Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.Peer reviewe

Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis

Importance: Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation.Objective: To identify the genetic variants associated with juvenile ALS.Design, Setting, and Participants: In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism.Main Outcomes and Measures: De novo variants present only in the index case and not in unaffected family members.Results: Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway.Conclusions and Relevance: These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.</p

Role of Angiotensin II type 1 receptor on renal NAD(P)H oxidase, oxidative stress and inflammation in nitric oxide inhibition induced-hypertension

Life Sciences12481-9

Newly regenerated axons via scaffolds promote sub-lesional reorganization and motor recovery with epidural electrical stimulation

Here, we report the effect of newly regenerated axons via scaffolds on reorganization of spinal circuitry and restoration of motor functions with epidural electrical stimulation (EES). Motor recovery was evaluated for 7 weeks after spinal transection and following implantation with scaffolds seeded with neurotrophin producing Schwann cell and with rapamycin microspheres. Combined treatment with scaffolds and EES-enabled stepping led to functional improvement compared to groups with scaffold or EES, although, the number of axons across scaffolds was not different between groups. Re-transection through the scaffold at week 6 reduced EES-enabled stepping, still demonstrating better performance compared to the other groups. Greater synaptic reorganization in the presence of regenerated axons was found in group with combined therapy. These findings suggest that newly regenerated axons through cell-containing scaffolds with EES-enabled motor training reorganize the sub-lesional circuitry improving motor recovery, demonstrating that neuroregenerative and neuromodulatory therapies cumulatively enhancing motor function after complete SCI

Testing and validation of DRIS for apple tree Calibração e validação do DRIS para macieira

To evaluate three procedures of the calculation of DRIS indices, as well as the efficiency of DRIS as a method for the interpretation of apple tree leaf analyses. This study uses data collected in apple producing areas of the Rio Grande do Sul and Santa Catarina States, Brazil. The concentrations of nitrogen, phosphorus, potassium, calcium, magnesium, boron, copper, iron, manganese, and zinc were determined in the leaf samples. The validation of the DRIS method used results of an experiment of potassium fertilization. The DRIS indices were calculated using two criteria for the choice of the ratio order of nutrients (F value ratio of variance of the relationships among nutrients between the reference group and the low productivity group, and R value - correlation coefficients between the productivity and the relationship between pairs of nutrients) and three forms of calculation of nutrient functions (methods of Beaufils, Jones and Elwali & Gascho). The Nutritional Balance Index (NBI) presented negative correlation with the productivity in all combinations. The DRIS method described by Elwali & Gascho, using the F value, presented a performance similar to the criterion of sufficiency range, and it can be used for the interpretation of foliar analysis of apple trees, because it presents values of the nutritional balance index that indicates the nutritional status of the plants, and for the efficiency in the nutritional diagnosis of the crop.<br>Este trabalho teve por objetivo avaliar três procedimentos de cálculo dos índices DRIS, bem como avaliar a eficiência do DRIS como método de interpretação de resultados de análises de folhas de plantas de macieira. O estudo foi realizado nas regiões produtoras de maçã do Rio Grande do Sul e de Santa Catarina. Foram determinadas as concentrações de nitrogênio, fósforo, potássio, cálcio, magnésio, boro, cobre, ferro, manganês e zinco nas amostras de folhas. A validação do método DRIS utilizou resultados de um experimento de adubação potássica. Os índices DRIS foram calculados utilizando-se dois critérios para a escolha da ordem da razão dos nutrientes (valor "F" - razão de variância das relações entre nutrientes entre o grupo de referência e de baixa produtividade e valor "R" - coeficientes de correlação entre os valores de produtividade e a relação entre os pares de nutrientes) e três formas de cálculo das funções dos nutrientes (métodos de Beaufils, Jones e Elwali & Gascho). O Índice de Balanço Nutricional (IBN) apresentou correlação negativa e significativa com a produtividade em todas as combinações de métodos testados. O método DRIS descrito por Elwali & Gascho, utilizando o "valor F", apresentou desempenho semelhante ao critério de faixa de suficiência e pode ser utilizado para a interpretação da análise foliar em macieira, por apresentar valores de IBN que indicam o estado nutricional das plantas e pela eficiência no diagnóstico nutricional da cultura

Is there evidence to support the use of lateral positioning in intensive care? A systematic review

A systematic review of randomised clinical trials was conducted to investigate the efficacy and safety of use of the lateral position in the management of ventilated intensive care patients. One review article and I I empiric studies, which were mostly of low methodological quality, met the eligibility criteria. Large individual variations in PaO2 response to lateral positioning were demonstrated. Greatest improvement in PaO2 occur-red in patients with unilateral pulmonary infiltrates positioned with the bad lung tip versus bad lung down (average difference =33.6 mmHg (range 0-58), effect size 1.13 (95% Cl: 0.44, 1.19, P=0.001)) or supine (average difference=27 mmHg (range 5-42), effect size 0.58 (95% Cl: 0.11, 1.06, P=0.017)). This effect appeared to be most prominent in patients with widespread, unilateral infiltrates. Lung compliance was not affected by lateral positioning. Haemodynamic compromise was evident with lateral positioning of greater than 60 degrees to the right side in patients requiting vasopressors and/or with right ventricular dysfunction; or with lateral positioning in postoperative coronary artery bypass graft patients. No studies were found that had investigated the effect of routine applications of the lateral positioning to improve, prevent or treat pneumonia, decrease mortality or influence other long-term outcomes. The results of this review demonstrate the limited evidence available to support the use of lateral positioning in the intensive care environment. More data reporting the long-term effects of lateral position on long-term outcomes would aid clinical decision making and may improve the application of patient positioning in critical care environments