关键词： sialorrhoea   drooling   salivary glands   swallowing   botulinum toxin   eccrine glands   onabotulinumtoxin A   incobotulinumtoxin A  

摘要： Background: Sialorrhoea and drooling are disabling manifestations of different neurological disorders. The aim of this study was to evaluate the effects of botulinum neurotoxin type A (BoNT/A) injection on hypersalivation in 90 patients with neurological diseases of different aetiologies, and to define the minimum number of injected salivary glands to reduce sialorrhoea. Determining the minimum number of glands that need to be engaged in order to have a significant reduction in drooling may be very useful for establishing the minimum total dosage of BoNT/A that may be considered effective in the treatment of hypersalivation. Methods: Twenty-five mouse units (MU) of BoNT/A (onabotulinumtoxin A, Botox;Allergan, Irvine, CA, USA;100 MU/2 mL, 0.9% saline;or incobotulinumtoxin A, Xeomin;Merz Pharma, Germany;100 MU/2 mL, 0.9% saline) were percutaneously injected into the parotid (p) glands and/or submandibular (s) glands under ultrasound control. On this basis, patients were divided into three groups. In group A (30 patients), BoNT/A injections were performed into four glands;in group B (30 patients), into three glands, and in group C (30 patients), into two glands. Patients treated in three glands (group B) were divided into two subgroups based on the treated glands (2 p + 1 s = 15 patients;2 s + 1 p = 15 patients). Similarly, patients being injected in two glands (group C) were subdivided into three groups (2 p = 10 patients;1 p + 1 s = 10 patients;2 s = 10 patients). In patients who were injected in three and two salivary glands, saline solution was injected into the remaining one and two glands, respectively. Assessments were performed at baseline and at 2 weeks after the injections. Results: BoNT/A significantly reduced sialorrhoea in 82 out of 90 patients. The effect was more evident in patients who had four glands injected than when three or two glands were injected. The injections into three glands were more effective than injections into two glands. Conclusions: O

关键词： DNA methylation   Isogenic stem cells   iPS cell-derived neurons  

摘要： Background: Genetic predisposition and epigenetic alterations are both considered to contribute to sporadic neurodegenerative diseases (NDDs) such as Parkinson's disease (PD). Since cell reprogramming and the generation of induced pluripotent stem cells (iPSCs) are themselves associated with major epigenetic remodeling, it remains unclear to what extent iPSC-derived neurons lend themselves to model epigenetic disease-associated changes. A key question to be addressed in this context is whether iPSC-derived neurons exhibit epigenetic signatures typically observed in neurons derived from non-reprogrammed human embryonic stem cells (hESCs). Results: Here, we compare mature neurons derived from hESC and isogenic human iPSC generated from hESC-derived neural stem cells. Genome-wide 450 K-based DNA methylation and HT12v4 gene array expression analyses were complemented by a deep analysis of selected genes known to be involved in NDD. Our studies show that DNA methylation and gene expression patterns of isogenic hESC- and iPSC-derived neurons are markedly preserved on a genome-wide and single gene level. Conclusions: Overall, iPSC-derived neurons exhibit similar DNA methylation patterns compared to isogenic hESC-derived neurons. Further studies will be required to explore whether the epigenetic patterns observed in iPSC-derived neurons correspond to those detectable in native brain neurons.

关键词： Endurance Training   Differentially Methylated Regions (DMRs)   Reduced Representation Bisulfite Sequencing (RRBS)   sRNA Expression   Sperm Epigenome  

摘要： Remodeling of the sperm epigenome by lifestyle factors before conception could account for altered metabolism in the next generation offspring. Here, we hypothesized that endurance training changes the epigenome of human spermatozoa. Using small RNA (sRNA) sequencing and reduced representation bisulfite sequencing (RRBS), we, respectively, investigated sRNA expression and DNA methylation in pure fractions of motile spermatozoa collected from young healthy individuals before, after 6 weeks of endurance training and after 3 months without exercise. Expression of 8 PIWI interacting RNA were changed by exercise training. RRBS analysis revealed 330 differentially methylated regions (DMRs) after training and 303 DMRs after the detraining period, which were, in both conditions, enriched at close vicinity of transcription start sites. Ontology analysis of genes located at proximity of DMRs returned terms related to neurological function at the trained state and, to a much lesser extent, at the detrained state. Our study reveal that short-term endurance training induces marked remodeling of the sperm epigenome, and identify genes related to the development of the central nervous system as potential hot spots for epigenetic variation upon environmental stress.

摘要： This study investigated for the first time brain ischemic involvement in 19 consecutive neurologically asymptomatic PNH patients by non-enhanced cerebral MRI, and by intracranial arterial and venous angio-MRI. Eleven cases (58%, 7 aged <65) showed pathological findings: 9 white matter (WM) abnormalities related to chronic ischemic small vessel disease, 2 a focal abnormality >5 mm, and 5 cases a score >4 by the age-related white matter changes (ARWMC) scale. Compared with age and sex-matched controls (1:2 ratio), patients showed an increased frequency of periventricular WM vascular degeneration (32% versus 5.2%, p = 0.04) and of severe lesions (ARWMC scale score >= 4) (26% versus 2.6%, p = 0.05), and a higher overall ARWMC scale score (3.5 +/- 1.07 versus 2.0 +/- 0.8, mean +/- SD, p < 0.0001). Notably, vascular abnormalities suspected for prior partial venous thrombosis, were observed in PNH cases only. MRI lesions were not related to blood counts, hemolytic markers, clone size, disease duration, and therapy with eculizumab. Neurological examination was unremarkable in all patients but one (Parkinson disease). Psychiatric assessment revealed a case of generalized anxiety disorder, 1 bipolar disorder type 2, and 1 adjustment disorder. In conclusion, brain MRI may be useful at diagnosis and during the course of the disease to explore subclinical neurological involvement.

关键词： Biochemistry   Biology and life sciences   Cell biology   Cell signaling   Chemistry   Computer and information sciences   Drug metabolism   Eukaryota   G-protein signaling   Gene expression   Gene regulation   Genetics   Herbs   Medicine and health sciences   Network analysis   Organisms   Pathology and laboratory medicine   Pharmacokinetics   Pharmacology   Physical sciences   Phytochemicals   Phytochemistry   Plant biochemistry   Plant science   Plants   Protein interaction networks   Protein interactions   Proteins   Proteomics   Research Article   Signal transduction   Toxicity   Toxicology  

摘要： Piper longum (P. longum, also called as long pepper) is one of the common culinary herbs that has been extensively used as a crucial constituent in various indigenous medicines, specifically in traditional Indian medicinal system known as Ayurveda. For exploring the comprehensive effect of its constituents in humans at proteomic and metabolic levels, we have reviewed all of its known phytochemicals and enquired about their regulatory potential against various protein targets by developing high-confidence tripartite networks consisting of phytochemical-protein target-disease association. We have also (i) studied immunomodulatory potency of this herb;(ii) developed subnetwork of human PPI regulated by its phytochemicals and could successfully associate its specific modules playing important role in diseases, and (iii) reported several novel drug targets. P10636 (microtubule-associated protein tau, that is involved in diseases like dementia etc.) was found to be the commonly screened target by about seventy percent of these phytochemicals. We report 20 drug-like phytochemicals in this herb, out of which 7 are found to be the potential regulators of 5 FDA approved drug targets. Multi-targeting capacity of 3 phytochemicals involved in neuroactive ligand receptor interaction pathway was further explored via molecular docking experiments. To investigate the molecular mechanism of P. longum's action against neurological disorders, we have developed a computational framework that can be easily extended to explore its healing potential against other diseases and can also be applied to scrutinize other indigenous herbs for drug-design studies.

关键词： Amyotrophic lateral sclerosis   Atlastin 1   Dendritic spine formation   Endoplasmic reticulum   Frontotemporal dementia   Hereditary spastic paraplegia   Protein synthesis efficiency   Valosin-containing protein  

摘要： The endoplasmic reticulum (ER) is the biggest organelle in cells and is involved in versatile cellular processes. Formation and maintenance of ER morphology are regulated by a series of proteins controlling membrane fusion and curvature. At least six different ER morphology regulators have been demonstrated to be involved in neurological disorders-including Valosin-containing protein (VCP), Atlastin-1 (ATL1), Spastin (SPAST), Reticulon 2 (RTN2), Receptor expression enhancing protein 1 (REEP1) and RAB10-suggesting a critical role of ER formation in neuronal activity and function. Among these genes, mutations in VCP gene involve in inclusion body myopathy with Paget disease of bone and frontotemporal dementia (IBMPFD), familial amyotrophic lateral sclerosis (ALS), autism spectrum disorders (ASD), and hereditary spastic paraplegia (HSP). ATL1 is also one of causative genes of HSP. RAB10 is associated with Parkinson's disease (PD). A recent study showed that VCP and ATL1 work together to regulate dendritic spine formation by controlling ER formation and consequent protein synthesis efficiency. RAB10 shares the same function with VCP and ATL1 to control ER formation and protein synthesis efficiency but acts independently. Increased protein synthesis by adding extra leucine to cultured neurons ameliorated dendritic spine deficits caused by VCP and ATL1 deficiencies, strengthening the significance of protein synthesis in VCP- and ATL1-regulated dendritic spine formation. These findings provide new insight into the roles of ER and protein synthesis in controlling dendritic spine formation and suggest a potential etiology of neurodegenerative disorders caused by mutations in VCP, ATL1 and other genes encoding proteins regulating ER formation and morphogenesis.

关键词： Adverse events   Animal cells   Antibody-producing cells   Arthritis   Autoimmune diseases   Biology and life sciences   Blood cells   Cancer treatment   Cell biology   Cellular types   Clinical immunology   Clinical medicine   Clinical research design   Demyelinating disorders   Immune cells   Immunology   Infectious diseases   Medicine and health sciences   Multiple sclerosis   Neurodegenerative diseases   Neurology   Oncology   Opportunistic infections   Pulmonology   Research and analysis methods   Research Article   Research design   Respiratory infections   Rheumatoid arthritis   Rheumatology   Upper respiratory tract infections   Urinary tract infections   Urology   White blood cells  

摘要： Background B-cells play a pivotal role in several autoimmune diseases, including patients with immune-mediated neurological disorders (PIMND), such as neuromyelitis optica (NMO), multiple sclerosis (MS), and myasthenia gravis (MG). Targeting B-cells has been an effective approach in ameliorating both central and peripheral autoimmune diseases. However, there is a paucity of literature on the safety of continuous B-cell depletion over a long period of time. Objective The aim of this study was to examine the long-term safety, incidence of infections, and malignancies in subjects receiving continuous therapy with a B-cell depleting agent rituximab over at least 3 years or longer. Methods This was a retrospective study involving PIMND who received continuous cycles of rituximab infusions every 6 to 9 months for up to 7 years. The incidence of infection related adverse events (AE), serious adverse events (SAE), and malignancies were observed. Results There were a total of 32 AE and 4 SAE with rituximab treatment. The 3 SAE were noted after 9 cycles (48 months) and 1 SAE was observed after 11 cycles (60 months) of rituximab. There were no cases of Progressive multifocal leukoencephalopathy (PML) and malignancies observed throughout the treatment period. Rituximab was well tolerated without any serious infusion reactions. Also, rituximab was found to be beneficial in treating PIMND over a 7-year period. Conclusions This study demonstrates that long-term depletion of peripheral B-cells appears safe and efficacious in treating PIMND. Longer and larger prospective studies with rituximab are needed to carefully ascertain risks associated with chronic B-cell depletion, including malignancies. Recognizing that this is a small, retrospective study, such data nonetheless complement the growing literature documenting the safety and tolerability of B-cell depleting agents in neurological diseases.

关键词： Alzheimer's disease   Anatomy   Animal models   Biochemistry   Bioinformatics   Biology and life sciences   Biomarkers   Biotechnology   Blood   Blood serum   Body fluids   Computational biology   Database and informatics methods   Dementia   DNA sequencing   Experimental organism systems   Genetics   Genome analysis   Genomics   Medicine and health sciences   Mental health and psychiatry   Model organisms   Molecular biology   Molecular biology techniques   Mouse models   Neurodegenerative diseases   Neurology   Next-generation sequencing   Physiology   Research and analysis methods   Research Article   Sequence analysis   Sequencing techniques   Transcriptome analysis  

摘要： The act of selecting aptamers against blood serum leads to deep libraries of oligonucleotide sequences that bind to a range of epitopes in blood. In this study we developed an enriched aptamer library by performing positive selection against a pool of blood serum samples from transgenic mice (P301S) carrying the human tau gene and counter selecting against pooled blood serum from negative segregant (wild type) mice. We demonstrated that a large proportion of the aptamer sequences observed with next generation sequence (NGS) analysis were the same from selection round 5 and selection round 6. As a second step, we applied aliquots of the selection round 5 enriched library to blood serum from 16 individual mice for a single round of selection. Each of these individual libraries were characterized through NGS analysis and the changes in relative frequency in aptamers from transgenic mice versus wild type were used to construct a diagnostic fingerprint of the effect of the action of the transgene on the composition of blood serum. This study serves as a model for similar applications with human subjects.

关键词： Biology and life sciences   Birth   Birth weight   Body weight   Critical care and emergency medicine   Death rates   Developmental biology   Health care   Labor and delivery   Maternal health   Medicine and health sciences   Neonatal care   Neonates   Neonatology   Obstetrics and gynecology   Pediatrics   Physiological parameters   Physiology   Population biology   Population metrics   Pregnancy   Pregnancy complications   Preterm birth   Research Article   Resuscitation   Women's health  

摘要： Background Of the 4 million neonatal deaths worldwide yearly, 98% occur in low and middle-income countries. Effective resuscitation reduces mortality and morbidity but long-term outcomes in resource-limited settings are poorly described. This study reports on newborn neurological outcomes following resuscitation at birth in a resource-limited setting where intensive newborn care including intubation is unavailable. Methods Retrospective analysis of births records from 2008 to 2015 at Shoklo Malaria Research Unit (SMRU) on the Thailand-Myanmar border. Findings From 21,225 newbonrs delivered, 15,073 (71%) met the inclusion criteria (liveborn, singleton, >= 28 weeks' gestation, delivered in SMRU). Neonatal resuscitation was performed in 460 (3%;422 basic, 38 advanced) cases. Overall early neonatal mortality was 6.6 deaths per 1000 live births (95% CI 5.40-8.06). Newborns receiving basic and advanced resuscitation presented an adjusted rate for death of 1.30 (95% CI 0.66-2.55;p = 0.442), and 6.32 (95% CI 3.01-13.26;p<0.001) respectively, compared to newborns given routine care. Main factors related to increased need for resuscitation were breech delivery, meconium, and fetal distress (p<0.001). Neurodevelopmental follow-up to one year was performed in 1,608 (10.5%) of the 15,073 newborns;median neurodevelopmental scores of non-resuscitated newborns and those receiving basic resuscitation were similar (64 (n = 1565) versus 63 (n = 41);p = 0.732), while advanced resuscitation scores were significantly lower (56 (n = 5);p = 0.017). Interpretations Newborns requiring basic resuscitation at birth have normal neuro-developmental outcomes at one year of age compared to low-risk newborns. Identification of risk factors (e.g., breech delivery) associated with increased need for neonatal resuscitation may facilitate allocation of staff to high-risk deliveries. This work endorses the use of basic resuscitation in low-resource settings, and supports on-going staff training to maint

关键词： RHOBTB2   intellectual disability   epileptic Encephalopathy   ubiquitination   proteasom   Drosophila melanogaster  

摘要： Although the role of typical Rho GTPases and other Rho-linked proteins in synaptic plasticity and cognitive function and dysfunction is widely acknowledged, the role of atypical Rho GTPases (such as RHOBTB2) in neurodevelopment has barely been characterized. We have now identified de novo missense variants clustering in the BTB-domain-encoding region of RHOBTB2 in ten individuals with a similar phenotype, including early-onset epilepsy, severe intellectual disability, postnatal microcephaly, and movement disorders. Three of the variants were recurrent. Upon transfection of HEK293 cells, we found that mutant RHOBTB2 was more abundant than the wildtype, most likely because of impaired degradation in the proteasome. Similarly, elevated amounts of the Drosophila ortholog RhoBTB in vivo were associated with seizure susceptibility and severe locomotor defects. Knockdown of RhoBTB in the Drosophila dendritic arborization neurons resulted in a decreased number of dendrites, thus suggesting a role of RhoBTB in dendritic development. We have established missense variants in the BTB-domain-encoding region of RHOBTB2 as causative for a developmental and epileptic encephalopathy and have elucidated the role of atypical Rho GTPase RhoBTB in Drosophila neurological function and possibly dendrite development.