com o início. CONCLUSÃO: Os resultados mostram que a mFUT e a mCIMT são eficazes para a reabilitação do equilíbrio e da marcha.

Modified constraint-induced movement therapy and modified forced-use therapy for stroke patients are both effective to promote balance and gait improvements.

BACKGROUND: Previous studies show that chronic hemiparetic patients after stroke, presents inabilities to perform movements in paretic hemibody. This inability is induced by positive reinforcement of unsuccessful attempts, a concept called learned non-use. Forced use therapy (FUT) and constraint induced movement therapy (CIMT) were developed with the goal of reversing the learned non-use. These approaches have been proposed for the rehabilitation of the paretic upper limb (PUL). It is unknown what would be the possible effects of these approaches in the rehabilitation of gait and balance. OBJECTIVES: To evaluate the effect of Modified FUT (mFUT) and Modified CIMT (mCIMT) on the gait and balance during four weeks of treatment and 3 months follow-up. METHODS: This study included thirty-seven hemiparetic post-stroke subjects that were randomly allocated into two groups based on the treatment protocol. The non-paretic UL was immobilized for a period of 23 hours per day, five days a week. Participants were evaluated at Baseline, 1st, 2nd, 3rd and 4th weeks, and three months after randomization. For the evaluation we used: The Stroke Impact Scale (SIS), Berg Balance Scale (BBS) and Fugl-Meyer Motor Assessment (FM). Gait was analyzed by the 10-meter walk test (T10) and Timed Up & Go test (TUG). RESULTS: Both groups revealed a better health status (SIS), better balance, better use of lower limb (BBS and FM) and greater speed in gait (T10 and TUG), during the weeks of treatment and months of follow-up, compared to the baseline. CONCLUSION: The results show mFUT and mCIMT are effective in the rehabilitation of balance and gait.