关键词： clinical research   practice   donors and donation   donation after circulatory death (DCD)   donors and donation   donor evaluation   donors and donation   living   ethics   ethics and public policy   kidney transplantation   nephrology   law   legislation   organ procurement and allocation   Organ Procurement and Transplantation Network (OPTN)  

摘要： Live and deceased kidney donation by the numerous patients with advanced, progressive systemic neurological diseases, and other chronic neurological conditions (eg, high C-spine injury) remains largely unexplored. In a review of our current clinical practice, we identified multiple regulatory and clinical barriers. For live donation, mandatory reporting of postdonation donor deaths within 2 years constitutes a strong programmatic disincentive. We propose that the United Network for Organ Sharing should provide explicit regulatory guidance and reassurance for programs wishing to offer live donation to patients at higher risk of death during the reporting period. Under the proposal, live donor deaths within 30 days would still be regarded as donation-related, but later deaths would be related to the underlying disease. For deceased donation, donation after circulatory death (DCD) immediately following self-directed withdrawal of life-sustaining treatment ("conscious DCD") is not universally covered by existing DCD agreements with donor hospitals. Organ procurement organizations should thus systematically strive to revise these agreements. Obtaining adequate first-person consent from these communicatively severely impaired patients may be challenging. Optimized preservation and allocation protocols may maximize utilization of these DCD kidneys. Robust public debate and action by all stakeholders is necessary to lower existing barriers and maximize donation opportunities for patients with chronic neurological conditions.

关键词： Vici syndrome   EPG5   autophagy   neurodevelopment   neurodegeneration   gene expression  

摘要： Congenital disorders of autophagy are multisystem disorders with significant neurological involvement. Ectopic p-granules protein 5 ( EPG5 )-associated Vici syndrome is a prototypical congenital disorder of autophagy and presents with the cardinal features of agenesis of the corpus callosum, cataracts, cardiomyopathy, immunodeficiency, and oculocutaneous hypopigmentation. The majority of EPG5 variants leading to Vici syndrome are null alleles with only a few missense variants published to date. Here we report a 3.5-year-old male with compound heterozygous EPG5 variants [NM_020964.2: c.772G > T/c.5943-9_5943-5del]. His clinical presentation deviates notably from classic Vici syndrome with a lack of hypopigmentation, cataracts, immunodeficiency, cardiomyopathy, or failure to thrive. Neurological manifestations within the known disease spectrum include early-onset global developmental delay, hypotonia, and postnatal microcephaly. Seizures, hearing loss, or optic nerve atrophy are absent, however. Magnetic resonance imaging demonstrates a thin but fully formed corpus callosum. Based on the ameliorated and primarily neurological phenotype, we hypothesized that the functional impact of the EPG5 variants present would be milder with a higher amount of residual EPG 5 expression. Analyses of EPG5 messenger ribonucleic acid (mRNA) in the patient and his parents were performed to examine expression level and splicing;mRNA from a healthy control and a patient with classic Vici syndrome was also included. Aberrant splicing due to the intronic mutation was detected, but no loss of expression. In contrast, we observed a 50% reduction in mRNA expression in classic Vici syndrome patient fibroblasts. These results support a model of disease severity, which correlates to the dosage of EPG5 expression.

关键词： Glucose-6-phosphate isomerase (GPI) deficiency   Neurological dysfunction   Hereditary non-spherocytic hemolytic anemia (HNSHA)   Glycolysis   Molecular modeling   India  

摘要： ObjectivesGlucose-6-phosphate isomerase (GPI) deficiency is an autosomal recessive genetic disorder causing hereditary non-spherocytic hemolytic anemia (HNSHA) coupled with a neurological disorder. The aim of this study was to identify GPI genetic defects in a cohort of Indian patients with HNSHA coupled with neurological ***-five patients were screened for GPI deficiency in the HNSHA patient group;some were having neurological dysfunction. Enzyme activity was measured by spectrophotometric method. The genetic study was done by single-stranded conformation polymorphism (SSCP) analysis, restriction fragment length polymorphism (RFLP) analysis by the restriction enzyme AciI for ***347His (p.R347H) and confirmation by Sanger's *** of 35 patients, 15 showed 35% to 70% loss of GPI activity, leading to neurological problems with HNSHA. Genetic analysis of PCR products of exon 12 of the GPI gene showed altered mobility on SSCP gel. Sanger's sequencing revealed a homozygous c1040G>A mutation predicting a ***347His replacement which abolishes AciI restriction site. The molecular modeling analysis suggests ***347 is involved in dimerization of the enzyme. Also, this mutation generates a more labile enzyme which alters its three-dimensional structure and *** report describes the high prevalence of ***347His pathogenic variant identified in Indian GPI deficient patients with hemolytic anemia and neuromuscular impairment. It suggests that neuromuscular impairment with hemolytic anemia cases could be investigated for ***347His pathogenic variant causing GPI deficiency because of neuroleukin activity present in the GPI monomer which has neuroleukin action at the same active site and generates neuromuscular problems as well as hemolytic anemia.

关键词： aneurysmal subarachnoid hemorrhage   stem cell   neuroinflammation   conditioned medium  

摘要： Aneurysmal subarachnoid hemorrhage (aSAH), characterized by the extravasation of blood into the subarachnoid space caused by an intracranial aneurysm rupture, may lead to neurocognitive impairments and permanent disability and usually carries poor outcome. Dental or gingiva-derived stem cells have been shown to contribute to immune modulation and neuroregeneration, but the underlying mechanisms are unclear. In the present study, we sought to investigate whether dental pulp stem cells (DPSCs) secrete certain factor(s) that can ameliorate the neural damage and other manifestations in a rat aSAH model. Twenty-four hours after the induction of aSAH, microthrombosis, cortical vasoconstriction, and the decrease in microcirculation and tissue oxygen pressure were detected. Intrathecal administration of DPSC-derived conditioned media (DPSC-CM) ameliorated aSAH-induced vasoconstriction, neuroinflammation, and improved the oxygenation in the injured brain. Rotarod test revealed that the aSAH-induced cognitive and motor impairments were significantly improved by this DPSC-CM administration. Cytokine array indicated the major constituent of DPSC-CM was predominantly insulin growth factor-1 (IGF-1). Immunohistochemistry staining of injured brain tissue revealed the robust increase in Iba1-positive cells that were also ameliorated by DPSC-CM administration. Antibody-mediated neutralization of IGF-1 moderately deteriorated the rescuing effect of DPSC-CM on microcirculation, Iba1-positive cells in the injured brain area, and the cognitive/motor impairments. Taken together, the DPSC-derived secretory factors showed prominent therapeutic potential for aSAH. This therapeutic efficacy may include improvement of microcirculation, alleviation of neuroinflammation, and microglial activation;partially through IGF-1-dependent mechanisms.

关键词： Brain tumour   meningioma   glioma   radiation therapy   intracranial   radiotherapy   pituitary  

摘要： Objectives The aim of this study was to evaluate the outcome of cats with intracranial tumours presenting with neurological signs treated with radiation therapy. Methods This study comprised a retrospective multicentre case series. Medical records of a total of 22 cats with intracranial space-occupying lesions, presenting with neurological signs and/or epileptic seizures and treated with external beam radiation therapy, were reviewed. In the treated cats, patient-, tumour- and treatment-related variables were investigated, including age, sex, tumour location, tumour volume, total radiation dose, equivalent dose in 2 Gy fractions (EQD(2)), corticosteroid dose, overall treatment time and institution for influence on local tumour control and survival. Results Based on advanced imaging characteristics, the 22 treated cats presented with meningioma (n = 11), pituitary tumour (n = 8), choroid plexus tumour (n = 2) or glioma (n = 1). Allocated to the neuraxis, 11 lesions were extra-axial, three were intra-axial and eight were located in the pituitary region. At diagnosis, 21 cats exhibited altered neurological status. One cat presented with epileptic seizures and another cat had both seizures and altered neurological status. The mean total physical dose of radiation was 41.63 Gy (+/- 4.33), range 24-45 Gy. In all but one cat (95.5%), neurological signs improved after radiation therapy. The median progression-free survival was 510 days (95% confidence interval [CI]: 51-969). The proportion free of progression at 1 year was 55.7% (95% CI: 33-78). Fourteen cats died (only in five cases was death related to the intracranial tumour) and eight cats were still alive or lost to follow-up. The median overall survival time was 515 days (95% CI: 66-964). None of the tested variables influenced outcome. Conclusions and relevance Radiation therapy seems to represent a viable treatment option in cats with intracranial tumours, relieving neurological signs and improving local tumour cont

关键词： amyotrophic lateral sclerosis   brain neoplasms   end of life   motor neuron disease   neurological disease   palliative care  

摘要： Objectives The aim of this study was to investigate symptom prevalence, symptom relief, and palliative care indicators during the last week of life, comparing them for patients with motor neuron disease (MND), central nervous system tumors (CNS tumor), and other neurological diseases (OND). Material & Methods Data were obtained from the Swedish Register for Palliative Care, which documents care during the last week of life. Logistic regression was used to compare patients with MND (n = 419), CNS tumor (n = 799), and OND (n = 1,407) as the cause of death. Results The most prevalent symptoms for all neurological disease groups were pain (52.7% to 72.2%) and rattles (58.1% to 65.6%). Compared to MND and OND, patients with CNS tumors were more likely to have totally relieved pain, shortness of breath, rattles, and anxiety. They were also more likely to have their pain assessed with a validated tool;to receive symptom treatment for anxiety, nausea, rattles, and pain;to have had family members receive end-of-life discussions;to have someone present at death;and to have had their family members offered bereavement support. Both patients with CNS tumor and MND were more likely than patients with OND to receive consultation with a pain unit and to have had end-of-life discussions. Conclusions The study reveals high symptom burden and differences in palliative care between the groups during the last week of life. There is a need for person-centered care planning based on a palliative approach, focused on improving symptom assessments, relief, and end-of-life conversations.

关键词： Neurological disorders   Genetic testing   Next-generation sequencing   Multi-gene panel  

摘要： Background Neurological disorders are clinically heterogeneous group of disorders and are major causes of disability and death. Several of these disorders are caused due to genetic aberration. A precise and confirmatory diagnosis in the patients in a timely manner is essential for appropriate therapeutic and management strategies. Due to the complexity of the clinical presentations across various neurological disorders, arriving at an accurate diagnosis remains a challenge. Methods We sequenced 1012 unrelated patients from India with suspected neurological disorders, using TruSight One panel. Genetic variations were identified using the Strand NGS software and interpreted using the StrandOmics platform. Results We were able to detect mutations in 197 genes in 405 (40%) cases and 178 mutations were novel. The highest diagnostic rate was observed among patients with muscular dystrophy (64%) followed by leukodystrophy and ataxia (43%, each). In our cohort, 26% of the patients who received definitive diagnosis were primarily referred with complex neurological phenotypes with no suggestive diagnosis. In terms of mutations types, 62.8% were truncating and in addition, 13.4% were structural variants, which are also likely to cause loss of function. Conclusion In our study, we observed an improved performance of multi-gene panel testing, with an overall diagnostic yield of 40%. Furthermore, we show that NGS (next-generation sequencing)-based testing is comprehensive and can detect all types of variants including structural variants. It can be considered as a single-platform genetic test for neurological disorders that can provide a swift and definitive diagnosis in a cost-effective manner.

摘要： The article presents a case report of a girl, age of 10 months for arrested development, passive behavior and peripheral and truncal hypotonia. It discusses the vegan diet included in differential diagnostics of neurologically abnormal infants with failure to thrive. It mentions the advice to avoiding a vegan diet in pregnant and lactating women.

关键词： Anti-Mycobacterial Agents   Neurotoxicity Syndromes   antimicrobial   Misdiagnosis   Anti-Retroviral Agents   Reversibility   Side Effect   management recommendations   Cognition   Anti Infective Agents   Antibiotic  

摘要： Antimicrobials are a widely used class of medications, but several of them are associated with neurological and psychiatric side effects. The exact incidence of neurotoxicity with anti-infectives is unknown, although it is estimated to be<1%. Neurotoxicity occurs with all classes of antimicrobials, such as antibiotics, antimycobacterials, antivirals, antifungals and antiretrovirals, with side effects ranging from headaches, anxiety and depression to confusion, delirium, psychosis, mania and seizures, among others. It is important to consider these possible side effects to prevent misdiagnosis or delayed treatment as drug withdrawal can be associated with reversibility in most cases. This article highlights the different neurotoxic effects of a range of antimicrobials, discusses proposed mechanisms of onset and offers general management recommendations. The effects of antibiotics on the gut microbiome and how they may ultimately affect cognition is also briefly examined.