Hibaoui, Youssef; Feki, Anis
The ability to generate human pluripotent stem cells (hPSCs) holds great promise for the understanding and the treatment of human neurological diseases in modern medicine. The hPSCs are considered for their in vitro use as research tools to provide relevant cellular model for human diseases, drug discovery, and toxicity assays and for their in vivo use in regenerative medicine applications. In this review, we highlight recent progress, promises, and challenges of hPSC applications in human neurological disease modeling and therapies. PMID:22934023
Jacobs, Andreas H.; Winkler, Alexandra; Castro, Maria G.; Lowenstein, Pedro
Molecular imaging aims to assess non-invasively disease-specific biological and molecular processes in animal models and humans in vivo. Apart from precise anatomical localisation and quantification, the most intriguing advantage of such imaging is the opportunity it provides to investigate the time course (dynamics) of disease-specific molecular events in the intact organism. Further, molecular imaging can be used to address basic scientific questions, e.g. transcriptional regulation, signal transduction or protein/protein interaction, and will be essential in developing treatment strategies based on gene therapy. Most importantly, molecular imaging is a key technology in translational research, helping to develop experimental protocols which may later be applied to human patients. Over the past 20 years, imaging based on positron emission tomography (PET) and magnetic resonance imaging (MRI) has been employed for the assessment and “phenotyping” of various neurological diseases, including cerebral ischaemia, neurodegeneration and brain gliomas. While in the past neuro-anatomical studies had to be performed post mortem, molecular imaging has ushered in the era of in vivo functional neuro-anatomy by allowing neuroscience to image structure, function, metabolism and molecular processes of the central nervous system in vivo in both health and disease. Recently, PET and MRI have been successfully utilised together in the non-invasive assessment of gene transfer and gene therapy in humans. To assess the efficiency of gene transfer, the same markers are being used in animals and humans, and have been applied for phenotyping human disease. Here, we review the imaging hallmarks of focal and disseminated neurological diseases, such as cerebral ischaemia, neurodegeneration and glioblastoma multiforme, as well as the attempts to translate gene therapy’s experimental knowledge into clinical applications and the way in which this process is being promoted through the use
Yuan, Hongjie; Low, Chian-Ming; Moody, Olivia A.; Jenkins, Andrew
The advent of whole exome/genome sequencing and the technology-driven reduction in the cost of next-generation sequencing as well as the introduction of diagnostic-targeted sequencing chips have resulted in an unprecedented volume of data directly linking patient genomic variability to disorders of the brain. This information has the potential to transform our understanding of neurologic disorders by improving diagnoses, illuminating the molecular heterogeneity underlying diseases, and identifying new targets for therapeutic treatment. There is a strong history of mutations in GABA receptor genes being involved in neurologic diseases, particularly the epilepsies. In addition, a substantial number of variants and mutations have been found in GABA receptor genes in patients with autism, schizophrenia, and addiction, suggesting potential links between the GABA receptors and these conditions. A new and unexpected outcome from sequencing efforts has been the surprising number of mutations found in glutamate receptor subunits, with the GRIN2A gene encoding the GluN2A N-methyl-d-aspartate receptor subunit being most often affected. These mutations are associated with multiple neurologic conditions, for which seizure disorders comprise the largest group. The GluN2A subunit appears to be a locus for epilepsy, which holds important therapeutic implications. Virtually all α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor mutations, most of which occur within GRIA3, are from patients with intellectual disabilities, suggesting a link to this condition. Similarly, the most common phenotype for kainate receptor variants is intellectual disability. Herein, we summarize the current understanding of disease-associated mutations in ionotropic GABA and glutamate receptor families, and discuss implications regarding the identification of human mutations and treatment of neurologic diseases. PMID:25904555
Acosta, Lealani Mae Y
Although humans have long valued creativity, the generation of such innovation is still incompletely understood. Looking at the healthy brain, researchers have localized certain parts for a basic understanding of these mechanisms. By researching the brain affected by neurological disease, scientists have observed unique manifestations of creativity, such as in frontotemporal lobar degeneration, Alzheimer's disease, Parkinson's disease and parkinsonian spectrum disorders, and stroke, which help clarify these creative underpinnings. Incorporating both healthy and disease models of cerebral functioning, neurological and neuroscientific research from recent years has built on established theories and expanded current knowledge.
Rangel, Maria Adriana; Moreira, Diana; Vila Real, Marta; Santos, Fátima
We present a case report of a meningoradiculopathy associated with human herpesvirus 7, with long-term motor neurologic sequelae. It is important to consider human herpesvirus 7 as a potential pathogen of severe neurologic disease and sequelae in immunocompetent children, especially in older patients presenting neurologic signs.
Piber, D; Hinkelmann, K; Gold, S M; Heesen, C; Spitzer, C; Endres, M; Otte, C
In many neurological diseases a depressive syndrome is a characteristic sign of the primary disease or is an important comorbidity. Post-stroke depression, for example, is a common and relevant complication following ischemic brain infarction. Approximately 4 out of every 10 stroke patients develop depressive disorders in the course of the disease which have a disadvantageous effect on the course and the prognosis. On the other hand depression is also a risk factor for certain neurological diseases as was recently demonstrated in a meta-analysis of prospective cohort studies which revealed a much higher stroke risk for depressive patients. Furthermore, depression plays an important role in other neurological diseases with respect to the course and quality of life, such as Parkinson's disease, multiple sclerosis and epilepsy. This article gives a review of the most important epidemiological, pathophysiological and therapeutic aspects of depressive disorders as a comorbidity of neurological diseases and as a risk factor for neurological diseases.
Bale, James F
While the systemic disorders associated with measles, mumps, and rubella viruses and human parvovirus B19 tend to be mild, each virus can produce potentially life-threatening neurologic disease in human hosts, especially when these viruses infect young children. Two of the viruses, rubella and parvovirus B19, can be vertically transmitted to fetuses during maternal infection and cause congenital infection. Neurologic complications are common after intrauterine infection with the rubella virus, a condition known as the congenital rubella syndrome. Two, measles and rubella viruses, can induce "slow viral" infections, serious, disorders that can occur several years after the initial exposure to the virus and typically have fatal outcomes.
Tang, Junwei; Lu, Shuai; Feng, Dongju; Cheng, Ci; Qing, Lanqun; Yao, Kun; Chen, Yun
Human Herpesvirus 6 (HHV-6) has been involved in the development of several central nervous system (CNS) diseases, such as Alzheimer's disease, multiple sclerosis and glioma. In order to identify the pathogenic mechanism of HHV-6A infection, we carried out mRNA-seq study of human astrocyte HA1800 cell with HHV-6A GS infection. Using mRNA-seq analysis of HA1800-control cells with HA1800-HHV-6A GS cells, we identified 249 differentially expressed genes. After investigating these candidate genes, we found seven genes associated with two or more CNS diseases: CTSS, PTX3, CHI3L1, Mx1, CXCL16, BIRC3, and BST2. This is the first transcriptome sequencing study which showed the significant association of these genes between HHV-6A infection and neurologic diseases. We believe that our findings can provide a new perspective to understand the pathogenic mechanism of HHV-6A infection and neurologic diseases. PMID:27344170
Abud, Edsel M; Ramirez, Ricardo N; Martinez, Eric S; Healy, Luke M; Nguyen, Cecilia H H; Newman, Sean A; Yeromin, Andriy V; Scarfone, Vanessa M; Marsh, Samuel E; Fimbres, Cristhian; Caraway, Chad A; Fote, Gianna M; Madany, Abdullah M; Agrawal, Anshu; Kayed, Rakez; Gylys, Karen H; Cahalan, Michael D; Cummings, Brian J; Antel, Jack P; Mortazavi, Ali; Carson, Monica J; Poon, Wayne W; Blurton-Jones, Mathew
Microglia play critical roles in brain development, homeostasis, and neurological disorders. Here, we report that human microglial-like cells (iMGLs) can be differentiated from iPSCs to study their function in neurological diseases, like Alzheimer's disease (AD). We find that iMGLs develop in vitro similarly to microglia in vivo, and whole-transcriptome analysis demonstrates that they are highly similar to cultured adult and fetal human microglia. Functional assessment of iMGLs reveals that they secrete cytokines in response to inflammatory stimuli, migrate and undergo calcium transients, and robustly phagocytose CNS substrates. iMGLs were used to examine the effects of Aβ fibrils and brain-derived tau oligomers on AD-related gene expression and to interrogate mechanisms involved in synaptic pruning. Furthermore, iMGLs transplanted into transgenic mice and human brain organoids resemble microglia in vivo. Together, these findings demonstrate that iMGLs can be used to study microglial function, providing important new insight into human neurological disease. Copyright © 2017 Elsevier Inc. All rights reserved.
Rech, Raquel; Barros, Claudio
This article focuses on the gross examination of the brain and spinal cord and outlines the main lesions and neuroanatomic location related to neurologic diseases in horses. Copyright © 2015 Elsevier Inc. All rights reserved.
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Jensen, Mark; Cox, Alexander P; Chaudhry, Naveed; Ng, Marcus; Sule, Donat; Duncan, William; Ray, Patrick; Weinstock-Guttman, Bianca; Smith, Barry; Ruttenberg, Alan; Szigeti, Kinga; Diehl, Alexander D
We are developing the Neurological Disease Ontology (ND) to provide a framework to enable representation of aspects of neurological diseases that are relevant to their treatment and study. ND is a representational tool that addresses the need for unambiguous annotation, storage, and retrieval of data associated with the treatment and study of neurological diseases. ND is being developed in compliance with the Open Biomedical Ontology Foundry principles and builds upon the paradigm established by the Ontology for General Medical Science (OGMS) for the representation of entities in the domain of disease and medical practice. Initial applications of ND will include the annotation and analysis of large data sets and patient records for Alzheimer's disease, multiple sclerosis, and stroke. ND is implemented in OWL 2 and currently has more than 450 terms that refer to and describe various aspects of neurological diseases. ND directly imports the development version of OGMS, which uses BFO 2. Term development in ND has primarily extended the OGMS terms 'disease', 'diagnosis', 'disease course', and 'disorder'. We have imported and utilize over 700 classes from related ontology efforts including the Foundational Model of Anatomy, Ontology for Biomedical Investigations, and Protein Ontology. ND terms are annotated with ontology metadata such as a label (term name), term editors, textual definition, definition source, curation status, and alternative terms (synonyms). Many terms have logical definitions in addition to these annotations. Current development has focused on the establishment of the upper-level structure of the ND hierarchy, as well as on the representation of Alzheimer's disease, multiple sclerosis, and stroke. The ontology is available as a version-controlled file at http://code.google.com/p/neurological-disease-ontology along with a discussion list and an issue tracker. ND seeks to provide a formal foundation for the representation of clinical and research data
Xie, Nina; Tang, Beisha
In principle, induced pluripotent stem cells (iPSCs) are generated from somatic cells by reprogramming and gaining the capacity to self-renew indefinitely as well as the ability to differentiate into cells of different lineages. Human iPSCs have absolute advantages over human embryonic stem cells (ESCs) and animal models in disease modeling, drug screening, and cell replacement therapy. Since Takahashi and Yamanaka first described in 2007 that iPSCs can be generated from human adult somatic cells by retroviral transduction of the four transcription factors, Oct3/4, Sox2, Klf4, and c-Myc, disease specific iPSC lines have sprung up worldwide like bamboo shoots after a spring rain, making iPSC one of the hottest and fastest moving topics in modern science. The craze for iPSCs has spread throughout main branches of clinical medicine, covering neurology, hematology, cardiology, endocrinology, hepatology, ophthalmology, and so on. Here in this paper, we will focus on the clinical application of human iPSCs in disease modeling, drug screening, and cell replacement therapy for neurological diseases. PMID:26880979
Repunte-Canonigo, Vez; Masliah, Eliezer; Lefebvre, Celine
The pathogenesis and nosology of HIV-associated neurological disease (HAND) remain incompletely understood. Here, to provide new insight into the molecular events leading to neurocognitive impairments (NCI) in HIV infection, we analyzed pathway dysregulations in gene expression profiles of HIV-infected patients with or without NCI and HIV encephalitis (HIVE) and control subjects. The Gene Set Enrichment Analysis (GSEA) algorithm was used for pathway analyses in conjunction with the Molecular Signatures Database collection of canonical pathways (MSigDb). We analyzed pathway dysregulations in gene expression profiles of patients from the National NeuroAIDS Tissue Consortium (NNTC), which consists of samples from 3 different brain regions, including white matter, basal ganglia and frontal cortex of HIV-infected and control patients. While HIVE is characterized by widespread, uncontrolled inflammation and tissue damage, substantial gene expression evidence of induction of interferon (IFN), cytokines and tissue injury is apparent in all brain regions studied, even in the absence of NCI. Various degrees of white matter changes were present in all HIV-infected subjects and were the primary manifestation in patients with NCI in the absence of HIVE. In particular, NCI in patients without HIVE in the NNTC sample is associated with white matter expression of chemokines, cytokines and β-defensins, without significant activation of IFN. Altogether, the results identified distinct pathways differentially regulated over the course of neurological disease in HIV infection and provide a new perspective on the dynamics of pathogenic processes in the course of HIV neurological disease in humans. These results also demonstrate the power of the systems biology analyses and indicate that the establishment of larger human gene expression profile datasets will have the potential to provide novel mechanistic insight into the pathogenesis of neurological disease in HIV infection and
Chronic pain is a frequent component of many neurological disorders, affecting 20–40% of patients for many primary neurological diseases. These diseases result from a wide range of pathophysiologies including traumatic injury to the central nervous system, neurodegeneration and neuroinflammation, and exploring the aetiology of pain in these disorders is an opportunity to achieve new insight into pain processing. Whether pain originates in the central or peripheral nervous system, it frequently becomes centralized through maladaptive responses within the central nervous system that can profoundly alter brain systems and thereby behaviour (e.g. depression). Chronic pain should thus be considered a brain disease in which alterations in neural networks affect multiple aspects of brain function, structure and chemistry. The study and treatment of this disease is greatly complicated by the lack of objective measures for either the symptoms or the underlying mechanisms of chronic pain. In pain associated with neurological disease, it is sometimes difficult to obtain even a subjective evaluation of pain, as is the case for patients in a vegetative state or end-stage Alzheimer's disease. It is critical that neurologists become more involved in chronic pain treatment and research (already significant in the fields of migraine and peripheral neuropathies). To achieve this goal, greater efforts are needed to enhance training for neurologists in pain treatment and promote greater interest in the field. This review describes examples of pain in different neurological diseases including primary neurological pain conditions, discusses the therapeutic potential of brain-targeted therapies and highlights the need for objective measures of pain. PMID:22067541
Beraldi, Rosanna; Chan, Chun-Hung; Rogers, Christopher S.; Kovács, Attila D.; Meyerholz, David K.; Trantzas, Constantin; Lambertz, Allyn M.; Darbro, Benjamin W.; Weber, Krystal L.; White, Katherine A.M.; Rheeden, Richard V.; Kruer, Michael C.; Dacken, Brian A.; Wang, Xiao-Jun; Davis, Bryan T.; Rohret, Judy A.; Struzynski, Jason T.; Rohret, Frank A.; Weimer, Jill M.; Pearce, David A.
Ataxia telangiectasia (AT) is a progressive multisystem disorder caused by mutations in the AT-mutated (ATM) gene. AT is a neurodegenerative disease primarily characterized by cerebellar degeneration in children leading to motor impairment. The disease progresses with other clinical manifestations including oculocutaneous telangiectasia, immune disorders, increased susceptibly to cancer and respiratory infections. Although genetic investigations and physiological models have established the linkage of ATM with AT onset, the mechanisms linking ATM to neurodegeneration remain undetermined, hindering therapeutic development. Several murine models of AT have been successfully generated showing some of the clinical manifestations of the disease, however they do not fully recapitulate the hallmark neurological phenotype, thus highlighting the need for a more suitable animal model. We engineered a novel porcine model of AT to better phenocopy the disease and bridge the gap between human and current animal models. The initial characterization of AT pigs revealed early cerebellar lesions including loss of Purkinje cells (PCs) and altered cytoarchitecture suggesting a developmental etiology for AT and could advocate for early therapies for AT patients. In addition, similar to patients, AT pigs show growth retardation and develop motor deficit phenotypes. By using the porcine system to model human AT, we established the first animal model showing PC loss and motor features of the human disease. The novel AT pig provides new opportunities to unmask functions and roles of ATM in AT disease and in physiological conditions. PMID:26374845
Beraldi, Rosanna; Chan, Chun-Hung; Rogers, Christopher S; Kovács, Attila D; Meyerholz, David K; Trantzas, Constantin; Lambertz, Allyn M; Darbro, Benjamin W; Weber, Krystal L; White, Katherine A M; Rheeden, Richard V; Kruer, Michael C; Dacken, Brian A; Wang, Xiao-Jun; Davis, Bryan T; Rohret, Judy A; Struzynski, Jason T; Rohret, Frank A; Weimer, Jill M; Pearce, David A
Ataxia telangiectasia (AT) is a progressive multisystem disorder caused by mutations in the AT-mutated (ATM) gene. AT is a neurodegenerative disease primarily characterized by cerebellar degeneration in children leading to motor impairment. The disease progresses with other clinical manifestations including oculocutaneous telangiectasia, immune disorders, increased susceptibly to cancer and respiratory infections. Although genetic investigations and physiological models have established the linkage of ATM with AT onset, the mechanisms linking ATM to neurodegeneration remain undetermined, hindering therapeutic development. Several murine models of AT have been successfully generated showing some of the clinical manifestations of the disease, however they do not fully recapitulate the hallmark neurological phenotype, thus highlighting the need for a more suitable animal model. We engineered a novel porcine model of AT to better phenocopy the disease and bridge the gap between human and current animal models. The initial characterization of AT pigs revealed early cerebellar lesions including loss of Purkinje cells (PCs) and altered cytoarchitecture suggesting a developmental etiology for AT and could advocate for early therapies for AT patients. In addition, similar to patients, AT pigs show growth retardation and develop motor deficit phenotypes. By using the porcine system to model human AT, we established the first animal model showing PC loss and motor features of the human disease. The novel AT pig provides new opportunities to unmask functions and roles of ATM in AT disease and in physiological conditions. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: firstname.lastname@example.org.
Ramsdell, John S
Domoic acid of macroalgal origin was used for traditional and medicinal purposes in Japan and largely forgotten until its rediscovery in diatoms that poisoned 107 people after consumption of contaminated mussels. The more severely poisoned victims had seizures and/or amnesia and four died; however, one survivor unexpectedly developed temporal lobe epilepsy (TLE) a year after the event. Nearly a decade later, several thousand sea lions have stranded on California beaches with neurological symptoms. Analysis of the animals stranded over an eight year period indicated five clusters of acute neurological poisoning; however, nearly a quarter have stranded individually outside these events with clinical signs of a chronic neurological syndrome similar to TLE. These poisonings are not limited to sea lions, which serve as readily observed sentinels for other marine animals that strand during domoic acid poisoning events, including several species of dolphin and whales. Acute domoic acid poisoning is five-times more prominent in adult female sea lions as a result of the proximity of their year-round breeding grounds to major domoic acid bloom events. The chronic neurological syndrome, on the other hand, is more prevalent in young animals, with many potentially poisoned in utero. The sea lion rookeries of the Channel Islands are at the crossroads of domoic acid producing harmful algal blooms and a huge industrial discharge site for dichlorodiphenyltrichloroethane (DDTs). Studies in experimental animals suggest that chronic poisoning observed in immature sea lions may result from a spatial and temporal coincidence of DDTs and domoic acid during early life stages. Emergence of an epilepsy syndrome from the ocean brings a human epilepsy model to life and provides unexpected insights into interaction with legacy contaminants and expression of disease at different life stages.
Ramsdell, John S.
Domoic acid of macroalgal origin was used for traditional and medicinal purposes in Japan and largely forgotten until its rediscovery in diatoms that poisoned 107 people after consumption of contaminated mussels. The more severely poisoned victims had seizures and/or amnesia and four died; however, one survivor unexpectedly developed temporal lobe epilepsy (TLE) a year after the event. Nearly a decade later, several thousand sea lions have stranded on California beaches with neurological symptoms. Analysis of the animals stranded over an eight year period indicated five clusters of acute neurological poisoning; however, nearly a quarter have stranded individually outside these events with clinical signs of a chronic neurological syndrome similar to TLE. These poisonings are not limited to sea lions, which serve as readily observed sentinels for other marine animals that strand during domoic acid poisoning events, including several species of dolphin and whales. Acute domoic acid poisoning is five-times more prominent in adult female sea lions as a result of the proximity of their year-round breeding grounds to major domoic acid bloom events. The chronic neurological syndrome, on the other hand, is more prevalent in young animals, with many potentially poisoned in utero. The sea lion rookeries of the Channel Islands are at the crossroads of domoic acid producing harmful algal blooms and a huge industrial discharge site for dichlorodiphenyltrichloroethane (DDTs). Studies in experimental animals suggest that chronic poisoning observed in immature sea lions may result from a spatial and temporal coincidence of DDTs and domoic acid during early life stages. Emergence of an epilepsy syndrome from the ocean brings a human epilepsy model to life and provides unexpected insights into interaction with legacy contaminants and expression of disease at different life stages. PMID:22069654
Barak, Yoram; Achiron, Anat
Happiness is an emotional state reflecting positive feelings and satisfaction with life, which, as an outcome in disease states or as an end point in clinical trials, is a neglected concept in most therapeutic areas. In neurological disease, happiness is important as it can be diminished either as a direct result of damage to neuronal tissue or as a reaction to a poor prognosis. The monitoring and maintenance of happiness and wellbeing have historically been considered to be peripheral to medicine. However, as happiness interacts with the patient's physical health, it is an important parameter to assess alongside all aspects of any given disease. Happiness provides a reliable overview of the patient's general status over and above standard parameters for quality of life, and is more wide-ranging than the narrow measures of disease activity or treatment efficacy that are the focus of most clinical trials. In many studies, happiness has been associated with health and success in most areas of life, including performance at work, sporting achievement and social functioning. For approximately a decade, previously studied aspects of psychology have been grouped under the label of positive psychology (PoP). Principles of this discipline are now being used to guide some treatments in neurological and psychiatric diseases. PoP aims to define patient wellbeing in scientific terms and to increase understanding of happiness, meaning in life, resilience and character strengths, as well as to determine how this knowledge can be applied clinically to promote health. Some evidence has emerged recently suggesting that improvements in patient status can result from interventions to improve the patient's level of happiness in diseases, including epilepsy, Huntington's disease, multiple sclerosis, Parkinson's disease and stroke. Several effective approaches to increase happiness employ activities to engage and stimulate patients who might otherwise be unoccupied and isolated. In
Nedelec, Stéphane; Onteniente, Brigitte; Peschanski, Marc; Martinat, Cécile
The fundamental inaccessibility of the human neural cell types affected by neurological disorders prevents their isolation for in vitro studies of disease mechanisms or for drug screening efforts. Pluripotent stem cells represent a new interesting way to generate models of human neurological disorders, explore the physiopathological mechanisms and develop new therapeutic strategies. Disease-specific human embryonic stem cells were the first source of material to be used to study certain disease states. The recent demonstration that human somatic cells, such as fibroblasts or blood cells, can be genetically converted to induced pluripotent stem cells (hiPSCs) together with the continuous improvement of methods to differentiate these cells into disease-affected neuronal subtypes opens new perspectives to model and understand a large number of human pathologies. This review focuses on the opportunities concerning the use disease-specific human pluripotent stem cells as well as the different challenges that still need to be overcome. We also discuss the recent improvements in the genetic manipulation of human pluripotent stem cells and the consequences of these on disease modeling and drug screening for neurological diseases.
Hafezparast, Majid; Ahmad-Annuar, Azlina; Wood, Nicholas W; Tabrizi, Sarah J; Fisher, Elizabeth M C
The mouse has many advantages over human beings for the study of genetics, including the unique property that genetic manipulation can be routinely carried out in the mouse genome. Most importantly, mice and human beings share the same mammalian genes, have many similar biochemical pathways, and have the same diseases. In the minority of cases where these features do not apply, we can still often gain new insights into mouse and human biology. In addition to existing mouse models, several major programmes have been set up to generate new mouse models of disease. Alongside these efforts are new initiatives for the clinical, behavioural, and physiological testing of mice. Molecular genetics has had a major influence on our understanding of the causes of neurological disorders in human beings, and much of this has come from work in mice.
Pengiran, T; Wills, A; Holmes, G
A variety of neurological disorders have been reported in association with coeliac disease including epilepsy, ataxia, neuropathy, and myelopathy. The nature of this association is unclear and whether a specific neurological complication occurs in coeliac disease remains unproved. Malabsorption may lead to vitamin and trace element deficiencies. Therefore, patients who develop neurological dysfunction should be carefully screened for these. However, malabsorption does not satisfactorily explain the pathophysiology and clinical course of many of the associated neurological disorders. Other mechanisms proposed include altered autoimmunity, heredity, and gluten toxicity. This review attempts to summarise the literature and suggests directions for future research. PMID:12151653
The current status of research into chromosomal abnormalities in neurological diseases is reviewed. The only possible association between chromosome aberration and neurological disorder is found in ataxia telangiectasia and in tumours of the nervous system. In the remaining diseases reviewed, no specific association was confirmed. This was expected to some extent, since the majority of these diseases (spinal muscular atrophies, muscular dystrophies, etc.) are due to single gene defects.
Bahmad, Hisham; Hadadeh, Ola; Chamaa, Farah; Cheaito, Katia; Darwish, Batoul; Makkawi, Ahmad-Kareem; Abou-Kheir, Wassim
With the help of several inducing factors, somatic cells can be reprogrammed to become induced pluripotent stem cell (iPSCs) lines. The success is in obtaining iPSCs almost identical to embryonic stem cells (ESCs), therefore various approaches have been tested and ultimately several ones have succeeded. The importance of these cells is in how they serve as models to unveil the molecular pathways and mechanisms underlying several human diseases, and also in its potential roles in the development of regenerative medicine. They further aid in the development of regenerative medicine, autologous cell therapy and drug or toxicity screening. Here, we provide a comprehensive overview of the recent development in the field of iPSCs research, specifically for modeling human neurological and neurodegenerative diseases, and its applications in neurotrauma. These are mainly characterized by progressive functional or structural neuronal loss rendering them extremely challenging to manage. Many of these diseases, including Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD) have been explored in vitro. The main purpose is to generate patient-specific iPS cell lines from the somatic cells that carry mutations or genetic instabilities for the aim of studying their differentiation potential and behavior. This new technology will pave the way for future development in the field of stem cell research anticipating its use in clinical settings and in regenerative medicine in order to treat various human diseases, including neurological and neurodegenerative diseases. PMID:28293168
Berkowitz, Aaron L; Raibagkar, Pooja; Pritt, Bobbi S; Mateen, Farrah J
The World Health Organization has identified 17 neglected tropical diseases (NTDs) that disproportionately affect the world's poorest populations. The neurologic aspects of many of these NTDs have received relatively little attention. A review was performed in PubMed (MedLine) for each NTD by disease name, name of its causative organism, and neurology, neurosurgery, neurologist, brain, spinal cord, peripheral nerve, muscle, nervous system, encephalitis, meningitis, encephalopathy, stroke, neuropathy, and myopathy (1968-Sept. 2013). The Oxford Center for Evidence-based Medicine guidelines were used to determine the level of evidence of neurological involvement and treatment based on the reports identified. Neurologic manifestations were reported for all NTDs except yaws. Neurologic involvement was described in systematic reviews for four NTDs (Chagas disease, echinococcosis, rabies, cysticercosis) (levels 2a-3a), retrospective cohort studies for six (dengue, human African trypanosomiasis, leishmaniasis, leprosy, onchocerciasis, schistosomiasis) (levels 2b-3b), case series for one (foodborne trematodiasis) (level 4), and case reports for five (Buruli ulcer, dracunculiasis, filariasis, soil-transmitted helminthes, and trachoma). Level 1 evidence for treatment of neurologic manifestations of NTDs was found for human African trypanosomiasis, leprosy, and cysticercosis and level 2 evidence exists for treatment of neurologic involvement in Chagas disease. For the remaining NTDs, treatment of neurologic complications is described in case series and case reports only. Neurologic manifestations of NTDs cause significant morbidity and mortality, although limited evidence exists on how best to treat these neurologic complications. Increased awareness of neurologic manifestations of the NTDs can increase their early identification and treatment, contributing to ongoing elimination and eradication campaigns. Copyright © 2015 Elsevier B.V. All rights reserved.
Piechowski-Jozwiak, Bartlomiej; Bogousslavsky, Julien
Visual art production involves multiple processes including basic motor skills, such as coordination of movements, visual-spatial processing, emotional output, sociocultural context, and creativity. Thus, the relationship between artistic output and brain diseases is particularly complex, and brain disorders may lead to impairment of artistic production in multiple domains. Neurological conditions may also occasionally modify artistic style and lead to surprisingly innovative features in people with an initial loss of creativity. This chapter focuses on anecdotal reports of various neurological disorders and their potential consequences on works produced by famous or well-established artists, including Carl Frederik Reutersward, Giorgio de Chirico, Krystyna Habura, Leo Schnug, Ignatius Brennan, and many others.
Boone, Philip M; Wiszniewski, Wojciech; Lupski, James R
"Genomic medicine" refers to the diagnosis, optimized management, and treatment of disease--as well as screening, counseling, and disease gene identification--in the context of information provided by an individual patient's personal genome. Genomic medicine, to some extent synonymous with "personalized medicine," has been made possible by recent advances in genome technologies. Genomic medicine represents a new approach to health care and disease management that attempts to optimize the care of a patient based upon information gleaned from his or her personal genome sequence. In this review, we describe recent progress in genomic medicine as it relates to neurological disease. Many neurological disorders either segregate as Mendelian phenotypes or occur sporadically in association with a new mutation in a single gene. Heritability also contributes to other neurological conditions that appear to exhibit more complex genetics. In addition to discussing current knowledge in this field, we offer suggestions for maximizing the utility of genomic information in clinical practice as the field of genomic medicine unfolds.
Boone, Philip M.; Wiszniewski, Wojciech; Lupski, James R.
“Genomic medicine” refers to the diagnosis, optimized management, and treatment of disease—as well as screening, counseling, and disease gene identification—in the context of information provided by an individual patient’s personal genome. Genomic medicine, to some extent synonymous with “personalized medicine,” has been made possible by recent advances in genome technologies. Genomic medicine represents a new approach to health care and disease management that attempts to optimize the care of a patient based upon information gleaned from his or her personal genome sequence. In this review, we describe recent progress in genomic medicine as it relates to neurological disease. Many neurological disorders either segregate as Mendelian phenotypes or occur sporadically in association with a new mutation in a single gene. Heritability also contributes to other neurological conditions that appear to exhibit more complex genetics. In addition to discussing current knowledge in this field, we offer suggestions for maximizing the utility of genomic information in clinical practice as the field of genomic medicine unfolds. PMID:21594611
Marcó, Sara; Pujol, Anna; Roca, Carles; Motas, Sandra; Ribera, Albert; Garcia, Miguel; Molas, Maria; Villacampa, Pilar; Melia, Cristian S.; Sánchez, Víctor; Sánchez, Xavier; Bertolin, Joan; Ruberte, Jesús; Haurigot, Virginia
ABSTRACT Mucopolysaccharidosis type IIIC (MPSIIIC) is a severe lysosomal storage disease caused by deficiency in activity of the transmembrane enzyme heparan-α-glucosaminide N-acetyltransferase (HGSNAT) that catalyses the N-acetylation of α-glucosamine residues of heparan sulfate. Enzyme deficiency causes abnormal substrate accumulation in lysosomes, leading to progressive and severe neurodegeneration, somatic pathology and early death. There is no cure for MPSIIIC, and development of new therapies is challenging because of the unfeasibility of cross-correction. In this study, we generated a new mouse model of MPSIIIC by targeted disruption of the Hgsnat gene. Successful targeting left LacZ expression under control of the Hgsnat promoter, allowing investigation into sites of endogenous expression, which was particularly prominent in the CNS, but was also detectable in peripheral organs. Signs of CNS storage pathology, including glycosaminoglycan accumulation, lysosomal distension, lysosomal dysfunction and neuroinflammation were detected in 2-month-old animals and progressed with age. Glycosaminoglycan accumulation and ultrastructural changes were also observed in most somatic organs, but lysosomal pathology seemed most severe in liver. Furthermore, HGSNAT-deficient mice had altered locomotor and exploratory activity and shortened lifespan. Hence, this animal model recapitulates human MPSIIIC and provides a useful tool for the study of disease physiopathology and the development of new therapeutic approaches. PMID:27491071
Carvalho, Karen S; Grunwald, Tal; De Luca, Francesco
The endocrine system is a complex group of organs and glands that relates to multiple other organs and systems in the body with the ultimate goal of maintaining homeostasis. This complex network functions through hormones excreted by several glands and released in the blood, targeting different body tissues and modulating their function. Any primary disorders affecting the endocrine glands and altering the amount of hormones synthesized and released will lead to disruption in the functions of multiple organs. The central nervous system of a developing child is particularly sensitive to endocrine disorders. A variety of neurological manifestations have been described as features of several endocrine diseases in childhood. Their knowledge may contribute to an early diagnosis of a particular endocrine condition, especially when more typical features are not present yet. In this article, we discuss specific neurological manifestations found in various endocrine disorders in children. Copyright © 2017 Elsevier Inc. All rights reserved.
Kahn, A; Haase, G; Akli, S; Guidotti, J E
In hereditary neurological diseases, gene transfer into neurons is made difficult by: the nature of the cells (postmitotic cells, that cannot be cultured, genetically modified ex vivo, then retransplanted), sometimes, their widespread localization, the blood-brain barrier. However, three viral vectors derived from adenovirus, Herpes simplex virus and adeno-associated virus have been shown to be very efficient in transferring DNA into brain cells. All of these vectors can infect resting cells, especially neurons, and are efficient in vivo. Retroviral vectors which can infect dividing cells only are mainly used for ex vivo genetic modification of cells (neural progenitor cells, myoblasts, fibroblasts) followed by intracerebral transplantation. Alternatively, genetically modified cells can be transplanted in a peripheral site if the transgene product is able to cross the blood-brain barrier or to be transported retrogradely from the nerve terminals. We have especially investigated the potential interest of adenoviral vectors to transfer foreign genes into brain cells and to treat animal models of neurological diseases. These vectors allowed us to transfer the lacZ gene into any neural cell type, including neurons, glia, photoreceptors and olfactory receptors, ex vivo, in cell culture, and in vivo, by stereotactic administration. In addition, axonal transport of adenoviral vectors has been demonstrated, e.g. in the substantia nigra after injection into the striatum, in the olfactory bulb after intranasal instillation and in spinal motor neurons after intramuscular injection. After intracerebroventricular injection, ependymal cells are massively infected and express the transgene for several months, as this is also observed in neurons. Through the spinal canal and cerebrospinal fluid, the vector can diffuse to a considerable distance from the injection point, e.g. to the lumbar spinal cord after injection in the suboccipital region. To test the biological function of
Cristini, Silvia; Navone, Stefania; Canzi, Laura; Acerbi, Francesco; Ciusani, Emilio; Hladnik, Uros; de Gemmis, Paola; Alessandri, Giulio; Colombo, Augusto; Parati, Eugenio; Invernici, Gloria
The study of Lesch-Nyhan-diseased (LND) human brain is crucial for understanding how mutant hypoxanthine-phosphoribosyltransferase (HPRT) might lead to neuronal dysfunction. Since LND is a rare, inherited disorder caused by a deficiency of the enzyme HPRT, human neural stem cells (hNSCs) that carry this mutation are a precious source for delineating the consequences of HPRT deficiency and for developing new treatments. In our study we have examined the effect of HPRT deficiency on the differentiation of neurons in hNSCs isolated from human LND fetal brain. We have examined the expression of a number of transcription factors essential for neuronal differentiation and marker genes involved in dopamine (DA) biosynthetic pathway. LND hNSCs demonstrate aberrant expression of several transcription factors and DA markers. HPRT-deficient dopaminergic neurons also demonstrate a striking deficit in neurite outgrowth. These results represent direct experimental evidence for aberrant neurogenesis in LND hNSCs and suggest developmental roles for other housekeeping genes in neurodevelopmental disease. Moreover, exposure of the LND hNSCs to retinoic acid medium elicited the generation of dopaminergic neurons. The lack of precise understanding of the neurological dysfunction in LND has precluded development of useful therapies. These results evidence aberrant neurogenesis in LND hNSCs and suggest a role for HPRT gene in neurodevelopment. These cells combine the peculiarity of a neurodevelopmental model and a human, neural origin to provide an important tool to investigate the pathophysiology of HPRT deficiency and more broadly demonstrate the utility of human neural stem cells for studying the disease and identifying potential therapeutics.
Damage to the frontal structures may lead to a diverse set of changes in cognitive, behavioral, or emotional domains. While lesion studies have demonstrated distinct impairments related to pathology in different frontal regions, it is clear that the frontal lobe syndrome is not restricted to damage to frontal regions. Therefore, the broad range of impairments in executive functioning evident in neurologic disease is often referred to as the dysexecutive syndrome. This review provides an overview of how executive functioning has been traditionally defined and measured. The components of executive function such as planning, cognitive flexibility and set-shifting, initiation and self-generation, response inhibition, serial ordering and sequencing, are discussed with respect to traditional measures and neural substrates. This is followed by profiles of frontal-executive dysfunction in aging, traumatic brain injury, frontotemporal dementia, and Parkinson's disease. Since no one specific neurologic disorder has a predilection to damage isolated to the frontal lobes, profiles of the dysexecutive syndrome are related to damage to several regions in addition to the frontal lobes. Finally, there is a discussion of ecological validity and the impact of executive deficits on everyday functioning. The recent development of executive tests with greater ecological validity is reviewed and discussed, and suggestions for future directions for research are provided.
Robbins, Miriam R
Neurologic diseases can have a major impact on functional capacity. Patients with neurologic disease require individualized management considerations depending on the extent of impairment and impact on functional capacity. This article reviews 4 of the more common and significant neurologic diseases (Alzheimer disease, cerebrovascular accident/stroke, multiple sclerosis, and Parkinson disease) that are likely to present to a dental office and provides suggestions on the dental management of patients with these conditions.
Poduri, Annapurna; Evrony, Gilad D.; Cai, Xuyu; Walsh, Christopher A.
Genetic mutations causing human disease are conventionally thought to be inherited through the germ line from one’s parents and present in all somatic (body) cells, except for most cancer mutations, which arise somatically. Increasingly, somatic mutations are being identified in diseases other than cancer, including neurodevelopmental diseases. Somatic mutations can arise during the course of prenatal brain development and cause neurological disease—even when present at low levels of mosaicism, for example—resulting in brain malformations associated with epilepsy and intellectual disability. Novel, highly sensitive technologies will allow more accurate evaluation of somatic mutations in neurodevelopmental disorders and during normal brain development. PMID:23828942
Prajumwongs, Piya; Weeranantanapan, Oratai; Jaroonwitchawan, Thiranut; Noisa, Parinya
Although the mechanism of neurogenesis has been well documented in other organisms, there might be fundamental differences between human and those species referring to species-specific context. Based on principles learned from other systems, it is found that the signaling pathways required for neural induction and specification of human embryonic stem cells (hESCs) recapitulated those in the early embryo development in vivo at certain degree. This underscores the usefulness of hESCs in understanding early human neural development and reinforces the need to integrate the principles of developmental biology and hESC biology for an efficient neural differentiation. PMID:27239201
Tor-Agbidye, J; Palmer, V S; Lasarev, M R; Craig, A M; Blythe, L L; Sabri, M I; Spencer, P S
Neurological disorders have been reported from parts of Africa with protein-deficient populations and attributed to cyanide (CN-) exposure from prolonged dietary use of cassava, a cyanophoric plant. Cyanide is normally metabolized to thiocyanate (SCN-) by the sulfur-dependent enzyme rhodanese. However, in protein-deficient subjects where sulfur amino acids (SAA) are low, CN may conceivably be converted to cyanate (OCN-), which is known to cause neurodegenerative disease in humans and animals. This study investigates the fate of potassium cyanide administered orally to rats maintained for up to 4 weeks on either a balanced diet (BD) or a diet lacking the SAAs, L-cystine and L-methionine. In both groups, there was a time-dependent increase in plasma cyanate, with exponential OCN- increases in SAA-deficient rats. A strongly positive linear relationship between blood CN- and plasma OCN- concentrations was observed in these animals. These data are consistent with the hypothesis that cyanate is an important mediator of chronic cyanide neurotoxicity during protein-calorie deficiency. The potential role of thiocyanate in cassava-associated konzo is discussed in relationship to the etiology of the comparable pattern of motor-system disease (spastic paraparesis) seen in lathyrism.
Shefner, J M
Motor unit number estimation (MUNE) was introduced in 1971 as a way of providing an objective and meaningful estimate of axon loss in diseases affecting the motor system. Over the last 30 years, different methods of MUNE have been proposed, with each having specific strengths and limitations. The goal of this paper is to review the available methods, and to present data generated using MUNE in a variety of disease entities. The incremental, multiple point stimulation, spike-triggered averaging, F-wave, and statistical methods of MUNE are reviewed, along with data obtained using these methods in patients with neuropathy, motor neuron disorders, and muscle disease. All methods reviewed have theoretical concerns associated with them. However, with the exception of the spike-triggered averaging method, all give results in normal subjects that are quite similar. MUNE has been of great value in assessing progression of motor neuron disease, and has also shown promise in the assessment of generalized neuropathy. Despite the lack of a perfect method for performing MUNE, it has great clinical value in the assessment of progressive motor axon loss. Further refinements in the method will likely increase its utility in the future.
Kawamura, Mitsuru; Sugimoto, Azusa; Kobayakawa, Mutsutaka; Tsuruya, Natsuko
To discuss the neurological basis of facial recognition, we present our case reports of impaired recognition and a review of previous literature. First, we present a case of infarction and discuss prosopagnosia, which has had a large impact on face recognition research. From a study of patient symptoms, we assume that prosopagnosia may be caused by unilateral right occipitotemporal lesion and right cerebral dominance of facial recognition. Further, circumscribed lesion and degenerative disease may also cause progressive prosopagnosia. Apperceptive prosopagnosia is observed in patients with posterior cortical atrophy (PCA), pathologically considered as Alzheimer's disease, and associative prosopagnosia in frontotemporal lobar degeneration (FTLD). Second, we discuss face recognition as part of communication. Patients with Parkinson disease show social cognitive impairments, such as difficulty in facial expression recognition and deficits in theory of mind as detected by the reading the mind in the eyes test. Pathological and functional imaging studies indicate that social cognitive impairment in Parkinson disease is possibly related to damages in the amygdalae and surrounding limbic system. The social cognitive deficits can be observed in the early stages of Parkinson disease, and even in the prodromal stage, for example, patients with rapid eye movement (REM) sleep behavior disorder (RBD) show impairment in facial expression recognition. Further, patients with myotonic dystrophy type 1 (DM 1), which is a multisystem disease that mainly affects the muscles, show social cognitive impairment similar to that of Parkinson disease. Our previous study showed that facial expression recognition impairment of DM 1 patients is associated with lesion in the amygdalae and insulae. Our study results indicate that behaviors and personality traits in DM 1 patients, which are revealed by social cognitive impairment, are attributable to dysfunction of the limbic system.
Pelligra, R. (Editor)
Neurological development is considered as the major human potential. Vision, vestibular function, intelligence, and nutrition are discussed as well as the treatment of neurological disfunctions, coma, and convulsive seizures.
Choudhury, Sourav R; Hudry, Eloise; Maguire, Casey A; Sena-Esteves, Miguel; Breakefield, Xandra O; Grandi, Paola
Neurological disorders - disorders of the brain, spine and associated nerves - are a leading contributor to global disease burden with a shockingly large associated economic cost. Various treatment approaches - pharmaceutical medication, device-based therapy, physiotherapy, surgical intervention, among others - have been explored to alleviate the resulting extent of human suffering. In recent years, gene therapy using viral vectors - encoding a therapeutic gene or inhibitory RNA into a "gutted" viral capsid and supplying it to the nervous system - has emerged as a clinically viable option for therapy of brain disorders. In this Review, we provide an overview of the current state and advances in the field of viral vector-mediated gene therapy for neurological disorders. Vector tools and delivery methods have evolved considerably over recent years, with the goal of providing greater and safer genetic access to the central nervous system. Better etiological understanding of brain disorders has concurrently led to identification of improved therapeutic targets. We focus on the vector technology, as well as preclinical and clinical progress made thus far for brain cancer and various neurodegenerative and neurometabolic disorders, and point out the challenges and limitations that accompany this new medical modality. Finally, we explore the directions that neurological gene therapy is likely to evolve towards in the future. This article is part of the Special Issue entitled "Beyond small molecules for neurological disorders". Copyright © 2016 Elsevier Ltd. All rights reserved.
SCHAMBRA, U. B.; MACKENSEN, G. B.; STAFFORD-SMITH, M.; HAINES, D. E.; SCHWINN, D. A.
Recent data suggest novel functional roles for cerebellar involvement in a number of neurologic diseases. Function of cerebellar neurons is known to be modulated by norepinephrine and adrenergic receptors. The distribution of adrenergic receptor subtypes has been described in experimental animals, but corroboration of such studies in the human cerebellum, necessary for drug treatment, is still lacking. In the present work we studied cell-specific localizations of α1 adrenergic receptor subtype mRNA (α1a, α1b, α1d), and α2 adrenergic receptor subtype mRNA (α2a, α2b, α2c) by in situ hybridization on cryostat sections of human cerebellum (cortical layers and dentate nucleus). We observed unique neuron-specific α1 adrenergic receptor and α2 adrenergic receptor subtype distribution in human cerebellum. The cerebellar cortex expresses mRNA encoding all six α adrenergic receptor subtypes, whereas dentate nucleus neurons express all subtype mRNAs, except α2a adrenergic receptor mRNA. All Purkinje cells label strongly for α2a and α2b adrenergic receptor mRNA. Additionally, Purkinje cells of the anterior lobe vermis (lobules I to V) and uvula/tonsil (lobules IX/HIX) express α1a and α2c subtypes, and Purkinje cells in the ansiform lobule (lobule HVII) and uvula/tonsil express α1b and α2c adrenergic receptor subtypes. Basket cells show a strong signal for α1a, moderate signal for α2a and light label for α2b adrenergic receptor mRNA. In stellate cells, besides a strong label of α2a adrenergic receptor mRNA in all and moderate label of α2b message in select stellate cells, the inner stellate cells are also moderately positive for α1b adrenergic receptor mRNA. Granule and Golgi cells express high levels of α2a and α2b adrenergic receptor mRNAs. These data contribute new information regarding specific location of adrenergic receptor subtypes in human cerebellar neurons. We discuss our observations in terms of possible modulatory roles of adrenergic
In this paper, I described clinical and basic problems on neurology of the aged patients. These studies have been done in various institutions with many co-workers. 1) A PET study revealed some age differences on CBF, CMRO2, or CMRgl. But these results are not so rigid in which much of individual variations should be considered in interpretation. Calendar age is not always compatible to biological age. 2) Saccular aneurysms in the brain artery were found in 7.3% of 1200 routine autopsy series of the aged subjects. Aneurysms with external diameter exceeding 6 mm had been fatally ruptured in 14 (78%) of 18 subjects. 3) Variations of the pyramidal crossing are found responsible for bizarre clinical manifestations. Non-crossing component was more prominent in the right pyramidal tract; consequently, right pyramidal tracts including ventral and lateral one seemed to have more extensive representation in the spinal cord level. 4) I123-IMP SPECT study showed a reduced uptake in the area 4 or area 4-6 of the ALS patients. 5) I introduced a new simplified Wartenberg's maneuver, which is useful for detection of subtle pyramidal dysfunctions. 6) Cases with central pontine myelinolysis and those of paraneoplastic syndrome were presented with an emphasis on their patho-chemical mechanisms. 7) Lewis-Sumner syndrome showing multifocal persistent conduction block is not rare in the aged, in which we have already had some useful therapeutic methods. 8) Dementia complicated with neurodegenerative disease was discussed on its clinical and chemical features of mental disturbances. In ALS-dementia, CSF-homovanilic acid reduced significantly than in the control and L-dopa was effective in some patients. 9) Vascular and Alzheimer-type dementias were presented and discussed on their pathogenetic mechanism according to our recent studies with review of literature.
The availability of high-throughput genome sequencing technologies is expected to revolutionize our understanding of not only hereditary neurological diseases but also sporadic neurological diseases. The molecular bases of sporadic diseases, particularly those of sporadic neurodegenerative diseases, largely remain unknown. As potential molecular bases, various mechanisms can be considered, which include those underlying apparently sporadic neurological diseases with low-penetrant mutations in the gene for hereditary diseases, sporadic diseases with de novo mutations, and sporadic diseases with variations in disease-susceptible genes. With unprecedentedly robust power, high-throughput genome sequencing technologies will enable us to explore all of these possibilities. These new technologies will soon be applied in clinical practice. It will be a new era of datacentric clinical practice.
Ford, Rodney Philip Kinvig
Gluten causes symptoms, in both celiac disease and non-celiac gluten-sensitivity, by its adverse actions on the nervous system. Many celiac patients experience neurological symptoms, frequently associated with malfunction of the autonomic nervous system. These neurological symptoms can present in celiac patients who are well nourished. The crucial point, however, is that gluten-sensitivity can also be associated with neurological symptoms in patients who do not have any mucosal gut damage (that is, without celiac disease). Gluten can cause neurological harm through a combination of cross reacting antibodies, immune complex disease and direct toxicity. These nervous system affects include: dysregulation of the autonomic nervous system, cerebella ataxia, hypotonia, developmental delay, learning disorders, depression, migraine, and headache. If gluten is the putative harmful agent, then there is no requirement to invoke gut damage and nutritional deficiency to explain the myriad of the symptoms experienced by sufferers of celiac disease and gluten-sensitivity. This is called "The Gluten Syndrome".
Wan, Haitong; Li, Jinhui; Zhang, Hong; Tian, Mei
With the speeding tendency of aging society, human neurological disorders have posed an ever increasing threat to public health care. Human neurological diseases include ischemic brain injury, Alzheimer's disease, Parkinson's disease, and spinal cord injury, which are induced by impairment or specific degeneration of different types of neurons in central nervous system. Currently, there are no more effective treatments against these diseases. Traditional Chinese medicine (TCM) is focused on, which can provide new strategies for the therapy in neurological disorders. TCM, including Chinese herb medicine, acupuncture, and other nonmedication therapies, has its unique therapies in treating neurological diseases. In order to improve the treatment of these disorders by optimizing strategies using TCM and evaluate the therapeutic effects, we have summarized molecular imaging, a new promising technology, to assess noninvasively disease specific in cellular and molecular levels of living models in vivo, that was applied in TCM therapy for neurological diseases. In this review, we mainly focus on applying diverse molecular imaging methodologies in different TCM therapies and monitoring neurological disease, and unveiling the mysteries of TCM. PMID:24222911
Wang, Zefeng; Wan, Haitong; Li, Jinhui; Zhang, Hong; Tian, Mei
With the speeding tendency of aging society, human neurological disorders have posed an ever increasing threat to public health care. Human neurological diseases include ischemic brain injury, Alzheimer's disease, Parkinson's disease, and spinal cord injury, which are induced by impairment or specific degeneration of different types of neurons in central nervous system. Currently, there are no more effective treatments against these diseases. Traditional Chinese medicine (TCM) is focused on, which can provide new strategies for the therapy in neurological disorders. TCM, including Chinese herb medicine, acupuncture, and other nonmedication therapies, has its unique therapies in treating neurological diseases. In order to improve the treatment of these disorders by optimizing strategies using TCM and evaluate the therapeutic effects, we have summarized molecular imaging, a new promising technology, to assess noninvasively disease specific in cellular and molecular levels of living models in vivo, that was applied in TCM therapy for neurological diseases. In this review, we mainly focus on applying diverse molecular imaging methodologies in different TCM therapies and monitoring neurological disease, and unveiling the mysteries of TCM.
Fan, Peihu; Li, Xiaojun; Sun, Shiyang; Su, Weiheng; An, Dong; Gao, Feng; Kong, Wei; Jiang, Chunlai
Enterovirus 71 (EV71) is a major causative pathogen of hand, foot and mouth disease with especially severe neurologic complications, which mainly account for fatalities from this disease. To date, the pathogenesis of EV71 in the central neurons system has remained unclear. Cytokine-mediated immunopathogenesis and nervous tissue damage by virus proliferation are two widely speculated causes of the neurological disease. To further study the pathogenesis, we identified a common epitope (co-epitope) between EV71 VP1 and human mediator complex subunit 25 (MED25) highly expressed in brain stem. A monoclonal antibody (2H2) against the co-epitope was prepared, and its interaction with MED25 was examined by ELISA, immunofluorescence assay and Western blot in vitro and by live small animal imaging in vivo. Additionally, 2H2 could bind to both VP1 and MED25 with the affinity constant (Kd) of 10−7 M as determined by the ForteBio Octet System. Intravenously injected 2H2 was distributed in brain stem of mice after seven days of EV71 infection. Interestingly, 2H2-like antibodies were detected in the serum of EV71-infected patients. These findings suggest that EV71 infection induces the production of antibodies that can bind to autoantigens expressed in nervous tissue and maybe further trigger autoimmune reactions resulting in neurological disease. PMID:25826188
Tan, Lin; Jiang, Teng; Tan, Lan; Yu, Jin-Tai
Technological development has paved the way for accelerated genomic discovery and is bringing precision medicine into view. The goal of precision medicine is to deliver optimally targeted and timed interventions tailored to an individual's molecular drivers of disease. Neurological diseases are promisingly suited models for precision medicine because of the rapidly expanding genetic knowledge base, phenotypic classification, the development of biomarkers and the potential modifying treatments. Moving forward, it is crucial that through these integrated research platforms to provide analysis both for accurate personal genome analysis and gene and drug discovery. Here we describe our vision of how precision medicine can bring greater clarity to the clinical and biological complexity of neurological diseases.
Arun, Siddharth; Liu, Lei; Donmez, Gizem
Mitochondria are extremely active organelles that perform a variety of roles in the cell including energy production, regulation of calcium homeostasis, apoptosis, and population maintenance through fission and fusion. Mitochondrial dysfunction in the form of oxidative stress and mutations can contribute to the pathogenesis of various neurodegenerative diseases such as Parkinson’s (PD), Alzheimer’s (AD), and Huntington’s diseases (HD). Abnormalities of Complex I function in the electron transport chain have been implicated in some neurodegenerative diseases, inhibiting ATP production and generating reactive oxygen species that can cause major damage to mitochondria Mutations in both nuclear and mitochondrial DNA can contribute to neurodegenerative disease, although the pathogenesis of these conditions tends to focus on nuclear mutations. In PD, nuclear genome mutations in the PINK1 and parkin genes have been implicated in neurodegeneration , while mutations in APP, PSEN1 and PSEN2 have been implicated in a variety of clinical symptoms of AD . Mutant htt protein is known to cause HD . Much progress has been made to determine some causes of these neurodegenerative diseases, though permanent treatments have yet to be developed. In this review, we discuss the roles of mitochondrial dysfunction in the pathogenesis of these diseases. PMID:26903445
Duarte, João M. N.; Schuck, Patrícia F.; Wenk, Gary L.; Ferreira, Gustavo C.
Degeneration of specific neuronal populations and progressive nervous system dysfunction characterize neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. These findings are also reported in inherited diseases such as phenylketonuria and glutaric aciduria type I. The involvement of mitochondrial dysfunction in these diseases was reported, elicited by genetic alterations, exogenous toxins or buildup of toxic metabolites. In this review we shall discuss some metabolic alterations related to the pathophysiology of diseases with neurological involvement and aging process. These findings may help identifying early disease biomarkers and lead to more effective therapies to improve the quality of life of the patients affected by these devastating illnesses. PMID:25110608
Lorincz, Matthew T
As Wilson's disease is both preventable and treatable, the diagnosis must not be missed. Despite this, it is usually misdiagnosed. Misdiagnosis and delay in treatment are clinically relevant because if left untreated, Wilson's disease progresses to hepatic failure or severe neurologic disability, and death. Those adequately treated have a normal life span. Wilson's disease is an autosomal recessive disease caused by mutations in the ATP7B gene. Mutations in ATP7B result in abnormal copper metabolism and subsequent toxic accumulation of copper. The clinical manifestations of neurologic Wilson's disease include variable combinations of dysarthria, dystonia, tremor, parkinsonism, ataxia, and choreoathetosis. Once the possibility of Wilson's disease is considered, diagnosis is straight forward. Currently available treatments, including zinc acetate and trientine, are generally well tolerated and effective. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.
Neretin, V Ia; Kir'iakov, V A; Skorochkina, L V; Loseva, T V
The authors describe a case of Ollier's syndrome which developed in a 31-year-old female patient. The patient manifested hypertrophy of osseous and soft tissues, deformity of the dorsum sellae and of the walls of the cavernous sinus and siphon of the internal carotid artery. In the clinical picture of the disease, one could see symptoms of the impairment of pairs III and VI of the craniocerebral nerves, pains due to the irritation of the first branch of nerve V.
Jeitner, Thomas M; Cooper, Arthur J L
At high concentrations, the glutamine synthetase inhibitor L-methionine-S,R-sulfoximine (MSO) is a convulsant, especially in dogs. Nevertheless, sub-convulsive doses of MSO are neuroprotective in rodent models of hyperammonemia, acute liver disease, and amyotrophic lateral sclerosis and suggest MSO may be clinically useful. Previous work has also shown that much lower doses of MSO are required to produce convulsions in dogs than in primates. Evidence from the mid-20th century suggests that humans are also less sensitive. In the present work, the inhibition of recombinant human glutamine synthetase by MSO is shown to be biphasic-an initial reversible competitive inhibition (K i 1.19 mM) is followed by rapid irreversible inactivation. This K i value for the human enzyme accounts, in part, for relative insensitivity of primates to MSO and suggests that this inhibitor could be used to safely inhibit glutamine synthetase activity in humans.
Arnold, Ria; Issar, Tushar; Krishnan, Arun V
Patients with chronic kidney disease (CKD) are frequently afflicted with neurological complications. These complications can potentially affect both the central and peripheral nervous systems. Common neurological complications in CKD include stroke, cognitive dysfunction, encephalopathy, peripheral and autonomic neuropathies. These conditions have significant impact not only on patient morbidity but also on mortality risk through a variety of mechanisms. Understanding the pathophysiological mechanisms of these conditions can provide insights into effective management strategies for neurological complications. This review describes clinical management of neurological complications in CKD with reference to the contributing physiological and pathological derangements. Stroke, cognitive dysfunction and dementia share several pathological mechanisms that may contribute to vascular impairment and neurodegeneration. Cognitive dysfunction and dementia may be differentiated from encephalopathy which has similar contributing factors but presents in an acute and rapidly progressive manner and may be accompanied by tremor and asterixis. Recent evidence suggests that dietary potassium restriction may be a useful preventative measure for peripheral neuropathy. Management of painful neuropathic symptoms can be achieved by pharmacological means with careful dosing and side effect considerations for reduced renal function. Patients with autonomic neuropathy may respond to sildenafil for impotence. Neurological complications often become clinically apparent at end-stage disease, however early detection and management of these conditions in mild CKD may reduce their impact at later stages. PMID:27867500
The nervous system contains some of the body's most metabolically demanding cells that are highly dependent on ATP produced via mitochondrial oxidative phosphorylation. Thus, the neurological system is consistently involved in patients with mitochondrial disease. Symptoms differ depending on the part of the nervous system affected. Although almost…
The nervous system contains some of the body's most metabolically demanding cells that are highly dependent on ATP produced via mitochondrial oxidative phosphorylation. Thus, the neurological system is consistently involved in patients with mitochondrial disease. Symptoms differ depending on the part of the nervous system affected. Although almost…
Wu, Haijian; Niu, Huanjiang; Shao, Anwen; Wu, Cheng; Dixon, Brandon J; Zhang, Jianmin; Yang, Shuxu; Wang, Yirong
Neurological diseases, which consist of acute injuries and chronic neurodegeneration, are the leading causes of human death and disability. However, the pathophysiology of these diseases have not been fully elucidated, and effective treatments are still lacking. Astaxanthin, a member of the xanthophyll group, is a red-orange carotenoid with unique cell membrane actions and diverse biological activities. More importantly, there is evidence demonstrating that astaxanthin confers neuroprotective effects in experimental models of acute injuries, chronic neurodegenerative disorders, and neurological diseases. The beneficial effects of astaxanthin are linked to its oxidative, anti-inflammatory, and anti-apoptotic characteristics. In this review, we will focus on the neuroprotective properties of astaxanthin and explore the underlying mechanisms in the setting of neurological diseases.
Wu, Haijian; Niu, Huanjiang; Shao, Anwen; Wu, Cheng; Dixon, Brandon J.; Zhang, Jianmin; Yang, Shuxu; Wang, Yirong
Neurological diseases, which consist of acute injuries and chronic neurodegeneration, are the leading causes of human death and disability. However, the pathophysiology of these diseases have not been fully elucidated, and effective treatments are still lacking. Astaxanthin, a member of the xanthophyll group, is a red-orange carotenoid with unique cell membrane actions and diverse biological activities. More importantly, there is evidence demonstrating that astaxanthin confers neuroprotective effects in experimental models of acute injuries, chronic neurodegenerative disorders, and neurological diseases. The beneficial effects of astaxanthin are linked to its oxidative, anti-inflammatory, and anti-apoptotic characteristics. In this review, we will focus on the neuroprotective properties of astaxanthin and explore the underlying mechanisms in the setting of neurological diseases. PMID:26378548
Zucconi, M; Bruni, O
Pediatric neurologic diseases are often associated with different kinds of sleep disruption (mainly insomnia, less frequently hypersomnia or parasomnias). Due to the key-role of sleep for development, the effort to ameliorate sleep patterns in these children could have important prognostic benefits. Study of sleep architecture and organization in neurologic disorders could lead to a better comprehension of the pathogenesis and a better treatment of the disorders. This article focuses on the following specific neurologic diseases: nocturnal frontal lobe epilepsy and abnormal motor behaviors of epileptic origin, evaluating differential diagnosis with parasomnias; achondroplasia, confirming the crucial role of craniofacial deformity in determining sleep-disordered breathing; neuromuscular diseases, mainly Duchenne's muscular dystrophy and myotonic dystrophy; cerebral palsy, evaluating either the features of sleep architecture and the importance of the respiratory problems associated; headaches, confirming the strict relationships with sleep in terms of neurochemical and neurobehavioral substrates; and finally a review on the effectiveness of melatonin for sleep problems in children with neurologic syndromes and mental retardation, blindness, and epilepsy.
Casella, Giovanni; Tontini, Gian Eugenio; Bassotti, Gabrio; Pastorelli, Luca; Villanacci, Vincenzo; Spina, Luisa; Baldini, Vittorio; Vecchi, Maurizio
Extraintestinal manifestations occur in about one-third of patients living with inflammatory bowel disease (IBD) and may precede the onset of gastrointestinal symptoms by many years. Neurologic disorders associated with IBD are not frequent, being reported in 3% of patients, but they often represent an important cause of morbidity and a relevant diagnostic issue. In addition, the increasing use of immunosuppressant and biological therapies for IBD may also play a pivotal role in the development of neurological disorders of different type and pathogenesis. Hence, we provide a complete and profound review of the main features of neurological complications associated with IBD, with particular reference to those related to drugs and with a specific focus on their clinical presentation and possible pathophysiological mechanisms. PMID:25083051
McGeachan, Alexander J; Mcdermott, Christopher J
Sialorrhoea is a common and problematic symptom that arises from a range of neurological conditions associated with bulbar or facial muscle dysfunction. Drooling can significantly affect quality of life due to both physical complications such as oral chapping, and psychological complications such as embarrassment and social isolation. Thicker, tenacious oral and pharyngeal secretions may result from the drying management approach to sialorrhoea. The management of sialorrhoea in neurological diseases depends on the underlying pathology and severity of symptoms. Interventions include anticholinergic drugs, salivary gland-targeted radiotherapy, salivary gland botulinum toxin and surgical approaches. The management of thick secretions involves mainly conservative measures such as pineapple juice as a lytic agent, cough assist, saline nebulisers and suctioning or mucolytic drugs like carbocisteine. Despite a current lack of evidence and variable practice, management of sialorrhoea should form a part of the multidisciplinary approach needed for long-term neurological conditions.
Planas Vilà, Mercè
The central nervous system regulates food intake, homoeostasis of glucose and electrolytes, and starts the sensations of hunger and satiety. Different nutritional factors are involved in the pathogenesis of several neurological diseases. Patients with acute neurological diseases (traumatic brain injury, cerebral vascular accident hemorrhagic or ischemic, spinal cord injuries, and cancer) and chronic neurological diseases (Alzheimer's Disease and other dementias, amyotrophic lateral sclerosis, Parkinson's Disease) increase the risk of malnutrition by multiple factors related to nutrient ingestion, abnormalities in the energy expenditure, changes in eating behavior, gastrointestinal changes, and by side effects of drugs administered. Patients with acute neurological diseases have in common the presence of hyper metabolism and hyper catabolism both associated to a period of prolonged fasting mainly for the frequent gastrointestinal complications, many times as a side effect of drugs administered. During the acute phase, spinal cord injuries presented a reduction in the energy expenditure but an increase in the nitrogen elimination. In order to correct the negative nitrogen balance increase intakes is performed with the result of a hyper alimentation that should be avoided due to the complications resulting. In patients with chronic neurological diseases and in the acute phase of cerebrovascular accident, dysphagia could be present which also affects intakes. Several chronic neurological diseases have also dementia, which lead to alterations in the eating behavior. The presence of malnutrition complicates the clinical evolution, increases muscular atrophy with higher incidence of respiratory failure and less capacity to disphagia recuperation, alters the immune response with higher rate of infections, increases the likelihood of fractures and of pressure ulcers, increases the incapacity degree and is an independent factor to increase mortality. The periodic nutritional
THE ROLE OF IONIC CHANNEL DYSFUNCTION: During various neurological diseases has been evoked for many years on electro-physiological data. Molecular biology has led to great progress in neurology, and can be considered "functional" since it is surpasses the classical anatomo-clinical methods. IONIC CHANNEL DYSFUNCTION: Can be determined genetically, resulting from the mutation of a gene code of a channel sub-unit. CHANNELOPATHIES ARE RESPONSIBLE: For muscular diseases (myotonia, familial periodic paralysis, malignant hyperthermia and congenital myasthenia), but also for central nervous system disorders such as familial hemiplegic migraine, hereditary paroxystic ataxia and certain forms of Mendel's law hereditary epilepsy. ACQUIRED IONIC CHANNEL DYSFUNCTION: Resulting from auto-immune aggression is implied in diseases such as Lambert-Eaton's myasthenic syndrome and Isaac's neuromyotonia syndrome. It probably plays a part in the clinical, and particularly the sensitive expression (paresthesia and pain) of some peripheral neuropathies and certain central nervous system affections, such as multiple sclerosis.
Tan, Lin; Jiang, Teng
Technological development has paved the way for accelerated genomic discovery and is bringing precision medicine into view. The goal of precision medicine is to deliver optimally targeted and timed interventions tailored to an individual’s molecular drivers of disease. Neurological diseases are promisingly suited models for precision medicine because of the rapidly expanding genetic knowledge base, phenotypic classification, the development of biomarkers and the potential modifying treatments. Moving forward, it is crucial that through these integrated research platforms to provide analysis both for accurate personal genome analysis and gene and drug discovery. Here we describe our vision of how precision medicine can bring greater clarity to the clinical and biological complexity of neurological diseases. PMID:27127757
Landgrave-Gómez, Jorge; Mercado-Gómez, Octavio; Guevara-Guzmán, Rosalinda
The role of epigenetic mechanisms in the function and homeostasis of the central nervous system (CNS) and its regulation in diseases is one of the most interesting processes of contemporary neuroscience. In the last decade, a growing body of literature suggests that long-term changes in gene transcription associated with CNS’s regulation and neurological disorders are mediated via modulation of chromatin structure. “Epigenetics”, introduced for the first time by Waddington in the early 1940s, has been traditionally referred to a variety of mechanisms that allow heritable changes in gene expression even in the absence of DNA mutation. However, new definitions acknowledge that many of these mechanisms used to perpetuate epigenetic traits in dividing cells are used by neurons to control a variety of functions dependent on gene expression. Indeed, in the recent years these mechanisms have shown their importance in the maintenance of a healthy CNS. Moreover, environmental inputs that have shown effects in CNS diseases, such as nutrition, that can modulate the concentration of a variety of metabolites such as acetyl-coenzyme A (acetyl-coA), nicotinamide adenine dinucleotide (NAD+) and beta hydroxybutyrate (β-HB), regulates some of these epigenetic modifications, linking in a precise way environment with gene expression. This manuscript will portray what is currently understood about the role of epigenetic mechanisms in the function and homeostasis of the CNS and their participation in a variety of neurological disorders. We will discuss how the machinery that controls these modifications plays an important role in processes involved in neurological disorders such as neurogenesis and cell growth. Moreover, we will discuss how environmental inputs modulate these modifications producing metabolic and physiological alterations that could exert beneficial effects on neurological diseases. Finally, we will highlight possible future directions in the field of epigenetics
Bandmann, Oliver; Weiss, Karl Heinz; Kaler, Stephen G
The copper metabolism disorder Wilson's disease was first defined in 1912. Wilson's disease can present with hepatic and neurological deficits, including dystonia and parkinsonism. Early-onset presentations in infancy and late-onset manifestations in adults older than 70 years of age are now well recognised. Direct genetic testing for ATP7B mutations are increasingly available to confirm the clinical diagnosis of Wilson's disease, and results from biochemical and genetic prevalence studies suggest that Wilson's disease might be much more common than previously estimated. Early diagnosis of Wilson's disease is crucial to ensure that patients can be started on adequate treatment, but uncertainty remains about the best possible choice of medication. Furthermore, Wilson's disease needs to be differentiated from other conditions that also present clinically with hepatolenticular degeneration or share biochemical abnormalities with Wilson's disease, such as reduced serum ceruloplasmin concentrations. Disordered copper metabolism is also associated with other neurological conditions, including a subtype of axonal neuropathy due to ATP7A mutations and the late-onset neurodegenerative disorders Alzheimer's disease and Parkinson's disease.
Valvular heart disease (VHD) is frequently associated with neurologic complications; cerebral embolism is the most common of these since thrombus formation results from the abnormalities in the valvular surfaces or from the anatomic and physiologic changes associated with valve dysfunction, such as atrial or ventricular enlargement, intracardiac thrombi, and cardiac dysrhythmias. Prosthetic heart valves, particularly mechanical valves, are very thrombogenic, which explains the high risk of thromboembolism and the need for anticoagulation for the prevention of embolism. Infective endocarditis is a disease process with protean manifestations that include not only cerebral embolism but also intracranial hemorrhage, mycotic aneurysms, and systemic manifestations such as fever and encephalopathy. Other neurologic complications include nonbacterial thrombotic endocarditis, a process associated with systemic diseases such as cancer and systemic lupus erythematosus. For many of these conditions, anticoagulation is the mainstay of treatment to prevent cerebral embolism, therefore it is the potential complications of anticoagulation that can explain other neurologic complications in patients with VHD. The prevention and management of these complications requires an understanding of their natural history in order to balance the risks posed by valvular disease itself against the risks and benefits associated with treatment.
Gilkes, C E; Love, S; Hardie, R J; Edwards, R J; Scolding, N J; Rice, C M
Brain biopsy is well established in clinical practice when there is suspicion of CNS malignancy. However, there is little consensus regarding the indications for brain biopsy in non-malignant neurological disease. This is due in no small part to limitations in the available literature pertaining to diagnostic brain biopsies. The published evidence largely comprises small, retrospective, single-centre analyses performed over long time periods, including non-homogeneous patient groups with considerable variation in reported outcomes. Here we present pragmatic guidance for those clinicians considering diagnostic brain biopsy in a patient with non-neoplastic neurological disease and highlight practice points with the aim of maximising the probability of gaining clinically useful information from the procedure.
Araya, Natsumi; Takahashi, Katsunori; Sato, Tomoo; Nakamura, Tatsufumi; Sawa, Chika; Hasegawa, Daisuke; Ando, Hitoshi; Aratani, Satoko; Yagishita, Naoko; Fujii, Ryoji; Oka, Hiroshi; Nishioka, Kusuki; Nakajima, Toshihiro; Mori, Naoki; Yamano, Yoshihisa
Human T-lymphotropic virus type-1 (HTLV-1) is a human retrovirus that causes HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T-cell leukaemia (ATL). A higher viral load in individuals with HTLV-1 infection increases their risk of developing HAM/TSP and ATL. Moreover, the high proviral load is associated with the clinical progression of HAM/TSP. Reduction of the number of HTLV-1-infected cells is therefore crucial for preventing and treating HTLV-1-associated diseases. Recently, fucoidan, a complex sulphated polysaccharide derived from marine seaweed, has been demonstrated to exert inhibitory effects on HTLV-1 infection in vitro. In this study, we examined the in vivo effects of fucoidan on HTLV-1 infection. In this single-centre open-label trial, 13 patients with HAM/TSP were treated with 6 g fucoidan daily for 6-13 months. The HTLV-1 proviral DNA load and frequencies of HTLV-1-specific CD8(+) T-cells, natural killer cells, invariant natural killer T-cells and dendritic cells in the peripheral blood were analysed. Furthermore, the in vitro inhibitory effect of fucoidan on cell-to-cell HTLV-1 infection was examined by using luciferase reporter cell assays. Fucoidan inhibited the cell-to-cell transmission of HTLV-1 in vitro. Furthermore, fucoidan therapy resulted in a 42.4% decrease in the HTLV-1 proviral load without affecting the host immune cells. During the treatment, no exacerbation was observed. Four patients with HAM/TSP developed diarrhoea, which improved immediately after stopping fucoidan administration. Fucoidan is a new potential therapeutic agent for the prevention and treatment of HTLV-1-associated diseases.
Brea, D; Cristobo, I; Sobrino, T; Rodríguez-González, R; Mosquera, E; Moldes, O; Castillo, J
Proteomic is a set of tools that allows the separation and identification of proteins expressed by a cell, tissue or organism. Two-dimensional electrophoresis is the central tool that allows qualitative and quantitative comparisons of protein patterns between samples. Differential analysis of protein expression patterns in different neurological diseases (stroke, Alzheimer, Parkinson, amyotrophic lateral sclerosis, Hungtington, epilepsy) allows the identification of diagnostic and/or prognostic biomarkers. Subsequently, validation of these markers may help to identify new diagnostic and therapeutic targets.
Anson, Donald S; McIntyre, Chantelle; Byers, Sharon
Intravenous enzyme replacement therapy has been developed as a viable treatment for most of the somatic pathologies associated with the mucopolysaccharide storage disorders. However, approximately two thirds of individuals affected by a mucopolysaccharide storage disorder also display neurological disease, in these instances intravenous enzyme replacement therapy is not viable as the blood-brain barrier severely limits enzyme distribution from the peripheral circulation into the central nervous system. Accordingly, much research is now focussed on developing therapies that specifically address neurological disease, or somatic and neurological disease in combination. Therapies designed to address the underlying cause of central nervous system pathology, that is the lysosomal storage itself, can be broadly divided into two groups, those that continue the rationale of enzyme replacement, and those that address the supply side of the storage equation; that is the production of storage material. Enzyme replacement can be further divided by technology (principally direct enzyme replacement, gene replacement and cell transplantation). Here we review the current state of the art for these strategies and suggest possible future directions for research in this field. In particular, we suggest that any one approach in itself is unlikely to be as efficacious as a carefully considered combination therapy, be it a combination of some sort of enzyme replacement with substrate deprivation, or a combination of two different replacement technologies or strategies.
Martínez-Morales, P L; Revilla, A; Ocaña, I; González, C; Sainz, P; McGuire, D; Liste, I
Human neurological disorders such as Alzheimer's disease (AD), Parkinson's disease, stroke or spinal cord injury are caused by the loss of neurons and glial cells in the brain or spinal cord in the Central Nervous System (CNS). Stem cell technology has become an attractive option to investigate and treat these diseases. Several types of neurons and glial cells have successfully been generated from stem cells, which in some cases, have ameliorated some dysfunctions both in animal models of neurological disorders and in patients at clinical level. Stem cell-based therapies can be beneficial by acting through several mechanisms such as cell replacement, modulation of inflammation and trophic actions. Here we review recent and current remarkable clinical studies involving stem cell-based therapy for AD and stroke and provide an overview of the different types of stem cells available nowadays, their main properties and how they are developing as a possible therapy for neurological disorders.
Leitão-Rocha, Ana; Guedes-Dias, Pedro; Pinho, Brígida R; Oliveira, Jorge M A
Neuronal homeostasis is critically dependent on healthy mitochondria. Mutations in mitochondrial DNA (mtDNA), in nuclear-encoded mitochondrial components, and age-dependent mitochondrial damage, have all been connected with neurological disorders. These include not only typical mitochondrial syndromes with neurological features such as encephalomyopathy, myoclonic epilepsy, neuropathy and ataxia; but also secondary mitochondrial involvement in neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's disease. Unravelling the molecular aetiology of mitochondrial dysfunction opens new therapeutic prospects for diseases thus far lacking effective treatments. In this review we address recent advances on preventive strategies, such as pronuclear, spindle-chromosome complex, or polar body genome transfer to replace mtDNA and avoid disease transmission to newborns; we also address experimental mitochondrial therapeutics aiming to benefit symptomatic patients and prevent disease manifestation in those at risk. Specifically, we focus on: (1) gene therapy to reduce mutant mtDNA, such as anti-replicative therapies and mitochondriatargeted nucleases allowing favourable heteroplasmic shifts; (2) allotopic expression of recoded wild-type mitochondrial genes, including targeted tRNAs and xenotopic expression of cognate genes to compensate for pathogenic mutations; (3) mitochondria targeted-peptides and lipophilic cations for in vivo delivery of antioxidants or other putative therapeutics; and (4) modulation of mitochondrial dynamics at the level of biogenesis, fission, fusion, movement and mitophagy. Further advances in therapeutic development are hindered by scarce in vivo models for mitochondrial disease, with the bulk of available data coming from cellular models. Nevertheless, wherever available, we also address data from in vivo experiments and clinical trials, focusing on neurological disease models.
Wolf, Heike; Stroobants, Stijn; D'Hooge, Rudi; Hermans-Borgmeyer, Irm; Lüllmann-Rauch, Renate; Dierks, Thomas; Lübke, Torben
ABSTRACT Fucosidosis is a rare lysosomal storage disorder caused by the inherited deficiency of the lysosomal hydrolase α-L-fucosidase, which leads to an impaired degradation of fucosylated glycoconjugates. Here, we report the generation of a fucosidosis mouse model, in which the gene for lysosomal α-L-fucosidase (Fuca1) was disrupted by gene targeting. Homozygous knockout mice completely lack α-L-fucosidase activity in all tested organs leading to highly elevated amounts of the core-fucosylated glycoasparagine Fuc(α1,6)-GlcNAc(β1-N)-Asn and, to a lesser extent, other fucosylated glycoasparagines, which all were also partially excreted in urine. Lysosomal storage pathology was observed in many visceral organs, such as in the liver, kidney, spleen and bladder, as well as in the central nervous system (CNS). On the cellular level, storage was characterized by membrane-limited cytoplasmic vacuoles primarily containing water-soluble storage material. In the CNS, cellular alterations included enlargement of the lysosomal compartment in various cell types, accumulation of secondary storage material and neuroinflammation, as well as a progressive loss of Purkinje cells combined with astrogliosis leading to psychomotor and memory deficits. Our results demonstrate that this new fucosidosis mouse model resembles the human disease and thus will help to unravel underlying pathological processes. Moreover, this model could be utilized to establish diagnostic and therapeutic strategies for fucosidosis. PMID:27491075
O'Connor, D T; Cervenka, J H; Stone, R A; Parmer, R J; Franco-Bourland, R E; Madrazo, I; Langlais, P J
Although measurement of chromogranin A in the bloodstream is of value in sympathoadrenal investigations, little is systematically known about chromogranin A in cerebrospinal fluid, despite substantial knowledge about its occurrence and distribution in brain. We therefore applied a homologous human chromogranin A radioimmunoassay to cerebrospinal fluid, in order to evaluate the properties and stability of cerebrospinal fluid chomogranin A, as well as its relationship to central noradrenergic neuronal activity, to peripheral (plasma) chromogranin A, and to disease states such as hypertension, renal failure and Parkinsonism. Authentic, physically stable chromogranin A immunoreactivity was found in cerebrospinal fluid (at 37-146 ng/ml; mean, 87.0 +/- 6.0 ng/ml in healthy subjects), and several lines of evidence (including 3.39 +/- 0.27-fold higher chromogranin A in cerebrospinal fluid than in plasma) indicated that it originated from a local central nervous system source, rather than the periphery. Cerebrospinal fluid chromogranin A values were not influenced by administration of effective antihypertensive doses of clonidine or propranolol, and were not related to the cerebrospinal fluid concentrations of norepinephrine, methoxyhydroxyphenylglycol, or dopamine-beta-hydroxylase; thus, cerebrospinal fluid chromogranin A was not closely linked to biochemical or pharmacologic indices of central noradrenergic neuronal activity. Cerebrospinal fluid chromogranin A was not changed (P > 0.1) in essential hypertension (84.2 +/- 14.0 ng/ml) or renal failure (72.2 +/- 13.4 ng/ml), despite a marked (7.1-fold; P < 0.001) increase in plasma chromogranin A in renal failure, and a modest (1.5-fold; P = 0.004) increase in plasma chromogranin A in essential hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)
Abou Al-Shaar, H; Shariff, RK; Albakr, A
Abstract Neurodegenerative disorders are commonly encountered in medical practices. Such diseases can lead to major morbidity and mortality among the affected individuals. The molecular pathogenesis of these disorders is not yet clear. Recent literature has revealed that mutations in RNA-binding proteins are a key cause of several human neuronal-based diseases. This review discusses the role of RNA metabolism in neurological diseases with specific emphasis on roles of RNA translation and microRNAs in neurodegeneration, RNA-mediated toxicity, repeat expansion diseases and RNA metabolism, molecular pathogenesis of amyotrophic lateral sclerosis and frontotemporal dementia, and neurobiology of survival motor neuron (SMN) and spinal muscular atrophy. PMID:27785391
Ndhlovu, L C; Snyder-Cappione, J E; Carvalho, K I; Leal, F E; Loo, C P; bruno, F R; Jha, A R; Devita, D; Hasenkrug, A M; Barbosa, H M R; Segurado, A C; Nixon, D F; Murphy, E L; Kallas, E G
Human T lymphotropic virus type 1 (HTLV-1) infects 10–20 million people worldwide. The majority of infected individuals are asymptomatic; however, approximately 3% develop the debilitating neurological disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). There is also currently no cure, vaccine or effective therapy for HTLV-1 infection, and the mechanisms for progression to HAM/TSP remain unclear. NK T cells are an immunoregulatory T cell subset whose frequencies and effector functions are associated critically with immunity against infectious diseases. We hypothesized that NK T cells are associated with HAM/TSP progression. We measured NK T cell frequencies and absolute numbers in individuals with HAM/TSP infection from two cohorts on two continents: São Paulo, Brazil and San Francisco, CA, USA, and found significantly lower levels when compared with healthy subjects and/or asymptomatic carriers. Also, the circulating NK T cell compartment in HAM/TSP subjects is comprised of significantly more CD4+ and fewer CD8+ cells than healthy controls. These findings suggest that lower numbers of circulating NK T cells and enrichment of the CD4+ NK T subset are associated with HTLV-1 disease progression. PMID:19778295
Stabbing paroxysmal pain due to neurological disease can often be controlled by anticonvulsants, whereas steady burning pain is often responsive to tricyclic antidepressants, and to neuroleptics. Overuse of opiates may actually aggravate the pain, necessitating detoxification. Transcutaneous electrical nerve stimulation is helpful for conditions in which pain is localized, especially if there is a ‘trigger area’ or neuroma, or if paresthesias can be stimulated within the painful area. Local anesthetic injection, possibly with corticosteroid, relieves painful scars and neuromas, neuritis, and tender trigger points. Sympathetic blocks are used for post-herpetic neuralgia and sympathetic dystrophies. Relaxation therapy is a very useful psychological treatment. PMID:21274032
Imaizumi, Yoichi; Okano, Hideyuki
Human induced pluripotent stem (iPS) cells obtained by reprogramming technology are a source of great hope, not only in terms of applications in regenerative medicine, such as cell transplantation therapy, but also for modeling human diseases and new drug development. In particular, the production of iPS cells from the somatic cells of patients with intractable diseases and their subsequent differentiation into cells at affected sites (e.g., neurons, cardiomyocytes, hepatocytes, and myocytes) has permitted the in vitro construction of disease models that contain patient-specific genetic information. For example, disease-specific iPS cells have been established from patients with neuropsychiatric disorders, including schizophrenia and autism, as well as from those with neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease. A multi-omics analysis of neural cells originating from patient-derived iPS cells may thus enable investigators to elucidate the pathogenic mechanisms of neurological diseases that have heretofore been unknown. In addition, large-scale screening of chemical libraries with disease-specific iPS cells is currently underway and is expected to lead to new drug discovery. Accordingly, this review outlines the progress made via the use of patient-derived iPS cells toward the modeling of neurological disorders, the testing of existing drugs, and the discovery of new drugs. The production of human induced pluripotent stem (iPS) cells from the patients' somatic cells and their subsequent differentiation into specific cells have permitted the in vitro construction of disease models that contain patient-specific genetic information. Furthermore, innovations of gene-editing technologies on iPS cells are enabling new approaches for illuminating the pathogenic mechanisms of human diseases. In this review article, we outlined the current status of neurological diseases-specific iPS cell research and described recently obtained
Dutta, Susmita; Singh, Gurbind; Sreejith, Sailaja; Mamidi, Murali Krishna; Husin, Juani Mazmin; Datta, Indrani; Pal, Rajarshi; Das, Anjan Kumar
Neurodegenerative diseases are devastating because they cause increasing loss of cognitive and physical functions and affect an estimated 1 billion individuals worldwide. Unfortunately, no drugs are currently available to halt their progression, except a few that are largely inadequate. This mandates the search of new treatments for these progressively degenerative diseases. Neural stem cells (NSCs) have been successfully isolated, propagated, and characterized from the adult brains of mammals, including humans. The confirmation that neurogenesis occurs in the adult brain via NSCs opens up fresh avenues for treating neurological problems. The proof-of-concept studies demonstrating the neural differentiation capacity of stem cells both in vitro and in vivo have raised widespread enthusiasm toward cell-based interventions. It is anticipated that cell-based neurogenic drugs may reverse or compensate for deficits associated with neurological diseases. The increasing interest of the private sector in using human stem cells in therapeutics is evidenced by launching of several collaborative clinical research activities between Pharma giants and research institutions or small start-up companies. In this review, we discuss the major developments that have taken place in this field to position stem cells as a prospective candidate drug for the treatment of neurological disorders.
Venkataraman, Akila; Adams, Robert J
Sickle cell disease (SCD) is a group of genetic blood disorders that vary in severity, but the most severe forms, primarily homozygous sickle cell anemia, are associated with neurologic complications. Over the last 90 years it has become established that some patients will develop severe arterial disease of the intracranial brain arteries and suffer brain infarction. Smaller infarctions and brain atrophy may also be seen and over time there appear to be negative cognitive effects in some patients, with or without abnormal brain imaging. Focal mononeuropathies and pneumococcal meningitis are also more common in these patients. Brain infarction in children can largely be prevented screening children beginning at age 2 years and instituting regular blood transfusion when the Doppler indicates high stroke risk (>200cm/sec). Iron overload and the uncertain duration of transfusion are disadvantages but overall this approach, tested in a randomized clinical trial, reduced first stroke by over 90%. Secondary stroke prevention has not been subjected to a randomized controlled trial except for one recently stopped comparison of regular transfusions compared to hydroxuyrea (results favored transfusion). The usual stroke prevention agents (such as aspirin or warfarin) have not been rigorously tested. Magnetic resonance imaging and positron emission tomography give evidence of subtle and sometimes overt brain injury due to stroke in many adults, but a preventive strategy for adults with SCD has not been developed. Bone marrow transplantation is the only cure, but some non-neurologic symptoms can be controlled in adults with hydroxuyrea. © 2014 Elsevier B.V. All rights reserved.
Ming, Guo-Li; Brüstle, Oliver; Muotri, Alysson; Studer, Lorenz; Wernig, Marius; Christian, Kimberly M
The remarkable advances in cellular reprogramming have made it possible to generate a renewable source of human neurons from fibroblasts obtained from skin samples of neonates and adults. As a result, we can now investigate the etiology of neurological diseases at the cellular level using neuronal populations derived from patients, which harbor the same genetic mutations thought to be relevant to the risk for pathology. Therapeutic implications include the ability to establish new humanized disease models for understanding mechanisms, conduct high-throughput screening for novel biogenic compounds to reverse or prevent the disease phenotype, identify and engineer genetic rescue of causal mutations, and develop patient-specific cellular replacement strategies. Although this field offers enormous potential for understanding and treating neurological disease, there are still many issues that must be addressed before we can fully exploit this technology. Here we summarize several recent studies presented at a symposium at the 2011 annual meeting of the Society for Neuroscience, which highlight innovative approaches to cellular reprogramming and how this revolutionary technique is being refined to model neurodevelopmental and neurodegenerative diseases, such as autism spectrum disorders, schizophrenia, familial dysautonomia, and Alzheimer's disease.
Bandmann, Oliver; Weiss, Karl Heinz; Kaler, Stephen G.
Summary The classic copper metabolism disorder, Wilson disease (WD), was first defined in 1912. Both early onset presentations in infancy and late onset manifestations in adults > 70 years are now well recognized. Modern biochemical and genetic prevalence studies suggest that WD may be considerably more common than previously appreciated. Early diagnosis of WD is crucial to ensure that patients can be started on adequate treatment but uncertainty remains about the best possible choice of medication. Direct genetic testing for ATP7B mutations is increasingly available to confirm the clinical diagnosis of WD. WD needs to be differentiated from other conditions that present clinically with hepatolenticular degeneration or share biochemical abnormalities with WD, such as reduced serum cerulo plasmin levels. Disordered copper metabolism is also implied in an increasing number of other neurological conditions, including a subtype of axonal neuropathy due to ATP7A mutations, and the common late-onset neurodegenerative disorders Alzheimer’s disease and Parkinson’s disease. PMID:25496901
Norenberg, M D; Rao, K V Rama
Mitochondria, being the principal source of cellular energy, are vital for cell life. Yet, ironically, they are also major mediators of cell death, either by necrosis or apoptosis. One means by which these adverse effects occur is through the mitochondrial permeability transition (mPT) whereby the inner mitochondrial membrane suddenly becomes excessively permeable to ions and other solutes, resulting in a collapse of the inner membrane potential, ultimately leading to energy failure and cell necrosis. The mPT may also bring about the release of various factors known to cause apoptotic cell death. The principal factors leading to the mPT are elevated levels of intracellular Ca2+ and oxidative stress. Characteristically, the mPT is inhibited by cyclosporin A. This article will briefly discuss the concept of the mPT, its molecular composition, its inducers and regulators, agents that influence its activity and describe the consequences of its induction. Lastly, we will review its potential contribution to acute neurological disorders, including ischemia, trauma, and toxic-metabolic conditions, as well as its role in chronic neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis.
The large conductance, Ca2+-activated K+ channels (BKCa, KCa1.1) are expressed in various brain neurons where they play important roles in regulating action potential duration, firing frequency and neurotransmitter release. Membrane potential depolarization and rising levels of intracellular Ca2+ gated BKCa channels, which in turn results in an outward K+ flux that re/hyperpolarizes the membrane. The sensitivity of BKCa channels to Ca2+ provides an important negative-feedback system for Ca2+ entry into brain neurons and suppresses repetitive firing. Thus, BKCa channel loss-of-function gives rise to neuronal hyperexcitability, which can lead to seizures. Evidence also indicates that BKCa channels can facilitate high-frequency firing (gain-of-function) in some brain neurons. Interestingly, both gain-of-function and loss-of-function mutations of genes encoding for various BKCa channel subunits have been associated with the development of neuronal excitability disorders, such as seizure disorders. The role of BKCa channels in the etiology of some neurological diseases raises the possibility that these channels can be used as molecular targets to prevent and suppress disease phenotypes. PMID:25324781
Freeze, Hudson H.; Eklund, Erik A.; Ng, Bobby G.; Patterson, Marc C.
This review will present principles of glycosylation, describe the relevant glycosylation pathways and their related disorders, and highlight some of the neurological aspects and issues that continue to challenge researchers. Over 100 rare human genetic disorders that result from deficiencies in the different glycosylation pathways are known today. Most of these disorders impact the central and/or peripheral nervous systems. Patients typically have developmental delay/intellectual disability, hypotonia, seizures, neuropathy, and metabolic abnormalities in multiple organ systems. Between these disorders there is great clinical diversity because all cell types differentially glycosylate proteins and lipids. The patients have hundreds of mis-glycosylated products afflicting a myriad of processes including cell signaling, cell-cell interaction and cell migration. This vast complexity in glycan composition and function, along with limited analytic tools has impeded the identification of key glycosylated molecules that cause pathologies, and to date few critical target proteins have been pinpointed. PMID:25840006
Small, Scott A; Petsko, Gregory A
Retromer is a protein assembly that has a central role in endosomal trafficking, and retromer dysfunction has been linked to a growing number of neurological disorders. First linked to Alzheimer disease, retromer dysfunction causes a range of pathophysiological consequences that have been shown to contribute to the core pathological features of the disease. Genetic studies have established that retromer dysfunction is also pathogenically linked to Parkinson disease, although the biological mechanisms that mediate this link are only now being elucidated. Most recently, studies have shown that retromer is a tractable target in drug discovery for these and other disorders of the nervous system.
van Eeden, Charmaine; Williams, June H; Gerdes, Truuske G H; van Wilpe, Erna; Viljoen, Adrianne; Swanepoel, Robert; Venter, Marietjie
To determine which agents cause neurologic disease in horses, we conducted reverse transcription PCR on isolates from of a horse with encephalitis and 111 other horses with acute disease. Shuni virus was found in 7 horses, 5 of which had neurologic signs. Testing for lesser known viruses should be considered for horses with unexplained illness.
Deleidi, Michela; Jäggle, Madeline; Rubino, Graziella
As we age, the immune system undergoes a process of senescence accompanied by the increased production of proinflammatory cytokines, a chronic subclinical condition named as “inflammaging”. Emerging evidence from human and experimental models suggest that immune senescence also affects the central nervous system and promotes neuronal dysfunction, especially within susceptible neuronal populations. In this review we discuss the potential role of immune aging, inflammation and metabolic derangement in neurological diseases. The discovery of novel therapeutic strategies targeting age-linked inflammation may promote healthy brain aging and the treatment of neurodegenerative as well as neuropsychiatric disorders. PMID:26089771
Youn, Jinyoung; Kim, Ji Sun; Kim, Hee-Tae; Lee, Jee-Young; Lee, Phil Hyu; Ki, Chang-Seok; Cho, Jin Whan
Although Kayser-Fleischer ring has been regarded as a key diagnostic feature of neurologic Wilson's disease, there have been previous reports of neurologic Wilson's disease patients without Kayser-Fleischer ring. We assessed the characteristics of neurologic Wilson's disease patients without Kayser-Fleischer ring. We enrolled neurologic Wilson's disease patients from 4 university hospitals by review of medical records in this study. Patients with neurologic Wilson's disease were diagnosed based on the neurologic symptoms and international scoring system for the diagnosis of Wilson's disease. All subjects were divided into two groups according to the presence of a Kayser-Fleischer ring. We compared demographic data, laboratory findings and imaging findings of the liver and brain between the two groups. There were 12 (26.7%) patients without Kayser-Fleischer ring out of a total of 45 neurologic Wilson's disease patients. The Wilson's disease patients without Kayser-Fleischer ring demonstrated a higher ceruloplasmin concentration and serum copper level than those with Kayser-Fleischer ring. In addition, liver cirrhosis and typical signal changes in brain magnetic resonance imaging were less common in neurologic Wilson's disease patients without Kayser-Fleischer ring. Based on our results, the absence of Kayser-Fleischer ring can be regarded as a form of neurologic Wilson's disease with less copper involvement. In addition, it is important to understand these features and to perform further investigations if patients without Kayser-Fleischer ring are suspected of having neurologic Wilson's disease. Copyright © 2012 Elsevier B.V. All rights reserved.
Neurological diseases and nutrition are in complex relationship. In the first part of this review the nutritional consequences of acute neurological diseases is presented, with special emphasis on traumatic injuries of the nervous system and stroke. Nutritional therapy of these patients is described in detail. In addition, chronic, degenerative neurological pathological conditions are also discussed, including nutritional consequences and possibilities of therapy. Some ethical and legal issues are also considered. The second part of this review article describes neurological consequences of nutritional problems, both deficits of macro- and micronutrients and toxic effects.
Bodensteiner, John B; Ng, Yu-Tze
The pace of developing technology with respect to many diagnostic tests, as well as available treatments including artificial ventilation, may have progressed at a faster rate than our ethical, humane ability to decide on the optimal choices for our patients. In fact, who should make these choices; physicians or patients and families? Certain ethical aspects of neuromuscular disorders and epilepsy are reviewed. For neuromuscular disease, the example of Duchenne muscular dystrophy (DMD) with regards to genetic testing, relatively early wheelchair placement and individualised invasive ventilation is discussed. In epilepsy, performing neurosurgery in severely impaired children is probably appropriate in some cases if desired by the family. Financial and human costs restrict therapies and testing for epilepsy as well as other neurological and medical diseases. Whether it is ethical to consider costs in medical treatment or not, it is certainly a reality.
Ohue, Shiro; Kumon, Yoshiaki; Kohno, Kanehisa; Watanabe, Hideaki; Iwata, Shiinji; Ohnishi, Takanori
Several authors have reported temporary neurologic deterioration after revascularization surgery in some patients with moyamoya disease. The present study examined the incidence and mechanisms of PONDs in adult patients with moyamoya disease. Postoperative neurological deficits were retrospectively evaluated 1 month or less postoperatively on 32 hemispheric sides of 17 symptomatic adult patients with moyamoya disease treated surgically with direct and/or indirect revascularization. Various PONDs were observed in 9 sides (28%) from 7 patients 1 month or less after surgery. Symptoms were recognized in 7 (39%) of 18 sides with ischemic onset, and 2 (14%) of 14 sides with hemorrhagic onset. Postoperative neurological deficits were usually observed 1 week or less after surgery, and resolved within 2 weeks. Postoperative neurological deficits were divided into 3 groups based on duration of symptoms: single transient neurologic deficits in 3 sides; repeated transient neurologic deficits in 3 sides; and continuous neurologic deficits in 3 sides. Radiologic examinations demonstrated no ischemic changes in any patients, and subsequent focal hyperemia after surgery on 3 sides. Postoperative neurological deficits occurred more frequently in younger patients or those with poor vascular response before surgery. Postoperative neurological deficits frequently occur in patients with moyamoya disease, but are temporary. These deficits appear to result from focal hyperperfusion after surgery, rather than from ischemic changes.
DALIRANI, Reza; MAHYAR, Abolfazl; AYAZI, Parviz; AHMADI, Ghazaleh
Objective Renal diseases are one of the most common causes of referrals and admissions of children, hence it is important to know their neurological presentations. This study aimed to determine neurological presentations of renal diseases in children. Material & Methods A total of 634 children with renal diseases, admitted to Qazvin Pediatric Hospital, Qazvin, central Iran from 2011 to 2013 were studied. Neurological presentations of patients were established and the results were analyzed using statistical tests. Results Neurological presentations were found in 18 (2.8%) out of 634 patients, of whom 15 had febrile seizures, two thromboembolism, and one encephalopathy. Among patients with urinary tract infection (UTI), 2.6% had febrile seizures, 11.1% of those with glomerulonephritis had encephalopathy, and 3.7% of those with nephrotic syndrome had cerebral thromboembolism. Conclusion Results showed neurological presentations in 2.8% of children with renal diseases, and febrile seizure as the most common presentation. PMID:27375752
Greenberg, David S; Soreq, Hermona
Developing microRNA therapeutics for neurological diseases is both a promising opportunity and an extremely challenging topic for several reasons. The promise stems from the very small size of microRNAs, which makes them amenable for manipulation via short synthetic oligonucleotides or engineered viruses. Also, the fact that each microRNA may regulate numerous target transcripts of the same pathway predicts that such manipulations may affect an entire pathway rather than a single gene and gives reason to hope that low dose therapeutic targeting of the top microRNA in such a hierarchic pyramid would suffice to induce a focused change in the entire pyramid. However, these same features, which make microRNAs such promising targets for therapeutic manipulations also present great challenges. Thus the plethora of functional targets for each microRNA in specific cell types is yet far from being elucidated, which implies that the targets to be affected may not be those planned to be manipulated (a risk of 'off-target' effects). Also, the hierarchic order of microRNA regulation is yet unknown, which predicts a risk of complex, multi-leveled consequences following the manipulation of a single microRNA; and the delivery of oligonucleotide therapeutics into the brain is a challenge due to the blood-brain barrier. In this chapter, we briefly outline the current state of knowledge regarding microRNA regulation in different neuropathologies and sketch the emerging principles for the development of microRNA therapeutics for these diseases.We address issues such as modes of delivery and consideration of the inherited and acquired variability between individuals in the susceptibility to such treatments. We further refer in a somewhat more in-depth manner to the issue of manipulating microRNA functioning in the parasympathetic system and the pathway of cholinergic signaling. Beyond the brain and within it, cholinergic signaling controls inflammatory reactions, and microRNA changes
Giles, Lucy; Orr, Jayne; Viora, Lorenzo; Gutierrez-Quintana, Rodrigo; Logue, David; Guevar, Julien
Between January 2006 and June 2016, 96 ruminants with neurological signs were donated to the Scottish Centre for Production Animal Health and Food Safety (SCPAHFS), University of Glasgow, by veterinarians in the field representing 5.4 per cent of all submissions. Forty-seven different neurological presenting signs were reported with 79 per cent of the donated patients presenting with abnormal gait. All cases presenting with abnormalities in more than 4 out of 10 neurological categories died or were euthanased on welfare grounds. Calves were significantly more likely to present with neurological disorders than adult cattle compared with the proportion of calves: cows in the Scottish cattle population and total case population donated to SCPAHFS. Lesions were most commonly localised to the spinal cord in sheep 47 per cent (16), the peripheral nervous system in cattle 45 per cent (28) and to the brain in the overall population 41 per cent (39). The most common aetiology of neurological pathologies observed was infectious or inflammatory 28 per cent (27). Definitive diagnoses could be reached in 84 per cent (81) of patients. When postmortem reports were available, they produced a diagnosis in 70 per cent (52) of cases and contradicted clinical diagnoses in 38 per cent (26) of cases. The most frequently diagnosed conditions in ruminants over the 10 years were spastic paresis, vertebral osteomyelitis and listeriosis. © British Veterinary Association (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
Lin, Chia-Ching John; Deneen, Benjamin
The central nervous system (CNS) is comprised of numerous cell types that work in concert to facilitate proper function and homeostasis. Disruption of these carefully orchestrated networks results in neuronal dysfunction, manifesting itself in a variety of neurological disorders. While neuronal dysregulation is causative of symptoms manifest in the clinic, the etiology of these disorders is often more complex than simply a loss of neurons or intrinsic dysregulation of their function. In the adult brain, astrocytes comprise the most abundant cell type and play key roles in CNS physiology, therefore it stands to reason that dysregulation of normal astrocyte function contributes to the etiology and progression of varied neurological disorders. We review here some neurological disorders associated with an astrocyte factor and discuss how the related astrocyte dysfunction contributes to the etiology and/or progression of these disorders. PMID:24365571
Prehistoric enemies within: The contribution of human endogenous retroviruses to neurological diseases. Meeting report: "Second International Workshop on Human Endogenous Retroviruses and Disease", Washington DC, March 13th and 14th 2017.
Kremer, David; Glanzman, Robert; Traboulsee, Anthony; Nath, Avindra; Groc, Laurent; Horwitz, Marc; Göttle, Peter; Perron, Hervé; Gold, Julian; Hartung, Hans-Peter; Küry, Patrick
The Second International Workshop on Human Endogenous Retroviruses and Disease, Washington DC, March 13-14 2017 brought together international basic and clinical scientists investigating the involvement of human endogenous retroviruses (HERVs) in complex human diseases. Copyright © 2017 Elsevier B.V. All rights reserved.
Teive, Hélio A G; Munhoz, Renato P; Paola, Luciano De
The relationship between fictional literature and Medicine, particularly Neurology, is very wide. The aim of this review is to analyze the Dalton Trevisan's work, considered the most important Brazilian short stories writer, focusing in the description of neurological diseases. A comprehensive evaluation of Dalton Trevisan's texts in books published between 1959 and 2012. Descriptions of the common neurological diseases embedded in Trevisan's work, such as, epilepsy and stroke, are presented. This review disclosed neurological conditions highly prevalent in the general population, namely epilepsy and stroke, which have deserved a practical and objective approach by the Brazilian master of the short stories. The fictional World of the famous Brazilian writer Dalton Trevisan is punctuated by everyday routine facts, which are however flavored with the tragic-grotesque touch so peculiar to the author. Neurological diseases, particularly epilepsy and stroke, are no exception to this universe and are exquisitely described by the writer.
Cai, Sa; Chan, Ying-Shing; Shum, Daisy Kwok-Yan
The availability of human stem cells heralds a new era for in vitro cell-based modeling of neurodevelopmental and neurodegenerative diseases. Adding to the excitement is the discovery that somatic cells of patients can be reprogrammed to a pluripotent state from which neural lineage cells that carry the disease genotype can be derived. These in vitro cell-based models of neurological diseases hold promise for monitoring of disease initiation and progression, and for testing of new drug treatments on the patient-derived cells. In this review, we focus on the prospective applications of different stem cell types for disease modeling and drug screening. We also highlight how the availability of patient-specific induced pluripotent stem cells (iPS cells) offers a unique opportunity for studying and modeling human neurodevelopmental and neurodegenerative diseases in vitro and for testing small molecules or other potential therapies for these disorders. Finally, the limitations of this technology from the standpoint of reprogramming efficiency and therapeutic safety are discussed.
Block, Valerie A. J.; Pitsch, Erica; Tahir, Peggy; Cree, Bruce A. C.; Allen, Diane D.; Gelfand, Jeffrey M.
Objective To perform a systematic review of studies using remote physical activity monitoring in neurological diseases, highlighting advances and determining gaps. Methods Studies were systematically identified in PubMed/MEDLINE, CINAHL and SCOPUS from January 2004 to December 2014 that monitored physical activity for ≥24 hours in adults with neurological diseases. Studies that measured only involuntary motor activity (tremor, seizures), energy expenditure or sleep were excluded. Feasibility, findings, and protocols were examined. Results 137 studies met inclusion criteria in multiple sclerosis (MS) (61 studies); stroke (41); Parkinson's Disease (PD) (20); dementia (11); traumatic brain injury (2) and ataxia (1). Physical activity levels measured by remote monitoring are consistently low in people with MS, stroke and dementia, and patterns of physical activity are altered in PD. In MS, decreased ambulatory activity assessed via remote monitoring is associated with greater disability and lower quality of life. In stroke, remote measures of upper limb function and ambulation are associated with functional recovery following rehabilitation and goal-directed interventions. In PD, remote monitoring may help to predict falls. In dementia, remote physical activity measures correlate with disease severity and can detect wandering. Conclusions These studies show that remote physical activity monitoring is feasible in neurological diseases, including in people with moderate to severe neurological disability. Remote monitoring can be a psychometrically sound and responsive way to assess physical activity in neurological disease. Further research is needed to ensure these tools provide meaningful information in the context of specific neurological disorders and patterns of neurological disability. PMID:27124611
Dumitrache, Lavinia C.; McKinnon, Peter J.
A variety of human neurologic diseases are caused by inherited defects in DNA repair. In many cases, these syndromes almost exclusively impact the nervous system, underscoring the critical requirement for genome stability in this tissue. A striking example of this is defective enzymatic activity of polynucleotide kinase-phosphatase (PNKP), leading to microcephaly or neurodegeneration. Notably, the broad neural impact of mutations in PNKP can result in markedly different disease entities, even when the inherited mutation is the same. For example microcephaly with seizures (MCSZ) results from various hypomorphic PNKP mutations, as does ataxia with oculomotor apraxia 4 (AOA4). Thus, other contributing factors influence the neural phenotype when PNKP is disabled. Here we consider the role for PNKP in maintaining brain function and how perturbation in its activity can account for the varied pathology of neurodegeneration or microcephaly present in MCSZ and AOA4 respectively. PMID:27125728
Liang, Nicholas; Trujillo, Cleber A; Negraes, Priscilla D; Muotri, Alysson R; Lameu, Claudiana; Ulrich, Henning
Human induced pluripotent stem cells (iPSCs) represent a revolutionary tool for disease modeling and drug discovery. The generation of tissue-relevant cell types exhibiting a patient's genetic and molecular background offers the ability to develop individual and effective therapies. In this review, we present some major achievements in the neuroscience field using iPSCs and discuss promising perspectives in personalized medicine. In addition to disease modeling, the understanding of the cellular and molecular basis of neurological disorders is explored, including the discovery of new targets and potential drugs. Ultimately, we highlight how iPSC technology, together with genome editing approaches, may bring a deep impact on pre-clinical trials by reducing costs and increasing the success of treatments in a personalized fashion. Copyright © 2017 Elsevier Inc. All rights reserved.
Maher, Ahmed; Abdel Rahman, Mohamed F; Gad, Mohamed Z
Until the beginning of the 1980s, nitric oxide (NO) was just a toxic molecule of a lengthy list of environmental pollutants such as cigarette smoke and smog. In fact, NO had a very bad reputation of being destroyer of ozone, suspected carcinogen and precursor of acid rain. However, by the early 1990s it was well recognized by the medical research community. Over the last two decades, the picture has been totally changed. Diverse lines of evidence have converged to show that this sometime poison is a fundamental player in the everyday business of the human body. NO activity was probed in the brain, arteries, immune system, liver, pancreas, uterus, peripheral nerves, lungs, and almost every system in the human body. NO is a major player in the cardiovascular system as it is involved in regulating blood pressure. In the CNS, it is involved in memory formation and the regulation of cerebral blood flow to ensure adequate supply of blood to the brain. Because NO is involved in many pathways, it has a role in several diseases related to modern life as hypertension, coronary heart diseases, Alzheimer's Disease, stroke and cancer. This chapter focuses on the discussion of the role of NO in neurological diseases and cancer and how can this Janus-faced molecule play a role in the pathology and personalized treatment of these diseases.
Ramírez-Romero, Rafael; Ramírez-Hernández, Cecilia; García-Márquez, Luis Jorge; Macedo-Barragán, Rafael Julio; Martínez-Burnes, Julio; López-Mayagoitia, Alfonso
The number of large feedlot operations, similar to that of USA and Canada, has notably increased in Mexico in the last three decades. Clinical and laboratory diagnoses of neurological diseases in feedlot cattle are crucial in Mexico and Central America because of the high incidence of bovine paralytic rabies (BPR). Because of its zoonotic potential, BPR must be promptly diagnosed and differentiated from other bovine neurological diseases such as thrombotic meningoencephalitis (TME), polioencephalomalacia (PEM) and botulism. More recently, BPR and botulism have been diagnosed with increasing frequency in Mexican feedlots. Neither BPR nor botulism has relevant gross lesions, thus post-mortem diagnosis without laboratory support is impossible. Herein, we describe five outbreaks of neurological diseases in Mexican feedlots in which BPR, botulism and PEM were diagnosed either independently or in combination. A diagram illustrating the most conspicuous pathologic findings and ancillary laboratory test required to confirm the diagnoses of these neurological diseases in feedlot cattle is proposed.
Yu, Diana X; Marchetto, Maria C; Gage, Fred H
Somatic cellular reprogramming is a fast-paced and evolving field that is changing the way scientists approach neurological diseases. For the first time in the history of neuroscience, it is feasible to study the behavior of live neurons from patients with neurodegenerative diseases, such as Alzheimer's and Parkinson's disease, and neuropsychiatric diseases, such as autism and schizophrenia. In this Perspective, we will discuss reprogramming technology in the context of its potential use for modeling and treating neurological and psychiatric diseases and will highlight areas of caution and opportunities for improvement.
Lagunju, I A; Brown, B J
Sickle cell disease (SCD) is reported to be the most common genetic disorder affecting Nigerians. Children with SCD are at a high risk of neurological morbidity. The main objective of this study was to determine the pattern of adverse neurological outcomes among a cohort of Nigerian children with SCD. All children with SCD seen in the Department of Paediatrics, University College Hospital, Ibadan, Nigeria, over a period of 2 years were carefully evaluated for symptoms and signs of neurological complications, defined as clinical outcomes referable to the central nervous system. Of the 214 children evaluated, 187 were diagnosed with Hb SS disease and 27 with Hb SC disease. Neurological complications were identified in 78 (36.4 %) of the cases. The most common complications were headache (17.8 %), seizure (9.3 %) and stroke (8.4 %). Other less frequent complications included bacterial meningitis (2.8 %), spontaneous visual loss (1.4 %), paraplegia (0.9 %) and transient ischaemic attacks (0.9 %). Neurological complications occurred more frequently in children with sickle cell anaemia than in those with Hb SC disease (P = 0.002, 95 % CI 1.450-82.870). Adverse neurological events are common in Nigerian children with SCD, with a significantly higher risk in Hb SS than Hb SC disease. Stroke represents a major underlying cause of symptomatic epilepsy in SCD. Institution of primary preventive measures for stroke in SCD will significantly reduce the burden of stroke and epilepsy associated with SCD in Nigeria.
Della Ragione, Floriana; Gagliardi, Miriam; D'Esposito, Maurizio; Matarazzo, Maria R.
Novel classes of small and long non-coding RNAs (ncRNAs) are increasingly becoming apparent, being engaged in diverse structural, functional and regulatory activities. They take part in target gene silencing, play roles in transcriptional, post-transcriptional and epigenetic processes, such as chromatin remodeling, nuclear reorganization with the formation of silent compartments and fine-tuning of gene recruitment into them. Among their functions, non-coding RNAs are thought to act either as guide or scaffold for epigenetic modifiers that write, erase, and read the epigenetic signature over the genome. Studies on human disorders caused by defects in epigenetic modifiers and involving neurological phenotypes highlight the disruption of diverse classes of non-coding RNAs. Noteworthy, these molecules mediate a wide spectrum of neuronal functions, including brain development, and synaptic plasticity. These findings imply a significant contribution of ncRNAs in pathophysiology of the aforesaid diseases and provide new concepts for potential therapeutic applications. PMID:24616662
Only a very few systematic studies have investigated the frequency of neurologic disorders in patients with Crohn’s disease (CD) and ulcerative colitis (UC), which are the two main types of inflammatory bowel disease (IBD). Results have been inconsistent and variable, owing to differences in case-finding methods and evaluated outcomes in different studies. The most frequent neurologic manifestations reported in CD and UC populations are cerebrovascular disease (with either arterial or venous events), demyelinating central nervous system disease, and peripheral neuropathy (whether axonal or demyelinating); however, the literature describes numerous nervous system disorders as being associated with IBD. The pathogenesis of nervous system tissue involvement in IBD has yet to be elucidated, although it seems to be related to immune mechanisms or prothrombotic states. The recently-introduced tumor necrosis factor (TNF) inhibitors have proven successful in controlling moderate to severe IBD activity. However, severe neurologic disorders associated with TNF inhibitors have been reported, which therefore raises concerns regarding the effect of anti-TNF-α antibodies on the nervous system. Although neurological involvement associated with IBD is rarely reported, gastroenterologists should be aware of the neurologic manifestations of IBD in order to provide early treatment, which is crucial for preventing major neurologic morbidity. PMID:24574797
Rivinus, T M; Jamison, D L; Graham, P J
Over a period of one year 12 children with complaints which had been diagnosed as due to a psychiatric disorder presented to a paediatric neurological unit where neurological disease was diagnosed. The group was characterized by behavioural symptoms such as deteriorating school performance, visual loss, and postural disturbance, which are unusual in children attending child psychiatric departments. It is suggested that where there is diagnostic uncertainty the presence of these physical symptoms calls for periodic neurological reassessment, and attention is drawn to the rare but serious disorders which may thus be diagnosed. Making an organic diagnosis, however, should not preclude psychosocial management of emotional reactions in these families. PMID:1130816
Zhang, Ai-hua; Sun, Hui; Wang, Xi-jun
Discovery of clinically relevant biomarkers for diseases has revealed metabolomics has potential advantages that classical diagnostic approaches do not. The great asset of metabolomics is that it enables assessment of global metabolic profiles of biofluids and discovery of biomarkers distinguishing disease status, with the possibility of enhancing clinical diagnostics. Most current clinical chemistry tests rely on old technology, and are neither sensitive nor specific for a particular disease. Clinical diagnosis of major neurological disorders, for example Alzheimer's disease and Parkinson's disease, on the basis of current clinical criteria is unsatisfactory. Emerging metabolomics is a powerful technique for discovering novel biomarkers and biochemical pathways to improve diagnosis, and for determination of prognosis and therapy. Identifying multiple novel biomarkers for neurological diseases has been greatly enhanced with recent advances in metabolomics that are more accurate than routine clinical practice. Cerebrospinal fluid (CSF), which is known to be a rich source of small-molecule biomarkers for neurological and neurodegenerative diseases, and is in close contact with diseased areas in neurological disorders, could potentially be used for disease diagnosis. Metabolomics will drive CSF analysis, facilitate and improve the development of disease treatment, and result in great benefits to public health in the long-term. This review covers different aspects of CSF metabolomics and discusses their significance in the postgenomic era, emphasizing the potential importance of endogenous small-molecule metabolites in this emerging field.
Cote, David J; Bredenoord, Annelien L; Smith, Timothy R; Ammirati, Mario; Brennum, Jannick; Mendez, Ivar; Ammar, Ahmed S; Balak, Naci; Bolles, Gene; Esene, Ignatius Ngene; Mathiesen, Tiit; Broekman, Marike L
The application of stem cell transplants in clinical practice has increased in frequency in recent years. Many of the stem cell transplants in neurologic diseases, including stroke, Parkinson disease, spinal cord injury, and demyelinating diseases, are unproven-they have not been tested in prospective, controlled clinical trials and have not become accepted therapies. Stem cell transplant procedures currently being carried out have therapeutic aims, but are frequently experimental and unregulated, and could potentially put patients at risk. In some cases, patients undergoing such operations are not included in a clinical trial, and do not provide genuinely informed consent. For these reasons and others, some current stem cell interventions for neurologic diseases are ethically dubious and could jeopardize progress in the field. We provide discussion points for the evaluation of new stem cell interventions for neurologic disease, based primarily on the new Guidelines for Stem Cell Research and Clinical Translation released by the International Society for Stem Cell Research in May 2016. Important considerations in the ethical translation of stem cells to clinical practice include regulatory oversight, conflicts of interest, data sharing, the nature of investigation (e.g., within vs outside of a clinical trial), informed consent, risk-benefit ratios, the therapeutic misconception, and patient vulnerability. To help guide the translation of stem cells from the laboratory into the neurosurgical clinic in an ethically sound manner, we present an ethical discussion of these major issues at stake in the field of stem cell clinical research for neurologic disease. © 2016 American Academy of Neurology.
Bryan, Laura K; Hamer, Sarah A; Shaw, Sarah; Curtis-Robles, Rachel; Auckland, Lisa D; Hodo, Carolyn L; Chaffin, Keith; Rech, Raquel R
A 10-year-old Quarter Horse gelding presented to the Texas A&M University Veterinary Teaching Hospital with a six month-history of ataxia and lameness in the hind limbs. The horse was treated presumptively for equine protozoal myeloencephalitis (EPM) based on clinical signs but was ultimately euthanized after its condition worsened. Gross lesions were limited to a small area of reddening in the gray matter of the thoracic spinal cord. Histologically, trypanosome amastigotes morphologically similar to Trypanosoma cruzi, the agent of Chagas disease in humans and dogs, were sporadically detected within segments of the thoracic spinal cord surrounded by mild lymphoplasmacytic inflammation. Ancillary testing for Sarcocystis neurona, Neospora spp., Toxoplasma gondii and Leishmania spp. was negative. Conventional and real time polymerase chain reaction (PCR) of affected paraffin embedded spinal cord were positive for T. cruzi, and sequencing of the amplified T. cruzi satellite DNA PCR fragment from the horse was homologous with various clones of T. cruzi in GenBank. While canine Chagas disease cases have been widely reported in southern Texas, this is the first report of clinical T. cruzi infection in an equid with demonstrable amastigotes in the spinal cord. In contrast to previous instances of Chagas disease in the central nervous system (CNS) of dogs and humans, no inflammation or T. cruzi amastigotes were detected in the heart of the horse. Based on clinical signs, there is a potential for misdiagnosis of Chagas disease with other infectious diseases that affect the equine CNS. T. cruzi should be considered as a differential diagnosis in horses with neurologic clinical signs and histologic evidence of meningomyelitis that originate in areas where Chagas disease is present. The prevalence of T. cruzi in horses and the role of equids in the parasite life cycle require further study. Copyright © 2015 Elsevier B.V. All rights reserved.
Trofimenko, Vera; Hotaling, James M
Infertility in individuals with neurologic disorders is complex in etiology and manifestation. Its management therefore often requires a multimodal approach. This review addresses the implications of spinal cord injury (SCI) and other neurologic disease on fertility, including the high prevalence of sexual dysfunction, ejaculation disorders and compromised semen parameters. Available treatment approaches discussed include assisted ejaculation techniques and assisted reproductive technology including surgical sperm retrieval and intracytoplasmic sperm injection (ICSI).
Infertility in individuals with neurologic disorders is complex in etiology and manifestation. Its management therefore often requires a multimodal approach. This review addresses the implications of spinal cord injury (SCI) and other neurologic disease on fertility, including the high prevalence of sexual dysfunction, ejaculation disorders and compromised semen parameters. Available treatment approaches discussed include assisted ejaculation techniques and assisted reproductive technology including surgical sperm retrieval and intracytoplasmic sperm injection (ICSI). PMID:26904416
Roep, Bart O
Viral infections have been associated with the development of several neurological and neuroendocrine autoimmune diseases. Structural similarities between environmental proteins and self-proteins have long been proposed to be targets for immune cross reactivity associated with initiation of autoimmune diseases. This mechanism called molecular mimicry has also been put forward for immune mediated neurological diseases associated with viral infection. Although many potential candidates for cross reactivity have been put forward, only few have been substantiated on the molecular level. For the definition of cellular immune cross-reactivity, it proved critical to appreciate that recognition patterns of T-cells are not linear. Subsequent microarray studies unequivocally demonstrated functional mimicry of seemingly disparate amino acid sequences. This review summarises the present evidence for molecular mimicry in neurological autoimmune diseases and virus
Csoti, Ilona; Jost, Wolfgang H; Reichmann, Heinz
General medical problems and complications have a major impact on the quality of life in all stages of Parkinson's disease. To introduce an effective treatment, a comprehensive analysis of the various clinical symptoms must be undertaken. One must distinguish between (1) diseases which arise independently of Parkinson's disease, and (2) diseases which are a direct or indirect consequence of Parkinson's disease. Medical comorbidity may induce additional limitations to physical strength and coping strategies, and may thus restrict the efficacy of the physical therapy which is essential for treating hypokinetic-rigid symptoms. In selecting the appropriate medication for the treatment of any additional medical symptoms, which may arise, its limitations, contraindications and interactions with dopaminergic substances have to be taken into consideration. General medical symptoms and organ manifestations may also arise as a direct consequence of the autonomic dysfunction associated with Parkinson's disease. As the disease progresses, additional non-parkinsonian symptoms can be of concern. Furthermore, the side effects of Parkinson medications may necessitate the involvement of other medical specialists. In this review, we will discuss the various general medical aspects of Parkinson's disease.
Gano, Lindsey B.; Patel, Manisha; Rho, Jong M.
The ketogenic diet (KD) is a broad-spectrum therapy for medically intractable epilepsy and is receiving growing attention as a potential treatment for neurological disorders arising in part from bioenergetic dysregulation. The high-fat/low-carbohydrate “classic KD”, as well as dietary variations such as the medium-chain triglyceride diet, the modified Atkins diet, the low-glycemic index treatment, and caloric restriction, enhance cellular metabolic and mitochondrial function. Hence, the broad neuroprotective properties of such therapies may stem from improved cellular metabolism. Data from clinical and preclinical studies indicate that these diets restrict glycolysis and increase fatty acid oxidation, actions which result in ketosis, replenishment of the TCA cycle (i.e., anaplerosis), restoration of neurotransmitter and ion channel function, and enhanced mitochondrial respiration. Further, there is mounting evidence that the KD and its variants can impact key signaling pathways that evolved to sense the energetic state of the cell, and that help maintain cellular homeostasis. These pathways, which include PPARs, AMP-activated kinase, mammalian target of rapamycin, and the sirtuins, have all been recently implicated in the neuroprotective effects of the KD. Further research in this area may lead to future therapeutic strategies aimed at mimicking the pleiotropic neuroprotective effects of the KD. PMID:24847102
Gano, Lindsey B; Patel, Manisha; Rho, Jong M
The ketogenic diet (KD) is a broad-spectrum therapy for medically intractable epilepsy and is receiving growing attention as a potential treatment for neurological disorders arising in part from bioenergetic dysregulation. The high-fat/low-carbohydrate "classic KD", as well as dietary variations such as the medium-chain triglyceride diet, the modified Atkins diet, the low-glycemic index treatment, and caloric restriction, enhance cellular metabolic and mitochondrial function. Hence, the broad neuroprotective properties of such therapies may stem from improved cellular metabolism. Data from clinical and preclinical studies indicate that these diets restrict glycolysis and increase fatty acid oxidation, actions which result in ketosis, replenishment of the TCA cycle (i.e., anaplerosis), restoration of neurotransmitter and ion channel function, and enhanced mitochondrial respiration. Further, there is mounting evidence that the KD and its variants can impact key signaling pathways that evolved to sense the energetic state of the cell, and that help maintain cellular homeostasis. These pathways, which include PPARs, AMP-activated kinase, mammalian target of rapamycin, and the sirtuins, have all been recently implicated in the neuroprotective effects of the KD. Further research in this area may lead to future therapeutic strategies aimed at mimicking the pleiotropic neuroprotective effects of the KD.
Nageshwaran, Sathiji; Festenstein, Richard
The term "junk DNA" has been reconsidered following the delineation of the functional significance of repetitive DNA regions. Typically associated with centromeres and telomeres, DNA repeats are found in nearly all organisms throughout their genomes. Repetitive regions are frequently heterochromatinized resulting in silencing of intrinsic and nearby genes. However, this is not a uniform rule, with several genes known to require such an environment to permit transcription. Repetitive regions frequently exist as dinucleotide, trinucleotide, and tetranucleotide repeats. The association between repetitive regions and disease was emphasized following the discovery of abnormal trinucleotide repeats underlying spinal and bulbar muscular atrophy (Kennedy's disease) and fragile X syndrome of mental retardation (FRAXA) in 1991. In this review, we provide a brief overview of epigenetic mechanisms and then focus on several diseases caused by DNA triplet-repeat expansions, which exhibit diverse epigenetic effects. It is clear that the emerging field of epigenetics is already generating novel potential therapeutic avenues for this group of largely incurable diseases.
Román, Gustavo C
Neurologists should be aware of parasitic diseases occurring in travelers and recent migrants because the world has become a global village as a result of tourism and immigration. Global warming is changing the distribution of diseases formerly confined to the tropics. The two most common parasitic diseases of the nervous system are Plasmodium falciparum malaria presenting as a febrile encephalopathy with normal CSF and neurocysticercosis causing seizures with focal MRI lesions or with intracranial hypertension. Numerous parasites may cause larva migrans with eosinophilic meningitis. Spinal cord involvement is the signature presentation of schistosomiasis. Trypanosoma cruzi, the agent of Chagas disease in the Americas, may cause myocardiopathy and embolic stroke. Sleeping sickness remains the most common manifestation of African trypanosomiasis. These conditions are challenging to diagnose unless a history of travel is elicited. Prospective travelers should be advised of preventive measures to avoid potentially severe infections of the nervous system.
Halperin, John J
The Lyme disease controversy can be largely linked to the misconception that neurobehavioral effects of illness constitute evidence of nervous system infection. Appropriate differentiation between neuroborreliosis (nervous system Borrelia burgdorferi infection) and Lyme encephalopathy (altered nervous system function in individuals with systemic but not nervous system infection)-or encephalopathies of other etiologies-would lessen the controversy considerably, as the attribution of nonspecific symptoms to supposed ongoing central nervous system infection is a major factor perpetuating the debate. Epidemiologic considerations suggest that the entities referred to as "posttreatment Lyme disease" and "chronic Lyme disease" may not actually exist but rather reflect anchoring bias, linking common, nonspecific symptoms to an antecedent medical event. On the other hand, there are data suggesting possible mechanisms by which posttreatment Lyme disease could occur.
Milton, John; Black, Deborah
Thirty-two (32) periodic diseases of the nervous system are identified in which symptoms and/or signs recur. In 10/32, the recurrence of a symptom complex is one of the defining features of the illness, whereas in 22/32 oscillatory signs occur in the setting of an ongoing nervous system disorder. We discuss the possibility that these disorders may be dynamic diseases.
Cannabinoids exert a neuroprotective influence on some neurological diseases, including Alzheimer's, Parkinson's, Huntington's, multiple sclerosis and epilepsy. Synthetic cannabinoid receptor agonists/antagonists or compounds can provide symptom relief or control the progression of neurological diseases. However, the molecular mechanism and the effectiveness of these agents in controlling the progression of most of these diseases remain unclear. Cannabinoids may exert effects via a number of mechanisms and interactions with neurotransmitters, neurotropic factors and neuropeptides. Leptin is a peptide hormone involved in the regulation of food intake and energy balance via its actions on specific hypothalamic nuclei. Leptin receptors are widely expressed throughout the brain, especially in the hippocampus, basal ganglia, cortex and cerebellum. Leptin has also shown neuroprotective properties in a number of neurological disorders, such as Parkinson's and Alzheimer's. Therefore, cannabinoid and leptin hold therapeutic potential for neurological diseases. Further elucidation of the molecular mechanisms underlying the effects on these agents may lead to the development of new therapeutic strategies for the treatment of neurological disorders.
Ferrell, Eric A; Gavin, Patrick R; Tucker, Russell L; Sellon, Debra C; Hines, Melissa T
Magnetic resonance (MR) imaging was used as a neurodiagnostic modality in the assessment of 12 horses with neurologic disease localized cranial to the foramen magnum. This retrospective study included a mixed population of horse breeds and consisted of three foals and nine adult horses. MR sequences of the head and central nervous system of each horse were acquired. Routine MR sequences included transverse T1 weighted (T1wt), T2 weighted (T2wt), and proton density images. Additional imaging sequences were obtained on a patient-dependent basis. Eight neurologic related diseases were diagnosed. MRI imaging of the horse head is a feasible and valuable neurodiagnostic modality in the assessment of equine neurologic diseases.
Nageshwaran, Sathiji; Festenstein, Richard
The term “junk DNA” has been reconsidered following the delineation of the functional significance of repetitive DNA regions. Typically associated with centromeres and telomeres, DNA repeats are found in nearly all organisms throughout their genomes. Repetitive regions are frequently heterochromatinized resulting in silencing of intrinsic and nearby genes. However, this is not a uniform rule, with several genes known to require such an environment to permit transcription. Repetitive regions frequently exist as dinucleotide, trinucleotide, and tetranucleotide repeats. The association between repetitive regions and disease was emphasized following the discovery of abnormal trinucleotide repeats underlying spinal and bulbar muscular atrophy (Kennedy’s disease) and fragile X syndrome of mental retardation (FRAXA) in 1991. In this review, we provide a brief overview of epigenetic mechanisms and then focus on several diseases caused by DNA triplet-repeat expansions, which exhibit diverse epigenetic effects. It is clear that the emerging field of epigenetics is already generating novel potential therapeutic avenues for this group of largely incurable diseases. PMID:26733936
Tarazona, Monica Jidid Mateus; Mota, Amanda Nascimento Cavalleiro de Macedo; Gripp, Alexandre Carlos; Unterstell, Natasha; Bressan, Aline Lopes
Bullous pemphigoid (BP) is an autoimmune, acquired, cutaneous disease caused by the production of autoantibodies against hemidesmosomes' components in the basement membrane. The estimated incidence in Europe ranges from 7 to 43 cases per million inhabitants per year. Several studies have reported an association between BP and neurological disorders (ND). Our cohort of Bullous pemphigoid and ND is the first in Brazil and showed a significantly high prevalence of neurological and/or psychiatric diseases, especially cerebrovascular accident (CVA) and dementia, in agreement with the prevalence reported in several studies published in the medical literature in recent years. PMID:25831008
Nelson, David L.; Orr, Harry T.; Warren, Stephen T.
Disorders characterized by expansion of an unstable nucleotide repeat account for a number of inherited neurological diseases. Here, we review examples of unstable repeat disorders that nicely illustrate the three of the major pathogenic mechanisms associated with these diseases: loss-of-function typically by disrupting transcription of the mutated gene, RNA toxic gain-of-function, and protein toxic gain-of-function. In addition to providing insight into the mechanisms underlying these devastating neurological disorders, the study of these unstable microsatellite repeat disorders has provided insight into very basic aspects of neuroscience. PMID:23473314
Dysfunction and/or disruption of nodes of Ranvier are now recognized as key contributors to the pathophysiology of various neurological diseases. One reason is that the excitable nodal axolemma contains a high density of Nav (voltage-gated Na+ channels) that are required for the rapid and efficient saltatory conduction of action potentials. Nodal physiology is disturbed by altered function, localization, and expression of voltage-gated ion channels clustered at nodes and juxtaparanodes, and by disrupted axon–glial interactions at paranodes. This paper reviews recent discoveries in molecular/cellular neuroscience, genetics, immunology, and neurology that highlight the critical roles of nodes of Ranvier in health and disease. PMID:23834220
Five years after their initial derivation from mouse somatic cells, induced pluripotent stem (iPS) cells are an important tool for the study of neurological diseases. By offering an unlimited source of patient-specific disease-relevant neuronal and glial cells, iPS cell-based disease models hold enormous promise for identification of disease mechanisms, discovery of molecular targets and development of phenotypic screens for drug discovery. The present review focuses on the recent advancements in modeling neurological disorders, including the demonstration of disease-specific phenotypes in iPS cell-derived neurons generated from patients with spinal muscular atrophy, familial dysautonomia, Rett syndrome, schizophrenia and Parkinson disease. The ability of this approach to detect treatment effects from known therapeutic compounds has also been demonstrated, providing proof of principle for the use of iPS cell-derived cells in drug discovery. PMID:21936964
Background Systems biological approach of molecular connectivity map has reached to a great interest to understand the gene functional similarities between the diseases. In this study, we developed a computational framework to build molecular connectivity maps by integrating mutated and differentially expressed genes of neurological and psychiatric diseases to determine its relationship with aging. Results The systematic large-scale analyses of 124 human diseases create three classes of molecular connectivity maps. First, molecular interaction of disease protein network generates 3632 proteins with 6172 interactions, which determines the common genes/proteins between diseases. Second, Disease-disease network includes 4845 positively scored disease-disease relationships. The comparison of these disease-disease pairs with Medical Subject Headings (MeSH) classification tree suggests 25% of the disease-disease pairs were in same disease area. The remaining can be a novel disease-disease relationship based on gene/protein similarity. Inclusion of aging genes set showed 79 neurological and 20 psychiatric diseases have the strong association with aging. Third and lastly, a curated disease biomarker network was created by relating the proteins/genes in specific disease contexts, such analysis showed 73 markers for 24 diseases. Further, the overall quality of the results was achieved by a series of statistical methods, to avoid insignificant data in biological networks. Conclusions This study improves the understanding of the complex interactions that occur between neurological and psychiatric diseases with aging, which lead to determine the diagnostic markers. Also, the disease-disease association results could be helpful to determine the symptom relationships between neurological and psychiatric diseases. Together, our study presents many research opportunities in post-genomic biomarkers development. PMID:21226925
McGann, James C.; Lioy, Daniel T.; Mandel, Gail
As astrocytes are becoming recognized as important mediators of normal brain function, studies into their roles in neurological disease have gained significance. Across mouse models for neurodevelopmental and neurodegenerative diseases, astrocytes are considered key regulators of disease progression. In Rett syndrome and Parkinson’s disease, astrocytes can even initiate certain disease phenotypes. Numerous potential mechanisms have been offered to explain these results, but research into the functions of astrocytes in disease is just beginning. Crucially, in vivo verification of in vitro data is still necessary, as well as a deeper understanding of the complex and relatively unexplored interactions between astrocytes, oligodendrocytes, microglia, and neurons. PMID:22475461
Jannin, Jean; Gabrielli, Albis Francesco
Neglected tropical diseases are a group of mostly infectious diseases that thrive among poor populations in tropical countries. A significant proportion of the conditions affecting the neurological system in such countries can be attributed to neglected tropical diseases of helminth, protozoan, bacterial, or viral origin. The neurological burden of neglected tropical diseases has not been thoroughly investigated yet, but is expected to be significant; its full appreciation, estimation, and recognition present significant challenges, as shown by the case of the "silent epidemic" of epilepsy. While tropical infections involving the nervous system are today largely preventable or treatable, as vaccines or chemotherapeutic agents are available to kill or neutralize the responsible agents, associated morbidity - when established - cannot be cured. In resource-poor settings it is likely that many infections will not be treated and will therefore progress into their advanced and severe stages, thus being increasingly associated with irreversible morbidity; this is also the case for neurological morbidity, which often entails permanent disability. Public health should aim at reducing the burden of tropical neurological diseases through interventions addressing the infection, the associated morbidity, and the disability deriving from it.
Bertalan, Fodor; László, Barkai; Attila, Valikovics
The incidence of neurological diseases increases. The up to date diagnostics and therapeutics approaches require the cost-effective and personalized solutions. The nanomedicine now, --and likely more in the future--opens a new horizon in the treatment of neurological diseases. The nano-size materials have several advantages that make it their use as drug delivery systems, and imaging agent. Very important aspect is that these materials can transfer across the blood-brain barrier. The functionalization and surface modification of nanomaterials enhances this effect. The authors summarize of neurological application of nanoparticles according to the current data. They provide an overview about the most common used nanomedical materials, targeted drug delivery mechanisms and nano-imaging opportunities.
Assaad, F.; Gispen, R.; Kleemola, M.; Syrůček, L.; Esteves, K.
In 1963 the World Health Organization established a system for the collection and dissemination of information on viral infections and by 1976, laboratories in 49 countries were participating in this scheme. The present study is in two parts: part 1 is an analysis of almost 60 000 reports on neurological disease associated with viral and Mycoplasma pneumoniae infections reported during the 10-year period 1967-76. This analysis showed a steady increase in the yearly number of reports of viral neurological diseases, which closely followed the general increase in the overall reporting of virus diseases. Likewise, the seasonal pattern was similar to that seen in general for any given virus. Over 75% of the cases were in children. Over half of all viral neurological diseases were associated with enteroviruses, while the myxoviruses accounted for almost 30%. Among the myxoviruses, mumps virus was by far the most frequently reported. The polioviruses were the agents most commonly detected in cases of paralytic disease. The other enteroviruses, mumps virus, and the herpesviruses were the most frequently reported viruses in cases of aseptic meningitis or encephalitis. On the other hand, one-third to over one-half of the reports on the myxoviruses (excluding mumps and measles) related to ill-defined clinical conditions. Part 2 of the study deals in particular with viruses whose role in neurological disease is less well documented. One laboratory reported an outbreak of adenoviral aseptic meningitis in Czechoslovakia, while another described neurological disease associated with M. pneumoniae infection in Finland. Part 2 also includes a detailed appraisal of viral infections diagnosed in the Netherlands during the period 1973-76. The results are very similar to those routinely reported. PMID:6249511
Sánchez-Porras, Renán; Robles-Cabrera, Adriana; Santos, Edgar
Cortical spreading depolarization is a wave of almost complete depolarization of the neuronal and glial cells that occurs in different neurological diseases such as migraine with aura, subarachnoid hemorrhage, intracerebral hemorrhage, head trauma and stroke. These depolarization waves are characterized by a change in the negative potential with an amplitude between -10 and -30mV, duration of ∼1min and changes in the ion homeostasis between the intra- and extracellular space. This results in neuronal edema and dendritic distortion. Under pathologic states of hypoperfusion, cortical spreading depolarization can produce oxidative stress, worsen hypoxia and induce neuronal death. This is due to intense arterial vasoconstriction produced by an inverse response called spreading ischemia. Only in the last years there has been an electrophysiological confirmation of cortical spreading depolarization in human brains. Occurrence of cortical spreading depolarization has been associated with worse outcome in patients. Currently, increased knowledge regarding the pathophysiologic mechanisms supports the hypothetical correlation of cortical spreading depolarization with brain damage in humans. There are diverse therapeutic alternatives that promise inhibition of cortical spreading depolarization and subsequent better outcomes. Copyright © 2013 Elsevier España, S.L. All rights reserved.
Godoy, Maria Dantas Costa Lima; Voegels, Richard Louis; Pinna, Fábio de Rezende; Imamura, Rui; Farfel, José Marcelo
Introduction Loss of smell is involved in various neurologic and neurodegenerative diseases, such as Parkinson disease and Alzheimer disease. However, the olfactory test is usually neglected by physicians at large. Objective The aim of this study was to review the current literature about the relationship between olfactory dysfunction and neurologic and neurodegenerative diseases. Data Synthesis Twenty-seven studies were selected for analysis, and the olfactory system, olfaction, and the association between the olfactory dysfunction and dementias were reviewed. Furthermore, is described an up to date in olfaction. Conclusion Otolaryngologist should remember the importance of olfaction evaluation in daily practice. Furthermore, neurologists and physicians in general should include olfactory tests in the screening of those at higher risk of dementia. PMID:25992176
Milstien, S; Sakai, N; Brew, B J; Krieger, C; Vickers, J H; Saito, K; Heyes, M P
Nitric oxide has been proposed to mediate cytotoxic effects in inflammatory diseases. To investigate the possibility that overproduction of nitric oxide might play a role in the neuropathology of inflammatory and noninflammatory neurological diseases, we compared levels of the markers of nitric oxide, nitrite plus nitrate, in the CSF of controls with those in patients with various neurologic diseases, including Huntington's and Alzheimer's disease, amyotrophic lateral sclerosis, and HIV infection. We found that there were no significant increases in the CSF levels of these nitric oxide metabolites, even in patients infected with HIV or in monkeys infected with poliovirus, both of which have significantly elevated levels of the neurotoxin quinolinic acid and the marker of macrophage activation, neopterin. However, CSF quinolinic acid, neopterin, and nitrite/nitrate levels were significantly increased in a small group of patients with bacterial and viral meningitis.
Mayer, Geert; Jennum, Poul; Riemann, Dieter; Dauvilliers, Yves
The objective of this review is to highlight the impact of insomnia in central neurological disorders by providing information on its prevalence and give recommendations for diagnosis and treatment. Insomnia in neurological disorders is a frequent, but underestimated symptom. Its occurrence may be a direct consequence of the disease itself or may be secondary to pain, depression, other sleep disorders or the effects of medications. Insomnia can have a significant impact on the patient's cognitive and physical function and may be associated with psychological distress and depression. Diagnosis of insomnia is primarily based on medical history and validated questionnaires. Actigraphy is a helpful diagnostic tool for assessing the circadian sleep-wake rhythm. For differential diagnosis and to measure the duration of sleep full polysomnography may be recommended. Prior to initiating treatment the cause of insomnia must be clearly identified. First line treatment aims at the underlying neurologic disease. The few high quality treatment studies show that short term treatment with hypnotics may be recommended in most disorders after having ruled out high risk for adverse effects. Sedating antidepressants may be an effective treatment for insomnia in stroke and Parkinson's disease (PD) patients. Melatonin and light treatment can stabilize the sleep-wake circadian rhythm and shorten sleep latency in dementias and PD. Cognitive behavioral therapy (CBT) can be effective in treating insomnia symptoms associated with most of the central neurological diseases. The prevalence and treatment of insomnia in neurological diseases still need to be studied in larger patient groups with randomized clinical trials to a) better understand their impact and causal relationship and b) to develop and improve specific evidence-based treatment strategies.
Perentos, Nicholas; Martins, Amadeu Q.; Watson, Thomas C.; Bartsch, Ullrich; Mitchell, Nadia L.; Palmer, David N.; Jones, Matthew W.
Creating valid mouse models of slowly progressing human neurological diseases is challenging, not least because the short lifespan of rodents confounds realistic modelling of disease time course. With their large brains and long lives, sheep offer significant advantages for translational studies of human disease. Here we used normal and CLN5 Batten disease affected sheep to demonstrate the use of the species for studying neurological function in a model of human disease. We show that electroencephalography can be used in sheep, and that longitudinal recordings spanning many months are possible. This is the first time such an electroencephalography study has been performed in sheep. We characterized sleep in sheep, quantifying characteristic vigilance states and neurophysiological hallmarks such as sleep spindles. Mild sleep abnormalities and abnormal epileptiform waveforms were found in the electroencephalographies of Batten disease affected sheep. These abnormalities resemble the epileptiform activity seen in children with Batten disease and demonstrate the translational relevance of both the technique and the model. Given that both spontaneous and engineered sheep models of human neurodegenerative diseases already exist, sheep constitute a powerful species in which longitudinal in vivo studies can be conducted. This will advance our understanding of normal brain function and improve our capacity for translational research into neurological disorders. PMID:25724202
Adami, Raffaella; Scesa, Giuseppe; Bottai, Daniele
Neurological diseases afflict a growing proportion of the human population. There are two reasons for this: first, the average age of the population (especially in the industrialized world) is increasing, and second, the diagnostic tools to detect these pathologies are now more sophisticated and can be used on a higher percentage of the population. In many cases, neurological disease has a pharmacological treatment which, as in the case of Alzheimer's disease, Parkinson's disease, Epilepsy, and Multiple Sclerosis can reduce the symptoms and slow down the course of the disease but cannot reverse its effects or heal the patient. In the last two decades the transplantation approach, by means of stem cells of different origin, has been suggested for the treatment of neurological diseases. The choice of slightly different animal models and the differences in methods of stem cell preparation make it difficult to compare the results of transplantation experiments. Moreover, the translation of these results into clinical trials with human subjects is difficult and has so far met with little success. This review seeks to discuss the reasons for these difficulties by considering the differences between human and animal cells (including isolation, handling and transplantation) and between the human disease model and the animal disease model. PMID:25364724
Pinto, José Antonio; Corso, Renato José; Guilherme, Ana Cláudia Rocha; Pinho, Sílvia Rebelo; Nóbrega, Monica de Oliveira
Dysprosody also known as pseudo-foreign dialect, is the rarest neurological speech disorder. It is characterized by alterations in intensity, in the timing of utterance segments, and in rhythm, cadency, and intonation of words. The terms refers to changes as to duration, fundamental frequency, and intensity of tonic and atonic syllables of the sentences spoken, which deprive an individual's particular speech of its characteristics. The cause of this disease is usually associated with neurological pathologies such as brain vascular accidents, cranioencephalic traumatisms, and brain tumors. The authors report a case of dysprosody attended to at the Núcleo de Otorrinolaringologia e Cirurgia de Cabeça e Pescoço de São Paulo (NOSP). It is about a female patient with bilateral III degree Reinke's edema and normal neurological examinations that started presenting characteristics of the German dialect following a larynx microsurgery.
Nonnemacher, Michael R.; Wigdahl, Brian
HIV-associated neurologic disease continues to be a significant complication in the era of highly active antiretroviral therapy. A substantial subset of the HIV-infected population shows impaired neuropsychological performance as a result of HIV-mediated neuroinflammation and eventual central nervous system (CNS) injury. CNS compartmentalization of HIV, coupled with the evolution of genetically isolated populations in the CNS, is responsible for poor prognosis in patients with AIDS, warranting further investigation and possible additions to the current therapeutic strategy. This chapter reviews key advances in the field of neuropathogenesis and studies that have highlighted how molecular diversity within the HIV genome may impact HIV-associated neurologic disease. We also discuss the possible functional implications of genetic variation within the viral promoter and possibly other regions of the viral genome, especially in the cells of monocyte–macrophage lineage, which are arguably key cellular players in HIV-associated CNS disease. PMID:23809924
Jackson, Jessica R; Eaton, William W; Cascella, Nicola G; Fasano, Alessio; Kelly, Deanna L
Celiac Disease (CD) is an immune-mediated disease dependent on gluten (a protein present in wheat, rye or barley) that occurs in about 1% of the population and is generally characterized by gastrointestinal complaints. More recently the understanding and knowledge of gluten sensitivity (GS), has emerged as an illness distinct from celiac disease with an estimated prevalence 6 times that of CD. Gluten sensitive people do not have villous atrophy or antibodies that are present in celiac disease, but rather they can test positive for antibodies to gliadin. Both CD and GS may present with a variety of neurologic and psychiatric co-morbidities, however, extraintestinal symptoms may be the prime presentation in those with GS. However, gluten sensitivity remains undertreated and underrecognized as a contributing factor to psychiatric and neurologic manifestations. This review focuses on neurologic and psychiatric manifestations implicated with gluten sensitivity, reviews the emergence of gluten sensitivity distinct from celiac disease, and summarizes the potential mechanisms related to this immune reaction.
Leinenga, Gerhard; Langton, Christian; Nisbet, Rebecca; Götz, Jürgen
Like cardiovascular disease and cancer, neurological disorders present an increasing challenge for an ageing population. Whereas nonpharmacological procedures are routine for eliminating cancer tissue or opening a blocked artery, the focus in neurological disease remains on pharmacological interventions. Setbacks in clinical trials and the obstacle of access to the brain for drug delivery and surgery have highlighted the potential for therapeutic use of ultrasound in neurological diseases, and the technology has proved useful for inducing focused lesions, clearing protein aggregates, facilitating drug uptake, and modulating neuronal function. In this Review, we discuss milestones in the development of therapeutic ultrasound, from the first steps in the 1950s to recent improvements in technology. We provide an overview of the principles of diagnostic and therapeutic ultrasound, for surgery and transient opening of the blood-brain barrier, and its application in clinical trials of stroke, Parkinson disease and chronic pain. We discuss the promising outcomes of safety and feasibility studies in preclinical models, including rodents, pigs and macaques, and efficacy studies in models of Alzheimer disease. We also consider the challenges faced on the road to clinical translation.
Jackson, Jessica R.; Eaton, William W.; Cascella, Nicola G.; Fasano, Alessio
Celiac Disease (CD) is an immune-mediated disease dependent on gluten (a protein present in wheat, rye or barley) that occurs in about 1% of the population and is generally characterized by gastrointestinal complaints. More recently the understanding and knowledge of gluten sensitivity (GS), has emerged as an illness distinct from celiac disease with an estimated prevalence 6 times that of CD. Gluten sensitive people do not have villous atrophy or antibodies that are present in celiac disease, but rather they can test positive for antibodies to gliadin. Both CD and GS may present with a variety of neurologic and psychiatric co-morbidities, however, extraintestinal symptoms may be the prime presentation in those with GS. However, gluten sensitivity remains undertreated and underrecognized as a contributing factor to psychiatric and neurologic manifestiations. This review focuses on neurologic and psychiatric manifestations implicated with gluten sensitivity, reviews the emergence of gluten sensitivity distinct from celiac disease, and summarizes the potential mechanisms related to this immune reaction. PMID:21877216
Westbroek, Wendy; Cullinane, Andrew R.; Groden, Catherine A.; Bhambhani, Vikas; Golas, Gretchen A.; Baker, Eva H.; Lehky, Tanya J.; Snow, Joseph; Ziegler, Shira G.; Adams, David R.; Dorward, Heidi M.; Hess, Richard A.; Huizing, Marjan; Gahl, William A.; Toro, Camilo
Objective: To delineate the developmental and progressive neurodegenerative features in 9 young adults with the atypical form of Chediak-Higashi disease (CHD) enrolled in a natural history study. Methods: Patients with atypical clinical features, but diagnostically confirmed CHD by standard evaluation of blood smears and molecular genotyping, underwent complete neurologic evaluation, MRI of the brain, electrophysiologic examination, and neuropsychological testing. Fibroblasts were collected to investigate the cellular phenotype and correlation with the clinical presentation. Results: In 9 mildly affected patients with CHD, we documented learning and behavioral difficulties along with developmental structural abnormalities of the cerebellum and posterior fossa, which are apparent early in childhood. A range of progressive neurologic problems emerge in early adulthood, including cerebellar deficits, polyneuropathies, spasticity, cognitive decline, and parkinsonism. Conclusions: Patients with undiagnosed atypical CHD manifesting some of these wide-ranging yet nonspecific neurologic complaints may reside in general and specialty neurology clinics. The absence of the typical bleeding or infectious diathesis in mildly affected patients with CHD renders them difficult to diagnose. Identification of these individuals is important not only for close surveillance of potential CHD-related systemic complications but also for a full understanding of the natural history of CHD and the potential role of the disease-causing protein, LYST, to the pathophysiology of other neurodevelopmental and neurodegenerative disorders. PMID:26944273
Campagna, Giovanna; Pesce, Mirko; Tatangelo, Raffaella; Rizzuto, Alessia; La Fratta, Irene; Grilli, Alfredo
The aim of the paper is to show the various neurological and psychiatric symptoms in coeliac disease (CD). CD is a T cell-mediated, tissue-specific autoimmune disease which affects genetically susceptible individuals after dietary exposure to proline- and glutamine-rich proteins contained in certain cereal grains. Genetics, environmental factors and different immune systems, together with the presence of auto-antigens, are taken into account when identifying the pathogenesis of CD. CD pathogenesis is related to immune dysregulation, which involves the gastrointestinal system, and the extra-intestinal systems such as the nervous system, whose neurological symptoms are evidenced in CD patients. A gluten-free diet (GFD) could avoid cerebellar ataxia, epilepsy, neuropathies, migraine and mild cognitive impairment. Furthermore, untreated CD patients have more symptoms and psychiatric co-morbidities than those treated with a GFD. Common psychiatric symptoms in untreated CD adult patients include depression, apathy, anxiety, and irritability and schizophrenia is also common in untreated CD. Several studies show improvement in psychiatric symptoms after the start of a GFD. The present review discusses the state of the art regarding neurological and psychiatric complications in CD and highlights the evidence supporting a role for GFD in reducing neurological and psychiatric complications.
Yao, Ping-Ping; Qian, Lei; Xia, Yong; Xu, Fang; Yang, Zhang-Nv; Xie, Rong-Hui; Li, Xiao; Liang, Wei-Feng; Huang, Xiao-Xiao; Zhu, Zhi-Yong; Zhu, Han-Ping
A reliable disease model mimicking Enterovirus 71 (EV71) infection in humans is essential for understanding pathogenesis and for developing a safe and effective vaccine. Commonly used rodent models including mouse or rat models are not suitable for vaccine evaluation because the rodents are resistant to EV71 infection after they reach the age of 6 days. In this study, 21-day-old gerbils inoculated intraperitoneally (IP) with a non mouse-adapted EV71 strain developed neurological lesion-related signs including hind limb paralysis, slowness, ataxia and lethargy similar to those of central nervous system (CNS) infection of EV71 in humans. The infected gerbils eventually died of the neurological lesions and EV71 could be isolated from lung, liver, spleen, kidney, heart, spinal cord, brain cortex, brainstem and skeletal muscle. Significantly high virus replication was detected in spinal cord, brainstem and skeletal muscle by cellular analysis, real-time quantitative PCR (RT-PCR) and immunohistochemical staining. Histopathologic changes such as neuronal degeneration, neuronal loss and neuronophagia were observed in spinal cord, brain cortex, brainstem, and skeletal muscle along with necrotizing myositis and splenic atrophy. Gerbils that received two doses of inactive whole-virus vaccine showed no EV71-specific symptoms after challenged with EV71. In contrast, gerbils that received mock vaccination died of EV71-induced neuropathology after challenged with EV71. The result indicates that gerbils can serve as a reliable disease model for evaluating safety and efficacy of EV71 vaccine. PMID:23284845
Li, Linlin; Diab, Santiago; McGraw, Sabrina; Barr, Bradd; Traslavina, Ryan; Higgins, Robert; Talbot, Tom; Blanchard, Pat; Rimoldi, Guillermo; Fahsbender, Elizabeth; Page, Brady; Phan, Tung Gia; Wang, Chunlin; Deng, Xutao; Delwart, Eric
Using viral metagenomics of brain tissue from a young adult crossbreed steer with acute onset of neurologic disease, we sequenced the complete genome of a novel astrovirus (BoAstV-NeuroS1) that was phylogenetically related to an ovine astrovirus. In a retrospective analysis of 32 cases of bovine encephalitides of unknown etiology, 3 other infected animals were detected by using PCR and in situ hybridization for viral RNA. Viral RNA was restricted to the nervous system and detected in the cytoplasm of affected neurons within the spinal cord, brainstem, and cerebellum. Microscopically, the lesions were of widespread neuronal necrosis, microgliosis, and perivascular cuffing preferentially distributed in gray matter and most severe in the cerebellum and brainstem, with increasing intensity caudally down the spinal cord. These results suggest that infection with BoAstV-NeuroS1 is a potential cause of neurologic disease in cattle. PMID:23965613
Kahle, Kristopher T.; Khanna, Arjun R.; Alper, Seth L.; Adragna, Norma C.; Lauf, Peter K.; Sun, Dandan; Delpire, Eric
K+-Cl− cotransporters (KCCs) were originally characterized as regulators of red blood cell (RBC) volume. Since then, four distinct KCCs have been cloned, and their importance for volume regulation has been demonstrated in other cell types. Genetic models of certain KCCs, such as KCC3, and their inhibitory WNK-STE20/SPS1-related proline/alanine-rich kinase (SPAK) serine-threonine kinases, have demonstrated the evolutionary necessity of these molecules for nervous system cell volume regulation, structure, and function, and their involvement in neurological disease. The recent characterization of a swelling-activated dephosphorylation mechanism that potently stimulates the KCCs has pinpointed a potentially druggable switch of KCC activity. An improved understanding of WNK/SPAK-mediated KCC cell volume regulation in the nervous system might reveal novel avenues for the treatment of multiple neurological diseases. PMID:26142773
Coulter, D L; Beals, T F; Allen, R J
Six children with morphological hair-shaft abnormalities and neurological disease are presented, including two with Pollitt syndrome, one with biotin deficiency, two with Menkes diseases and one with argininosuccinic aciduria. The child with biotin deficiency grew normal hair following oral biotin therapy. Although the hair-shaft abnormalities may be seen with light microscopy (LM), they are best visualised with scanning electron-microscopy (SEM). Pili torti may be mistaken for monilethrix by LM, but SEM shows the true defect. A review of the literature shows that these hair-shaft abnormalities (trichorrhexis nodosa, monilethrix and pili torti) are not specific or pathognomonic, but do indicate a group of neurological disorders, including potentially treatable inborn errors of metabolism. The term 'neurotrichosis' is suggested to classify this group of disorders.
Dionyssiotis, Yannis; Papachristos, Aris; Petropoulou, Konstantina; Papathanasiou, Jannis; Papagelopoulos, Panayiotis
Neurological and neurosurgical diseases lead to complications producing malnutrition increasing pathology and mortality. In order to avoid complications because of malnutrition or overcome deficiencies in nutrients supplements are often used for these subjects. The physiopathological mechanisms of malnutrition, methods of nutritional assessment and the supplemental support are reviewed in this paper based on the assumption that patients need to receive adequate nutrition to promote optimal recovery, placing nutrition as a first line treatment and not an afterthought in the rehabilitation. PMID:27563361
Briani, C; Santoro, M; Latov, N
Anti-chondroitin sulfates (ChSs) antibodies have been reported in neuropathy and neurodegenerative diseases. Differences in specificities may account for their association with different diseases. Sera from 303 neurological patients were tested for antibodies to ChSs A, B, C. Titers >/=51,200 were found in 16 patients (eight peripheral neuropathy, three motor neuron disease, four multiple sclerosis, one myelitis). Three patients also had anti-sulfatides antibodies, which in two cases cross-reacted with ChSs. By indirect immunofluorescence, positive sera stained nuclei on normal human peripheral nerve sections. These findings indicate that human anti-ChSs antibodies are broadly reactive and not specific to any neurological disease.
Murphy, Sinéad M; Puwanant, Araya; Griggs, Robert C.
Since the introduction of the Orphan Drug Act in 1983, designed to promote development of treatments for rare diseases, at least 378 orphan drugs have been approved. Incentives include financial support, tax credits and, perhaps most importantly, extended market exclusivity. These incentives have encouraged industry interest and accelerated research on rare diseases, allowing patients with orphan diseases access to treatments. However, extended market exclusivity has been associated with unacceptably high drug costs; both for newly developed drugs and even for drugs which were previously widely available. We suggest that a paradoxical effect of orphan product exclusivity can be reduced patient access to existing drugs. In addition, the costs of each new drug are arguably unsustainable for patients and for the American health care system. Of all the specialties, neurology has the third highest number of orphan product designations, and neurological diseases account for at least one fifth of rare diseases. Citing the use of tetrabenazine for chorea in Huntington’s disease, adrenocorticotropic hormone for infantile spasms and enzyme replacement therapy with alglucosidase alpha for Pompe’s disease we highlight these paradoxical effects. PMID:23109143
Murphy, Sinéad M; Puwanant, Araya; Griggs, Robert C
Since the introduction of the Orphan Drug Act in 1983, designed to promote development of treatments for rare diseases, at least 378 orphan drugs have been approved. Incentives include financial support, tax credits, and perhaps most importantly, extended market exclusivity. These incentives have encouraged industry interest and accelerated research on rare diseases, allowing patients with orphan diseases access to treatments. However, extended market exclusivity has been associated with unacceptably high drug costs, both for newly developed drugs and for drugs that were previously widely available. We suggest that a paradoxical effect of orphan product exclusivity can be reduced patient access to existing drugs. In addition, the costs of each new drug are arguably unsustainable for patients and for the American health care system. Of all the specialties, neurology has the third highest number of orphan product designations, and neurological diseases account for at least one-fifth of rare diseases. Citing the use of tetrabenazine for chorea in Huntington disease, adrenocorticotropic hormone for infantile spasms, and enzyme replacement therapy with alglucosidase alpha for Pompe disease, we highlight these paradoxical effects.
Lallana, Enrico C; Fadul, Camilo E
In parallel to our better understanding of the role of the immune system in neurologic diseases, there has been an increased availability in therapeutic options for autoimmune neurologic diseases such as multiple sclerosis, myasthenia gravis, polyneuropathies, central nervous system vasculitides and neurosarcoidosis. In many cases, the purported benefits of this class of therapy are anecdotal and not the result of good controlled clinical trials. Nonetheless, their potential efficacy is better known than their adverse event profile. A rationale therapeutic decision by the clinician will depend on a comprehensive understanding of the ratio between efficacy and toxicity. In this review, we outline the most commonly used immune suppressive medications in neurologic disease: cytotoxic chemotherapy, nucleoside analogues, calcineurin inhibitors, monoclonal antibodies and miscellaneous immune suppressants. A discussion of their mechanisms of action and related toxicity is highlighted, with the goal that the reader will be able to recognize the most commonly associated toxicities and identify strategies to prevent and manage problems that are expected to arise with their use. PMID:22379461
Ivkić, Goran; Erdeljić, Viktorija
As expected, since we recently celebrated the 250th anniversary of birth of Wolfgang Amadeus Mozart, there has been again a renewal of interest in his short but intensive life, as well as in the true reason of his untimely dead. Mozart lived and died in time when the medical knowledge was based mostly on subjective observations, without the established basics of standardized medical terminology and methodology. This leaves a great space for hypothesizing about his health problems, as well as about the cause of his death. The medical academic community attributed to Mozart approximately 150 different medical diagnoses. There is much speculation on the possible causes of Mozart's death: uremia, infection, rheumatic fever, trichinellosis, etc. Recently some authors have raised the question about a possible concomitant neurological disease. According to available records, Mozart has shown some elements of cyclotimic disorder, epilepsy and Gilles de la Tourette syndrome. Furthermore, the finding of a temporal fracture on (allegedly) Mozart's skull, gives a way to speculations about the possibility of a chronic subdural hematoma and its compressive effect on the temporal lobe. Despite numerous theories on Mozart's pathography that also include a concomitant neurological disorder, the medical and history records about Mozart's health status indicate that he probably had suffered from an infective illness, followed most likely by the reactivation of rheumatic fever, which was followed by strong immunologic reaction in the last days of his life. Taking all the above into consideration, it is reasonably to conclude that Mozart's neurological disturbances were caused by the intensity of the infective disease, and not primarily by a neurological disease.
García-Cabo, Carmen; Morís, Germán
One of the most frequent neurologic complications reported in inflammatory bowel disease population is peripheral neuropathy; however, clinical aspects of peripheral nerve damage are not well characterized. The aim of the review is to present the existing literature on peripheral neuropathy in inflammatory bowel disease patients. A literature search identified the publications reporting on epidemiology, clinical features, underlying mechanisms and management of ulcerative colitis and Crohn's disease patients with peripheral nerve involvement. The pathogenesis of peripheral nervous system damage in inflammatory bowel disease has yet to be elucidated, although it seems to be related to immune mechanisms; therefore, treatment with immunotherapy is recommended. In addition, peripheral neuropathy may appear as iatrogenic-related disorders associated with several drugs used in controlling inflammatory bowel disease activity; finally, peripheral neuropathy may also be caused by micronutrient deficiencies secondary to malabsorption-related disorders. Although peripheral nervous nerve damage associated with inflammatory bowel disease is rarely reported, clinicians should be aware of the peripheral neuropathy clinical manifestations in order to recognize it and provide early treatment, which is crucial for preventing major neurologic morbidity. Heightened awareness is necessary for the successful management of these patients. Copyright © 2015 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
Qureshi, Irfan A.; Mehler, Mark F.
The burgeoning field of epigenetics is making a significant impact on our understanding of brain evolution, development, and function. In fact, it is now clear that epigenetic mechanisms promote seminal neurobiological processes, ranging from neural stem cell maintenance and differentiation to learning and memory. At the molecular level, epigenetic mechanisms regulate the structure and activity of the genome in response to intracellular and environmental cues, including the deployment of cell type–specific gene networks and those underlying synaptic plasticity. Pharmacological and genetic manipulation of epigenetic factors can, in turn, induce remarkable changes in neural cell identity and cognitive and behavioral phenotypes. Not surprisingly, it is also becoming apparent that epigenetics is intimately involved in neurological disease pathogenesis. Herein, we highlight emerging paradigms for linking epigenetic machinery and processes with neurological disease states, including how (1) mutations in genes encoding epigenetic factors cause disease, (2) genetic variation in genes encoding epigenetic factors modify disease risk, (3) abnormalities in epigenetic factor expression, localization, or function are involved in disease pathophysiology, (4) epigenetic mechanisms regulate disease-associated genomic loci, gene products, and cellular pathways, and (5) differential epigenetic profiles are present in patient-derived central and peripheral tissues. PMID:23571666
Qureshi, Irfan A; Mehler, Mark F
The burgeoning field of epigenetics is making a significant impact on our understanding of brain evolution, development, and function. In fact, it is now clear that epigenetic mechanisms promote seminal neurobiological processes, ranging from neural stem cell maintenance and differentiation to learning and memory. At the molecular level, epigenetic mechanisms regulate the structure and activity of the genome in response to intracellular and environmental cues, including the deployment of cell type-specific gene networks and those underlying synaptic plasticity. Pharmacological and genetic manipulation of epigenetic factors can, in turn, induce remarkable changes in neural cell identity and cognitive and behavioral phenotypes. Not surprisingly, it is also becoming apparent that epigenetics is intimately involved in neurological disease pathogenesis. Herein, we highlight emerging paradigms for linking epigenetic machinery and processes with neurological disease states, including how (1) mutations in genes encoding epigenetic factors cause disease, (2) genetic variation in genes encoding epigenetic factors modify disease risk, (3) abnormalities in epigenetic factor expression, localization, or function are involved in disease pathophysiology, (4) epigenetic mechanisms regulate disease-associated genomic loci, gene products, and cellular pathways, and (5) differential epigenetic profiles are present in patient-derived central and peripheral tissues.
Autoinflammatory diseases are rare illnesses characterized by apparently unprovoked inflammation without high-titer auto-antibodies or antigen-specific T cells. They may cause neurological manifestations, such as meningitis and hearing loss, but they are also characterized by non-neurological manifestations. In this work we studied a 30-year-old man who had a chronic disease characterized by meningitis, progressive hearing loss, persistently raised inflammatory markers and diffuse leukoencephalopathy on brain MRI. He also suffered from chronic recurrent osteomyelitis of the mandible. The hypothesis of an autoinflammatory disease prompted us to test for the presence of mutations in interleukin-1−pathway genes and to investigate the function of this pathway in the mononuclear cells obtained from the patient. Search for mutations in genes associated with interleukin-1−pathway demonstrated a novel NLRP3 (CIAS1) mutation (p.I288M) and a previously described MEFV mutation (p.R761H), but their combination was found to be non-pathogenic. On the other hand, we uncovered a selective interleukin-6 hypersecretion within the central nervous system as the likely pathogenic mechanism. This is also supported by the response to the anti-interleukin-6−receptor monoclonal antibody tocilizumab, but not to the recombinant interleukin-1−receptor antagonist anakinra. Exome sequencing failed to identify mutations in other genes known to be involved in autoinflammatory diseases. We propose that the disease described in this patient might be a prototype of a novel category of autoinflammatory diseases characterized by prominent neurological involvement. PMID:23432807
Grant, Christian; Barmak, Kate; Alefantis, Timothy; Yao, Jing; Jacobson, Steven; Wigdahl, Brian
Human T cell lymphotropic/leukemia virus type I (HTLV-I) has been identified as the causative agent of both adult T cell leukemia (ATL) and HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Although the exact sequence of events that occur during the early stages of infection are not known in detail, the initial route of infection may predetermine, along with host, environmental, and viral factors, the subset of target cells and/or the primary immune response encountered by HTLV-I, and whether an HTLV-I-infected individual will remain asymptomatic, develop ATL, or progress to the neuroinflammatory disease, HAM/TSP. Although a large number of studies have indicated that CD4(+) T cells represent an important target for HTLV-I infection in the peripheral blood (PB), additional evidence has accumulated over the past several years demonstrating that HTLV-I can infect several additional cellular compartments in vivo, including CD8(+) T lymphocytes, PB monocytes, dendritic cells, B lymphocytes, and resident central nervous system (CNS) astrocytes. More importantly, extensive latent viral infection of the bone marrow, including cells likely to be hematopoietic progenitor cells, has been observed in individuals with HAM/TSP as well as some asymptomatic carriers, but to a much lesser extent in individuals with ATL. Furthermore, HTLV-I(+) CD34(+) hematopoietic progenitor cells can maintain the intact proviral genome and initiate viral gene expression during the differentiation process. Introduction of HTLV-I-infected bone marrow progenitor cells into the PB, followed by genomic activation and low level viral gene expression may lead to an increase in proviral DNA load in the PB, resulting in a progressive state of immune dysregulation including the generation of a detrimental cytotoxic Tax-specific CD8(+) T cell population, anti-HTLV-I antibodies, and neurotoxic cytokines involved in disruption of myelin-producing cells and neuronal degradation
Ragnaud, J M; Morlat, P; Buisson, M; Ferrer, X; Orgogozo, J M; Julien, J; Beylot, J; Aubertin, J
We studied retrospectively the cases of neurological forms of Lyme disease observed in two internal and two neurological departments from 1986 till 1993. Twenty five cases have been collected among 15 men and ten women whose mean age was 61 years. Tick bites were previously noticed in 11 cases. Erythema chronicum migrans (ECM) was mentioned in 16 cases mostly on lower limbs. The mean time between ECM and the onset of neurological symptoms was less than 1 month in 11 cases, 2 months in three cases, and 6 months in two cases. Neurological abnormalities were often associated in the same patient. Hyperalgic radiculitis (n = 16), mainly noticed in the ECM territory (n = 10) was only sensitive in six cases and associated with motor deficit in ten. Atypical polyradiculoneuritis was achieved in six cases. Clinical (n = 5) or biological (n = 22) meningitis could occur: CSF was clear with pleiocytosis (132 per mm3), mainly lymphocytic, and hyperproteinorachia (1.2 g/l) with normoglycorachia. An increase of the CSF immunoglobulins G with oligoclonal fragmentation was noticed in 11 cases. Cranial neuropathy was frequent: VII (n = 8), VI (n = 2), III, IV, VIII (n = 1). Encephalitis (with white matter demyelination) resolved partially in two cases. Diagnosis was always confirmed by Borrelia burgdorferi serology (indirect immunofluorescence) with a significant increase of the antibodies titer (n = 17) or a CSF titer > 1/4 (n = 11). Syphilitic serology was always negative. All patients were treated with parenteral beta lactamins and four with corticosteroids. Outcome was favorable in 20 patients with incomplete resolution of neurological symptoms in two patients.
Tumani, Hayrettin; Teunissen, Charlotte; Süssmuth, Sigurd; Otto, Markus; Ludolph, Albert C; Brettschneider, Johannes
Chronic neurological diseases (CND) like amyotrophic lateral sclerosis (ALS), dementia or multiple sclerosis (MS) share a chronic progressive course of disease that frequently leads to the common pathological pathway of neurodegeneration, including neuroaxonal damage, apoptosis and gliosis. There is an ongoing search for biomarkers that could support early diagnosis of CND and help to identify responders to interventions in therapeutic treatment trials. Cerebrospinal fluid (CSF) is a promising source of biomarkers in CND, since the CSF compartment is in close anatomical contact with the brain interstitial fluid, where biochemical changes related to CND are reflected. We review recent advances in CSF biomarkers research in CND and thereby focus on markers associated with neurodegeneration.
Borges, Alexandre S; Watanabe, Marcos J
The close relationship between guttural pouches, cranial nerves, and sympathetic structures make neurologic abnormalities due to diseases of the guttural pouches (especially mycosis) possible. Recognition of epistaxis or mucopurulent nasal discharge, together with signs of dysfunction of the cranial nerves in contact with the guttural pouches, are important key points in order to consider a comprehensive evaluation of these structures and further definitive diagnosis. Diseases of the guttural pouches can also cause signs such as dysphagia, abnormal soft palate positioning, laryngeal paralysis, and Horner syndrome due to lesions in one or more of the cranial nerves or sympathetic structures involved with these functions. Therefore, an accurate diagnosis is essential for treatment.
Cheng, E.M.; Tonn, S.; Swain-Eng, R.; Factor, S.A.; Weiner, W.J.; Bever, C.T.
Background: Measuring the quality of health care is a fundamental step toward improving health care and is increasingly used in pay-for-performance initiatives and maintenance of certification requirements. Measure development to date has focused on primary care and common conditions such as diabetes; thus, the number of measures that apply to neurologic care is limited. The American Academy of Neurology (AAN) identified the need for neurologists to develop measures of neurologic care and to establish a process to accomplish this. Objective: To adapt and test the feasibility of a process for independent development by the AAN of measures for neurologic conditions for national measurement programs. Methods: A process that has been used nationally for measure development was adapted for use by the AAN. Topics for measure development are chosen based upon national priorities, available evidence base from a systematic literature search, gaps in care, and the potential impact for quality improvement. A panel composed of subject matter and measure development methodology experts oversees the development of the measures. Recommendation statements and their corresponding level of evidence are reviewed and considered for development into draft candidate measures. The candidate measures are refined by the expert panel during a 30-day public comment period and by review by the American Medical Association for Current Procedural Terminology (CPT) II codes. All final AAN measures are approved by the AAN Board of Directors. Results: Parkinson disease (PD) was chosen for measure development. A review of the medical literature identified 258 relevant recommendation statements. A 28-member panel approved 10 quality measures for PD that included full specifications and CPT II codes. Conclusion: The AAN has adapted a measure development process that is suitable for national measurement programs and has demonstrated its capability to independently develop quality measures. GLOSSARY
Lacau St Guily, J; Ferroir, J P; Angelard, B; Chaussade, S
A 67-year old man consulted for dysphagia to solid food and weight loss. Four years earlier he had developed Lyme disease with severe neurological involvement. Magnetic resonance imaging showed, on T2-weighted sequences, multifocal high-intensity signals located in the periventricular white matter and the brain stem. The disorders of deglutition were evaluated by cineradiography and manometry which showed deficient relaxation of the superior esophageal sphincter and delayed initiation of the pharyngeal phase; intrapharyngeal propulsion was preserved. On the basis of these findings cricopharyngeal myotomy was performed with subsequent improvement of the disorders. Treatment with doxycycline was prescribed. The significance of these deglutition disorders as regards infection and neurology is discussed and it should have therapeutic implications.
Anlar, Omer; Akdeniz, Necmettin; Tombul, Temel; Calka, Omer; Bilgili, Serap G
Behçet's disease (BD) is a chronic, recurrent multisystem inflammatory disorder firstly described by Turkish dermatologist Dr. Hulusi Behçet in 1937. The classic triad consists of recurrent oral and genital ulcerations and uveitis. The article presents the value of visual evoked potential findings of a series of 44 patients with BD without neurological manifestations seen at the Medical Hospital in Neurology and Dermatology clinics over the past 8 years. The mean latency value of positive peak P100 in BD patients was significantly delayed compared to that of control subjects (patients's mean: 105.6 ms in right eye and 107.7 ms in left eye; control subject's mean: 101.4 ms in right eye and 101.7 ms in left eye).
Dandashi, Jad A; Nizamutdinov, Damir; Dayawansa, Samantha; Fonkem, Ekokobe; Huang, Jason H
Today, Lyme disease is the most commonly reported tick-borne disease in the United States and Europe. The culprits behind Lyme disease are the Borrelia species of bacteria. In the USA, Borrelia burgdorferi causes the majority of cases, while in Europe and Asia Borrelia afzelii and Borrelia garinii carry the greatest burden of disease. The clinical manifestations of Lyme disease have been identified as early localized, early disseminated, and late chronic. The neurological effects of Lyme disease include both peripheral and central nervous systems involvement, including focal nerve abnormalities, cranial neuropathies, painful radiculoneuritis, meningitis, and/or toxic metabolic encephalopathy, known as Lyme encephalopathy. Given the geographic predominance of Lyme disease in the Northeast and Midwest of the USA, no major studies have been conducted regarding Southern states. Between 2005 and 2014, the Center for Disease Control has reported 582 confirmed cases of Lyme disease in Texas. Because of the potential for increased incidence and prevalence in Texas, it has become essential for research and clinical efforts to be diverted to the region. The Texas A&M College of Veterinary Medicine and Biomedical Sciences Lyme Lab has been investigating the ecology of Lyme disease in Texas and developing a pan-specific serological test for Lyme diagnosis. This report aimed to exposure materials and raise awareness of Lyme disease to healthcare providers.
Song, Limin; Pei, Lei; Yao, Shanglong; Wu, Yan; Shang, You
Neuroinflammation has been identified as a causative factor of multiple neurological diseases. The nucleotide-binding oligomerization domain-, leucine-rich repeat- and pyrin domain-containing 3 (NLRP3) inflammasome, a subcellular multiprotein complex that is abundantly expressed in the central nervous system (CNS), can sense and be activated by a wide range of exogenous and endogenous stimuli such as microbes, aggregated and misfolded proteins, and adenosine triphosphate, which results in activation of caspase-1. Activated caspase-1 subsequently leads to the processing of interleukin-1β (IL-1β) and interleukin-18 (IL-18) pro-inflammatory cytokines and mediates rapid cell death. IL-1β and IL-18 drive inflammatory responses through diverse downstream signaling pathways, leading to neuronal damage. Thus, the NLRP3 inflammasome is considered a key contributor to the development of neuroinflammation. In this review article, we briefly discuss the structure and activation the NLRP3 inflammasome and address the involvement of the NLRP3 inflammasome in several neurological disorders, such as brain infection, acute brain injury and neurodegenerative diseases. In addition, we review a series of promising therapeutic approaches that target the NLRP3 inflammasome signaling including anti-IL-1 therapy, small molecule NLRP3 inhibitors and other compounds, however, these approaches are still experimental in neurological diseases. At present, it is plausible to generate cell-specific conditional NLRP3 knockout (KO) mice via the Cre system to investigate the role of the NLRP3 inflammasome, which may be instrumental in the development of novel pharmacologic investigations for neuroinflammation-associated diseases. PMID:28337127
Wondolowski, Joyce; Dickman, Dion
Homeostatic signaling systems are ubiquitous forms of biological regulation, having been studied for hundreds of years in the context of diverse physiological processes including body temperature and osmotic balance. However, only recently has this concept been brought to the study of excitatory and inhibitory electrical activity that the nervous system uses to establish and maintain stable communication. Synapses are a primary target of neuronal regulation with a variety of studies over the past 15 years demonstrating that these cellular junctions are under bidirectional homeostatic control. Recent work from an array of diverse systems and approaches has revealed exciting new links between homeostatic synaptic plasticity and a variety of seemingly disparate neurological and psychiatric diseases. These include autism spectrum disorders, intellectual disabilities, schizophrenia, and Fragile X Syndrome. Although the molecular mechanisms through which defective homeostatic signaling may lead to disease pathogenesis remain unclear, rapid progress is likely to be made in the coming years using a powerful combination of genetic, imaging, electrophysiological, and next generation sequencing approaches. Importantly, understanding homeostatic synaptic plasticity at a cellular and molecular level may lead to developments in new therapeutic innovations to treat these diseases. In this review we will examine recent studies that demonstrate homeostatic control of postsynaptic protein translation, retrograde signaling, and presynaptic function that may contribute to the etiology of complex neurological and psychiatric diseases.
Joers, Valerie L.; Emborg, Marina E.
Stem cells, as subjects of study for use in treating neurological diseases, are envisioned as a replacement for lost neurons and glia, a means of trophic support, a therapeutic vehicle, and, more recently, a tool for in vitro modeling to understand disease and to screen and personalize treatments. In this review we analyze the requirements of stem cell–based therapy for clinical translation, advances in stem cell research toward clinical application for neurological disorders, and different animal models used for analysis of these potential therapies. We focus on Parkinson’s disease (typically defined by the progressive loss of dopaminergic nigral neurons), stroke (neurodegeneration associated with decreased blood perfusion in the brain), and multiple sclerosis (an autoimmune disorder that generates demyelination, axonal damage, astrocytic scarring, and neurodegeneration in the brain and spinal cord). We chose these disorders for their diversity and the number of people affected by them. An additional important consideration was the availability of multiple animal models in which to test stem cell applications for these diseases. We also discuss the relationship between the limited number of systematic stem cell studies performed in animals, in particular nonhuman primates and the delayed progress in advancing stem cell therapies to clinical success. PMID:20075496
Human, Stacey; Zaayman, Dewald; Gerdes, Gertruida H.; Williams, June; Steyl, Johan; Leman, Patricia A.; Paweska, Janusz Tadeusz; Setzkorn, Hildegard; Rous, Gavin; Murray, Sue; Parker, Rissa; Donnellan, Cynthia; Swanepoel, Robert
Serologic evidence suggests that West Nile virus (WNV) is widely distributed in horses in southern Africa. However, because few neurologic cases have been reported, endemic lineage 2 strains were postulated to be nonpathogenic in horses. Recent evidence suggests that highly neuroinvasive lineage 2 strains exist in humans and mice. To determine whether neurologic cases are being missed in South Africa, we tested 80 serum or brain specimens from horses with unexplained fever (n = 48) and/or neurologic signs (n = 32) for WNV. From March 2007 through June 2008, using reverse transcription–PCR (RT-PCR) and immunoglobulin (Ig) M ELISA, we found WNV RNA or IgM in 7/32 horses with acute neurologic disease; 5 horses died or were euthanized. In 5/7 horses, no other pathogen was detected. DNA sequencing for all 5 RT-PCR–positive cases showed the virus belonged to lineage 2. WNV lineage 2 may cause neurologic disease in horses in South Africa. PMID:19523285
Venter, Marietjie; Human, Stacey; Zaayman, Dewald; Gerdes, Gertruida H; Williams, June; Steyl, Johan; Leman, Patricia A; Paweska, Janusz Tadeusz; Setzkorn, Hildegard; Rous, Gavin; Murray, Sue; Parker, Rissa; Donnellan, Cynthia; Swanepoel, Robert
Serologic evidence suggests that West Nile virus (WNV) is widely distributed in horses in southern Africa. However, because few neurologic cases have been reported, endemic lineage 2 strains were postulated to be nonpathogenic in horses. Recent evidence suggests that highly neuroinvasive lineage 2 strains exist in humans and mice. To determine whether neurologic cases are being missed in South Africa, we tested 80 serum or brain specimens from horses with unexplained fever (n = 48) and/or neurologic signs (n = 32) for WNV. From March 2007 through June 2008, using reverse transcription-PCR (RT-PCR) and immunoglobulin (Ig) M ELISA, we found WNV RNA or IgM in 7/32 horses with acute neurologic disease; 5 horses died or were euthanized. In 5/7 horses, no other pathogen was detected. DNA sequencing for all 5 RT-PCR-positive cases showed the virus belonged to lineage 2. WNV lineage 2 may cause neurologic disease in horses in South Africa.
Sánchez-Guzmán, María Alejandra; Paz-Rodríguez, Francisco; Espinola-Nadurille, Mariana; Trujillo-De Los Santos, Zoila
Patients with neurological diseases are susceptible to abuse and neglect. Studies on violence in this context have mainly focused on abuse perpetrated by a caregiver to the patient directionally. In this study we describe violence in dyads of caregivers and patients with neurological disorders according to frequency, directionality, and type of relation. One-hundred-and-eighty-five caregiver-patient dyads were assessed by means of the National Survey of Violence Against Women (NSVAW) guidelines and the Zarit and Pfeiffer questionnaires. Bivariate analysis and Spearman correlation tests were performed. Violence was reported by 32.5% of caregivers and 33.5% of patients. In both groups, psychological abuse was the most common. Mutual violence (54.5%) is the most common type of abuse and the caregiver reported as having more violent behavior is the intimate partner. Epilepsy was the neurological disorder where violence was more prevalent (47.6%). The prevalence of violence in our sample is higher than the one for the general population of 21%, as reported by the NSVAW. Clinical neurologists and healthcare services are key elements for the detection of abuse in this context.
Zhang, Li; Hong, Huixiao
In the past decades, we have witnessed dramatic changes in clinical diagnoses and treatments due to the revolutions of genomics and personalized medicine. Undoubtedly we also met many challenges when we use those advanced technologies in drug discovery and development. In this review, we describe when genomic information is applied in personal healthcare in general. We illustrate some case examples of genomic discoveries and promising personalized medicine applications in the area of neurological disease particular. Available data suggest that individual genomics can be applied to better treat patients in the near future.
Wootla, Bharath; Watzlawik, Jens O; Warrington, Arthur E; Wittenberg, Nathan J; Denic, Aleksandar; Xu, Xiaohua; Jordan, Luke R; Papke, Louisa M; Zoecklein, Laurie J; Pierce, Mabel L; Oh, Sang-Hyun; Kantarci, Orhun H; Rodriguez, Moses
Modulating the immune system does not reverse long-term disability in neurologic disorders. Better neuroregenerative and neuroprotective treatment strategies are needed for neuroinflammatory and neurodegenerative diseases. To review the role of monoclonal, naturally occurring antibodies (NAbs) as novel therapeutic molecules for treatment of neurologic disorders. Peer-reviewed articles, including case reports, case series, retrospective reviews, prospective randomized clinical trials, and basic science reports, were identified in a PubMed search for articles about NAbs and neurologic disorders that were published from January 1, 1964, through June 30, 2015. We concentrated our review on multiple sclerosis, Parkinson disease, Alzheimer disease, and amyotrophic lateral sclerosis. Many insults, including trauma, ischemia, infection, inflammation, and neurodegeneration, result in irreversible damage to the central nervous system. Central nervous system injury often results in a pervasive inhibitory microenvironment that hinders regeneration. A common targeted drug development strategy is to identify molecules with high potency in animal models. Many approaches often fail in the clinical setting owing to a lack of efficacy in human diseases (eg, less than the response demonstrated in animal models) or a high incidence of toxic effects. An alternative approach is to identify NAbs in humans because these therapeutic molecules have potential physiologic function without toxic effects. NAbs of the IgG, IgA, or IgM isotype contain germline or close to germline sequences and are reactive to self-components, altered self-components, or foreign antigens. Our investigative group developed recombinant, autoreactive, natural human IgM antibodies directed against oligodendrocytes or neurons with therapeutic potential for central nervous system repair. One such molecule, recombinant HIgM22, directed against myelin and oligodendrocytes completed a successful phase 1 clinical trial
Song, Juan; Sun, Huiqing; Xu, Falin; Kang, Wenqing; Gao, Liang; Guo, Jiajia; Zhang, Yanhua; Xia, Lei; Wang, Xiaoyang
Objective To evaluate the efficacy and safety of repeated low‐dose human recombinant erythropoietin (rhEPO) in the improvement of neurological outcomes in very preterm infants. Methods A total of 800 infants of ≤32‐week gestational age who had been in an intensive care unit within 72 hours after birth were included in the trial between January 2009 and June 2013. Preterm infants were randomly assigned to receive rhEPO (500IU/kg; n = 366) or placebo (n = 377) intravenously within 72 hours after birth and then once every other day for 2 weeks. The primary outcome was death or moderate to severe neurological disability assessed at 18 months of corrected age. Results Death and moderate/severe neurological disability occurred in 91 of 338 very preterm infants (26.9%) in the placebo group and in 43 of 330 very preterm infants (13.0%) in the rhEPO treatment group (relative risk [RR] = 0.40, 95% confidence interval [CI] = 0.27–0.59, p < 0.001) at 18 months of corrected age. The rate of moderate/severe neurological disability in the rhEPO group (22 of 309, 7.1%) was significantly lower compared to the placebo group (57 of 304, 18.8%; RR = 0.32, 95% CI = 0.19–0.55, p < 0.001), and no excess adverse events were observed. Interpretation Repeated low‐dose rhEPO treatment reduced the risk of long‐term neurological disability in very preterm infants with no obvious adverse effects. Ann Neurol 2016;80:24–34 PMID:27130143
Ishibashi, Hidetoshi; Minakawa, Eiko N.; Motohashi, Hideyuki H.; Takayama, Osamu; Popiel, H. Akiko; Puentes, Sandra; Owari, Kensuke; Nakatani, Terumi; Nogami, Naotake; Yamamoto, Kazuhiro; Yonekawa, Takahiro; Tanaka, Yoko; Fujita, Naoko; Suzuki, Hikaru; Aizawa, Shu; Nagano, Seiichi; Yamada, Daisuke; Wada, Keiji; Kohsaka, Shinichi
Abstract Age-associated neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and the polyglutamine (polyQ) diseases, are becoming prevalent as a consequence of elongation of the human lifespan. Although various rodent models have been developed to study and overcome these diseases, they have limitations in their translational research utility owing to differences from humans in brain structure and function and in drug metabolism. Here, we generated a transgenic marmoset model of the polyQ diseases, showing progressive neurological symptoms including motor impairment. Seven transgenic marmosets were produced by lentiviral introduction of the human ataxin 3 gene with 120 CAG repeats encoding an expanded polyQ stretch. Although all offspring showed no neurological symptoms at birth, three marmosets with higher transgene expression developed neurological symptoms of varying degrees at 3–4 months after birth, followed by gradual decreases in body weight gain, spontaneous activity, and grip strength, indicating time-dependent disease progression. Pathological examinations revealed neurodegeneration and intranuclear polyQ protein inclusions accompanied by gliosis, which recapitulate the neuropathological features of polyQ disease patients. Consistent with neuronal loss in the cerebellum, brain MRI analyses in one living symptomatic marmoset detected enlargement of the fourth ventricle, which suggests cerebellar atrophy. Notably, successful germline transgene transmission was confirmed in the second-generation offspring derived from the symptomatic transgenic marmoset gamete. Because the accumulation of abnormal proteins is a shared pathomechanism among various neurodegenerative diseases, we suggest that this new marmoset model will contribute toward elucidating the pathomechanisms of and developing clinically applicable therapies for neurodegenerative diseases. PMID:28374014
Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation tool that is now being widely used in neuroscientific and clinical research in humans. While initial studies focused on modulation of cortical excitability, the technique quickly progressed to studies on motor and cognitive functions in healthy humans and in patients with neurological diseases. In the present review we will first provide the reader with a brief background on the basic principles of tDCS. In the main part, we will outline recent studies with tDCS that aimed at enhancing behavioral outcome or disease-specific symptoms in patients suffering from mild cognitive impairment, Alzheimer's disease, movement disorders, and epilepsy, or persistent deficits after stroke. The review will close with a summary statement on the present use of tDCS in the treatment of neurological disorders, and an outlook to further developments in this realm. tDCS may be an ideal tool to be administered in parallel to intensive cognitive or motor training in neurological disease, but efficacy for the areas of activities and participation still needs to be established in controlled randomized trials. Its use in reducing disease-specific symptoms like dystonia or epileptic seizures is still unclear.
Irwin, Ronald W.; Solinsky, Christine M.; Brinton, Roberta Diaz
Allopregnanolone (Allo), a neurosteroid, has emerged as a promising promoter of endogenous regeneration in brain. In a mouse model of Alzheimer’s disease, Allo induced neurogenesis, oligodendrogenesis, white matter generation and cholesterol homeostasis while simultaneously reducing β-amyloid and neuroinflammatory burden. Allo activates signaling pathways and gene expression required for regeneration of neural stem cells and their differentiation into neurons. In parallel, Allo activates systems to sustain cholesterol homeostasis and reduce β-amyloid generation. To advance Allo into studies for chronic human neurological conditions, we examined translational and clinical parameters: dose, regimen, route, formulation, outcome measures, and safety regulations. A treatment regimen of once per week at sub-sedative doses of Allo was optimal for regeneration and reduction in Alzheimer’s pathology. This regimen had a high safety profile following chronic exposure in aged normal and Alzheimer’s mice. Formulation of Allo for multiple routes of administration has been developed for both preclinical and clinical testing. Preclinical evidence for therapeutic efficacy of Allo spans multiple neurological diseases including Alzheimer’s, Parkinson’s, multiple sclerosis, Niemann-Pick, diabetic neuropathy, status epilepticus, and traumatic brain injury. To successfully translate Allo as a therapeutic for multiple neurological disorders, it will be necessary to tailor dose and regimen to the targeted therapeutic mechanisms and disease etiology. Treatment paradigms conducted in accelerated disease models in young animals have a low probability of successful translation to chronic diseases in adult and aged humans. Gender, genetic risks, stage and burden of disease are critical determinants of efficacy. This review focuses on recent advances in development of Allo for Alzheimer’s disease (AD) that have the potential to accelerate therapeutic translation for multiple unmet
Chen, Chen; Chan, Albert; Wen, Han; Chung, Seung-Hyuk; Deng, Wenbin; Jiang, Peng
Astroglia are a major cellular constituent of the central nervous system (CNS) and play crucial roles in brain development, function and integrity. Increasing evidence demonstrates that astroglia dysfunction occurs in a variety of neurological disorders ranging from CNS injuries to genetic diseases and chronic degenerative conditions. These new insights herald the concept that transplantation of astroglia could be of therapeutic value in treating the injured or diseased CNS. Recent technological advances in the generation of human astroglia from stem and progenitor cells have been prominent. We propose that a better understanding of the suitability of astroglial cells in transplantation, as well as of their therapeutic effects in animal models may lead to the establishment of astroglia-based therapies to treat neurological diseases. PMID:26443123
Vadori, Marta; Denaro, Luca; D'Avella, Domenico; Cozzi, Emanuele
The replacement of damaged cells in the central nervous system (CNS) affected by degenerative disorders represents an attractive therapeutic strategy. The advent of stem cell technology may offer the possibility of generating a large number of renewable, specifically differentiated cells to potentially cure large cohorts of patients. In this review, we discuss current knowledge and issues involved in neural cell transplantation. The most important preclinical and clinical results of cellular transplantation applied to Parkinson's, Huntington's disease and amyotrophic lateral sclerosis will be summarized. Cellular transplantation is emerging as a possible therapy for a variety of incurable neurological disorders. The disorders that will primarily take advantage from neural stem cell grafting are those involving a well defined cell population in a restricted area of the CNS. Several clinical trials have been initiated to assess safety and efficacy of different stem cell-derived products, and promising results have been obtained for disorders such as Parkinson's disease. However, several scientific questions remain unanswered. Among these, the impact of the immunological interaction between host and graft in the particular environment of the CNS still requires additional investigations. Several chronic neurological disorders appear to be amenable to cell regenerative therapies. However, safety, efficacy and immunological issues will need to be carefully evaluated beforehand.
Barth, Albert M.I.; Mody, Istvan
Background Just like human neurological disorders, corresponding mouse models present multiple deficiencies. Estimating disease progression or potential treatment effectiveness in such models necessitates the use of time consuming and multiple tests usually requiring a large number of scarcely available genetically modified animals. New method Here we present a novel and simple single camera arrangement and analysis software for detailed motor function evaluation in mice walking on a wire mesh that provides complex 3D information (instantaneous position, speed, distance traveled, foot fault depth, duration, location, relationship to speed of movement, etc.). Results We investigated 3 groups of mice with various neurological deficits: 1) unilateral motor cortical stroke; 2) effects of moderate ethanol doses; and 3) aging (96–99 weeks old). We show that post stroke recovery can be divided into separate stages based on strikingly different characteristics of motor function deficits, some resembling the human motor neglect syndrome. Mice treated with moderate dose of alcohol and aged mice showed specific motor and exploratory deficits. Comparison with Existing Methods Other tests rely either partially or entirely on manual video analysis introducing a significant subjective component into the analysis, and analyze a single aspect of motor function. Conclusions Our novel experimental approach provides qualitatively new, complex information about motor impairments and locomotor/exploratory activity. It should be useful for the detailed characterization of a broad range of human neurological disease models in mice, and for the more accurate assessment of disease progression or treatment effectiveness. PMID:24140423
Ercolini, Anne M; Miller, Stephen D
Although the immune system evolved to protect the host from foreign infection, it can sometimes recognize and attack host tissues, a phenomenon known as autoimmunity. In addition to genetic factors, environmental elements such as viruses and bacteria are thought to play a role in the development of autoimmune diseases. The major hypothesized mechanism by which infection with these agents can lead to autoimmunity is termed molecular mimicry. Here, immune responses initiated against foreign antigens are cross-reactive with self-antigens. This is thought to occur especially if the foreign antigen is similar in structure or amino acid sequence to the self-antigen. In this review, we explore evidence for the role of molecular mimicry in neurological diseases.
Mandrekar-Colucci, Shweta; Sauerbeck, Andrew; Popovich, Phillip G.; McTigue, Dana M.
Traumatic injury or disease of the spinal cord and brain elicits multiple cellular and biochemical reactions that together cause or are associated with neuropathology. Specifically, injury or disease elicits acute infiltration and activation of immune cells, death of neurons and glia, mitochondrial dysfunction, and the secretion of substrates that inhibit axon regeneration. In some diseases, inflammation is chronic or non-resolving. Ligands that target PPARs (peroxisome proliferator-activated receptors), a group of ligand-activated transcription factors, are promising therapeutics for neurologic disease and CNS injury because their activation affects many, if not all, of these interrelated pathologic mechanisms. PPAR activation can simultaneously weaken or reprogram the immune response, stimulate metabolic and mitochondrial function, promote axon growth and induce progenitor cells to differentiate into myelinating oligodendrocytes. PPAR activation has beneficial effects in many pre-clinical models of neurodegenerative diseases and CNS injury; however, the mechanisms through which PPARs exert these effects have yet to be fully elucidated. In this review we discuss current literature supporting the role of PPAR activation as a therapeutic target for treating traumatic injury and degenerative diseases of the CNS. PMID:24215544
Bambauer, Rolf; Latza, Reinhard; Burgard, Daniel; Schiel, Ralf
Since the mid 1970s, when membrane modules became available, plasma separation techniques have gained in importance especially in the past few years. The advantages of this method are a complete separation of the corpuscular components from the plasma and due to increased blood flow rate and higher efficacy. Systemic autoimmune diseases based on an immune pathogenesis produce autoantibodies and circulating immune complexes, which cause inflammation in the tissues of various organs. In most cases, these diseases have a poor prognosis without treatment. Therapeutic apheresis (TA) in combination with immunosuppressive therapies has led to a steady increase in survival rates over the last 40 years. The updated information on immunology and molecular biology of different immunologic diseases are discussed in relation to the rationale for apheresis therapy and its place in combination with other modern treatments. The different diseases can be treated by various apheresis methods such as therapeutic plasma exchange (TPE) with substitution solution, or with online plasma or blood purification using adsorption columns, which contain biological or non-biological agents. Here, the authors provide an overview of the most important pathogenic aspects indicating that TA can be a supportive therapy in systemic autoimmune diseases such as renal and neurological disorders. For the immunological diseases that can be treated with TA, the guidelines of the German Working Group of Clinical Nephrology and of the Apheresis Committee of the American Society for Apheresis are cited.
Pradhan, Suman; Pellino, Christine; MacMaster, Kayleigh; Coyle, Dennis; Weiss, Alison A
Seizures and neurologic involvement have been reported in patients infected with Shiga toxin (Stx) producing E. coli, and hemolytic uremic syndrome (HUS) with neurologic involvement is associated with more severe outcome. We investigated the extent of renal and neurologic damage in mice following injection of the highly potent form of Stx, Stx2a, and less potent Stx1. As observed in previous studies, Stx2a brought about moderate to acute tubular necrosis of proximal and distal tubules in the kidneys. Brain sections stained with hematoxylin and eosin (H&E) appeared normal, although some red blood cell congestion was observed. Microglial cell responses to neural injury include up-regulation of surface-marker expression (e.g., Iba1) and stereotypical morphological changes. Mice injected with Stx2a showed increased Iba1 staining, mild morphological changes associated with microglial activation (thickening of processes), and increased microglial staining per unit area. Microglial changes were observed in the cortex, hippocampus, and amygdala regions, but not the nucleus. Magnetic resonance imaging (MRI) of Stx2a-treated mice revealed no hyper-intensities in the brain, although magnetic resonance spectroscopy (MRS) revealed significantly decreased levels of phosphocreatine in the thalamus. Less dramatic changes were observed following Stx1 challenge. Neither immortalized microvascular endothelial cells from the cerebral cortex of mice (bEnd.3) nor primary human brain microvascular endothelial cells were found to be susceptible to Stx1 or Stx2a. The lack of susceptibility to Stx for both cell types correlated with an absence of receptor expression. These studies indicate Stx causes subtle, but identifiable changes in the mouse brain.
Pradhan, Suman; Pellino, Christine; MacMaster, Kayleigh; Coyle, Dennis; Weiss, Alison A.
Seizures and neurologic involvement have been reported in patients infected with Shiga toxin (Stx) producing E. coli, and hemolytic uremic syndrome (HUS) with neurologic involvement is associated with more severe outcome. We investigated the extent of renal and neurologic damage in mice following injection of the highly potent form of Stx, Stx2a, and less potent Stx1. As observed in previous studies, Stx2a brought about moderate to acute tubular necrosis of proximal and distal tubules in the kidneys. Brain sections stained with hematoxylin and eosin (H&E) appeared normal, although some red blood cell congestion was observed. Microglial cell responses to neural injury include up-regulation of surface-marker expression (e.g., Iba1) and stereotypical morphological changes. Mice injected with Stx2a showed increased Iba1 staining, mild morphological changes associated with microglial activation (thickening of processes), and increased microglial staining per unit area. Microglial changes were observed in the cortex, hippocampus, and amygdala regions, but not the nucleus. Magnetic resonance imaging (MRI) of Stx2a-treated mice revealed no hyper-intensities in the brain, although magnetic resonance spectroscopy (MRS) revealed significantly decreased levels of phosphocreatine in the thalamus. Less dramatic changes were observed following Stx1 challenge. Neither immortalized microvascular endothelial cells from the cerebral cortex of mice (bEnd.3) nor primary human brain microvascular endothelial cells were found to be susceptible to Stx1 or Stx2a. The lack of susceptibility to Stx for both cell types correlated with an absence of receptor expression. These studies indicate Stx causes subtle, but identifiable changes in the mouse brain. PMID:27747196
Tsai, Jeng-Dau; Kuo, Hung-Tsung; Chen, Shan-Ming; Lue, Ko-Huang; Sheu, Ji-Nan
Since 1998 in Taiwan, enterovirus (EV) 71 epidemics have caused encephalomyelitis and placed a significant burden on parents and physicians. In this study, we present clinical manifestations, magnetic resonance (MR) imaging findings, and neurological sequelae on epidemic EV-infected patients with encephalomyelitis. Of the 46 patients, 14 patients presented with neurological sequelae; of them, 3 patients suffered from complications of mental regression. Predictors of unfavorable neurological sequelae were myoclonic jerks (> 4 times/night) and pleocytosis (167/μL) of the cerebrospinal fluid (CSF). Results from viral culture and MR imaging indicated that positive identification of EV71 infection was associated significantly with lesions on MR imaging. Our results show that hand-foot-mouth disease carries a higher risk of encephalomyelitis and that frequent myoclonic jerks and pleocytosis of the CSF are risk factors for subsequent neurological sequelae. Positive identification of EV71 might be useful as a predictor of lesions in MR imaging.
Gilden, Don; Cohrs, Randall J.; Mahalingam, Ravi; Nagel, Maria A.
Reactivation of varicella zoster virus (VZV) from latently infected human ganglia usually produces herpes zoster (shingles), characterized by dermatomal distribution pain and rash. Zoster is often followed by chronic pain (postherpetic neuralgia or PHN) as well as meningitis or meningoencephalitis, cerebellitts, isolated cranial nerve palsies that produce ophthalmoplegia or the Ramsay Hunt syndrome, multiple cranial nerve palsies (polyneuritis cranialis), vasculopathy. myelopathy, and various inflammatory disorders of the eye. Importantly, VZV reactivation can produce chronic radicular pain without rash (zoster sine herpete), as well as all the neurological disorders listed above without rash. The protean neurological and ocular disorders produced by VZV in the absence of rash are a challenge to the practicing clinician. The presentation of these conditions vanes from acute to subacute to chronic. Virological confirmation requires the demonstration of amplifiable VZV DNA in cerebrospinal fluid (CSF) or in blood mononuclear cells, or the presence of anti-VZV IgG antibody in CSF or of anti-VZV IgM antibody in CSF or serum. PMID:20186614
Gruhn, K M; Knossalla, Frauke; Schwenkreis, Peter; Hamsen, Uwe; Schildhauer, Thomas A; Tegenthoff, Martin; Sczesny-Kaiser, Matthias
Lightning strikes rarely occur but 85 % of patients have lightning-related neurological complications. This report provides an overview about different modes of energy transfer and neurological conditions related to lightning strikes. Moreover, two case reports demonstrate the importance of interdisciplinary treatment and the spectrum of neurological complications after lightning strikes.
Broussolle, E; Trocello, J-M; Woimant, F; Lachaux, A; Quinn, N
This historical article describes the life and work of the British physician Samuel Alexander Kinnier Wilson (1878-1937), who was one of the world's greatest neurologists of the first half of the 20th century. Early in his career, Wilson spent one year in Paris in 1903 where he learned from Pierre-Marie at Bicêtre Hospital. He subsequently retained uninterrupted links with French neurology. He also visited in Leipzig the German anatomist Paul Flechsig. In 1904, Wilson returned to London, where he worked for the rest of his life at the National Hospital for the Paralysed and Epileptic (later the National Hospital for Nervous Diseases, and today the National Hospital for Neurology and Neurosurgery) in Queen Square, and also at Kings' College Hospital. He wrote on 'the old motor system and the new', on disorders of motility and muscle tone, on the epilepsies, on aphasia, apraxia, tics, and pathologic laughing and crying, and most importantly on Wilson's disease. The other objective of our paper is to commemorate the centenary of Wilson's most important work published in 1912 in Brain, and also in Revue Neurologique, on an illness newly recognized and characterized by him entitled "Progressive lenticular degeneration, a familial nervous disease associated with liver cirrhosis". He analyzed 12 clinical cases, four of whom he followed himself, but also four cases previously published by others and a further two that he considered in retrospect had the same disease as he was describing. The pathological profile combined necrotic damage in the lenticular nuclei of the brain and hepatic cirrhosis. This major original work is summarized and discussed in the present paper. Wilson not only delineated what was later called hepato-lenticular degeneration and Wilson's disease, but also introduced for the first time the terms extrapyramidal syndrome and extrapyramidal system, stressing the role of the basal ganglia in motility. The present historical work emphasizes the special
Lyketsos, Constantin G.; Kozauer, Nicholas; Rabins, Peter V.
Neuropsychiatry represents a field of medicine situated at the crossroads of neurology and psychiatry, and deals with the interface of behavioral phenomena driven by brain dysfunction. Psychiatric symptoms are highly prevalent in these conditions, are a major source of disability and diminished quality of life, and potentially represent the target of treatment interventions that stand to significantly decrease the suffering they generate. In this article, the disease paradigm is explained, with particular attention to its role as an organizing principle for the field. Specific diseases including traumatic brain injury, stroke, Parkinson's disease, Alzheimer's disease, multiple sclerosis, and epilepsy are explored in relation to the presentation of multiple psychiatric phenotypes in each, associations with underlying brain pathology, and existing treatment approaches. Finally, the afticle explores the inherent complexities in this area of research and proposes a framework for future work based on the understanding of phenomenology and associated risk factors, the involvement of the rapidly advancing field of neuroscience, and targeted treatment development to serve as a road map for advancement in the field. PMID:17726911
Tan, Ji-Ping; Zhu, Lin-Qi; Zhang, Jun; Zhang, Shi-Min; Lan, Xiao-Yang; Cui, Bo; Deng, Yu-Cheng; Li, Ying-Hao; Ye, Guang-Hua; Wang, Lu-Ning
Background: The awareness, treatment and prevention of chronic diseases are generally poor among the elderly population of China, whereas the prevention and control of chronic diseases in elderly veteran communities have been ongoing for more than 30 years. Therefore, investigating the awareness status of chronic disabling neurological diseases (CDND) and common chronic diseases (CCD) among elderly veterans may provide references for related programs among the elderly in the general population. Methods: A cross-sectional survey was conducted among veterans ≥60 years old in veteran communities in Beijing. The awareness of preventive strategies against dementia, Alzheimer's disease (AD), Parkinson's disease (PD), sleep disorders, cerebrovascular disease (CVD) and CCD such as hypertension, and the approaches used to access this information, including media, word of mouth (verbal communication among the elderly) and health care professionals, were investigated via face-to-face interviews. Results: The awareness rates for CCD and CVD were approximately 100%, but that for AD was the lowest at <10%. The awareness rates for sleep disorders, PD and dementia, were 51.0–89.4%. Media was the most commonly selected mode of communication by which veterans acquired knowledge about CCD and CVD. Media was used by approximately 80% of veterans. Both health care professionals and word of mouth were used by approximately 50% of veterans. With respect to the source of information about CDND excluding AD, the rates of the use of health care professionals, word of mouth and media were 10.6–28.2%, 56.5–76.5%, and approximately 50%, respectively. Conclusions: The awareness of CDND among elderly veterans was significantly lower than that of CCD. More information about CDND should be disseminated by health care professionals. Appropriate guidance will promote the rapid and extensive dissemination of information about the prevention of CDND by media and word-of-mouth peer education
Tan, Ji-Ping; Zhu, Lin-Qi; Zhang, Jun; Zhang, Shi-Min; Lan, Xiao-Yang; Cui, Bo; Deng, Yu-Cheng; Li, Ying-Hao; Ye, Guang-Hua; Wang, Lu-Ning
The awareness, treatment and prevention of chronic diseases are generally poor among the elderly population of China, whereas the prevention and control of chronic diseases in elderly veteran communities have been ongoing for more than 30 years. Therefore, investigating the awareness status of chronic disabling neurological diseases (CDND) and common chronic diseases (CCD) among elderly veterans may provide references for related programs among the elderly in the general population. A cross-sectional survey was conducted among veterans ≥60 years old in veteran communities in Beijing. The awareness of preventive strategies against dementia, Alzheimer's disease (AD), Parkinson's disease (PD), sleep disorders, cerebrovascular disease (CVD) and CCD such as hypertension, and the approaches used to access this information, including media, word of mouth (verbal communication among the elderly) and health care professionals, were investigated via face-to-face interviews. The awareness rates for CCD and CVD were approximately 100%, but that for AD was the lowest at <10%. The awareness rates for sleep disorders, PD and dementia, were 51.0-89.4%. Media was the most commonly selected mode of communication by which veterans acquired knowledge about CCD and CVD. Media was used by approximately 80% of veterans. Both health care professionals and word of mouth were used by approximately 50% of veterans. With respect to the source of information about CDND excluding AD, the rates of the use of health care professionals, word of mouth and media were 10.6-28.2%, 56.5-76.5%, and approximately 50%, respectively. The awareness of CDND among elderly veterans was significantly lower than that of CCD. More information about CDND should be disseminated by health care professionals. Appropriate guidance will promote the rapid and extensive dissemination of information about the prevention of CDND by media and word-of-mouth peer education.
Fishman, Paul S; Frenkel, Victor
Therapeutic ultrasound is only beginning to be applied to neurologic conditions, but the potential of this modality for a wide spectrum of brain applications is high. Engineering advances now allow sound waves to be targeted through the skull to a brain region selected with real time magnetic resonance imaging and thermography, using a commercial array of focused emitters. High intensities of sonic energy can create a coagulation lesion similar to that of older radiofrequency stereotactic methods, but without opening the skull. This has led to the recent Food and Drug Administration approval of focused ultrasound (FUS) thalamotomy for unilateral treatment of essential tremor. Clinical studies of stereotactic FUS for aspects of Parkinson's disease, chronic pain, and refractory psychiatric indications are underway, with promising results. Moderate-intensity FUS has the potential to safely open the blood-brain barrier for localized delivery of therapeutics, while low levels of sonic energy can be used as a form of neuromodulation.
Katona, István; Freund, Tamás F
Cannabis sativa is one of the oldest herbal plants in the history of medicine. It was used in various therapeutic applications from pain to epilepsy, but its psychotropic effect has reduced its usage in recent medical practice. However, renewed interest has been fueled by major discoveries revealing that cannabis-derived compounds act through a signaling pathway in the human body. Here we review recent advances showing that endocannabinoid signaling is a key regulator of synaptic communication throughout the central nervous system. Its underlying molecular architecture is highly conserved in synapses from the spinal cord to the neocortex, and as a negative feed-back signal, it provides protection against excess presynaptic activity. The endocannabinoid signaling machinery operates on demand in a synapse-specific manner; therefore, its modulation offers new therapeutic opportunities for the selective control of deleterious neuronal activity in several neurological disorders.
Morales, J. P.; Taylor, P. R.; Bell, R. E.; Chan, Y. C.; Sabharwal, T.; Carrell, T. W. G.; Reidy, J. F.
Open surgery for thoracic aortic disease is associated with significant morbidity and the reported rates for paraplegia and stroke are 3%-19% and 6%-11%, respectively. Spinal cord ischemia and stroke have also been reported following endoluminal repair. This study reviews the incidence of paraplegia and stroke in a series of 186 patients treated with thoracic stent grafts. From July 1997 to September 2006, 186 patients (125 men) underwent endoluminal repair of thoracic aortic pathology. Mean age was 71 years (range, 17-90 years). One hundred twenty-eight patients were treated electively and 58 patients had urgent procedures. Anesthesia was epidural in 131, general in 50, and local in 5 patients. Seven patients developed paraplegia (3.8%; two urgent and five elective). All occurred in-hospital apart from one associated with severe hypotension after a myocardial infarction at 3 weeks. Four of these recovered with cerebrospinal fluid (CSF) drainage. One patient with paraplegia died and two had permanent neurological deficit. The rate of permanent paraplegia and death was 1.6%. There were seven strokes (3.8%; four urgent and three elective). Three patients made a complete recovery, one had permanent expressive dysphasia, and three died. The rate of permanent stroke and death was 2.1%. Endoluminal treatment of thoracic aortic disease is an attractive alternative to open surgery; however, there is still a risk of paraplegia and stroke. Permanent neurological deficits and death occurred in 3.7% of the patients in this series. We conclude that prompt recognition of paraplegia and immediate insertion of a CSF drain can be an effective way of recovering spinal cord function and improving the prognosis.
Beirão, Pedro; Pereira, Patrícia; Nunes, Andreia; Antunes, Pedro
A 70-year-old man with known cardiovascular risk factors, presented with acute onset expression aphasia, agraphia, dyscalculia, right-left disorientation and finger agnosia, without fever or meningeal signs. Stroke was thought to be the cause, but cerebrovascular disease investigation was negative. Interviewing the family revealed he had undergone yellow fever vaccination 18 days before. Lumbar puncture revealed mild protein elevation. Cultural examinations, Coxiella burnetti, and neurotropic virus serologies were negative. Regarding the yellow fever virus, IgG was identified in serum and cerebrospinal fluid (CSF), with negative IgM and virus PCR in CSF. EEG showed an encephalopathic pattern. The patient improved gradually and a week after discharge was his usual self. Only criteria for suspect neurotropic disease were met, but it's possible the time spent between symptom onset and lumbar puncture prevented a definite diagnosis of yellow fever vaccine-associated neurological disease. This gap would have been smaller if the vaccination history had been collected earlier. 2017 BMJ Publishing Group Ltd.
Rosenberg, Gary A
Disruption of the blood–brain barrier (BBB) has an important part in cellular damage in neurological diseases, including acute and chronic cerebral ischemia, brain trauma, multiple sclerosis, brain tumors, and brain infections. The neurovascular unit (NVU) forms the interface between the blood and brain tissues. During an injury, the cascade of molecular events ends in the final common pathway for BBB disruption by free radicals and proteases, which attack membranes and degrade the tight junction proteins in endothelial cells. Free radicals of oxygen and nitrogen and the proteases, matrix metalloproteinases and cyclooxgyenases, are important in the early and delayed BBB disruption as the neuroinflammatory response progresses. Opening of the BBB occurs in neurodegenerative diseases and contributes to the cognitive changes. In addition to the importance of the NVU in acute injury, angiogenesis contributes to the recovery process. The challenges to treatment of the brain diseases involve not only facilitating drug entry into the brain, but also understanding the timing of the molecular cascades to block the early NVU injury without interfering with recovery. This review will describe the molecular and cellular events associated with NVU disruption and potential strategies directed toward restoring its integrity. PMID:22252235
Soldan, S S; Graf, M D; Waziri, A; Flerlage, A N; Robinson, S M; Kawanishi, T; Leist, T P; Lehky, T J; Levin, M C; Jacobson, S
The human T-cell lymphotropic virus type I (HTLV-I) is associated with a chronic, progressive neurological disease known as HTLV-I-associated myelopathy/tropical spastic paraparesis. Screening for HTLV-I involves the detection of virus-specific serum antibodies by EIA and confirmation by Western blot. HTLV-I/II seroindeterminate Western blot patterns have been described worldwide. However, the significance of this blot pattern is unclear. We identified 8 patients with neurological disease and an HTLV-I/II seroindeterminate Western blot pattern, none of whom demonstrated increased spontaneous proliferation and HTLV-I-specific cytotoxic T lymphocyte activity. However, HTLV-I tax sequence was amplified from the peripheral blood lymphocytes of 4 of them. These data suggest that patients with chronic progressive neurological disease and HTLV-I/II Western blot seroindeterminate reactivity may harbor either defective HTLV-I, novel retrovirus with partial homology to HTLV-I, or HTLV-I in low copy number.
In this review the properties of iron in various human brain structures (e.g. Substantia nigra, globus pallidus, hippocampus) were analyzed to assess the possibility of initiation of oxidative stress leading to such diseases as Parkinson’s and Alzheimer’s disease, and progressive supranuclear palsy. Our own studies with the use of Mössbauer spectroscopy, electron microscopy and enzyme-linked immuno-absorbent assay (ELISA) were confronted with other methods used in other laboratories. Our results suggest that hippocampus is the most fragile for oxidative stress structure in human brain (the death of nervous cells in hippocampus leads to Alzheimer’s disease). Changes in iron metabolism were also found in substantia nigra (the death of nervous cells of this structure produces Parkinson’s disease) and in globus pallidus (neurodegeneration of this structure causes progressive supranuclear palsy).
Zeliger, Harold I
Many studies have associated environmental exposure to chemicals with neurological impairments (NIs) including neuropathies, cognitive, motor and sensory impairments; neurodevelopmental disorders (NDDs) including autism and attention deficit hyperactivity disorder (ADHD); neurodegenerative diseases (NDGs) including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis (ALS). The environmental chemicals shown to induce all these diseases include persistent organic pollutants (POPs), the plastic exudates bisphenol A and phthalates, low molecular weight hydrocarbons (LMWHCs) and polynuclear aromatic hydrocarbons (PAHs). It is reported here that though these chemicals differ widely in their chemical properties, reactivities and known points of attack in humans, a common link does exist between them. All are lipophilic species found in serum and they promote the sequential absorption of otherwise non-absorbed toxic hydrophilic species causing these diseases.
Many studies have associated environmental exposure to chemicals with neurological impairments (NIs) including neuropathies, cognitive, motor and sensory impairments; neurodevelopmental disorders (NDDs) including autism and attention deficit hyperactivity disorder (ADHD); neurodegenerative diseases (NDGs) including Alzheimer′s disease, Parkinson's disease and amyotrophic lateral sclerosis (ALS). The environmental chemicals shown to induce all these diseases include persistent organic pollutants (POPs), the plastic exudates bisphenol A and phthalates, low molecular weight hydrocarbons (LMWHCs) and polynuclear aromatic hydrocarbons (PAHs). It is reported here that though these chemicals differ widely in their chemical properties, reactivities and known points of attack in humans, a common link does exist between them. All are lipophilic species found in serum and they promote the sequential absorption of otherwise non-absorbed toxic hydrophilic species causing these diseases. PMID:24678247
Bobinger, Tobias; May, Lisa; Lücking, Hannes; Kloska, Stephan P.; Burkardt, Petra; Spitzer, Philipp; Maler, Juan M.; Corbeil, Denis; Huttner, Hagen B.
Background: Analysis of cerebrospinal fluid (CSF) is a frequently used diagnostic tool in a variety of neurological diseases. Recent studies suggested that investigating membrane particles enriched with the stem cell marker CD133 may offer new avenues for studying neurological disease. In this study, we evaluated the amount of membrane particle-associated CD133 in human CSF in neuroinflammatory and degenerative diseases. Methods: We compared the amount of membrane particle-associated CD133 in CSF samples collected from 45 patients with normal pressure hydrocephalus, parkinsonism, dementia, and cognitive impairment, chronic inflammatory diseases and 10 healthy adult individuals as controls. After ultracentrifugation of CSF, gel electrophoresis and immunoblotting using anti-CD133 monoclonal antibody 80B258 were performed. Antigen-antibody complexes were detected using chemiluminescence. Results: The amount of membrane particle-associated CD133 was significantly increased in patients with normal pressure hydrocephalus (p < 0.001), parkinsonism (p = 0.011) as well as in patients with chronic inflammatory disease (p = 0.008). Analysis of CSF of patients with dementia and cognitive impairment revealed no significant change compared with healthy individuals. Furthermore, subgroup analysis of patients with chronic inflammatory diseases demonstrated significantly elevated levels in individuals with relapsing-remitting multiple sclerosis (p = 0.023) and secondary progressive multiple sclerosis (SPMS; p = 0.010). Conclusion: Collectively, our study revealed elevated levels of membrane particle-associated CD133 in patients with normal pressure hydrocephalus, parkinsonism as well as relapsing-remitting and SPMS. Membrane glycoprotein CD133 may be of clinical value for several neurological diseases. PMID:28396625
Fan, Nana; Lai, Liangxue
Genetically modified animal models are important for understanding the pathogenesis of human disease and developing therapeutic strategies. Although genetically modified mice have been widely used to model human diseases, some of these mouse models do not replicate important disease symptoms or pathology. Pigs are more similar to humans than mice in anatomy, physiology, and genome. Thus, pigs are considered to be better animal models to mimic some human diseases. This review describes genetically modified pigs that have been used to model various diseases including neurological, cardiovascular, and diabetic disorders. We also discuss the development in gene modification technology that can facilitate the generation of transgenic pig models for human diseases.
Skiest, Daniel J
Focal neurological disease in patients with acquired immunodeficiency syndrome may be caused by various opportunistic pathogens and malignancies, including Toxoplasma gondii, progressive multifocal leukoencephalopathy (PML), cytomegalovirus (CMV), and Epstein-Barr virus-related primary central nervous system (CNS) lymphoma. Diagnosis may be difficult, because the findings of lumbar puncture, computed tomography (CT), and magnetic resonance imaging are relatively nonspecific. Newer techniques have led to improved diagnostic accuracy of these conditions. Polymerase chain reaction (PCR) of cerebrospinal fluid specimens is useful for diagnosis of PML, CNS lymphoma, and CMV encephalitis. Recent studies have indicated the diagnostic utility of new neuroimaging techniques, such as single-photon emission CT and positron emission tomography. The combination of PCR and neuroimaging techniques may obviate the need for brain biopsy in selected cases. However, stereotactic brain biopsy, which is associated with relatively low morbidity rates, remains the reference standard for diagnosis. Highly active antiretroviral therapy has improved the prognosis of several focal CNS processes, most notably toxoplasmosis, PML, and CMV encephalitis.
Gagnon, Martin; Bergeron, Marc J; Lavertu, Guillaume; Castonguay, Annie; Tripathy, Sasmita; Bonin, Robert P; Perez-Sanchez, Jimena; Boudreau, Dominic; Wang, Bin; Dumas, Lionel; Valade, Isabelle; Bachand, Karine; Jacob-Wagner, Mariève; Tardif, Christian; Kianicka, Irenej; Isenring, Paul; Attardo, Giorgio; Coull, Jeffrey A M; De Koninck, Yves
The K(+)-Cl(-) cotransporter KCC2 is responsible for maintaining low Cl(-) concentration in neurons of the central nervous system (CNS), which is essential for postsynaptic inhibition through GABA(A) and glycine receptors. Although no CNS disorders have been associated with KCC2 mutations, loss of activity of this transporter has emerged as a key mechanism underlying several neurological and psychiatric disorders, including epilepsy, motor spasticity, stress, anxiety, schizophrenia, morphine-induced hyperalgesia and chronic pain. Recent reports indicate that enhancing KCC2 activity may be the favored therapeutic strategy to restore inhibition and normal function in pathological conditions involving impaired Cl(-) transport. We designed an assay for high-throughput screening that led to the identification of KCC2 activators that reduce intracellular chloride concentration ([Cl(-)]i). Optimization of a first-in-class arylmethylidine family of compounds resulted in a KCC2-selective analog (CLP257) that lowers [Cl(-)]i. CLP257 restored impaired Cl(-) transport in neurons with diminished KCC2 activity. The compound rescued KCC2 plasma membrane expression, renormalized stimulus-evoked responses in spinal nociceptive pathways sensitized after nerve injury and alleviated hypersensitivity in a rat model of neuropathic pain. Oral efficacy for analgesia equivalent to that of pregabalin but without motor impairment was achievable with a CLP257 prodrug. These results validate KCC2 as a druggable target for CNS diseases.
Graves, T; Hanna, M
Ion channels are membrane-bound proteins that perform key functions in virtually all human cells. Such channels are critically important for the normal function of the excitable tissues of the nervous system, such as muscle and brain. Until relatively recently it was considered that dysfunction of ion channels in the nervous system would be incompatible with life. However, an increasing number of human diseases associated with dysfunctional ion channels are now recognised. Such neurological channelopathies are frequently genetically determined but may also arise through autoimmune mechanisms. In this article clinical, genetic, immunological, and electrophysiological aspects of this expanding group of neurological disorders are reviewed. Clinical situations in which a neurological channelopathy should enter into the differential diagnosis are highlighted. Some practical guidance on how to investigate and treat this complex group of disorders is also included. PMID:15640425
Lee, Myoung-Hwa; Wang, Tongguang; Jang, Mi-Hyeon; Steiner, Joseph; Haughey, Norman; Ming, Guo-li; Song, Hongjun; Nath, Avindra; Venkatesan, Arun
The prevalence of central nervous system (CNS) neurologic dysfunction associated with human immunodeficiency virus (HIV) infection continues to increase, despite the use of antiretroviral therapy. Previous work has focused on the deleterious effects of HIV on mature neurons and on development of neuroprotective strategies, which have consistently failed to show a meaningful clinical benefit. It is now well established that new neurons are continuously generated in discrete regions in the adult mammalian brain, and accumulating evidence supports important roles for these neurons in specific cognitive functions. In a transgenic mouse model of HIV neurologic disease with glial expression of the HIV envelope protein gp120, we demonstrate a significant reduction in proliferation of hippocampal neural progenitors in the dentate gyrus of adult animals, resulting in a dramatic decrease in the number of newborn neurons in the adult brain. We identify amplifying neural progenitor cells (ANPs) as the first class of progenitors affected by gp120, and we also demonstrate that newly generated neurons exhibit aberrant dendritic development. Furthermore, voluntary exercise and treatment with a selective serotonin reuptake inhibitor increase the ANP population and rescue the observed deficits in gp120 transgenic mice. Thus, during HIV infection, the envelope protein gp120 may potently inhibit adult hippocampal neurogenesis, and neurorestorative approaches may be effective in ameliorating these effects. Our study has significant implications for the development of novel therapeutic approaches for HIV-infected individuals with neurologic dysfunction and may be applicable to other neurodegenerative diseases in which hippocampal neurogenesis is impaired. PMID:21146610
Shroff, Geeta; Dhanda Titus, Jyoti; Shroff, Rhea
The first human embryonic stem cell (hESC) line was developed in the late nineties. hESCs are capable of proliferating indefinitely and differentiate into all the three embryonic germ layers. Further, the differentiation of hESC lines into neural precursor cells and neurons, astrocytes and oligodendrocytes showed their potential in treating several incurable neurological disorders such as spinal cord injury (SCI), cerebral palsy (CP), Parkinson's disease (PD). In this review, we will discuss the global scenario of research and therapeutic use of hESCs in the treatment of neurological disorders. Following this, we will discuss the development of a unique hESC line, how it differs from the other available hESC lines and its use in the treatment of neurological disorders. hESCs were isolated from mixture of neuronal and non-neuronal progenitor cells in their pre progenitor state in a Good Laboratory Practices, Good Tissue Practices and Good Manufacturing Practices compliant laboratory. Blastomere cells have served as a source to derive the hESCs and the xeno-free culture was demonstrated to be more safe and effective in clinical therapeutic application of hESCs. All the patients showed a remarkable improvement in their conditions and no serious adverse events were reported. This study concluded that hESC lines could be scalable and used in the treatment of various neurological disorders such as SCI, CP, and PD.
Shroff, Geeta; Dhanda Titus, Jyoti; Shroff, Rhea
The first human embryonic stem cell (hESC) line was developed in the late nineties. hESCs are capable of proliferating indefinitely and differentiate into all the three embryonic germ layers. Further, the differentiation of hESC lines into neural precursor cells and neurons, astrocytes and oligodendrocytes showed their potential in treating several incurable neurological disorders such as spinal cord injury (SCI), cerebral palsy (CP), Parkinson’s disease (PD). In this review, we will discuss the global scenario of research and therapeutic use of hESCs in the treatment of neurological disorders. Following this, we will discuss the development of a unique hESC line, how it differs from the other available hESC lines and its use in the treatment of neurological disorders. hESCs were isolated from mixture of neuronal and non-neuronal progenitor cells in their pre progenitor state in a Good Laboratory Practices, Good Tissue Practices and Good Manufacturing Practices compliant laboratory. Blastomere cells have served as a source to derive the hESCs and the xeno-free culture was demonstrated to be more safe and effective in clinical therapeutic application of hESCs. All the patients showed a remarkable improvement in their conditions and no serious adverse events were reported. This study concluded that hESC lines could be scalable and used in the treatment of various neurological disorders such as SCI, CP, and PD. PMID:28533935
van Niekerk, Stephanie; Human, Stacey; Williams, June; van Wilpe, Erna; Pretorius, Marthi; Swanepoel, Robert
Old World alphaviruses were identified in 52 of 623 horses with febrile or neurologic disease in South Africa. Five of 8 Sindbis virus infections were mild; 2 of 3 fatal cases involved co-infections. Of 44 Middelburg virus infections, 28 caused neurologic disease; 12 were fatal. Middelburg virus likely has zoonotic potential. PMID:26583836
van Niekerk, Stephanie; Human, Stacey; Williams, June; van Wilpe, Erna; Pretorius, Marthi; Swanepoel, Robert; Venter, Marietjie
Old World alphaviruses were identified in 52 of 623 horses with febrile or neurologic disease in South Africa. Five of 8 Sindbis virus infections were mild; 2 of 3 fatal cases involved co-infections. Of 44 Middelburg virus infections, 28 caused neurologic disease; 12 were fatal. Middelburg virus likely has zoonotic potential.
Ulezko, E. A.; Shan'ko, G. G.
The authors have studied 197 infants (1-12 months old) with normal psychomotor development and with various neurological disturbances. Neurosonography and dopplerometry were used to investigate the blood flow pattern and structural changes in the brain.
Bray, Garth M; Huggett, Deanna L
The National Population Health Study of Neurological Conditions, a partnership between Neurological Health Charities Canada and the Government of Canada, was the largest study of neurological diseases, disorders, and injuries ever conducted in Canada. Undertaken between 2009 and 2013, the expansive program of research addressed the epidemiology, impacts, health services, and risk factors of 18 neurological conditions and estimated the health outcomes and costs of these conditions in Canada through 2031. This review summarizes highlights from the component projects of the study as presented in the synthesis report, Mapping Connections: An Understanding of Neurological Conditions in Canada. The key findings included new prevalence and incidence estimates, documentation of the diverse and often debilitating effects of neurological conditions, and identification of the utilization, economic costs, and current limitations of related health services. The study findings will support health charities, governments, and other stakeholders to reduce the impact of neurological conditions in Canada.
Tzoufi, M; Mantas, Ch; Pappa, S; Kateri, M; Hyphantis, T; Pavlou, M; Mavreas, V; Siamopoulou-Mavridou, A
Although the impact of childhood chronic neurological diseases (CND) on patients' psychological well-being has been increasingly addressed, little attention has been given to the influence of these conditions on family members and family functioning. The purpose of the present study was to investigate the family characteristics of Greek children suffering from CND. A total of 52 parents of children with CND were studied by using the Family Environmental Scale (FES), the Family Burden Scale, the General Health Questionnaire (GHQ-28) and a questionnaire on the knowledge of their children's illness, their coping strategies and their satisfaction with our services. During the same period, 30 parents of hospitalized children for common paediatric illnesses completed the FES. In both groups social and demographic features were registered. Appropriate statistical processes were applied to compare the above-mentioned family groups and to study the differences between the families of children with epilepsy (n=37) and the families of children with other CND (n=15). Parents of children with CND discuss their problems less freely, talk less openly around home, score highly on FES subscale of Conflict and, pay more attention to ethical and religious issues and values. Furthermore, the families of children with other CND were more burdened regarding the financial state and the health status of other family members in comparison with families of children with epilepsy. In addition, families of children with epilepsy were more involved in social and recreational activities, appeared to be more knowledgeable on the availability of help in critical conditions and were more satisfied with rendered medical services, in comparison with families of children with other CND. These preliminary findings provide important information concerning the special characteristics of Greek families of children suffering from CND, which may prove especially helpful in organizing specific support
Levin, Michael C; Lee, Sang Min; Kalume, Franck; Morcos, Yvette; Dohan, F Curtis; Hasty, Karen A; Callaway, Joseph C; Zunt, Joseph; Desiderio, Dominic; Stuart, John M
One hypothesis that couples infection with autoimmune disease is molecular mimicry. Molecular mimicry is characterized by an immune response to an environmental agent that cross-reacts with a host antigen, resulting in disease. This hypothesis has been implicated in the pathogenesis of diabetes, lupus and multiple sclerosis (MS). There is limited direct evidence linking causative agents with pathogenic immune reactions in these diseases. Our study establishes a clear link between viral infection, autoimmunity and neurological disease in humans. As a model for molecular mimicry, we studied patients with human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a disease that can be indistinguishable from MS (refs. 5,6,7). HAM/TSP patients develop antibodies to neurons. We hypothesized these antibodies would identify a central nervous system (CNS) autoantigen. Immunoglobulin G isolated from HAM/TSP patients identified heterogeneous nuclear ribonuclear protein-A1 (hnRNP-A1) as the autoantigen. Antibodies to hnRNP-A1 cross-reacted with HTLV-1-tax, the immune response to which is associated with HAM/TSP (refs. 5,9). Immunoglobulin G specifically stained human Betz cells, whose axons are preferentially damaged. Infusion of autoantibodies in brain sections inhibited neuronal firing, indicative of their pathogenic nature. These data demonstrate the importance of molecular mimicry between an infecting agent and hnRNP-A1 in autoimmune disease of the CNS.
Matsumoto, Takuya; Fujimori, Koki; Andoh-Noda, Tomoko; Ando, Takayuki; Kuzumaki, Naoko; Toyoshima, Manabu; Tada, Hirobumi; Imaizumi, Kent; Ishikawa, Mitsuru; Yamaguchi, Ryo; Isoda, Miho; Zhou, Zhi; Sato, Shigeto; Kobayashi, Tetsuro; Ohtaka, Manami; Nishimura, Ken; Kurosawa, Hiroshi; Yoshikawa, Takeo; Takahashi, Takuya; Nakanishi, Mahito; Ohyama, Manabu; Hattori, Nobutaka; Akamatsu, Wado; Okano, Hideyuki
Summary Modeling of neurological diseases using induced pluripotent stem cells (iPSCs) derived from the somatic cells of patients has provided a means of elucidating pathogenic mechanisms and performing drug screening. T cells are an ideal source of patient-specific iPSCs because they can be easily obtained from samples. Recent studies indicated that iPSCs retain an epigenetic memory relating to their cell of origin that restricts their differentiation potential. The classical method of differentiation via embryoid body formation was not suitable for T cell-derived iPSCs (TiPSCs). We developed a neurosphere-based robust differentiation protocol, which enabled TiPSCs to differentiate into functional neurons, despite differences in global gene expression between TiPSCs and adult human dermal fibroblast-derived iPSCs. Furthermore, neurons derived from TiPSCs generated from a juvenile patient with Parkinson's disease exhibited several Parkinson's disease phenotypes. Therefore, we conclude that TiPSCs are a useful tool for modeling neurological diseases. PMID:26905201
Puppala, Anupama K.; French, Rachel L.; Matthies, Doreen; Baxa, Ulrich; Subramaniam, Sriram; Simonović, Miljan
Selenocysteine synthase (SepSecS) catalyzes the terminal reaction of selenocysteine, and is vital for human selenoproteome integrity. Autosomal recessive inheritance of mutations in SepSecS–Ala239Thr, Thr325Ser, Tyr334Cys and Tyr429*–induced severe, early-onset, neurological disorders in distinct human populations. Although harboring different mutant alleles, patients presented remarkably similar phenotypes typified by cerebellar and cerebral atrophy, seizures, irritability, ataxia, and extreme spasticity. However, it has remained unclear how these genetic alterations affected the structure of SepSecS and subsequently elicited the development of a neurological pathology. Herein, our biophysical and structural characterization demonstrates that, with the exception of Tyr429*, pathogenic mutations decrease protein stability and trigger protein misfolding. We propose that the reduced stability and increased propensity towards misfolding are the main causes for the loss of SepSecS activity in afflicted patients, and that these factors contribute to disease progression. We also suggest that misfolding of enzymes regulating protein synthesis should be considered in the diagnosis and study of childhood neurological disorders. PMID:27576344
Krewski, Daniel; Barakat-Haddad, Caroline; Donnan, Jennifer; Martino, Rosemary; Pringsheim, Tamara; Tremlett, Helen; van Lieshout, Pascal; Walsh, Stephanie J; Birkett, Nicholas J; Gomes, James; Little, Julian; Bowen, Sonya; Candundo, Hamilton; Chao, Ting-Kuang; Collins, Kayla; Crispo, James A G; Duggan, Tom; El Sherif, Reem; Farhat, Nawal; Fortin, Yannick; Gaskin, Janet; Gupta, Pallavi; Hersi, Mona; Hu, Jing; Irvine, Brittany; Jahanfar, Shayesteh; MacDonald, Don; McKay, Kyla; Morrissey, Andrea; Quach, Pauline; Rashid, Ruksana; Shin, Sabina; Sikora, Lindsey; Tkachuk, Stacey; Taher, Mohamed K; Wang, Ming-Dong; Darshan, Shalu; Cashman, Neil R
Systematic reviews were conducted to identify risk factors associated with the onset and progression of 14 neurological conditions, prioritized as a component of the National Population Health Study of Neurological Conditions. These systematic reviews provided a basis for evaluating the weight of evidence of evidence for risk factors for the onset and progression of the 14 individual neurological conditions considered. A number of risk factors associated with an increased risk of onset for more than one condition, including exposure to pesticides (associated with an increased risk of AD, amyotrophic lateral sclerosis, brain tumours, and PD; smoking (AD, MS); and infection (MS, Tourette syndrome). Coffee and tea intake was associated with a decreased risk of onset of both dystonia and PD. Further understanding of the etiology of priority neurological conditions will be helpful in focusing future research initiatives and in the development of interventions to reduce the burden associated with neurological conditions in Canada and internationally. Copyright © 2017. Published by Elsevier B.V.
Abboud, M R; Jackson, S M; Barredo, J; Holden, K R; Cure, J; Laver, J
A boy with sickle cell anemia underwent bone marrow transplantation (BMT). He was normal on neurological examination, but had radiologic evidence of an old left frontal lobe infarct, multiple cerebral vascular stenoses and moyamoya collaterals. After BMT he developed seizures with extension of the infarct and subarachnoid hemorrhage. One year later angiography revealed worsening stenosis of the M1 segments of both middle cerebral arteries. At that time an increase in von Willebrand's factor with decreased large molecular weight multimers (LvWF) was observed. We speculate that LvWF dependent, shear-induced platelet aggregation, together with endothelial damage may have contributed to the development of neurologic complications in this patient.
Velásquez-Pérez, Leora; Ramírez-Crescencio, María Antonieta
There is regulated study and mandatory reporting of epidemiological surveillance of diseases worldwide. However, it is difficult to observe the behavior of conditions especially over time, and especially when it comes to diseases that are addressed by their severity in tertiary care units. Describe and analyze the behavior of the major communicable neurological diseases subject to epidemiological surveillance for a period of seven years in the main National Institution of Health that takes in neurological, neurosurgical and psychiatric disorders in Mexico. The main conditions that are handled and reported were acute inflammatory polyneuropathy (Guillain Barre Syndrome) and viral encephalitis, 19.7 and 18.5%, respectively. The condition showing a tendency to decrease was neurocysticercosis, and conditions most strongly associated with mortality were diseases associated to the human immunodeficiency virus and unspecified viral encephalitis. The conditions were more frequent especially in men in the age group 25 to 44 years old. It is necessary to stress the importance of timely reporting of diseases under epidemiological surveillance in Mexico, since knowledge of the behavior of action allows decisions at all levels of care.
Thygesen, Lau Caspar; Flachs, Esben Meulengracht; Hanehøj, Kirsten; Kjuus, Helge; Juel, Knud
For many years an amalgam containing metallic mercury, which has been associated with neurological and renal diseases, has been used in dentistry. In this nationwide study we compared hospital admissions due to neurological and renal diseases among dentists and dental assistants to admissions in controls. This register-based cohort study included all Danish workers employed in dental clinics, general practitioners' clinics or lawyers' offices between 1964 and 2006. We compared dentists with general practitioners and lawyers, and dental assistants with medical secretaries, nurses and legal secretaries. We also compared dentists and dental assistants employed during periods with high occupational mercury exposure with dentists and dental assistants employed during periods with less mercury exposure. We followed all subjects in a nationwide register of hospital admissions. We analysed risk of neurological diseases, Parkinson's disease and renal diseases using a Cox regression model. The cohort consisted of 122,481 workers including 5371 dentists and 33,858 dental assistants. For neurological diseases, no association was observed for dental assistants, while for dentists an increasing risk for periods with less mercury exposure was observed. Among dental assistants, a negative association between employment length and risk of neurological disease was observed. Admissions for renal disease among dental assistants were increased during periods with less mercury exposure compared with controls. For dentists a non-significant increased risk was observed between employment length and renal disease risk. Our nationwide study does not indicate that occupational exposure to mercury increases the risk of hospital admissions for neurological, Parkinson's or renal diseases.
Serra, B; Primo, J; García, M; Amorós, I; Aragó, M; Merino, C
In patients with Wilson's disease and neurological manifestations, treatment with D-penicillamine can cause worsening of neurological symptoms, usually in the first few weeks of treatment. Because the neurological damage can be severe and irreversible, the use of D-penicillamine is controversial, and several authors believe that it should be avoided. Studies of the use of ammonium tetrathiomolybdate as an alternative chelating agent for the initial treatment of neurologic Wilson's disease are still in the experimental phase. Published experience on the simultaneous use of trientine, another chelating agent, and zinc, which blocks intestinal absorption of copper, is promising but limited. We present the case of a 17 year-old boy with severe neurologic Wilson's disease that had first presented six years previously. The patient showed a complete recovery after six months of treatment with a combination of trientine and zinc acetate.
Yamamoto, Yoshiharu; Soma, Rika; Hidaka, Ichiro; Nozaki, Daichi; Iso-o, Noriko; Kwak, Shin
In the past decade, it has been recognized that noise can enhance the response of nonlinear systems to weak signals, via a mechanism known as stochastic resonance (SR). Particularly, the concept of SR has generated considerable interest in sensory biology, because it has been shown in several experimental studies that noise can assist neural systems in detecting weak signals which could not be detected in its absence. Recently, we have shown a similar type of noise-induced sensitization of human brain; externally added noise to the brain stem baroreflex centers sensitized their responses in maintaining adequate blood perfusion to the brain itself. Furthermore, the addition of noise has also shown to be useful in compensating for dysfunctions of the baroreflex centers in certain neurological diseases. It is concluded that the statistical physics concept of SR could be useful in sensitizing human brain in health and disease.
Mullins, G M; Elamin, M; Saidha, S; Ali, E; Jennings, L; Counihan, T J; Hennessy, M
We report an explosive presentation of neurological Behcet disease, in an Irish male patient. We present the clinical and radiological findings in our patient and discuss a novel and effective therapeutic approach. We review other treatment modalities of patients with neurological involvement.
Kim, Bomi; Chung, Sun Ju; Shin, Hae-Won
Trientine (triethylenetetramine dihydrochloride) is a copper-chelating agent used to treat patients with Wilson's disease (WD). It has been considered safe, rarely causing neurological deterioration during initial treatment. We describe a patient diagnosed with WD who became neurologically disabled after treatment with trientine. On a fluid attenuated inversion recovery sequence, brain MRI showed increased areas of high signal intensity compared with initial brain MRI. The patient's neurological signs partially resolved after cessation of trientine treatment. Our findings suggest that treatment with trientine is associated with a risk of neurological deterioration in patients with WD. Copyright © 2012 Elsevier Ltd. All rights reserved.
Chang, Keun-A; Lee, Jun-Ho; Suh, Yoo-Hun
Stem cell therapy has been noted as a novel strategy to various diseases including neurological disorders such as Alzheimer's disease, Parkinson's disease, stroke, amyotrophic lateral sclerosis, and Huntington's disease that have no effective treatment available to date. The adipose-derived stem cells (ASCs), mesenchymal stem cells (MSCs) isolated from adipose tissue, are well known for their pluripotency with the ability to differentiate into various types of cells and immuno-modulatory property. These biological features make ASCs a promising source for regenerative cell therapy in neurological disorders. Here we discuss the recent progress of regenerative therapies in various neurological disorders utilizing ASCs.
The human brain is a complex dynamical system generating the EEG signal. Numerical methods developed to study complex physical dynamics have been used to characterize EEG since the mid-eighties. This endeavor raised several issues related to the specificity of EEG. Firstly, theoretical and methodological studies should address the major differences between the dynamics of the human brain and physical systems. Secondly, this approach of EEG signal should prove to be relevant for dealing with physiological or clinical problems. A set of studies performed in our group is presented here within the context of these two problematic aspects. After the discussion of methodological drawbacks, we review numerical simulations related to the high dimension and spatial extension of brain dynamics. Experimental studies in neurologic and psychiatric disease are then presented. We conclude that if it is now clear that brain dynamics changes in relation with clinical situations, methodological problems remain largely unsolved.
The brain contains all that makes us human, but its complexity is the source of both inspiration and frailty. Aging population is increasingly in need of effective care and therapies for brain diseases, including stroke, Parkinson's disease and Alzheimer's disease. The world's scientific community working hard to unravel the secrets of the brain's computing power and to devise technologies that can heal it when it fails and restore critical functions to patients with neurological conditions. Neurotechnology is the emerging field that brings together the development of technologies to study the brain and devices that improve and repair brain function. What is certain is the momentum behind neurotechnological research is building, and whether through implants, BCIs, or innovative computational systems inspired by the human brain, more light will be shed on our most complex and most precious organ, which will no doubt lead to effective treatment for many neurological conditions.
Brownell, Sara E.; Becker, Rachel A.; Steinman, Lawrence
Historically, small heat shock proteins (sHSPs) have been extensively studied in the context of being intracellular molecular chaperones. However, recent studies looking at the role of sHSPs in neurological diseases have demonstrated a near universal upregulation of certain sHSPs in damaged and diseased brains. Initially, it was thought that sHSPs are pathological in these disease states because they are found in the areas of damage. However, transgenic overexpression and exogenous administration of sHSPs in various experimental disease paradigms have shown just the contrary – that sHSPs are protective, not pathological. This review examines sHSPs in neurological diseases and highlights the potential for using these neuroprotective sHSPs as novel therapeutics. It first addresses the endogenous expression of sHSPs in a variety of neurological disorders. Although many studies have examined the expression of sHSPs in neurological diseases, there are no review articles summarizing these data. Furthermore, it focuses on recent studies that have investigated the therapeutic potential of sHSPs for neurological diseases. Finally, it will explain what we think is the function of endogenous sHSPs in neurological diseases. PMID:22566955
Zucchi, Fabiola C R; Yao, Youli; Ward, Isaac D; Ilnytskyy, Yaroslav; Olson, David M; Benzies, Karen; Kovalchuk, Igor; Kovalchuk, Olga; Metz, Gerlinde A S
The gestational state is a period of particular vulnerability to diseases that affect maternal and fetal health. Stress during gestation may represent a powerful influence on maternal mental health and offspring brain plasticity and development. Here we show that the fetal transcriptome, through microRNA (miRNA) regulation, responds to prenatal stress in association with epigenetic signatures of psychiatric and neurological diseases. Pregnant Long-Evans rats were assigned to stress from gestational days 12 to 18 while others served as handled controls. Gestational stress in the dam disrupted parturient maternal behaviour and was accompanied by characteristic brain miRNA profiles in the mother and her offspring, and altered transcriptomic brain profiles in the offspring. In the offspring brains, prenatal stress upregulated miR-103, which is involved in brain pathologies, and downregulated its potential gene target Ptplb. Prenatal stress downregulated miR-145, a marker of multiple sclerosis in humans. Prenatal stress also upregulated miR-323 and miR-98, which may alter inflammatory responses in the brain. Furthermore, prenatal stress upregulated miR-219, which targets the gene Dazap1. Both miR-219 and Dazap1 are putative markers of schizophrenia and bipolar affective disorder in humans. Offspring transcriptomic changes included genes related to development, axonal guidance and neuropathology. These findings indicate that prenatal stress modifies epigenetic signatures linked to disease during critical periods of fetal brain development. These observations provide a new mechanistic association between environmental and genetic risk factors in psychiatric and neurological disease.
Zucchi, Fabiola C. R.; Yao, Youli; Ward, Isaac D.; Ilnytskyy, Yaroslav; Olson, David M.; Benzies, Karen; Kovalchuk, Igor; Kovalchuk, Olga; Metz, Gerlinde A. S.
The gestational state is a period of particular vulnerability to diseases that affect maternal and fetal health. Stress during gestation may represent a powerful influence on maternal mental health and offspring brain plasticity and development. Here we show that the fetal transcriptome, through microRNA (miRNA) regulation, responds to prenatal stress in association with epigenetic signatures of psychiatric and neurological diseases. Pregnant Long-Evans rats were assigned to stress from gestational days 12 to 18 while others served as handled controls. Gestational stress in the dam disrupted parturient maternal behaviour and was accompanied by characteristic brain miRNA profiles in the mother and her offspring, and altered transcriptomic brain profiles in the offspring. In the offspring brains, prenatal stress upregulated miR-103, which is involved in brain pathologies, and downregulated its potential gene target Ptplb. Prenatal stress downregulated miR-145, a marker of multiple sclerosis in humans. Prenatal stress also upregulated miR-323 and miR-98, which may alter inflammatory responses in the brain. Furthermore, prenatal stress upregulated miR-219, which targets the gene Dazap1. Both miR-219 and Dazap1 are putative markers of schizophrenia and bipolar affective disorder in humans. Offspring transcriptomic changes included genes related to development, axonal guidance and neuropathology. These findings indicate that prenatal stress modifies epigenetic signatures linked to disease during critical periods of fetal brain development. These observations provide a new mechanistic association between environmental and genetic risk factors in psychiatric and neurological disease. PMID:23451123
Yamayoshi, Seiya; Fujii, Ken; Koike, Satoshi
Enterovirus 71 (EV71) is one of the major causative agents of hand, foot, and mouth disease (HFMD). Infection with EV71 is occasionally associated with severe neurological diseases such as acute encephalitis, acute flaccid paralysis, and cardiopulmonary failure. Because cellular receptors for viruses play an important role in cell, tissue, and species tropism, it is important to identify and characterize the receptor molecule. Recently, cellular receptors and host factors that stimulate EV71 infection have been identified. Several lines of evidence suggest that scavenger receptor class B, member 2 (SCARB2) plays critical roles in efficient EV71 infection and the development of disease in humans. In this review, we will summarize the findings of recent studies on EV71 infection and on the roles of SCARB2.
Wiles, C; Brown, P; Chapel, H; Guerrini, R; Hughes, R; Martin, T; McCrone, P; Newsom-Davis, J; Palace, J; Rees, J; Rose, M; Scolding, N; Webster, A
Treatment of neurological disorders with intravenous immunoglobulin (IVIg) is an increasing feature of our practice for an expanding range of indications. For some there is evidence of benefit from randomised controlled trials, whereas for others evidence is anecdotal. The relative rarity of some of the disorders means that good randomised control trials will be difficult to deliver. Meanwhile, the treatment is costly and pressure to "do something" in often distressing disorders considerable. This review follows a 1 day meeting of the authors in November 2000 and examines current evidence for the use of IVIg in neurological conditions and comments on mechanisms of action, delivery, safety and tolerability, and health economic issues. Evidence of efficacy has been classified into levels for healthcare interventions (tables 1 and 2). PMID:11909900
Pelidou, Sigliti-Henrietta; Giannopoulos, Sotiris; Tzavidi, Sotiria; Tsifetaki, Niki; Kitsos, Georgios; Stefanou, Dimitrios; Kostadima, Vassiliki; Drosos, Alexandros A; Kyritsis, Athanassios P
The objective of the study was to analyze retrospectively the clinical, laboratory and imaging findings of multiple sclerosis (MS), such as the manifestations in a cohort of 132 patients referred to the neurology in and outpatient clinic. The proposed clinical and laboratory diagnostic criteria for MS and connective tissue disorders were systematically assessed in 132 consecutive patients. Cerebrospinal fluid serology and brain or spinal cord MRI were studied in all cases. In patients suspected for connective tissue disorder, schirmer test, rose bengal staining and biopsy of minor salivary glands were performed. A total of 115 (87%) patients were diagnosed to have definite MS, while 17 (13%) were diagnosed to have connective tissue disorder. Positive neurological and MRI findings were observed in both groups. The majority of patients with connective tissue disorder demonstrated extra-neurological manifestations like Raynaud's phenomenon, arthritis, livedo reticularis, purpura and presence of multiple autoantibodies in their sera. All patients with MS should be screened systematically for connective tissue disorder. In the absence of pathognomonic clinical and laboratory findings, the diagnosis of MS is a diagnosis of exclusion.
Abdullah, Jafri Malin; Hussin, Ahmad Munnawir; Tharakan, John; Abdullah, Mohamed Rusli; Saad, Ramli; Kamari, Zaidun; Hussin, Zabidi Azhar Mohd; Razak, Dzulkifli Abdul
The number of cases of neurological disease is expected to rise in the next 10 years, making this the second leading cause of morbidity and mortality after heart disease in Malaysia. The lack of human resources in the neurological field currently serving the Malaysian population may cause a deficiency in specialized care, especially in rural areas where neurological and neurosurgical care may be lacking. Thus, a resolve was made to increase the numbers of specialists by the Universiti Sains Malaysia (USM) with the help of the Ministry of Health of Malaysia. A study was made to evaluate the number of referral centers needed in strategic parts of Malaysia. Our calculation was based on service demands and operative procedures following the guidelines of the Association of British Neurologists (ABN) where 15 minutes of service time was equivalent to 1 unit. Based on 2 million population covered in the state of Kelantan by this University Hospital, 4.27 neurologists are needed to meet service demands with a consultant to population ratio (CPR) of 1:468,384, compared to 7.46 neurosurgeons, with a CPR of 1:268,097. According to the current service demands, one neurologist has to work more than 407 hours per year and one neurosurgeon 1,219 hours per year in our hospital. Hospitals with a larger catchment area would need to have more neurologists and neurosurgeons for optimal care in their area. Thus, more neurologists and neurosurgeons are needed to be produced, since the existing numbers are too small for quality care in Malaysia.
Herrera, Jenifer; Gómez-Núñez, Luis; Lara-Romero, Rocío; Diosdado, Fernando; Martínez-Lara, Atalo; Jasso, Miguel; Ramírez-Mendoza, Humberto; Pérez-Torres, Armando; Rivera-Benítez, José Francisco
The objective of this study was to evaluate the clinical disease, humoral response and viral distribution of recent Porcine rubulavirus (PorPV) isolates in experimentally infected pigs. Four, 6-piglet (5-days old) groups were employed (G1-84, G2-93, G3-147, and G4-T). Three viral strains were used for the experimental infection: the reference strain LPMV-1984 (Michoacán 1984) and two other strains isolated in 2013, one in Queretaro (Qro/93/2013) and the other in Michoacán (Mich/147/2013). Each strain was genetically characterized by amplification and sequencing of the gene encoding hemagglutinin-neuroamidase (HN). The inoculation was performed through the oronasal and ocular routes, at a dose of 1×10(6)TCID50/ml. Subsequently, the signs were evaluated daily and necropsies were performed on 3 different days post infection (dpi). We recorded all micro- and macroscopic lesions. Organs from the nervous, lymphatic, and respiratory system were analyzed by quantifying the viral RNA load and the presence of the infectious virus. The presence of the viral antigen in organs was evidenced through immunohistochemistry. Seroconversion was evaluated through the use of a hemagglutination inhibition test. In the characterization of gene HN, only three substitutions were identified in strain Mich/147/2013, two in strain LPMV/1984 (fourth passage) and one in strain Qro/93/2013, with respect to reference strain LPMV-84, these changes had not been identified as virulence factors in previously reported strains. Neurological alterations associated with the infection were found in all three experimental groups starting from 3dpi. Groups G1-84 and G3-147 presented the most exacerbated nervous signs. Group G2-93 only presented milder signs including slight motor incoordination, and an increased rectal temperature starting from day 5 post infection (PI). The main histopathological findings were the presence of a mononuclear inflammatory infiltrate (lymphocytic/monocytic) surrounding the
Liebetrau, G; Pielesch, W
The development of alveolitis or lung fibrosis through drugs is wellknown, however rare described in the spectrum of drug side effects. In six cases of patients with neurological diseases were studied the relationship between alveolitis or lung fibrosis and a long-time therapy with especially drugs in a neurological practice. By the etiological examination of alveolitis or lung fibrosis it is necessary to pay attention to the possible relationship between drug and disease.
Alam, Md. Suhail; Getz, Michelle; Yi, Sue; Kurkewich, Jeffrey; Safeukui, Innocent; Haldar, Kasturi
Early diagnosis of neurological disorders would greatly improve their management and treatment. A major hurdle is that inflammatory products of cerebral disease are not easily detected in blood. Inflammation in multiple organs and heterogeneity in disease present additional challenges in distinguishing the extent to which a blood-based marker reflects disease in brain or other afflicted organs. Murine models of the monogenetic disorder Niemann-Pick Type C present aggressive forms of cerebral and liver inflammatory disease. Microarray analyses previously revealed age-dependent changes in innate immunity transcripts in the mouse brain. We have now validated four putative secretory inflammatory markers that are also elevated in mouse liver. We include limited, first time analysis of human Niemann-Pick Type C liver and cerebellum. Furthermore, we utilized 2-hydroxypropyl-β-cyclodextrin (HPβCD, an emerging therapeutic) administered intraperitoneally in mice, which abrogates inflammatory pathology in the liver but has limited effect on the brain. By analyzing the corresponding effects on inflammatory plasma proteins, we identified cathepsin S as a lead indicator of liver disease. In contrast, lysozyme was a marker of both brain and liver disease. 2-Hydroxypropyl-β-cyclodextrin had no effect on transcripts of neuron-specific 24-hydroxylase, and its product 24(S)-hydroxycholesterol was not a useful indicator in mouse plasma. Our data suggest that dual analysis of levels of the inflammatory markers lysozyme and cathepsin S may enable detection of multiple distinct states of neurodegeneration in plasma. PMID:24488491
Akhtar, Aslam Abbasi; Sances, Samuel; Barrett, Robert; Breunig, Joshua J
The modeling of biological processes in vitro provides an important tool to better understand mechanisms of development and disease, allowing for the rapid testing of therapeutics. However, a critical constraint in traditional monolayer culture systems is the absence of the multicellularity, spatial organization, and overall microenvironment present in vivo. This limitation has resulted in numerous therapeutics showing efficacy in vitro, but failing in patient trials. In this review, we discuss several organoid and "organ-on-a-chip" systems with particular regard to the modeling of neurological diseases and gastrointestinal disorders. Recently, the in vitro generation of multicellular organ-like structures, coined organoids, has allowed the modeling of human development, tissue architecture, and disease with human-specific pathophysiology. Additionally, microfluidic "organ-on-a-chip" technologies add another level of physiological mimicry by allowing biological mediums to be shuttled through 3D cultures. Organoids and organ-chips are rapidly evolving in vitro platforms which hold great promise for the modeling of development and disease.
Devine, Helen; Patani, Rickie
The induced pluripotent state represents a decade-old Nobel prize-winning discovery. Human-induced pluripotent stem cells (hiPSCs) are generated by the nuclear reprogramming of any somatic cell using a variety of established but evolving methods. This approach offers medical science unparalleled experimental opportunity to model an individual patient's disease "in a dish." HiPSCs permit developmentally rationalized directed differentiation into any cell type, which express donor cell mutation(s) at pathophysiological levels and thus hold considerable potential for disease modeling, drug discovery, and potentially cell-based therapies. This review will focus on the translational potential of hiPSCs in clinical neurology and the importance of integrating this approach with complementary model systems to increase the translational yield of preclinical testing for the benefit of patients. This strategy is particularly important given the expected increase in prevalence of neurodegenerative disease, which poses a major burden to global health over the coming decades.
Although genetic reserch in neurological diseases has been dramatically advanced, its application to clinical neurology is still limited. Given the increased awareness of genetic testing in neurological diseases such as spinocerebellar ataxia, patients and their relatives' requests for information is increasing. In this report, we provide a framework for assessing genetic risk of neurological diseases in at-risk relatives baesd on our experience in TMDU medical hospital. Reagrding asymptomatic individuals, there are concerns that prerictive testing may trigger some unexpected psychological responses, such as severe depression and anxiety. Thus we also conducted a questionnaire for neurologists about predictive genetic testing in their clinic. Thre obtained results contained the complexed difficulties which can be shared among broader communities of medical specialists.
Xu, Huamin; Jiang, Hong; Xie, Junxia
Both iron dyshomeostasis and N-methyl-D-aspartate receptors (NMDARs)-mediated neurotoxicity have been shown to have an important role in neurological diseases such as Parkinson’s disease (PD) and Alzheimer’s disease (AD). Evidence proved that activation of NMDARs could promote iron overload and iron-induced neurotoxicity by enhancing iron importer divalent metal transporter 1 (DMT1)-mediated iron uptake and iron releasing from lysosome. Also, iron overload could regulate NMDARs-mediated synaptic transmission. This indicates that there might be a possible relationship between iron and activation of NMDARs in neurological diseases. Understanding this interaction between iron and activation of NMDARs may provide new therapeutic avenues for a more targeted neurotherapeutic strategy for these diseases. Therefore, in this review article, we will describe the dysfunction of iron metabolism and NMDARs in neurological diseases including PD and AD, and summarize the new insight into the mechanisms underlying the interaction between iron and activation of NMDARs. PMID:28360837
Chandrasekaran, Abinaya; Avci, Hasan X.; Leist, Marcel; Kobolák, Julianna; Dinnyés, Andras
Astrocytes have a central role in brain development and function, and so have gained increasing attention over the past two decades. Consequently, our knowledge about their origin, differentiation and function has increased significantly, with new research showing that astrocytes cultured alone or co-cultured with neurons have the potential to improve our understanding of various central nervous system diseases, such as amyotrophic lateral sclerosis, Alzheimer’s disease, or Alexander disease. The generation of astrocytes derived from pluripotent stem cells (PSCs) opens up a new area for studying neurologic diseases in vitro; these models could be exploited to identify and validate potential drugs by detecting adverse effects in the early stages of drug development. However, as it is now known that a range of astrocyte populations exist in the brain, it will be important in vitro to develop standardized protocols for the in vitro generation of astrocyte subsets with defined maturity status and phenotypic properties. This will then open new possibilities for co-cultures with neurons and the generation of neural organoids for research purposes. The aim of this review article is to compare and summarize the currently available protocols and their strategies to generate human astrocytes from PSCs. Furthermore, we discuss the potential role of human-induced PSCs derived astrocytes in disease modeling. PMID:27725795
Wiley, Clayton A; Chimelli, Leila
The recent epidemic of West Nile Virus (WNV) infection in the United States was associated with severe neurological disease in immunocompromised hosts, while the emergence of Zika virus infection in the Americas has been notable for an association with increased microcephaly in the fetuses of infected mothers. Rare autopsies of WNV infected humans have shown multiple organ involvement with a clear neurotropism. We have recently had the opportunity to examine the distribution of Zika virus in autopsies of newborns from infected pregnancies. While both viruses infect multiple organs, Zika appears to cause neurological disease in the fetus through two different mechanisms. Infection during the first trimester showed the potential to infect neural progenitor cells causing severe developmental abnormalities, while infection later in gestation was associated with meningeal infection and destructive ischemic lesions of the brain. Both viruses infect kidney tubules but Zika shares a prominent hepatotropism characteristic of other flaviviruses (e.g., Dengue). Limited transplacental Zika infection would be consistent with restriction to primary maternal infections with high viremia. In the absence of a vaccine, restriction of travel by immunosuppressed and pregnant non-immune individuals to endemic regions seems prudent. © 2017 Japanese Society of Neuropathology.
Mollereau, B.; Rzechorzek, N.M.; Roussel, B.D.; Sedru, M.; Van den Brink, D.M.; Bailly-Maitre, B.; Palladino, F.; Medinas, D.B.; Domingos, P.M.; Hunot, S.; Chandran, S.; Birman, S.; Baron, T.; Vivien, D.; Duarte, C.B.; Ryoo, H.D.; Steller, H.; Urano, F.; Chevet, E.; Kroemer, G.; Ciechanover, A.; Calabrese, E.J.; Kaufman, R.J.; Hetz, C.
In neurological disorders, both acute and chronic neural stress can disrupt cellular proteostasis, resulting in the generation of pathological protein. However in most cases, neurons adapt to these proteostatic perturbations by activating a range of cellular protective and repair responses, thus maintaining cell function. These interconnected adaptive mechanisms comprise a ‘proteostasis network’ and include the unfolded protein response, the ubiquitin proteasome system and autophagy. Interestingly, several recent studies have shown that these adaptive responses can be stimulated by preconditioning treatments, which confer resistance to a subsequent toxic challenge – the phenomenon known as hormesis. In this review we discuss the impact of adaptive stress responses stimulated in diverse human neuropathologies including Parkinson’s disease, Wolfram syndrome, brain ischemia, and brain cancer. Further, we examine how these responses and the molecular pathways they recruit might be exploited for therapeutic gain. PMID:26923166
Wenderski, Wendy; Maze, Ian
In postmitotic neurons, nucleosomal turnover was long considered to be a static process that is inconsequential to transcription. However, our recent studies in human and rodent brain indicate that replication-independent (RI) nucleosomal turnover, which requires the histone variant H3.3, is dynamic throughout life and is necessary for activity-dependent gene expression, synaptic connectivity, and cognition. H3.3 turnover also facilitates cellular lineage specification and plays a role in suppressing the expression of heterochromatic repetitive elements, including mutagenic transposable sequences, in mouse embryonic stem cells. In this essay, we review mechanisms and functions for RI nucleosomal turnover in brain and present the hypothesis that defects in histone dynamics may represent a common mechanism underlying neurological aging and disease. PMID:26990528
Wyss, Markus; Schulze, Andreas
Major achievements made over the last several years have highlighted the important roles of creatine and the creatine kinase reaction in health and disease. Inborn errors of metabolism have been identified in the three main steps involved in creatine metabolism: arginine:glycine amidinotransferase (AGAT), S-adenosyl-L-methionine:N-guanidinoacetate methyltransferase (GAMT), and the creatine transporter. All these diseases are characterized by a lack of creatine and phosphorylcreatine in the brain, and by (severe) mental retardation. Similarly, knockout mice lacking the brain cytosolic and mitochondrial isoenzymes of creatine kinase displayed a slightly increased creatine concentration, but no phosphorylcreatine in the brain. These mice revealed decreased weight gain and reduced life expectancy, disturbed fat metabolism, behavioral abnormalities and impaired learning capacity. Oral creatine supplementation improved the clinical symptoms in both AGAT and GAMT deficiency, but not in creatine transporter deficiency. In addition, creatine supplementation displayed neuroprotective effects in several animal models of neurological disease, such as Huntington's disease, Parkinson's disease, or amyotrophic lateral sclerosis. All these findings pinpoint to a close correlation between the functional capacity of the creatine kinase/phosphorylcreatine/creatine system and proper brain function. They also offer a starting-point for novel means of delaying neurodegenerative disease, and/or for strengthening memory function and intellectual capabilities.Finally, creatine biosynthesis has been postulated as a major effector of homocysteine concentration in the plasma, which has been identified as an independent graded risk factor for atherosclerotic disease. By decreasing homocysteine production, oral creatine supplementation may, thus, also lower the risk for developing, e.g., coronary heart disease or cerebrovascular disease. Although compelling, these results require further
Yokochi, F; Nakamura, R; Narabayashi, H
Electromyographic reaction times of the left and the right finger extensor muscles in extension movement of the wrist were examined in 42 patients with Parkinson's disease, and 20 normal subjects. Compared to the normal subjects and the patients with neurological signs confined to the right side, the patients with neurological signs on the left side or on both sides showed slowing of reaction times regardless of the side of responding hand. The patients with asymmetry of bilateral neurological signs showed slower RTs on the more affected side.
Álvarez-Arellano, Lourdes; Maldonado-Bernal, Carmen
The purpose of this paper is to review current information about the role of inflammation caused by Helicobacter pylori (H. pylori) infection in neurological diseases such as Parkinson’s disease, Alzheimer’s disease, Guillain-Barré syndrome, multiple sclerosis, and other inflammatory diseases including ischemic stroke. Infection with H. pylori usually persists throughout life, resulting in a chronic inflammatory response with local secretion of numerous inflammatory mediators including chemokines [interleukin (IL)-8, macrophage chemotactic protein (MCP)-1, growth-regulated oncogene (GRO)-α] and cytokines [IL-1β, tumor necrosis factor (TNF)-α, IL-6, IL-12, interferon (IFN)-γ], which can pass into the circulation and have a systemic effect. The persistence of detectable systemic and local concentrations of inflammatory mediators is likely to alter the outcome of neurological diseases. These proinflammatory factors can induce brain inflammation and the death of neurons and could eventually be associated to Parkinson’s disease and also may be involved in the development of Alzheimer’s disease. However, most neurological diseases are the result of a combination of multiple factors, but the systemic inflammatory response is a common component and determinant in the onset, evolution, and outcome of diseases. However, more studies are needed to allow understanding of the effects and mechanisms by which the inflammatory response generated by H. pylori infection affects neurological diseases. PMID:25400983
Appel, S.H. )
The topics covered in this book include: Duchenne muscular dystrophy: DNA diagnosis in practice; Central nervous system magnetic resonance imaging; and Magnetic resonance spectroscopy of neurologic diseases.
Sposato, Luciano A; Fustinoni, Osvaldo
Iatrogenic disease is one of the most frequent causes of hospital admissions and constitutes a growing public health problem. The most common type of iatrogenic neurologic disease is pharmacologic, and the central and peripheral nervous systems are particularly vulnerable. Despite this, iatrogenic disease is generally overlooked as a differential diagnosis among neurologic patients. The clinical picture of pharmacologically mediated iatrogenic neurologic disease can range from mild to fatal. Common and uncommon forms of drug toxicity are comprehensively addressed in this chapter. While the majority of neurologic adverse effects are listed and referenced in the tables, the most relevant issues are further discussed in the text.
Erol, Ilknur; Alehan, Füsun; Ozcay, Figen; Canan, Oguz; Haberal, Mehmet
The literature contains very little documentation on neurologic complications in liver transplant recipients for Wilson's disease. We retrospectively reviewed 17 consecutive cases of pediatric liver transplantation for the hepatic form of Wilson's disease to assess the types of neurologic complications that occurred, the incidence of those problems, and associated factors in this patient group. The patients were 12 boys and 5 girls; indications for liver transplantation were fulminant hepatic failure in 3 patients and chronic hepatic failure in 14 patients. Neurologic complications were observed in 10 of the 17 patients as 16 episodes. The most common neurologic complications were seizure (7 episodes in 6 patients) and sudden-onset headache (5 episodes in 4 patients). Tacrolimus was identified as the only possible cause of headache in 3 episodes. Encephalitis was the cause in 1 and intracranial hemorrhage was the cause in the other headache episode. We also noted 1 episode of tremor, 1 episode of acute dystonic reaction, 1 episode of diffuse encephalopathy, and 1 episode of common peroneal nerve palsy. Immunosuppressive agents were the primary cause of 12 of the 16 episodes of neurologic complications. Uremia with hypertension, compression of the right common peroneal nerve, encephalitis, and intracranial hemorrhages attributable to coagulopathy caused 1 neurologic episode each. Neurologic complications in patients with the hepatic form of Wilson's disease were frequent during the first 30 days after pediatric liver transplantation but did not affect survival. Transplantation teams should be aware of the high incidence of neurologic complications in pediatric patients with the hepatic form of Wilson's disease.
de Parscau, L; Beaufrère, B; Vianey-Liaud, C; Rolland, M O; Langue, J; Divry, P; Guibaud, P
The authors report 2 familial cases of biotin deficiency. The first neurological signs appeared at the age of 2 years in a boy. The diagnosis was established in his sister in the neonatal period. A review of 41 published cases summarizes the neurologic signs (seizures, ataxia, hypotonia and later, developmental delay and deafness) and the cutaneous signs (rash, alopecia). An early treatment with biotin cures or prevents the clinical signs of the disease in most cases.
Curtis, Chad; Zhang, Mengying; Liao, Rick; Wood, Thomas; Nance, Elizabeth
Neurological diseases account for 13% of the global burden of disease. As a result, treating these diseases costs $750 billion a year. Nanotechnology, which consists of small (~1-100 nm) but highly tailorable platforms, can provide significant opportunities for improving therapeutic delivery to the brain. Nanoparticles can increase drug solubility, overcome the blood-brain and brain penetration barriers, and provide timed release of a drug at a site of interest. Many researchers have successfully used nanotechnology to overcome individual barriers to therapeutic delivery to the brain, yet no platform has translated into a standard of care for any neurological disease. The challenge in translating nanotechnology platforms into clinical use for patients with neurological disease necessitates a new approach to: (1) collect information from the fields associated with understanding and treating brain diseases and (2) apply that information using scalable technologies in a clinically-relevant way. This approach requires systems-level thinking to integrate an understanding of biological barriers to therapeutic intervention in the brain with the engineering of nanoparticle material properties to overcome those barriers. To demonstrate how a systems perspective can tackle the challenge of treating neurological diseases using nanotechnology, this review will first present physiological barriers to drug delivery in the brain and common neurological disease hallmarks that influence these barriers. We will then analyze the design of nanotechnology platforms in preclinical in vivo efficacy studies for treatment of neurological disease, and map concepts for the interaction of nanoparticle physicochemical properties and pathophysiological hallmarks in the brain. WIREs Nanomed Nanobiotechnol 2017, 9:e1422. doi: 10.1002/wnan.1422 For further resources related to this article, please visit the WIREs website.
Sellon, Debra C.; Knowles, Donald P.; Greiner, Ellis C.; Long, Maureen T.; Hines, Melissa T.; Hochstatter, Tressa; Tibary, Ahmed; Dame, John B.
Equine protozoal myeloencephalitis is a progressive neurologic disease of horses most commonly caused by infection with the apicomplexan parasite Sarcocystis neurona. Factors affecting neuroinvasion and neurovirulence have not been determined. We investigated the pathogenesis of infection with S. neurona in horses with severe combined immune deficiency (SCID). Two immunocompetent (IC) Arabian horses and two Arabian horses with SCID were infected orally with 5 × 105 sporocysts of S. neurona. Four IC horses and one SCID horse were infected intravenously (i.v.) with 5 × 108 merozoites of the WSU-1 isolate of S. neurona. Despite prolonged parasitemia and persistent infection of visceral tissues (skeletal muscle, cardiac muscle, lung, liver, and spleen) as demonstrated by PCR and culture, SCID horses did not develop neurologic signs after oral or i.v. infection. S. neurona was undetectable in the neuronal tissues of SCID horses by either PCR, immunohistochemistry, or culture. In contrast, although parasitemia was undetectable in orally infected IC horses and of only short duration in i.v. infected IC horses, four of six IC horses developed neurologic signs. S. neurona was detectable by PCR and/or culture of neural tissue but not visceral tissue of IC horses with neurologic disease. Infected SCID horses are unable to clear S. neurona from visceral tissues, but the infection does not result in neurologic signs; in contrast, IC horses rapidly control parasitemia and infection of visceral tissues but frequently experience neuroinvasion and exhibit clinical signs of neurologic disease. PMID:15539518
Allen, George P
To identify risk factors associated with development of clinical neurologic signs in horses exposed to equine herpesvirus-1 (EHV-1). 36 adult horses. Blood samples collected before and after challenge inoculation with nonneuropathogenic or neuropathogenic EHV-1 were analyzed for leukocyte-associated viremia, serum neutralizing antibody, and EHV-1-specific cytotoxic T-lymphocyte precursors (CTLPs). Associations between variables and neurologic disease and correlations between age category or breed and development of neurologic disease were examined. 9 horses developed CNS signs (ataxia, hind limb paresis or paralysis, bladder atony, or recumbency). Neurologic deficits were correlated with infection by a neuropathogenic strain of EHV-1, age>20 years, high postexposure viremic load, and low preexposure concentration of CTLPs. No significant correlations were observed between preinfection titers or horse breed and postinfection development of neurologic signs. Horses with high concentrations of preexisting CTLPs, regardless of age, strain of virus, or titer, were more likely to control the magnitude of postinfection leukocyte-associated viremia and subsequent development of neurologic disease; therefore, CTLPs appear to be a critical requirement for protective immunity against EHV-1-induced myeloencephalopathy. The importance of achieving immunity related to high concentrations of vaccine-induced CTLPs in horses at high risk for exposure to neuropathogenic strains of EHV-1 is indicated.
Sellon, Debra C; Knowles, Donald P; Greiner, Ellis C; Long, Maureen T; Hines, Melissa T; Hochstatter, Tressa; Tibary, Ahmed; Dame, John B
Equine protozoal myeloencephalitis is a progressive neurologic disease of horses most commonly caused by infection with the apicomplexan parasite Sarcocystis neurona. Factors affecting neuroinvasion and neurovirulence have not been determined. We investigated the pathogenesis of infection with S. neurona in horses with severe combined immune deficiency (SCID). Two immunocompetent (IC) Arabian horses and two Arabian horses with SCID were infected orally with 5 x 10(5) sporocysts of S. neurona. Four IC horses and one SCID horse were infected intravenously (i.v.) with 5 x 10(8) merozoites of the WSU-1 isolate of S. neurona. Despite prolonged parasitemia and persistent infection of visceral tissues (skeletal muscle, cardiac muscle, lung, liver, and spleen) as demonstrated by PCR and culture, SCID horses did not develop neurologic signs after oral or i.v. infection. S. neurona was undetectable in the neuronal tissues of SCID horses by either PCR, immunohistochemistry, or culture. In contrast, although parasitemia was undetectable in orally infected IC horses and of only short duration in i.v. infected IC horses, four of six IC horses developed neurologic signs. S. neurona was detectable by PCR and/or culture of neural tissue but not visceral tissue of IC horses with neurologic disease. Infected SCID horses are unable to clear S. neurona from visceral tissues, but the infection does not result in neurologic signs; in contrast, IC horses rapidly control parasitemia and infection of visceral tissues but frequently experience neuroinvasion and exhibit clinical signs of neurologic disease.
Dimitrijevic, M.R.; Kakulas, B.A.; Vrbova, G.
This book contains 27 chapters. Some of the chapter titles are: Computed Tomography of Muscles in Neuromuscular Disease; Mapping the Genes for Muscular Dystrophy; Trophic Factors and Motor Neuron Development; Size of Motor Units and Firing Rate in Muscular Dystrophy; Restorative Possibilities in Relation to the Pathology of Progressive Neuromuscular Disease; and An Approach to the Pathogenesis of some Congenital Myopathies.
Ghersi-Egea, J F; Gazzin, S; Strazielle, N
The endothelium of the brain microvessels and the choroid plexus epithelium form highly specialized cellular barriers referred to as blood-brain interfaces through which molecular exchanges take place between the blood and the neuropil or the cerebrospinal fluid, respectively. Within the brain, the ependyma and the pia-glia limitans modulate exchanges between the neuropil and the cerebrospinal fluid. All these interfaces are key elements of neuroprotection and fulfill trophic functions; both properties are critical to harmonious brain development and maturation. By analogy to hepatic bilirubin detoxification pathways, we review the transport and metabolic mechanisms which in all these interfaces may participate in the regulation of bilirubin cerebral bioavailability in physiologic conditions, both in adult and in developing brain. We specifically address the role of ABC and OATP transporters, glutathione-S-transferases, and the potential involvement of glucuronoconjugation and oxidative metabolic pathways. Regulatory mechanisms are explored which are involved in the induction of these pathways and represent potential pharmacological targets to prevent bilirubin accumulation into the brain. We then review the possible alteration of the neuroprotective and trophic barrier functions in the course of bilirubin-induced neurological dysfunctions resulting from hyperbilirubinemia. Finally, we highlight the role of the blood-brain and blood-CSF barriers in regulating the brain biodisposition of candidate drugs for the treatment or prevention of bilirubin-induced brain injury.
Baez, Sandra; García, Adolfo M; Ibanez, Agustín
The role of contextual modulations has been extensively studied in basic sensory and cognitive processes. However, little is known about their impact on social cognition, let alone their disruption in disorders compromising such a domain. In this chapter, we flesh out the social context network model (SCNM), a neuroscientific proposal devised to address the issue. In SCNM terms, social context effects rely on a fronto-temporo-insular network in charge of (a) updating context cues to make predictions, (b) consolidating context-target associative learning, and (c) coordinating internal and external milieus. First, we characterize various social cognition domains as context-dependent phenomena. Then, we review behavioral and neural evidence of social context impairments in behavioral variant frontotemporal dementia (bvFTD) and autism spectrum disorder (ASD), highlighting their relation with key SCNM hubs. Next, we show that other psychiatric and neurological conditions involve context-processing impairments following damage to the brain regions included in the model. Finally, we call for an ecological approach to social cognition assessment, moving beyond widespread abstract and decontextualized methods.
Ugriumov, M V; Konovalov, A N; Gusev, E I
An attempt was undertaken in the last decade of the 20th century to use a principally new approach to the treatment of neurological diseases--cell therapy. Main efforts were focused on developing a method related with replacement of neurons dying in neurodegenerative pathology, primarily, in Parkinson disease (PD). Outlined below are the key elements of the technology:--ensuring, in experiment, of a prolonged therapeutic effect in transplantation, to the affected part, first of embryonic neurons of the animal of the same species (allografting) and then of homologous embryonic neurons of man (heterografting);--obtaining, standardization and preparation (for transplantation) of embryonic nervous tissue of man; transplantation of embryonic nervous tissue of man to the brain of patient and evaluation, in situ, of the functional activity of its neurons; and evaluation of the therapeutic effect of grafting. Cell suspension of meseencephalon of 6-9 week human fetus containing around 10% of differentiating dopaminergic neurons was used for grafting in PD. Embryonic dopaminergic neurons, administered stereotactically into the striatum of patient, established synaptic links with neurons of the recipient, which was accompanied by the onset of synthesis and reverse uptake of dopamine (DA) as well as by the onset of spontaneous and stimulated release of DA. Neurografting ensured a temporary improvement of the condition in a part of PD patients but did not cure them. Moreover, such positive therapeutic effect was registered only in patients with the akineticorigid but not trembling variation of the disease. Hence, although there was a certain progress in clinical neurografting, the approach cannot be now recommended for introduction in neurology and neurosurgery. The limited therapeutic effect of the treatment method is primarily explained by a low rate of survival of transplanted dopaminergic neurons and, consequently, by the persisting DA deficit in patient's body. Therefore
Chevalier, V; Barbe, C; Reguiai, Z; Plée, J; Grange, F; Bernard, P
Bullous pemphigoid (BP) mainly affects elderly patients. It is often associated with neurological disorders, which constitute a major risk factor of the disease. The aim of our study was to determine whether neurological disorders, particularly dementia, influence outcome and mortality in BP patients. We conducted a retrospective study of all patients with BP seen in our dermatology department consecutively between 1997 and 2011. Clinical, immunological and therapeutic data, number of relapses and survival status were compared according to the presence at diagnosis of neurological disorders, particularly dementia. Among the 178 patients included, an associated neurological disease was present in 84 (47.2%) and dementia in 43 (24.2%) at the time of diagnosis of BP. Patients with associated dementia were older and had a lower Karnofsky index. Sixty-four patients (37.8%) had had at least one clinical relapse of BP, chiefly within the first 18 months after starting therapy. Coexistent neurological disease was not associated with BP relapse (P=0.55) contrary to an extensive BP phenotype at diagnosis (P=0.008). Coexistent neurological disease and/or dementia were associated with higher mortality (P=0.03 and P<0.001, respectively), but did not modify the type or the total duration of BP treatment. A coexistent neurological disease or dementia at the time of diagnosis of BP significantly increase the risk of mortality and shortens the duration of clinical follow-up of patients with BP, thus limiting the analysis of their influence on the outcome of BP itself. Copyright © 2016 Elsevier Masson SAS. All rights reserved.
... classification for human dura mater. This action is being taken to improve the accuracy of the regulations. DATES... HUMAN SERVICES Food and Drug Administration 21 CFR Part 882 (formerly Docket No. 1997N-0484P) Medical Devices; Neurological Devices; Clarification of Classification for Human Dura Mater; Technical Amendment...
The family of dedicator of cytokinesis (Dock), a protein family that belongs to the atypical Rho guanine nucleotide exchange factors (GEFs) for Rac and/or Cdc42 GTPases, plays pivotal roles in various processes of brain development. To date, 11 members of Docks have been identified in the mammalian system. Emerging evidence has suggested that members of the Dock family are associated with several neurodegenerative and neuropsychiatric diseases, including Alzheimer disease and autism spectrum disorders. This review summarizes recent advances on the understanding of the roles of the Dock protein family in normal and diseased processes in the nervous system. Furthermore, interacting proteins and the molecular regulation of Docks are discussed.
Samsel, Anthony; Seneff, Stephanie
Manganese (Mn) is an often overlooked but important nutrient, required in small amounts for multiple essential functions in the body. A recent study on cows fed genetically modified Roundup®-Ready feed revealed a severe depletion of serum Mn. Glyphosate, the active ingredient in Roundup®, has also been shown to severely deplete Mn levels in plants. Here, we investigate the impact of Mn on physiology, and its association with gut dysbiosis as well as neuropathologies such as autism, Alzheimer's disease (AD), depression, anxiety syndrome, Parkinson's disease (PD), and prion diseases. Glutamate overexpression in the brain in association with autism, AD, and other neurological diseases can be explained by Mn deficiency. Mn superoxide dismutase protects mitochondria from oxidative damage, and mitochondrial dysfunction is a key feature of autism and Alzheimer’s. Chondroitin sulfate synthesis depends on Mn, and its deficiency leads to osteoporosis and osteomalacia. Lactobacillus, depleted in autism, depend critically on Mn for antioxidant protection. Lactobacillus probiotics can treat anxiety, which is a comorbidity of autism and chronic fatigue syndrome. Reduced gut Lactobacillus leads to overgrowth of the pathogen, Salmonella, which is resistant to glyphosate toxicity, and Mn plays a role here as well. Sperm motility depends on Mn, and this may partially explain increased rates of infertility and birth defects. We further reason that, under conditions of adequate Mn in the diet, glyphosate, through its disruption of bile acid homeostasis, ironically promotes toxic accumulation of Mn in the brainstem, leading to conditions such as PD and prion diseases. PMID:25883837
Samsel, Anthony; Seneff, Stephanie
Manganese (Mn) is an often overlooked but important nutrient, required in small amounts for multiple essential functions in the body. A recent study on cows fed genetically modified Roundup(®)-Ready feed revealed a severe depletion of serum Mn. Glyphosate, the active ingredient in Roundup(®), has also been shown to severely deplete Mn levels in plants. Here, we investigate the impact of Mn on physiology, and its association with gut dysbiosis as well as neuropathologies such as autism, Alzheimer's disease (AD), depression, anxiety syndrome, Parkinson's disease (PD), and prion diseases. Glutamate overexpression in the brain in association with autism, AD, and other neurological diseases can be explained by Mn deficiency. Mn superoxide dismutase protects mitochondria from oxidative damage, and mitochondrial dysfunction is a key feature of autism and Alzheimer's. Chondroitin sulfate synthesis depends on Mn, and its deficiency leads to osteoporosis and osteomalacia. Lactobacillus, depleted in autism, depend critically on Mn for antioxidant protection. Lactobacillus probiotics can treat anxiety, which is a comorbidity of autism and chronic fatigue syndrome. Reduced gut Lactobacillus leads to overgrowth of the pathogen, Salmonella, which is resistant to glyphosate toxicity, and Mn plays a role here as well. Sperm motility depends on Mn, and this may partially explain increased rates of infertility and birth defects. We further reason that, under conditions of adequate Mn in the diet, glyphosate, through its disruption of bile acid homeostasis, ironically promotes toxic accumulation of Mn in the brainstem, leading to conditions such as PD and prion diseases.
Corvol, Jean-Christophe; Goni, Sylvia; Bordet, Régis
The important medical and social burden of nervous system diseases contrasts with the currently limited therapeutic armamentarium and with the difficulty encountered in developing new therapeutic options. These failures can be explained by the conjunction of various phenomena related to the limitations of animal models, the narrow focus of research on precise pathophysiological mechanisms, and methodological issues in clinical trials. It is perhaps the paradigm itself of the way research is conducted that may be the real reason for our incapacity to find effective strategies. The purpose of this workshop was to define overall lines of research that could lead to the development of effective novel therapeutic solutions. Research has long focused on diseases per se rather than on cognitive and behavioural dimensions common to several diseases. Their expression is often partial and variable, but can today be well-characterised using neurophysiological or imaging methods. This dimensional or syndromic vision should enable a new insight to the question, taking a transnosographic approach to re-position research and to propose: translational models exploring the same functions in animal models and in humans; identification of homogeneous groups of patients defined according to the clinical, anatomico-functional and molecular characteristics; and preclinical and clinical developments enriched by the use of cognitive-behavioural, biological neurological, and imaging biomarkers. For this mutation to be successful, it must be accompanied by synchronised action from the public authorities and by ad hoc measures from the regulatory agencies.
McCurdy, Victoria J.; Johnson, Aime K.; Gray-Edwards, Heather; Randle, Ashley N.; Brunson, Brandon L.; Morrison, Nancy E.; Salibi, Nouha; Johnson, Jacob A.; Hwang, Misako; Beyers, Ronald J.; Leroy, Stanley G.; Maitland, Stacy; Denney, Thomas S.; Cox, Nancy R.; Baker, Henry J.; Sena-Esteves, Miguel; Martin, Douglas R.
Progressive debilitating neurological defects characterize feline GM1 gangliosidosis, a lysosomal storage disease caused by deficiency of lysosomal β-galactosidase. No effective therapy exists for affected children, who often die before age 5. In the current study, an adeno-associated viral vector carrying the therapeutic gene was injected bilaterally into two brain targets (thalamus and deep cerebellar nuclei) of a feline model of GM1 gangliosidosis. Gene therapy normalized β-galactosidase activity and storage throughout the brain and spinal cord. The mean survival of 12 treated GM1 animals was >38 months compared to 8 months for untreated animals. Seven of the 8 treated animals remaining alive demonstrated normalization of disease, with abrogation of many symptoms including gait deficits and postural imbalance. Sustained correction of the GM1 gangliosidosis disease phenotype after limited intracranial targeting by gene therapy in a large animal model suggests that this approach may be useful for treating the human version of this lysosomal storage disorder. PMID:24718858
Spetsieris, Phoebe G.; Dhawan, Vijay; Moeller, James R.; Eidelberg, David
By applying non-conventional statistical analysis and visualization techniques to PET data obtained from a combined group of patients and normals, we are able to illustrate topographic covariance profiles unique to the disease at various stages of progression. Each profile represents a neuroanatomical regional network that is not discernible in the unprocessed data sets using standard analytical methods. The magnitude of a profile's manifestation in a given subject is expressed as a subject score which can correlate with independent clinical disease severity measures such as quantitative rigidity and bradykinesia ratings in Parkinson's disease. To create representations of these profiles a semi-automated routine is used which first generates a 2D pseudocolor map of the network where each region is weighted in accordance with its relative contribution to the overall profile. This representation is then transformed to a 3D isometric form so that the metabolic topography becomes more visually apparent. To fully perceive the evolving topographical pattern from initial to final stages of the disease, intermediate stages of disease progression are derived by interpolation to create a smooth progression of images that are displayed in an animated sequence.
Barral, Serena; Kurian, Manju A.
The study of neurological disorders often presents with significant challenges due to the inaccessibility of human neuronal cells for further investigation. Advances in cellular reprogramming techniques, have however provided a new source of human cells for laboratory-based research. Patient-derived induced pluripotent stem cells (iPSCs) can now be robustly differentiated into specific neural subtypes, including dopaminergic, inhibitory GABAergic, motorneurons and cortical neurons. These neurons can then be utilized for in vitro studies to elucidate molecular causes underpinning neurological disease. Although human iPSC-derived neuronal models are increasingly regarded as a useful tool in cell biology, there are a number of limitations, including the relatively early, fetal stage of differentiated cells and the mainly two dimensional, simple nature of the in vitro system. Furthermore, clonal variation is a well-described phenomenon in iPSC lines. In order to account for this, robust baseline data from multiple control lines is necessary to determine whether a particular gene defect leads to a specific cellular phenotype. Over the last few years patient-derived neural cells have proven very useful in addressing several mechanistic questions related to central nervous system diseases, including early-onset neurological disorders of childhood. Many studies report the clinical utility of human-derived neural cells for testing known drugs with repurposing potential, novel compounds and gene therapies, which then can be translated to clinical reality. iPSCs derived neural cells, therefore provide great promise and potential to gain insight into, and treat early-onset neurological disorders. PMID:27656126
The family of dedicator of cytokinesis (Dock), a protein family that belongs to the atypical Rho guanine nucleotide exchange factors (GEFs) for Rac and/or Cdc42 GTPases, plays pivotal roles in various processes of brain development. To date, 11 members of Docks have been identified in the mammalian system. Emerging evidence has suggested that members of the Dock family are associated with several neurodegenerative and neuropsychiatric diseases, including Alzheimer disease and autism spectrum disorders. This review summarizes recent advances on the understanding of the roles of the Dock protein family in normal and diseased processes in the nervous system. Furthermore, interacting proteins and the molecular regulation of Docks are discussed. PMID:24563715
Increasingly, patients affected by metabolic diseases affecting the central nervous system and neuroinflammatory disorders receive hematopoietic cell transplantation (HCT) in the attempt to slow the course of their disease, delay or attenuate symptoms, and improve pathologic findings. The possible replacement of brain-resident myeloid cells by the transplanted cell progeny contributes to clinical benefit. Genetic engineering of the cells to be transplanted (hematopoietic stem cell) may endow the brain myeloid progeny of these cells with enhanced or novel functions, contributing to therapeutic effects. Copyright © 2017 Elsevier Inc. All rights reserved.
Vincent, Angela; Dalton, Paola; Clover, Linda; Palace, Jackie; Lang, Bethan
The role of antibodies to specific neuronal and muscle ion channels in the etiology of neuromuscular transmission disorders is now well accepted. In addition, maternal antibodies can cross the placenta and cause neonatal disease or even alter the development of the infant, raising the possibility that some neurodevelopmental conditions could be caused by maternal antibodies. Voltage-gated ion channels are expressed in the brain as well as at the neuromuscular junction, and in recent years it has become clear that antibodies to some central nervous system (CNS) channels can be associated with CNS disease. This review highlights features of these conditions, preliminary investigations into neurodevelopmental disorders, and areas for further study.
Badalian, L O; Kravchuk, L N; Sergovskaia, V D; Belousova, V S; Minina, A P
Clinical characteristics of Lyme disease (LD) course in children have been studied. Altogether 86 patients were examined. Serodiagnosis was made in patients basing on indirect immunofluorescence and enzyme immunoassay with LD agent antigens. Erythema--free forms, combination of mite-borne Borrelia infection with tick-borne encephalitis were detected. Two clinicoimmunological LD variants were verified: seropositive and seronegative mite-borne Borrelia infection with typical clinical manifestations. The disease took a benign course responsive to antibiotics in combined treatment of neuromuscular lesions.
Kaplan, M H
Human retroviral infections result in significant neoplastic disease. Human T cell lymphotropic virus I (HTLV-I), the first human retrovirus to be discovered, is associated with the development of acute T cell leukemia with characteristic hypercalcemia and skin lesions after many years of chronic infection of CD4+ cells. HTLV-I also produces myelopathy. A minor T cell immunodeficiency occurs in HTLV-I acute T cell leukemia with associated strongyloidiasis and Pneumocystis carinii pneumonia. Human T cell lymphotropic virus II (HTLV-II) is found to be endemic in Amerindians and intravenous drug users (IVDUs) and has been linked to some cases of hairy-cell leukemia. HTLV-II infects the CD8+ population, with significant cell-associated viremia. Clinical neurological disease is rare, with one patient with myelopathy having been described. Immunodeficiency does not seem to occur. Human immunodeficiency virus 1 (HIV-1) produces aggressive large cell and Burkitt's lymphoma in as many as 10% of HIV-1-infected patients. More than 20% of homosexual men infected with HIV-1 develop Kaposi's sarcoma (KS). The pathogenesis of KS is better understood through studying KS-like cell lines that induce angiogenic factors. In some patients HIV-1 and HTLV-I or HTLV-II infections occur concomitantly. HIV-1 accelerates the tumorigenesis of HTLV-I and produces unusual skin diseases when combined with HTLV-II. Immunodeficiency occurs in all HIV-1-infected patients.
Keogh, M.J.; Chinnery, P.F.
Over the past year huge advances have been made in our ability to determine the genetic aetiology of many neurological diseases through the utilisation of next generation sequencing platforms. This technology is, on a daily basis, providing new breakthroughs in neurological disease. The aim of this article is to clearly describe the technological platforms, methods of data analysis, established breakthroughs, and potential future clinical and research applications of this innovative and exciting technique which has relevance to all those working within clinical neuroscience. PMID:23200550
Public health issues and clinical and neurological characteristics of the new variant of Creutzfeldt-Jakob disease and other human and animal transmissible spongiform encephalopathies: memorandum from two WHO meetings.
The transmissible spongiform encephalopathies (TSEs) include bovine spongiform encephalopathy (BSE), which was first described in 1986 in cattle in the United Kingdom, but has occurred subsequently also in other countries, and Creutzfeldt-Jakob disease (CJD) in humans, which is rare but with a worldwide distribution. Recently a new variant form of CJD, with a characteristic clinical and pathological phenotype, has been identified in the United Kingdom in a series of 11 young patients. This Memorandum reports the findings of two WHO Consultations. The first, held on 2-3 April 1996, issued conclusions and recommendations on certain animal products in order to protect the health of consumers. The second, held on 14-16 May 1996, examined, inter alia, the findings associated with the new variant of CJD, compared these findings with those for other TSEs, and proposed a protocol for the diagnosis and surveillance of CJD and related diseases. PMID:9002325
Baeza-Yates, Ricardo; Sangal, Puneet Mohan; Villoslada, Pablo
Analyzing the disease-related web searches of Internet users provides insight into the interests of the general population as well as the healthcare industry, which can be used to shape health care policies. We analyzed the searches related to neurological diseases and drugs used in neurology using the most popular search engines in the US, Google and Bing/Yahoo. We found that the most frequently searched diseases were common diseases such as dementia or Attention Deficit/Hyperactivity Disorder (ADHD), as well as medium frequency diseases with high social impact such as Parkinson's disease, MS and ALS. The most frequently searched CNS drugs were generic drugs used for pain, followed by sleep disorders, dementia, ADHD, stroke and Parkinson's disease. Regarding the interests of the healthcare industry, ADHD, Alzheimer's disease, MS, ALS, meningitis, and hypersomnia received the higher advertising bids for neurological diseases, while painkillers and drugs for neuropathic pain, drugs for dementia or insomnia, and triptans had the highest advertising bidding prices. Web searches reflect the interest of people and the healthcare industry, and are based either on the frequency or social impact of the disease.
Quansah, Emmanuel; Sarpong, Esther; Karikari, Thomas K
Neglected tropical diseases (NTDs) affect people in the bottom billion poorest in the world. These diseases are concentrated in rural areas, conflict zones and urban slums in Africa and other tropical areas. While the World Health Organization recognizes seventeen priority NTDs, the list of conditions present in Africa and elsewhere that are eligible to be classified as NTDs is much longer. Although NTDs are generally marginalized, their associated neurological burden has been almost completely disregarded. However, reports indicate that trichuriasis, schistosomiasis and hookworm infection, among others, cause impairments in memory and cognition, negatively affecting school attendance rates and educational performance particularly among children, as well as agricultural productivity among adults. Consequently, the neurological impairments have substantial influence on education and economic productivity, thus aggravating and perpetuating poverty in affected societies. However, inadequate research, policy and public health attention has been paid to the neurological burdens associated with NTDs. In order to appropriately address these burdens, we recommend the development of policy interventions that focus on the following areas: (i) the introduction of training programs to develop the capacity of scientists and clinicians in research, diagnostic and treatment approaches (ii) the establishment of competitive research grant schemes to fund cutting-edge research into these neurological impairments, and (iii) the development of public health interventions to improve community awareness of the NTD-associated neurological problems, possibly enhancing disease prevention and expediting treatment.
MacCormick, Ian J C; Czanner, Gabriela; Faragher, Brian
The inaccessibility of the brain poses a problem for neuroscience. Scientists have traditionally responded by developing biomarkers for brain physiology and disease. The retina is an attractive source of biomarkers since it shares many features with the brain. Some even describe the retina as a 'window' to the brain, implying that retinal signs are analogous to brain disease features. However, new analytical methods are needed to show whether or not retinal signs really are equivalent to brain abnormalities, since this requires greater evidence than direct associations between retina and brain. We, therefore propose a new way to think about, and test, how clearly one might see the brain through the retinal window, using cerebral malaria as a case study.
MacCormick, Ian JC; Czanner, Gabriela; Faragher, Brian
The inaccessibility of the brain poses a problem for neuroscience. Scientists have traditionally responded by developing biomarkers for brain physiology and disease. The retina is an attractive source of biomarkers since it shares many features with the brain. Some even describe the retina as a ‘window’ to the brain, implying that retinal signs are analogous to brain disease features. However, new analytical methods are needed to show whether or not retinal signs really are equivalent to brain abnormalities, since this requires greater evidence than direct associations between retina and brain. We, therefore propose a new way to think about, and test, how clearly one might see the brain through the retinal window, using cerebral malaria as a case study. PMID:26174843
Serra, Jorge A; Domínguez, Raúl O; Marschoff, Enrique R; Guareschi, Eduardo M; Famulari, Arturo L; Boveris, Alberto
Markers of oxidative stress were measured in blood samples of 338 subjects (965 observations): Alzheimer's, vascular dementia, diabetes (type II) superimposed to dementias, Parkinson's disease and controls. Patients showed increased thiobarbituric acid reactive substances (+21%; P < 0.05), copper-zinc superoxide dismutase (+64%; P < 0.001) and decreased antioxidant capacity (-28%; P < 0.001); pairs of variables resulted linearly related across groups (P < 0.001). Catalase and glutathione peroxidase, involved in discrimination between diseases, resulted non-significant. When diabetes is superimposed with dementias, changes resulted less marked but significant. Also, superoxide dismutase resulted not linearly correlated with any other variable or age-related (pure Alzheimer's peaks at 70 years, P < 0.001). Systemic oxidative stress was significantly associated (P < 0.001) with all diseases indicating a disbalance in peripheral/adaptive responses to oxidative disorders through different free radical metabolic pathways. While other changes - methionine cycle, insulin correlation - are also associated with dementias, the responses presented here show a simple linear relation between prooxidants and antioxidant defenses.
Sciacca, G; Nicoletti, A; Fermo, S Lo; Mostile, G; Giliberto, C; Zappia, Mario
Guillain-Barrè syndrome (GBS) is an acute, paralyzing, inflammatory peripheral nerve disease, featured by monophasic disease course, symmetrical limb weakness and areflexia. Several pathologies can mimic the clinical presentation of GBS, making hard the differential diagnosis for patients complaining of acute flaccid paralysis. In this paper we describe three cases of different neurological diseases presenting with acute motor symptoms mimicking GBS, reviewing the relevant literature on misdiagnosis of GBS.
Marchetto, Maria C.; Brennand, Kristen J.; Boyer, Leah F.; Gage, Fred H.
The systematic generation of neurons from patients with neurological disorders can provide important insights into disease pathology, progression and mechanism. This review will discuss recent progress in modeling neurodegenerative and neurodevelopmental diseases using induced pluripotent stem cells (iPSCs) and highlight some of the current challenges in the field. Combined with other technologies previously used to study brain disease, iPSC modeling has the promise to influence modern medicine on several fronts: early diagnosis, drug development and effective treatment. PMID:21828073
Dirani, Maya; Nasreddine, Wassim; Abdulla, Fatima; Beydoun, Ahmad
Lafora disease is a rare and fatal disease characterized by seizures, progressive cognitive and behavioral deterioration, as well as cerebellar dysfunction. Currently, there is no efficacious treatment that will control the seizures and improve the cognitive decline in this disease. We report a patient with Lafora disease who experienced a dramatic amelioration in her seizure frequency as well as the associated neurological and cognitive dysfunction following initiation of treatment with perampanel administered as monotherapy. Perampanel is the first potentially efficacious treatment for Lafora disease. We discuss a potential mechanism for the efficacy of perampanel in this disease. PMID:25667898
Urbano, Francisco J; Pagani, Mario R; Uchitel, Osvaldo D
Voltage-dependent calcium channels are essential in neuronal signaling and synaptic transmission, and their functional alterations underlie numerous human disorders whether monogenic (e.g., ataxia, migraine, etc.) or autoimmune. We review recent work on Ca(V)2.1 or P/Q channelopathies, mostly using neuromuscular junction preparations, and focus specially on the functional hierarchy among the calcium channels recruited to mediate neurotransmitter release when Ca(V)2.1 channels are mutated or depleted. In either case, synaptic transmission is greatly compromised; evidently, none of the reported functional replacements with other calcium channels compensates fully.
Lopes, Carla; Rego, A Cristina
Pluripotent stem cells (PSCs) are powerful cellular tools that can generate all the different cell types of the body, and thus overcome the often limited access to human disease tissues; this becomes highly relevant when aiming to investigate cellular (dys)function in diseases affecting the central nervous system. Recent studies have demonstrated that PSC and differentiated cells show altered mitochondrial function and metabolic profiles and production of reactive oxygen species. This raises an emerging paradigm about the role of mitochondria in stem cell biology and urges the need to identify mitochondrial pathways involved in these processes. In this respect, this review focuses on the metabolic profile of PSC and how mitochondrial function can influence the reprogramming and differentiation processes. Indeed, both embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) favor the glycolytic pathway as a major source of energy production over oxidative phosphorylation. PSC mitochondria are characterized by a spherical shape, low copy number of mitochondrial DNA, and a hyperpolarized state. Indeed, mitochondria appear to have a crucial role in reprogramming iPSC, in the maintenance of a pluripotent state, and in differentiation. Moreover, an increase in mitochondrial oxidative phosphorylation has to occur for differentiation to succeed. Therefore, in vitro differentiation of neural stem cells (NSCs) into neurons can be compromised if those mechanisms are impaired. Future research should shed light on how mitochondrial impairment occurring in pre differentiation neural stages (e.g., in NSC or premature neurons) may contribute for the etiopathogenesis of neurodevelopmental and neurological disorders.
The recent identification of multiple new genetic causes of neurological disorders highlights the need for model systems that give experimental access to the underlying biology. In particular, the ability to couple disease-causing mutations with human neuronal differentiation systems would be beneficial. Gene targeting is a well-known approach for dissecting gene function, but low rates of homologous recombination in somatic cells (including neuronal cells) have traditionally impeded the development of robust cellular models of neurological disorders. Recently, however, CRISPR/Cas9 gene editing technologies have expanded the number of systems within which gene targeting is possible. Here we adopt as a model system LUHMES cells, a commercially available diploid human female mesencephalic cell line that differentiates into homogeneous mature neurons in 1-2 weeks. We describe optimised methods for transfection and selection of neuronal progenitor cells carrying targeted genomic alterations using CRISPR/Cas9 technology. By targeting the endogenous X-linked MECP2 locus, we introduced four independent missense mutations that cause the autism spectrum disorder Rett syndrome and observed the desired genetic structure in 3-26% of selected clones, including gene targeting of the inactive X chromosome. Similar efficiencies were achieved by introducing neurodevelopmental disorder-causing mutations at the autosomal EEF1A2 locus on chromosome 20. Our results indicate that efficiency of genetic “knock-in” is determined by the location of the mutation within the donor DNA molecule. Furthermore, we successfully introduced an mCherry tag at the MECP2 locus to yield a fusion protein, demonstrating that larger insertions are also straightforward in this system. We suggest that our optimised methods for altering the genome of LUHMES cells make them an attractive model for the study of neurogenetic disorders. PMID:27976757
Shah, Ruth R; Cholewa-Waclaw, Justyna; Davies, Faith C J; Paton, Katie M; Chaligne, Ronan; Heard, Edith; Abbott, Catherine M; Bird, Adrian P
The recent identification of multiple new genetic causes of neurological disorders highlights the need for model systems that give experimental access to the underlying biology. In particular, the ability to couple disease-causing mutations with human neuronal differentiation systems would be beneficial. Gene targeting is a well-known approach for dissecting gene function, but low rates of homologous recombination in somatic cells (including neuronal cells) have traditionally impeded the development of robust cellular models of neurological disorders. Recently, however, CRISPR/Cas9 gene editing technologies have expanded the number of systems within which gene targeting is possible. Here we adopt as a model system LUHMES cells, a commercially available diploid human female mesencephalic cell line that differentiates into homogeneous mature neurons in 1-2 weeks. We describe optimised methods for transfection and selection of neuronal progenitor cells carrying targeted genomic alterations using CRISPR/Cas9 technology. By targeting the endogenous X-linked MECP2 locus, we introduced four independent missense mutations that cause the autism spectrum disorder Rett syndrome and observed the desired genetic structure in 3-26% of selected clones, including gene targeting of the inactive X chromosome. Similar efficiencies were achieved by introducing neurodevelopmental disorder-causing mutations at the autosomal EEF1A2 locus on chromosome 20. Our results indicate that efficiency of genetic "knock-in" is determined by the location of the mutation within the donor DNA molecule. Furthermore, we successfully introduced an mCherry tag at the MECP2 locus to yield a fusion protein, demonstrating that larger insertions are also straightforward in this system. We suggest that our optimised methods for altering the genome of LUHMES cells make them an attractive model for the study of neurogenetic disorders.
Henninger, Rick W; Reed, Stephen M; Saville, William J; Allen, George P; Hass, Gregory F; Kohn, Catherine W; Sofaly, Cheryl
Equine herpesvirus type 1 (EHV-1) infection causes neurologic disease in horses. However, risk factors for the disease and long-term prognosis are poorly characterized. There are identifiable risk factors for equine herpes-1 myeloencephalopathy. The entire population of 135 horses housed within the equestrian facility. A descriptive study investigated the clinical, serologic, virologic, and management aspects of an outbreak of EHV-1 myeloencephalopathy. Out of 135 horses at the facility, 117 displayed signs of EHV-1 infection. Forty-six horses developed neurologic deficits characterized by symmetrical hind limb ataxia and weakness. Twelve horses that developed neurologic deficits became recumbent and did not survive. The development of severe neurologic deficits during the outbreak was associated with the presence of residual deficits at the 6-month examination. Within 1 year of the outbreak onset, all horses that survived had returned to an exercise level comparable to that experienced before the outbreak. Factors associated with the development of neurologic disease included age of > 5 years, location in the south or arena stall areas, and highest rectal temperature on day 3 or later of the febrile period. Being > 5 years of age, having had a rectal temperature of > 103.5 degrees F, and highest rectal temperature occurring on or after the 3rd day of the febrile period were the factors most predictive of the development of neurologic disease and death. Data obtained during this outbreak substantiate previous findings relating to clinical aspects and diagnosis of EHV-1 myeloencephalopathy. The prophylactic and therapeutic use of acyclovir during this outbreak is described.
Nikolic, Katarina; Mavridis, Lazaros; Bautista-Aguilera, Oscar M.; Marco-Contelles, José; Stark, Holger; do Carmo Carreiras, Maria; Rossi, Ilaria; Massarelli, Paola; Agbaba, Danica; Ramsay, Rona R.; Mitchell, John B. O.
Recently developed multi-targeted ligands are novel drug candidates able to interact with monoamine oxidase A and B; acetylcholinesterase and butyrylcholinesterase; or with histamine N-methyltransferase and histamine H3-receptor (H3R). These proteins are drug targets in the treatment of depression, Alzheimer's disease, obsessive disorders, and Parkinson's disease. A probabilistic method, the Parzen-Rosenblatt window approach, was used to build a "predictor" model using data collected from the ChEMBL database. The model can be used to predict both the primary pharmaceutical target and off-targets of a compound based on its structure. Molecular structures were represented based on the circular fingerprint methodology. The same approach was used to build a "predictor" model from the DrugBank dataset to determine the main pharmacological groups of the compound. The study of off-target interactions is now recognised as crucial to the understanding of both drug action and toxicology. Primary pharmaceutical targets and off-targets for the novel multi-target ligands were examined by use of the developed cheminformatic method. Several multi-target ligands were selected for further study, as compounds with possible additional beneficial pharmacological activities. The cheminformatic targets identifications were in agreement with four 3D-QSAR (H3R/D1R/D2R/5-HT2aR) models and by in vitro assays for serotonin 5-HT1a and 5-HT2a receptor binding of the most promising ligand ( 71/MBA-VEG8).
Klein, Christine; Schlossmacher, Michael G
The identification of single genes linked to heritable forms of Parkinson disease (PD) has challenged the previously held view of a nongenetic etiology for this progressive movement disorder. Detailed analyses of individuals with mutations in SNCA, Parkin, PINK1, DJ1 or LRRK2 have greatly advanced our knowledge of preclinical and clinical, morphological, and pathological changes in PD. These genetic breakthroughs have had profound implications for scientists, neurologists and patients alike. Such advances have provided unique opportunities to pursue the mechanisms of neuronal degeneration in models of PD pathogenesis, thereby reinforcing the significance of oxidative stress and mitochondrial dysfunction. With emerging clues from familial variants, researchers have begun to explore factors that lead to the expression of the more common, sporadic disease phenotype (idiopathic PD), including interactions between various genes, modifying effects of susceptibility alleles and epigenetic factors, and the influence of environmental agents and aging on the expression of PD-linked genes. These genetic leads have added to the urgency of developing translational drug treatments, and neurologists and their patients are confronting considerations relating to DNA testing. In this article, we summarize recent progress in establishing a neurogenetic component of PD, emphasize the need for developing PD biomarkers to improve diagnostic accuracy (in both clinical practice and therapeutic trials), and discuss scenarios in which specific DNA tests might be considered for diagnostic purposes. In the absence of consensus guidelines for DNA testing in PD and of any neuroprotective treatment for this nonfatal disorder, we remind ourselves of the omnipresent mandate, 'Primum nil nocere!' ('First, do no harm!').
Sharata, H H; Colvin, J H; Fujiwara, K; Goldman, B; Hashimoto, K
Human T-lymphotropic virus type I (HTLV-I) is the etiologic agent of HTLV-I associated myelopathy (HAM)/tropical spastic paresis (TSP), and adult T-cell leukemia/lymphoma (ATLL). ATLL has been associated with HTLV-I in the southeastern United States. However, to our knowledge, no case reports of HAM/TSP in association with ATLL occurring in the United States have been described. We describe a 40-year-old black woman with a 10-year history of recalcitrant psoriasiform eruption and erythrodermic flares. Medical history is additionally significant for a 2-year history of HTLV-I-associated myelopathy and lower extremity spastic paresis. Polymerase chain reaction with Southern blot analysis was used to detect HTLV-I proviral genome from frozen skin biopsy specimens and peripheral blood mononuclear cells.
Wray, Selina; Self, Matthew; Lewis, Patrick A.; Taanman, Jan-Willem; Ryan, Natalie S.; Mahoney, Colin J.; Liang, Yuying; Devine, Michael J.; Sheerin, Una-Marie; Houlden, Henry; Morris, Huw R.; Healy, Daniel; Marti-Masso, Jose-Felix; Preza, Elisavet; Barker, Suzanne; Sutherland, Margaret; Corriveau, Roderick A.; D'Andrea, Michael; Schapira, Anthony H. V.; Uitti, Ryan J.; Guttman, Mark; Opala, Grzegorz; Jasinska-Myga, Barbara; Puschmann, Andreas; Nilsson, Christer; Espay, Alberto J.; Slawek, Jaroslaw; Gutmann, Ludwig; Boeve, Bradley F.; Boylan, Kevin; Stoessl, A. Jon; Ross, Owen A.; Maragakis, Nicholas J.; Van Gerpen, Jay; Gerstenhaber, Melissa; Gwinn, Katrina; Dawson, Ted M.; Isacson, Ole; Marder, Karen S.; Clark, Lorraine N.; Przedborski, Serge E.; Finkbeiner, Steven; Rothstein, Jeffrey D.; Wszolek, Zbigniew K.; Rossor, Martin N.; Hardy, John
Our understanding of the molecular mechanisms of many neurological disorders has been greatly enhanced by the discovery of mutations in genes linked to familial forms of these diseases. These have facilitated the generation of cell and animal models that can be used to understand the underlying molecular pathology. Recently, there has been a surge of interest in the use of patient-derived cells, due to the development of induced pluripotent stem cells and their subsequent differentiation into neurons and glia. Access to patient cell lines carrying the relevant mutations is a limiting factor for many centres wishing to pursue this research. We have therefore generated an open-access collection of fibroblast lines from patients carrying mutations linked to neurological disease. These cell lines have been deposited in the National Institute for Neurological Disorders and Stroke (NINDS) Repository at the Coriell Institute for Medical Research and can be requested by any research group for use in in vitro disease modelling. There are currently 71 mutation-defined cell lines available for request from a wide range of neurological disorders and this collection will be continually expanded. This represents a significant resource that will advance the use of patient cells as disease models by the scientific community. PMID:22952635
Complementary and alternative medicine (CAM) is a phrase used to describe additional health care methods such as mind/body practices and natural products not regarded as treatments by conventional medicine. The use of CAM in children with common neurologic diseases is more frequent than its use in healthy children (24%–78% vs. 12%). However, less than half of patients report such use to their physicians. The preferred modalities of CAM vary in different countries due to their different cultures and traditions. The most common factor significantly associated with the use of CAM is parental CAM use in most studies. The frequency of the use of CAM in children and adults with neurologic diseases is similar, and both rates are higher than the rates in those without these conditions. The preferred modalities of CAM in adults are diverse, and megavitamins and mind/body therapy (prayer and chiropractic care) are included. The most common factor significantly associated with the use of CAM in adults with neurologic diseases is high educational level. Physicians need to be concerned with patients' use of CAM and provide correct information about CAM so that patients may make the right decisions. Further study is needed to determine the evidence-based efficacy of CAM use in children with common neurologic diseases. PMID:27610179
Casas-de-la-Asunción, E; Ruano-Ruiz, J; Rodríguez-Martín, A M; Vélez García-Nieto, A; Moreno-Giménez, J C
In the past 10 years, bullous pemphigoid has been associated with other comorbidities and neurologic and psychiatric conditions in particular. Case series, small case-control studies, and large population-based studies in different Asian populations, mainland Europe, and the United Kingdom have confirmed this association. However, no data are available for the Spanish population. This was an observational, retrospective, case-control study with 1:2 matching. Fifty-four patients with bullous pemphigoid were selected. We compared the percentage of patients in each group with concurrent neurologic conditions, ischemic heart disease, diabetes, chronic obstructive pulmonary disease, and solid tumors using univariate logistic regression. An association model was constructed with conditional multiple logistic regression. The case group had a significantly higher percentage of patients with cerebrovascular accident and/or transient ischemic attack (odds ratio [OR], 3.06; 95% CI, 1.19-7.87], dementia (OR, 5.52; 95% CI, 2.19-13.93), and Parkinson disease (OR, 5; 95% CI, 1.57-15.94). A significantly higher percentage of cases had neurologic conditions (OR, 6.34; 95% CI, 2.89-13.91). Dementia and Parkinson disease were independently associated with bullous pemphigoid in the multivariate analysis. Patients with bullous pemphigoid have a higher frequency of neurologic conditions. Copyright © 2013 Elsevier España, S.L.U. and AEDV. All rights reserved.
Sargento-Freitas, Joao; Silva, Fernando; Koehler, Sebastian; Isidoro, Luís; Mendonça, Nuno; Machado, Cristina; Cordeiro, Gustavo; Cunha, Luís
Cardioembolism due to atrial fibrillation assumes a dominant etiologic role in cerebrovascular diseases due to its growing incidence, high embolic risk and particular aspects of clinical events caused. Our objectives are to analyze the frequency of atrial fibrillation in patients with ischemic stroke, study the vital and functional impact of stroke due to different etiologies and evaluate antithrombotic options before and after stroke. We conducted a retrospective study including patients admitted in a central hospital due to ischemic stroke in 2010 (at least one year of follow-up). Etiology of stroke was defined using the Trial of ORG 10172 in Acute Stroke (TOAST) classification, and functional outcome by modified Rankin scale. We performed a descriptive analysis of different stroke etiologies and antithrombotic medication in patients with atrial fibrillation. We then conducted a cohort study to evaluate the clinical impact of antithrombotic options in secondary prevention after cardioembolic stroke. In our population (n = 631) we found superior frequency of cardioembolism (34.5%) to that reported in the literature. Mortality, morbidity and antithrombotic options are similar to other previous series, confirming the severity of cardioembolic strokes and the underuse of vitamin K antagonists. Oral anticoagulation was effective in secondary prevention independently from post-stroke functional condition. Despite unequivocal recommendations, oral anticoagulation is still underused in stroke prevention. This study confirms the clinical efficacy of vitamin K antagonists in secondary prevention independently from residual functional impairment.
Schutzer, S E; Coyle, P K; Krupp, L B; Deng, Z; Belman, A L; Dattwyler, R; Luft, B J
Lyme disease is the major tick-borne disease, caused by Borrelia burgdorferi (Bb). Neurological involvement is common in all stages. In vivo expression of Bb antigens (Ags) and the immune response to them has not been well investigated in the cerebrospinal fluid (CSF). Upregulation of outer surface protein (Osp) C and concomitant downregulation of OspA before tick inoculation of the spirochete has been reported in skin and blood in animals. CSF OspA Ag in early disease suggests otherwise in CSF. Early Ag expression and IgM response in human CSF was investigated here. Paired CSF and serum was collected from 16 early, predominantly erythema migrans Lyme disease patients with neurologic problems, 13 late Lyme disease patients, and 19 other neurologic disease (OND) controls. Samples were examined for IgM reactivity to recombinant Bb-specific Osps using ELISA and immunoblot. Of 12 early Lyme disease patients with neurologic involvement with both CSF and serum IgM against OspC, 7 (58%) had IgM to OspA (n = 5) or OspB (n = 2) that was restricted to the CSF, not serum. Overall, 12 of 16 (75%) of these early Lyme disease patients with neurologic involvement had CSF and serum IgM against OspC. Only 3 of 13 (23%) late Lyme disease patients and none of 19 OND controls had CSF IgM directed against OspC. In conclusion, in CSF, OspC and OspA can be coexpressed, and IgM response to them occurs in early Lyme disease patients with neurologic involvement. This biologic finding may also provide a discriminating marker for CNS infection in Lyme disease. PMID:9259573
Murrow, Gail B; Murrow, Richard
Dehumanization is anecdotally and historically associated with reduced empathy for the pain of dehumanized individuals and groups and with psychological and legal denial of their human rights and extreme violence against them. We hypothesize that 'empathy' for the pain and suffering of dehumanized social groups is automatically reduced because, as the research we review suggests, an individual's neural mechanisms of pain empathy best respond to (or produce empathy for) the pain of people whom the individual automatically or implicitly associates with her or his own species. This theory has implications for the philosophical conception of 'human' and of 'legal personhood' in human rights jurisprudence. It further has implications for First Amendment free speech jurisprudence, including the doctrine of 'corporate personhood' and consideration of the potential harm caused by dehumanizing hate speech. We suggest that the new, social neuroscience of empathy provides evidence that both the vagaries of the legal definition or legal fiction of 'personhood' and hate speech that explicitly and implicitly dehumanizes may (in their respective capacities to artificially humanize or dehumanize) manipulate the neural mechanisms of pain empathy in ways that could pose more of a true threat to human rights and rights-based democracy than previously appreciated.
123I-meta-iodobenzylguanidine (MIBG) has become widely applied in Japan since its introduction to clinical cardiology and neurology practice in the 1990s. Neurological studies found decreased cardiac uptake of 123I-MIBG in Lewy-body diseases including Parkinson's disease and dementia with Lewy bodies. Thus, cardiac MIBG uptake is now considered a biomarker of Lewy body diseases. Although scintigraphic images of 123I-MIBG can be visually interpreted, an average count ratio of heart-to-mediastinum (H/M) has commonly served as a semi-quantitative marker of sympathetic activity. Since H/M ratios significantly vary according to acquisition and processing conditions, quality control should be appropriate, and quantitation should be standardized. The threshold H/M ratio for differentiating Lewy-body disease is 2.0-2.1, and was based on standardized H/M ratios to comparable values of medium-energy collimators. Parkinson's disease can be separated from various types of parkinsonian syndromes using cardiac 123I-MIBG, whereas activity is decreased on images of Lewy-body diseases using both 123I-ioflupane for the striatum and 123I-MIBG. Despite being a simple index, the H/M ratio of 123I-MIBG uptake is reproducible and can serve as an effective tool to support a diagnosis of Lewy-body diseases in neurological practice. PMID:27689024
Afrin, Lawrence B; Pöhlau, Dieter; Raithel, Martin; Haenisch, Britta; Dumoulin, Franz L; Homann, Juergen; Mauer, Uwe M; Harzer, Sabrina; Molderings, Gerhard J
Neurologists and psychiatrists frequently encounter patients whose central and/or peripheral neurologic and/or psychiatric symptoms (NPS) are accompanied by other symptoms for which investigation finds no unifying cause and for which empiric therapy often provides little to no benefit. Systemic mast cell activation disease (MCAD) has rarely been considered in the differential diagnosis in such situations. Traditionally, MCAD has been considered as just one rare (neoplastic) disease, mastocytosis, generally focusing on the mast cell (MC) mediators tryptase and histamine and the suggestive, blatant symptoms of flushing and anaphylaxis. Recently another form of MCAD, MC activation syndrome (MC), has been recognized, featuring inappropriate MC activation with little to no neoplasia and likely much more heterogeneously clonal and far more prevalent than mastocytosis. There also has developed greater appreciation for the truly very large menagerie of MC mediators and their complex patterns of release, engendering complex, nebulous presentations of chronic and acute illness best characterized as multisystem polymorbidity of generally inflammatory ± allergic themes--including very wide arrays of central and peripheral NPS. Significantly helpful treatment--including for neuropsychiatric issues--usually can be identified once MCAD is accurately diagnosed. We describe MCAD's pathogenesis, presentation (focusing on NPS), and therapy, especially vis-à-vis neuropsychotropes. Since MCAD patients often present NPS, neurologists and psychiatrists have the opportunity, in recognizing the diagnostic possibility of MCAD, to short-circuit the often decades-long delay in establishing the correct diagnosis required to identify optimal therapy.
Murrow, Gail B.; Murrow, Richard
Dehumanization is anecdotally and historically associated with reduced empathy for the pain of dehumanized individuals and groups and with psychological and legal denial of their human rights and extreme violence against them. We hypothesize that ‘empathy’ for the pain and suffering of dehumanized social groups is automatically reduced because, as the research we review suggests, an individual's neural mechanisms of pain empathy best respond to (or produce empathy for) the pain of people whom the individual automatically or implicitly associates with her or his own species. This theory has implications for the philosophical conception of ‘human’ and of ‘legal personhood’ in human rights jurisprudence. It further has implications for First Amendment free speech jurisprudence, including the doctrine of ‘corporate personhood’ and consideration of the potential harm caused by dehumanizing hate speech. We suggest that the new, social neuroscience of empathy provides evidence that both the vagaries of the legal definition or legal fiction of ‘personhood’ and hate speech that explicitly and implicitly dehumanizes may (in their respective capacities to artificially humanize or dehumanize) manipulate the neural mechanisms of pain empathy in ways that could pose more of a true threat to human rights and rights-based democracy than previously appreciated. PMID:27774198
Morita, Hiroyuki; Hirota, Takuo; Mune, Tomoatsu; Suwa, Tetsuya; Ishizuka, Tatsuo; Inuzuka, Takashi; Tanaka, Keiko; Ishimori, Masatoshi; Nakamura, Shigenori; Yasuda, Keigo
A 48-year-old man with autoimmune Addison disease developed the following paraneoplastic neurologic syndromes (PNNS): limbic encephalitis, opsoclonus/myoclonus, and sensorimotor and autonomic neuropathies. An anterior mediastinal mass detected on a chest computed tomographic scan was found on resection to be a noninvasive lymphocytic thymoma. The PNNS went into remission 1 year after the thymectomy. This is the first case of thymoma associated with autoimmune Addison disease and PNNS to be described in the literature.
Cao, Dan-Dan; Li, Lu; Chan, Wai-Yee
MicroRNAs (miRNAs) are a class of small, well-conserved noncoding RNAs that regulate gene expression post-transcriptionally. They have been demonstrated to regulate a lot of biological pathways and cellular functions. Many miRNAs are dynamically regulated during central nervous system (CNS) development and are spatially expressed in adult brain indicating their essential roles in neural development and function. In addition, accumulating evidence strongly suggests that dysfunction of miRNAs contributes to neurological diseases. These observations, together with their gene regulation property, implicated miRNAs to be the key regulators in the complex genetic network of the CNS. In this review, we first focus on the ways through which miRNAs exert the regulatory function and how miRNAs are regulated in the CNS. We then summarize recent findings that highlight the versatile roles of miRNAs in normal CNS physiology and their association with several types of neurological diseases. Subsequently we discuss the limitations of miRNAs research based on current studies as well as the potential therapeutic applications and challenges of miRNAs in neurological disorders. We endeavor to provide an updated description of the regulatory roles of miRNAs in normal CNS functions and pathogenesis of neurological diseases. PMID:27240359
Khan, Maria Usman; Devlin, James Anthony Joseph; Fraser, Alexander
The overall incidence of neurological manifestations is relatively low among patients with mixed connective tissue disease (MCTD). We recently encountered a case of autoimmune adhesive arachnoiditis in a young woman with 7 years history of MCTD who presented with severe back pain and myeloradiculopathic symptoms of lower limbs. To the best of our knowledge, adhesive arachnoiditis in an MCTD patient has never been previously reported. We report here this rare case, with the clinical picture and supportive ancillary data, including serology, cerebral spinal fluid analysis, electrophysiological evaluation and spinal neuroimaging, that is, MRI and CT (CT scan) of thoracic and lumbar spine. Her neurological deficit improved after augmenting her immunosuppressant therapy. Our case suggests that adhesive arachnoiditis can contribute to significant neurological deficits in MCTD and therefore requires ongoing surveillance.
Devlin, James Anthony Joseph; Fraser, Alexander
The overall incidence of neurological manifestations is relatively low among patients with mixed connective tissue disease (MCTD). We recently encountered a case of autoimmune adhesive arachnoiditis in a young woman with 7 years history of MCTD who presented with severe back pain and myeloradiculopathic symptoms of lower limbs. To the best of our knowledge, adhesive arachnoiditis in an MCTD patient has never been previously reported. We report here this rare case, with the clinical picture and supportive ancillary data, including serology, cerebral spinal fluid analysis, electrophysiological evaluation and spinal neuroimaging, that is, MRI and CT (CT scan) of thoracic and lumbar spine. Her neurological deficit improved after augmenting her immunosuppressant therapy. Our case suggests that adhesive arachnoiditis can contribute to significant neurological deficits in MCTD and therefore requires ongoing surveillance. PMID:27986694
Choi, Youngjee; Townend, John; Vincent, Tim; Zaidi, Irfan; Sarge-Njie, Ramu; Jaye, Assan
While well documented in human immunodeficiency virus (HIV)-1, neurologic sequelae have not been systematically evaluated in HIV-2. After excluding for confounding comorbidities, 67 individuals from a rural cohort in Guinea-Bissau (22 HIV-2 participants, 45 seronegative controls) were evaluated. HIV+individuals were divided into CD4<350 and CD4≥350 for analysis. HIV-associated neurocognitive disorders (HAND), assessed by the International HIV Dementia Scale (IHDS), distal sensory polyneuropathy (DSPN), and myelopathy were the main outcome variables. In univariate analysis, there was no difference in IHDS scores among groups. When analyzed by primary education attainment, IHDS scores were nonsignificantly higher (p=0.06) with more education. There was no significant difference in DSPN prevalence among groups; overall, 45% of participants had DSPN. There were no cases of myelopathy. In multivariate linear regression, higher IHDS scores were significantly correlated with older age (coefficient=−0.11, p<0.001). Logistic regression analysis showed that older age (odds ratio (OR) 95% CI 1.04–1.20), lower CD4 count (OR 95% CI 0.996–0.999), and higher BMI (OR 95% CI 1.02–1.43) significantly predicted the presence of DSPN. While a significant increase in cognitive impairment was not observed in HIV-2-infected individuals, the study suggests the IHDS may be a less effective screening tool for HAND in settings of lower educational attainment as encountered in rural Guinea-Bissau. Similar to HIV-1, DSPN seems to occur with lower CD4 counts in HIV-2. Further study of the viral–host interactions in HIV-2 and its consequent neurological diseases may provide an avenue for understanding the epidemic problems of HIV-1. PMID:21424866
Ognjenović, Jana; Wu, Jiang; Matthies, Doreen; Baxa, Ulrich; Subramaniam, Sriram; Ling, Jiqiang; Simonović, Miljan
Cytosolic glutaminyl-tRNA synthetase (GlnRS) is the singular enzyme responsible for translation of glutamine codons. Compound heterozygous mutations in GlnRS cause severe brain disorders by a poorly understood mechanism. Herein, we present crystal structures of the wild type and two pathological mutants of human GlnRS, which reveal, for the first time, the domain organization of the intact enzyme and the structure of the functionally important N-terminal domain (NTD). Pathological mutations mapping in the NTD alter the domain structure, and decrease catalytic activity and stability of GlnRS, whereas missense mutations in the catalytic domain induce misfolding of the enzyme. Our results suggest that the reduced catalytic efficiency and a propensity of GlnRS mutants to misfold trigger the disease development. This report broadens the spectrum of brain pathologies elicited by protein misfolding and provides a paradigm for understanding the role of mutations in aminoacyl-tRNA synthetases in neurological diseases. PMID:26869582
Ognjenovic, Jana; Wu, Jiang; Matthies, Doreen; Baxa, Ulrich; Subramaniam, Sriram; Ling, Jiqiang; Simonovic, Miljan
Cytosolic glutaminyl-tRNA synthetase (GlnRS) is the singular enzyme responsible for translation of glutamine codons. Compound heterozygous mutations in GlnRS cause severe brain disorders by a poorly understood mechanism. Herein, we present crystal structures of the wild type and two pathological mutants of human GlnRS, which reveal, for the first time, the domain organization of the intact enzyme and the structure of the functionally important N-terminal domain (NTD). Pathological mutations mapping in the NTD alter the domain structure, and decrease catalytic activity and stability of GlnRS, whereas missense mutations in the catalytic domain induce misfolding of the enzyme. Our results suggest that the reduced catalytic efficiency and a propensity of GlnRS mutants to misfold trigger the disease development. As a result, this report broadens the spectrum of brain pathologies elicited by protein misfolding and provides a paradigm for understanding the role of mutations in aminoacyl-tRNA synthetases in neurological diseases. Keywords
Ognjenovic, Jana; Wu, Jiang; Matthies, Doreen; ...
Cytosolic glutaminyl-tRNA synthetase (GlnRS) is the singular enzyme responsible for translation of glutamine codons. Compound heterozygous mutations in GlnRS cause severe brain disorders by a poorly understood mechanism. Herein, we present crystal structures of the wild type and two pathological mutants of human GlnRS, which reveal, for the first time, the domain organization of the intact enzyme and the structure of the functionally important N-terminal domain (NTD). Pathological mutations mapping in the NTD alter the domain structure, and decrease catalytic activity and stability of GlnRS, whereas missense mutations in the catalytic domain induce misfolding of the enzyme. Our results suggestmore » that the reduced catalytic efficiency and a propensity of GlnRS mutants to misfold trigger the disease development. As a result, this report broadens the spectrum of brain pathologies elicited by protein misfolding and provides a paradigm for understanding the role of mutations in aminoacyl-tRNA synthetases in neurological diseases. Keywords« less
Caio, Giacomo; Giorgio, Roberto De; Venturi, Alessandro; Giancola, Fiorella; Latorre, Rocco; Boschetti, Elisa; Serra, Mauro; Ruggeri, Eugenio; Volta, Umberto
Aim: To assess anti-neuronal antibodies (NA) prevalence and their correlation with neurological disorders and bowel habits in celiac disease (CD) patients. Background: Neurological manifestations are estimated to occur in about 10% of celiac disease patients and NA to central nervous system (CNS) and enteric nervous system (ENS) are found in a significant proportion of them. Little is known about the clinical and immunological features in CD patients with neurological manifestations. Patients and methods: NA to CNS and ENS were investigated in 106 CD patients and in 60 controls with autoimmune disorders by indirect immunofluorescence on rat / primate cerebellar cortex and intestinal (small and large bowel) sections. Results: IgG NA to CNS (titer 1:50 - 1:400) were positive in 23 celiacs (21%), being more frequently detected in those with neurological disorders that in those without neurological dysfunction (49% vs. 8%, P< 0.0001). Of the 26 celiacs (24%) with IgG NA to ENS, 11 out of 12 with an antibody titer > 1:200 had severe constipation. Only one patient with cerebellar ataxia and intestinal sub-occlusion was positive for NA to CNS and ENS. NA to CNS and ENS were found in 7% and 5% of controls, respectively. Conclusion: In CD the positivity of NA to CNS can be regarded as a marker of neurological manifestations. High titer NA to ENS are associated with severe constipation. The demonstration of NA to CNS and ENS suggests an immune-mediated pathogenesis leading to central neural impairment as well as gut dysfunction (hence constipation), respectively. PMID:25926940
Abe, Jun-Ichi; Sandhu, Uday G; Hoang, Nguyet Minh; Thangam, Manoj; Quintana-Quezada, Raymundo A; Fujiwara, Keigi; Le, Nhat Tu
Sumoylation, a reversible post-transcriptional modification process, of proteins are involved in cellular differentiation, growth, and even motility by regulating various protein functions. Sumoylation is not limited to cytosolic proteins as recent evidence shows that nuclear proteins, those associated with membranes, and mitochondrial proteins are also sumoylated. Moreover, it is now known that sumoylation plays an important role in the process of major human ailments such as malignant, cardiovascular and neurological diseases. In this chapter, we will highlight and discuss how the localization of SUMO protease and SUMO E3 ligase in different compartments within a cell regulates biological processes that depend on sumoylation. First, we will discuss the key role of sumoylation in the nucleus, which leads to the development of endothelial dysfunction and atherosclerosis . We will then discuss how sumoylation of plasma membrane potassium channel proteins are involved in epilepsy and arrhythmia. Mitochondrial proteins are known to be also sumoylated, and the importance of dynamic-related protein 1 (DRP1) sumoylation on mitochondrial function will be discussed. As we will emphasize throughout this review, sumoylation plays crucial roles in different cellular compartments, which is coordinately regulated by the translocation of various SUMO proteases and SUMO E3 ligase. Comprehensive approach will be necessary to understand the molecular mechanism for efficiently moving around various enzymes that regulate sumoylation within cells.
Golden, Erin C; Josephs, Keith A
The phenomenon of musical hallucinations, in which individuals perceive music in the absence of an external auditory stimulus, has been described sparingly in the literature through small case reports and series. Musical hallucinations have been linked to multiple associated conditions, including psychiatric and neurologic disease, brain lesions, drug effect, and hearing impairment. This study aimed to review the demographics of subjects with musical hallucinations and to determine the prevalence of neurological disorders, particularly neurodegenerative disease. Through the Mayo medical record, 393 subjects with musical hallucinations were identified and divided into five categories based on comorbid conditions that have been associated with musical hallucinations: neurological, psychiatric, structural, drug effect and not otherwise classifiable. Variables, including hearing impairment and the presence of visual and other auditory hallucinations, were evaluated independently in all five groups. The mean age at onset of the hallucinations was 56 years, ranging from 18 to 98 years, and 65.4% of the subjects were female. Neurological disease and focal brain lesions were found in 25% and 9% of the total subjects, respectively. Sixty-five subjects were identified with a neurodegenerative disorder, with the Lewy body disorders being the most common. Visual hallucinations were more common in the group with neurological disease compared to the psychiatric, structural, and not otherwise classifiable groups (P < 0.001), whereas auditory hallucinations were more common in the psychiatric group compared to all other groups (P < 0.001). Structural lesions associated with musical hallucinations involved both hemispheres with a preference towards the left, and all but two included the temporal lobe. Hearing impairment was common, particularly in the not otherwise classifiable category where 67.2% had documented hearing impairment, more than in any other group (P < 0.001). Those
Generation of lineage-related, mucosally transmissible subtype C R5 simian-human immunodeficiency viruses capable of AIDS development, induction of neurological disease, and coreceptor switching in rhesus macaques.
Ren, Wuze; Mumbauer, Alexandra; Gettie, Agegnehu; Seaman, Michael S; Russell-Lodrigue, Kasi; Blanchard, James; Westmoreland, Susan; Cheng-Mayer, Cecilia
Most human immunodeficiency virus (HIV) transmissions are initiated with CCR5 (R5)-using viruses across mucosal surfaces, with the majority in regions where HIV type 1 (HIV-1) clade C predominates. Mucosally transmissible, highly replication competent, pathogenic R5 simian-human immunodeficiency viruses (SHIVs) encoding biologically relevant clade C envelopes are therefore needed as challenge viruses in vaccine efficacy studies with nonhuman primates. Here we describe the generation of three lineage-related subtype C SHIVs through four successive rapid transfers in rhesus macaques of SHIVC109F.PB4, a molecular clone expressing the soluble-CD4 (sCD4)-sensitive CCR5-tropic clade C envelope of a recently infected subject in Zambia. The viruses differed in their monkey passage histories and neutralization sensitivities but remained R5 tropic. SHIVC109P3 and SHIVC109P3N were recovered from a passage-3 rapid-progressor animal during chronic infection (24 weeks postinfection [wpi]) and at end-stage disease (34 wpi), respectively, and are classified as tier 1B strains, whereas SHIVC109P4 was recovered from a passage-4 normal-progressor macaque at 22 wpi and is a tier 2 virus, more difficult to neutralize. All three viruses were transmitted efficiently via intrarectal inoculation, reaching peak viral loads of 10(7) to 10(9) RNA copies/ml plasma and establishing viremia at various set points. Notably, one of seven (GC98) and two of six (CL31, FI08) SHIVC109P3- and SHIVC109P3N-infected macaques, respectively, progressed to AIDS, with neuropathologies observed in GC98 and FI08, as well as coreceptor switching in the latter. These findings support the use of these new SHIVC109F.PB4-derived viruses to study the immunopathology of HIV-1 clade C infection and to evaluate envelope-based AIDS vaccines in nonhuman primates.
Bernat, Viachaslau; Disney, Matthew D.
RNAs adopt diverse folded structures that are essential for function and thus play critical roles in cellular biology. A striking example of this is the ribosome, a complex, three-dimensionally folded macromolecular machine that orchestrates protein synthesis. Advances in RNA biochemistry, structural and molecular biology, and bioinformatics have revealed other non-coding RNAs whose functions are dictated by their structure. It is not surprising that aberrantly folded RNA structures contribute to disease. In this review, we provide a brief introduction into RNA structural biology and then describe how RNA structures function in cells and cause or contribute to neurological disease. Finally, we highlight successful applications of rational design principles to provide chemical probes and lead compounds targeting structured RNAs. Based on several examples of well-characterized RNA-driven neurological disorders, we demonstrate how designed small molecules can facilitate study of RNA dysfunction, elucidating previously unknown roles for RNA in disease, and provide lead therapeutics. PMID:26139368
Bougea, Anastasia; Anagnostou, Evangelos; Spandideas, Nikolaos; Triantafyllou, Nikolaos; Kararizou, Evangelia
Vasculitides comprise a heterogeneous group of autoimmune disorders, occurring as primary or secondary to a broad variety of systemic infectious, malignant or connective tissue diseases. The latter occur more often but their pathogenic mechanisms have not been fully established. Frequent and varied central and peripheral nervous system complications occur in vasculitides and connective tissue diseases. In many cases, the neurological disorders have an atypical clinical course or even an early onset, and the healthcare professionals should be aware of them. The purpose of this brief review was to give an update of the main neurological disorders of common vasculitis and connective tissue diseases, aiming at accurate diagnosis and management, with an emphasis on pathophysiologic mechanisms. PMID:26313435
Barnes, G N; Slevin, J T
Glutamate receptor signaling is essential to normal synaptic function in the central nervous system. The major ionotropic glutamate receptors (AMPA, Kainic, and NMDA) have different synaptic functions depending upon cellular and subcellular localization, subunit composition, and second messenger systems linked to the receptors. In this review, we examine major advances in glutamate receptor biology whose physiology plays a central role in neurologic disease such as epilepsy and stroke. A key feature of glutamate receptor activation in neurologic disease is the downstream effects on cell survival, genetic expression of axon guidance cues, synaptic connectivity/formation of networks, and neuronal excitability. Identification of therapeutic pharmacologic targets and development of antagonists specific to the disease process remain central themes in epilepsy and stroke research.
Bernat, Viachaslau; Disney, Matthew D
RNAs adopt diverse folded structures that are essential for function and thus play critical roles in cellular biology. A striking example of this is the ribosome, a complex, three-dimensionally folded macromolecular machine that orchestrates protein synthesis. Advances in RNA biochemistry, structural and molecular biology, and bioinformatics have revealed other non-coding RNAs whose functions are dictated by their structure. It is not surprising that aberrantly folded RNA structures contribute to disease. In this Review, we provide a brief introduction into RNA structural biology and then describe how RNA structures function in cells and cause or contribute to neurological disease. Finally, we highlight successful applications of rational design principles to provide chemical probes and lead compounds targeting structured RNAs. Based on several examples of well-characterized RNA-driven neurological disorders, we demonstrate how designed small molecules can facilitate the study of RNA dysfunction, elucidating previously unknown roles for RNA in disease, and provide lead therapeutics.
... spinal cord, and nerves make up the nervous system. Together they control all the workings of the ... goes wrong with a part of your nervous system, you can have trouble moving, speaking, swallowing, breathing, ...
Chang, Philip K-Y; Verbich, David; McKinney, R Anne
Most excitatory transmission in the brain is mediated by the AMPA receptor subtype of the ionotropic glutamate receptors. In many neurological diseases, synapse structure and AMPA receptor function are altered, thus making AMPA receptors potential therapeutic targets for clinical intervention. The work summarized in this review suggests a link between AMPA receptor function and debilitating neuropathologies, and discusses the current state of therapies targeting AMPA receptors in four diseases. In amyotrophic lateral sclerosis, AMPA receptors allow cytotoxic levels of calcium into neurons, leading to motor neuron death. Likewise, in some epilepsies, overactivation of AMPA receptors leads to neuron damage. The same is true for ischemia, where oxygen deprivation leads to excitotoxicity. Conversely, Alzheimer's disease is characterized by decreased AMPA activation and synapse loss. Unfortunately, many clinical studies have had limited success by directly targeting AMPA receptors in these diseases. We also discuss how the use of AMPA receptor modulators, commonly known as ampakines, in neurological diseases initially seemed promising in animal studies, but mostly ineffective in clinical trials. We propose that indirectly affecting AMPA receptors, such as by modulating transmembrane AMPA receptor regulatory proteins or, more generally, by regulating glutamatergic transmission, may provide new therapeutic potential for neurological disorders.
Perry, David C.; Sturm, Virginia E.; Peterson, Matthew J.; Pieper, Carl F.; Bullock, Thomas; Boeve, Bradley F.; Miller, Bruce L.; Guskiewicz, Kevin M.; Berger, Mitchel S.; Kramer, Joel H.; Welsh-Bohmer, Kathleen A.
Object Mild traumatic brain injury (TBI) has been proposed as a risk factor for development of Alzheimer’s disease, Parkinson’s disease, depression, and other illnesses. This study’s objective was to determine the association of prior mild TBI with subsequent diagnosis (i.e., at least one year post-injury) of neurologic or psychiatric disease. Methods All studies from 1995–2012 reporting TBI as a risk factor for diagnoses of interest were identified by searching PubMed, study references, and review articles. Reviewers abstracted the data and assessed study design and characteristics. Results 57 studies met inclusion criteria. A random effects meta-analysis revealed a significant association of prior TBI with subsequent neurologic and psychiatric diagnosis. The pooled odds ratio (OR) for TBI on development of any illness was 1.67 (95% CI 1.44–1.93, p<.001). Prior TBI was independently associated with both neurologic [OR 1.55 (95% CI 1.31–1.83, p<.001)] and psychiatric [OR 2.00 (95% CI 1.50–2.66, p<.001)] outcomes. Analyses of individual diagnoses found higher odds of Alzheimer’s disease, Parkinson’s disease, mild cognitive impairment, depression, mixed affective disorders, and bipolar disorder in individuals with previous TBI compared to those without TBI. This association was present when examining only studies of mild TBI and when considering the influence of study design and characteristics. Analysis of a subset of studies found no evidence that multiple TBIs were associated with higher odds of disease than a single TBI. Conclusions History of TBI, including mild TBI, is associated with the development of neurologic and psychiatric illness. This indicates that either TBI is a risk factor for heterogeneous pathologic processes or that TBI may contribute to a common pathologic mechanism. PMID:26315003
Noubiap, Jean Jacques; Mengnjo, Michel K; Nicastro, Nicolas; Kamtchum-Tatuene, Joseph
To summarize prevalence data on the neurologic complications of sickle cell disease (SCD) in Africa. We searched EMBASE, PubMed, and African Index Medicus to identify all relevant articles published from inception to May 31, 2016. Each study was reviewed for methodologic quality. A random-effects model was used to estimate the prevalence of neurologic complications of SCD across studies. Thirty-one studies were included. Methodologic quality was high or moderate in 90% of studies. Stroke, conditional and abnormal cerebral blood flow, seizures, and headache were the complications most frequently reported, with overall prevalence rates of 4.2%, 10.6%, 6.1%, 4.4%, and 18.9%, respectively. Some complications, like silent brain infarcts, peripheral neuropathies, neurocognitive deficits, or moyamoya disease, have been rarely or not studied at all in the African setting. Incidence data were scarce and of poor quality. The burden of neurologic complications of SCD is important in Africa and most likely underestimated. A better evaluation of this burden requires larger prospective studies using standard up-to-date screening methods. Accessibility to diagnostic tools such as neuroimaging, transcranial Doppler, EEG, and neuropsychological evaluation, as well as to preventive and therapeutic interventions and trained health care providers, should be improved in routine clinical practice. Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
Ignatova, Nina; Sindic, Christian J M; Goffinet, André M
Reelin is a large extracellular glycoprotein that is defective in reeler mutant mice and plays a well-established role during brain development in human as well as rodents. In the adult brain, Reelin is expressed in a subset of GABAergic interneurons. Its role in disease states is not clearly defined, although it is implicated in autism and psychoses such as schizophrenia. In this report, we show that Reelin immunoreactive proteins can be detected in the human cerebrospinal fluid (CSF) with monoclonal antibodies directed against the N- and C-terminal regions of the protein. In CSF, Reelin is present as different products due to processing at two main sites; preservation at -20 degrees C increases processing further. CSF Reelin originates from the brain tissue and not from plasma. The protein was detected in comparable concentrations in children and adults, and the signal varied largely from subject to subject with no obvious correlation with age or neurological disease state.
Assogna, Francesca; Fagioli, Sabrina; Cravello, Luca; Meco, Giuseppe; Pierantozzi, Mariangela; Stefani, Alessandro; Imperiale, Francesca; Caltagirone, Carlo; Pontieri, Francesco E; Spalletta, Gianfranco
Background Patients with neurological and non-neurological medical illnesses very often complain of depressive symptoms that are associated with cognitive and functional impairments. We compared the profile of depressive symptoms in Parkinson’s disease (PD) patients with that of control subjects (CS) suffering from non-neurological medical illnesses. Methods One-hundred PD patients and 100 CS were submitted to a structured clinical interview for identification of major depressive disorder (MDD) and minor depressive disorder (MIND), according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision (DSM-IV-TR), criteria. The Hamilton Depression Rating Scale (HDRS) and the Beck Depression Inventory (BDI) were also administered to measure depression severity. Results When considering the whole groups, there were no differences in depressive symptom frequency between PD and CS apart from worthlessness/guilt, and changes in appetite reduced rates in PD. Further, total scores and psychic and somatic subscores of HDRS and BDI did not differ between PD and CS. After we separated PD and CS in those with MDD, MIND, and no depression (NODEP), comparing total scores and psychic/somatic subscores of HDRS and BDI, we found increased total depression severity in NODEP PD and reduced severity of the psychic symptoms of depression in MDD PD, with no differences in MIND. However, the severity of individual symptom frequency of depression was not different between PD and CS in MDD, MIND, and NODEP groups. Conclusion Although MDD and MIND phenomenology in PD may be very similar to that of CS with non-neurological medical illnesses, neurological symptoms of PD may worsen (or confound) depression severity in patients with no formal/structured DSM-IV-TR, diagnosis of depressive mood disorders. Thus, a thorough assessment of depression in PD should take into consideration the different impacts of neurological manifestations on MDD, MIND, and NODEP. PMID
Sochat, Vanessa; David, Maude; Wall, Dennis P
The task of mapping neurological disorders in the human brain must be informed by multiple measurements of an individual’s phenotype - neuroimaging, genomics, and behavior. We developed a novel meta-analytical approach to integrate disparate resources and generated transcriptional maps of neurological disorders in the human brain yielding a purely computational procedure to pinpoint the brain location of transcribed genes likely to be involved in either onset or maintenance of the neurological condition. PMID:26958307
Birbeck, G L
The awesome burden of treatable yet untreated neurologic disease in the developing world presents a humanitarian crisis to those of us with neurologic expertise from more privileged situations. Although increased economic resources are critically needed, a shortage of personnel to care for these patients is as great a problem. It is neither feasible nor desirable to propose training neurologists to work in these regions. However, COs could be selected to receive additional training and return to their home regions to serve as resources for referrals and as community educators. Such a training program would not require massive financial commitments. A handful of dedicated neurologists could conceivably accomplish this in 6- to 8-week training sessions. Ideally, educational materials, such as posters and pamphlets in both English and the native language of the various regions, would be provided at no cost. Existing textbooks in neurology are written for physicians and often focus on diagnostic evaluations and therapies far beyond the services available in developing countries. A text for practical use by COs and community health workers that discusses the application of available medicines and therapies for common neurologic problems would be invaluable. Similar books exist that address general medical and obstetrical problems (for example, Where There Is No Doctor: A Village Health Care Handbook). Where There Is No Neurologist could be developed as a primary teaching tool and a valuable reference for COs with neurologic expertise. Neuroscience researchers, clinical neurologists, and neurology residents from industrialized countries have much to offer and to gain by working in the Third World. Research to monitor the incidence and resource utilization of emerging problems such as stroke is needed to influence public policy. The economic burden and lost productivity caused by neurologic disease in this part of the world has not been appreciated or explored. Disease
SYBR Green-based quantitation of human T-lymphotropic virus type 1 proviral load in Peruvian patients with neurological disease and asymptomatic carriers: influence of clinical status, sex, and familial relatedness.
Adaui, Vanessa; Verdonck, Kristien; Best, Iván; González, Elsa; Tipismana, Martín; Arévalo, Jorge; Vanham, Guido; Campos, Miguel; Zimic, Mirko; Gotuzzo, Eduardo
To evaluate the human T-lymphotropic virus type 1 (HTLV-1) proviral DNA load in patients with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and asymptomatic HTLV-1 carriers, a SYBR Green-based real-time quantitative polymerase chain reaction (qPCR) assay was developed. HTLV-1 proviral DNA in peripheral blood mononuclear cells (PBMCs) was quantified using primers targeting the pX region and the HTLV-1 copy number normalized to the amount of ERV-3 (Endogenous Retrovirus 3) cellular DNA. Thirty-three asymptomatic HTLV-1 carriers (ACs) and 39 patients with HAM/TSP were enrolled. Some participants were relatives of HAM/TSP cases (16 ACs and 7 patients with HAM/TSP). On multiple linear regression analysis, the authors found a significant association between clinical status and HTLV-1 proviral load (P < .01), but only among women. ACs showed a median proviral load of 561 copies per 104 PBMCs (interquartile range: 251-1623). In HAM/TSP patients, the median proviral load was 1783 (1385-2914). ACs related to HAM/TSP patients presented a relatively high proviral load (median 1152); however, the association between relatedness to a HAM/TSP patient and proviral load was not significant (P = .1). In HAM/TSP patients, no association was found between proviral load and disease duration, progression or severity. The fact that the effect of HAM/TSP upon the HTLV-1 proviral load differed between sexes and the finding of a high proviral load among asymptomatic relatives of HAM/TSP patients suggest that not yet identified genetic or environmental factors influence the pathogenesis of HTLV-1 infection.
Based upon a thorough review of published clinical observations regarding the inhibitory system, I hypothesize that this system may play a key role in the pathogenesis of a variety of neuromuscular and neurological diseases. Specifically, excitatory overstimulation, which is commonly reported in neuromuscular and neurological diseases, may be a homeostatic response to inhibitory overstimulation. Involvement of the inhibitory system in disease pathogenesis is highly relevant, given that most approaches currently being developed for treating neuromuscular and neurological diseases focus on reducing excitatory activity rather than reducing inhibitory activity. PMID:27547379
Best, J D; Alderton, Wendy K
As the population ages, there is a growing need for effective therapies for the treatment of neurological diseases. A limited number of therapeutics are currently available to improve cognitive function and research is limited by the need for in vivo models. Zebrafish have recently become a focus of neurobehavioral studies since larvae display neuropathological and behavioral phenotypes that are quantifiable and relate to those seen in man. Due to the small size of Zebrafish larvae, assays can be undertaken in 96 well plates and as the larvae can live in as little as 200 μl of fluid, only a few milligrams of compound are needed for screening. Thus in vivo analysis of the effects of compounds can be undertaken at much earlier stages in the drug discovery process. This review will look at the utility of the zebrafish in the study of neurological diseases and its role in improving the throughput of candidate compounds in in vivo screens. PMID:18830398
Mathew, Stephen K; Pandian, Jeyaraj D
Many people over the years have studied the Bible from a medical point of view offering diagnoses for the symptoms and signs that appear to have afflicted numerous individuals in the Bible. We review the biblical characters in the Old Testament and offer newer insights to their neurological diseases. We first look at the battle between Goliath and David. Interestingly, Goliath probably suffered from acromegaly. We propose autism as a diagnosis for Samson which would precede the first known case of autism by centuries. Isaac was a diabetic, and he probably had autonomic neuropathy. Few verses from the books of I Samuel, Psalms, and Ezekiel reveal symptoms suggestive of stroke. Jacob suffered from sciatica, and the child of the Shunnamite woman in II Kings had a subarachnoid hemorrhage. These instances among others found in the Old Testament of the Bible offer newer insights on the history of current neurological diseases.
Campbell, I L; Abraham, C R; Masliah, E; Kemper, P; Inglis, J D; Oldstone, M B; Mucke, L
Cytokines are thought to be important mediators in physiologic and pathophysiologic processes affecting the central nervous system (CNS). To explore this hypothesis, transgenic mice were generated in which the cytokine interleukin 6 (IL-6), under the regulatory control of the glial fibrillary acidic protein gene promoter, was overexpressed in the CNS. A number of transgenic founder mice and their offspring exhibited a neurologic syndrome the severity of which correlated with the levels of cerebral IL-6 expression. Transgenic mice with high levels of IL-6 expression developed severe neurologic disease characterized by runting, tremor, ataxia, and seizure. Neuropathologic manifestations included neuro-degeneration, astrocytosis, angiogenesis, and induction of acute-phase-protein production. These findings indicate that cytokines such as IL-6 can have a direct pathogenic role in inflammatory, infectious, and neurodegenerative CNS diseases. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 PMID:7694279
Mathew, Stephen K.; Pandian, Jeyaraj D.
Many people over the years have studied the Bible from a medical point of view offering diagnoses for the symptoms and signs that appear to have afflicted numerous individuals in the Bible. We review the biblical characters in the Old Testament and offer newer insights to their neurological diseases. We first look at the battle between Goliath and David. Interestingly, Goliath probably suffered from acromegaly. We propose autism as a diagnosis for Samson which would precede the first known case of autism by centuries. Isaac was a diabetic, and he probably had autonomic neuropathy. Few verses from the books of I Samuel, Psalms, and Ezekiel reveal symptoms suggestive of stroke. Jacob suffered from sciatica, and the child of the Shunnamite woman in II Kings had a subarachnoid hemorrhage. These instances among others found in the Old Testament of the Bible offer newer insights on the history of current neurological diseases. PMID:21085524
Abbott, Jamie A.; Francklyn, Christopher S.; Robey-Bond, Susan M.
Pathological mutations in tRNA genes and tRNA processing enzymes are numerous and result in very complicated clinical phenotypes. Mitochondrial tRNA (mt-tRNA) genes are “hotspots” for pathological mutations and over 200 mt-tRNA mutations have been linked to various disease states. Often these mutations prevent tRNA aminoacylation. Disrupting this primary function affects protein synthesis and the expression, folding, and function of oxidative phosphorylation enzymes. Mitochondrial tRNA mutations manifest in a wide panoply of diseases related to cellular energetics, including COX deficiency (cytochrome C oxidase), mitochondrial myopathy, MERRF (Myoclonic Epilepsy with Ragged Red Fibers), and MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes). Diseases caused by mt-tRNA mutations can also affect very specific tissue types, as in the case of neurosensory non-syndromic hearing loss and pigmentary retinopathy, diabetes mellitus, and hypertrophic cardiomyopathy. Importantly, mitochondrial heteroplasmy plays a role in disease severity and age of onset as well. Not surprisingly, mutations in enzymes that modify cytoplasmic and mitochondrial tRNAs are also linked to a diverse range of clinical phenotypes. In addition to compromised aminoacylation of the tRNAs, mutated modifying enzymes can also impact tRNA expression and abundance, tRNA modifications, tRNA folding, and even tRNA maturation (e.g., splicing). Some of these pathological mutations in tRNAs and processing enzymes are likely to affect non-canonical tRNA functions, and contribute to the diseases without significantly impacting on translation. This chapter will review recent literature on the relation of mitochondrial and cytoplasmic tRNA, and enzymes that process tRNAs, to human disease. We explore the mechanisms involved in the clinical presentation of these various diseases with an emphasis on neurological disease. PMID:24917879
... neurological disorders such as Behcet's disease. The National Human Genome Research Institute, another Institute of the National ... neurological disorders such as Behcet's disease. The National Human Genome Research Institute, another Institute of the National ...
The onset of human degenerative diseases in humans, including type 2 diabetes, cardiovascular disease, neurological disorders, neurodevelopmental disease and neurodegenerative disease has been shown to be related to exposures to persistent organic pollutants, including polychlorinated biphenyls, chlorinated pesticides, polybrominated diphenyl ethers and others, as well as to polynuclear aromatic hydrocarbons, phthalates, bisphenol-A and other aromatic lipophilic species. The onset of these diseases has also been related to exposures to transition metal ions. A physiochemical mechanism for the onset of degenerative environmental disease dependent upon exposure to a combination of lipophilic aromatic hydrocarbons and transition metal ions is proposed here. The findings reported here also, for the first time, explain why aromatic hydrocarbons exhibit greater toxicity than aliphatic hydrocarbons of equal carbon numbers. PMID:27486355
papers that focus on stem and progenitor cells from the central nervous system (both brain and retina ) of nonrodent mammals, or cells modified to resemble...FEB 2012 2. REPORT TYPE N/A 3. DATES COVERED - 4. TITLE AND SUBTITLE Stem cells in large animal models of retinal and neurological disease...Prescribed by ANSI Std Z39-18 Hindawi Publishing Corporation Stem Cells International Volume 2012, Article ID 460504, 2 pages doi:10.1155/2012/460504
Fink, Ericka L; Kochanek, Patrick M; Tasker, Robert C; Beca, John; Bell, Michael J; Clark, Robert S B; Hutchison, Jamie; Vavilala, Monica S; Fabio, Anthony; Angus, Derek C; Watson, R Scott
The international scope of critical neurologic insults in children is unknown. Our objective was to assess the prevalence and outcomes of children admitted to PICUs with acute neurologic insults. Prospective study. Multicenter (n = 107 PICUs) and multinational (23 countries, 79% in North America and Europe). Children 7 days to 17 years old admitted to the ICU with new traumatic brain injury, stroke, cardiac arrest, CNS infection or inflammation, status epilepticus, spinal cord injury, hydrocephalus, or brain mass. None. We evaluated the prevalence and outcomes of children with predetermined acute neurologic insults. Child and center characteristics were recorded. Unfavorable outcome was defined as change in pre-post insult Pediatric Cerebral Performance Category score greater than or equal to 2 or death at hospital discharge or 3 months, whichever came first. Screening data yielded overall prevalence of 16.2%. Of 924 children with acute neurologic insults, cardiac arrest (23%) and traumatic brain injury (19%) were the most common. All-cause mortality at hospital discharge was 12%. Cardiac arrest subjects had highest mortality (24%), and traumatic brain injury subjects had the most unfavorable outcomes (49%). The most common neurologic insult was infection/inflammation in South America, Asia, and the single African site but cardiac arrest in the remaining regions. Neurologic insults are a significant pediatric international health issue. They are frequent and contribute substantial morbidity and mortality. These data suggest a need for an increased focus on acute critical neurologic diseases in infants and children including additional research, enhanced availability of clinical resources, and the development of new therapies.
Salmen, A; Gold, R; Chan, A
The therapeutic armamentarium for autoimmune diseases of the central nervous system, specifically multiple sclerosis and neuromyelitis optica, is steadily increasing, with a large spectrum of immunomodulatory and immunosuppressive agents targeting different mechanisms of the immune system. However, increasingly efficacious treatment options also entail higher potential for severe adverse drug reactions. Especially in cases failing first-line treatment, thorough evaluation of the risk–benefit profile of treatment alternatives is necessary. This argues for the need of algorithms to identify patients more likely to benefit from a specific treatment. Moreover, paradigms to stratify the risk for severe adverse drug reactions need to be established. In addition to clinical/paraclinical measures, biomarkers may aid in individualized risk–benefit assessment. A recent example is the routine testing for anti-John Cunningham virus antibodies in natalizumab-treated multiple sclerosis patients to assess the risk for the development of progressive multi-focal leucoencephalopathy. Refined algorithms for individualized risk assessment may also facilitate early initiation of induction treatment schemes in patient groups with high disease activity rather than classical escalation concepts. In this review, we will discuss approaches for individiualized risk–benefit assessment both for newly introduced agents as well as medications with established side-effect profiles. In addition to clinical parameters, we will also focus on biomarkers that may assist in patient selection. Other Articles published in this series Paraneoplastic neurological syndromes. Clinical and Experimental Immunology 2014, 175: 336–48. Disease-modifying therapy in multiple sclerosis and chronic inflammatory demyelinating polyradiculoneuropathy: common and divergent current and future strategies. Clinical and Experimental Immunology 2014, 175: 359–72. Monoclonal antibodies in treatment of multiple
Byeon, Jung Hye; Shin, Eunsim; Kim, Gun-Ha; Lee, Kyungok; Hong, Young Sook; Lee, Joo Won; Eun, Baik-Lin
Array comparative genomic hybridization (array-CGH) is a technique used to analyze quantitative increase or decrease of chromosomes by competitive DNA hybridization of patients and controls. This study aimed to evaluate the benefits and yield of array-CGH in comparison with conventional karyotyping in pediatric neurology patients. We included 87 patients from the pediatric neurology clinic with at least one of the following features: developmental delay, mental retardation, dysmorphic face, or epilepsy. DNA extracted from patients and controls was hybridized on the Roche NimbleGen 135K oligonucleotide array and compared with G-band karyotyping. The results were analyzed with findings reported in recent publications and internet databases. Chromosome imbalances, including 9 cases detected also by G-band karyotyping, were found in 28 patients (32.2%), and at least 19 of them seemed to be causally related to the abnormal phenotypes. Regarding each clinical symptom, 26.2% of 42 developmental delay patients, 44.4% of 18 mental retardation patients, 42.9% of 28 dysmorphic face patients, and 34.6% of 26 epilepsy patients showed abnormal array results. Although there were relatively small number of tests in patients with pediatric neurologic disease, this study demonstrated that array-CGH is a very useful tool for clinical diagnosis of unknown genome abnormalities performed in pediatric neurology clinics.
Byeon, Jung Hye; Shin, Eunsim; Kim, Gun-Ha; Lee, Kyungok; Hong, Young Sook; Lee, Joo Won
Purpose Array comparative genomic hybridization (array-CGH) is a technique used to analyze quantitative increase or decrease of chromosomes by competitive DNA hybridization of patients and controls. This study aimed to evaluate the benefits and yield of array-CGH in comparison with conventional karyotyping in pediatric neurology patients. Materials and Methods We included 87 patients from the pediatric neurology clinic with at least one of the following features: developmental delay, mental retardation, dysmorphic face, or epilepsy. DNA extracted from patients and controls was hybridized on the Roche NimbleGen 135K oligonucleotide array and compared with G-band karyotyping. The results were analyzed with findings reported in recent publications and internet databases. Results Chromosome imbalances, including 9 cases detected also by G-band karyotyping, were found in 28 patients (32.2%), and at least 19 of them seemed to be causally related to the abnormal phenotypes. Regarding each clinical symptom, 26.2% of 42 developmental delay patients, 44.4% of 18 mental retardation patients, 42.9% of 28 dysmorphic face patients, and 34.6% of 26 epilepsy patients showed abnormal array results. Conclusion Although there were relatively small number of tests in patients with pediatric neurologic disease, this study demonstrated that array-CGH is a very useful tool for clinical diagnosis of unknown genome abnormalities performed in pediatric neurology clinics. PMID:24339284
Objective Neurometabolic disorders are an important group of diseases that mostly are presented in newborns and infants. Neurological manifestations are the prominent signs and symptoms in this group of diseases. Seizures are a common sign and are often refractory to antiepileptic drugs in untreated neurometabolic patients. The onset of symptoms for neurometabolic disorders appears after an interval of normal or near normal growth and development.Additionally, affected children may fare well until a catabolic crisis occurs. Patients with neurometabolic disorders during metabolic decompensation have severe clinical presentation, which include poor feeding, vomiting, lethargy, seizures, and loss of consciousness. This symptom is often fatal but severe neurological insult and regression in neurodevelopmental milestones can result as a prominent sign in patients who survived. Acute symptoms should be immediately treated regardless of the cause. A number of patients with neurometabolic disorders respond favorably and, in some instances, dramatically respond to treatment. Early detection and early intervention is invaluable in some patients to prevent catabolism and normal or near normal neurodevelopmental milestones. This paper discusses neurometabolic disorders, approaches to this group of diseases (from the view of a pediatric neurologist), clinical and neurological manifestations, neuroimaging and electroencephalography findings, early detection, and early treatment. PMID:25767534
Román, G C
Political decisions may cause disease. During 1992 and 1993, an epidemic of neuropathy in Cuba--largely overlooked by U.S. physicians--affected more than 50,000 persons and caused optic neuropathy, deafness, myelopathy, and sensory neuropathy. Patients with the neurologic disease responded to B group vitamins, and oral vitamin supplementation of the population curbed the epidemic. Dietary restrictions and excessive carbohydrate intake were the immediated cause of the epidemic; however, the primary cause might have been political. Political changes in eastern Europe had major repercussions on Cuba's economy and food supply. In turn, these changes compounded the effects of internal political decisions in the island, leading toward isolationism and economic dependence on the former Soviet Union. Also, for more than 30 years, the United States has maintained an economic embargo against Cuba. In 1992, the U.S. embargo was tightened by the Torricelli amendment (or the Cuba Democracy Act), which prohibited third-country subsidiaries of U.S. companies from trading with Cuba and prevented food and medicines from reaching the island; this amendment produced a virtual economic blockade. Penuries resulting from all these political events resulted in the largest epidemic of neurologic disease in this century. Physicians may need to use their influence to modify political decisions when these decisions result in adverse health consequences. The American Academy of Neurology has issued a plea to encourage physicians and other health personnel to support efforts leading to lifting of the U.S. embargo against Cuba for humanitarian reasons.
Maurer, E; Botteron, C; Ehrensperger, F; Fatzer, R; Jaggy, A; Kolly, C; Meylan, M; Zurbriggen, A; Doherr, M G
Small ruminants infected with scrapie show a large range of often unspecific clinical symptoms. The most-often described signs, locomotion, sensibility and behavioural disorders and emaciation, rarely occur together, and cases have been described in which only one of those signs was detectable.Thus, formulating a well-circumscribed definition of a clinical suspect case is difficult. Most animals with CNS-effecting diseases such as listeriosis, polioencephalomacia, cerebrospinal nematidiasis and enterotoxemia will, in a thorough neurological examination, show at least some scrapie-like symptoms. Among the 22 neurological field cases examined in this study, a goat with cerebral gliomatosis and hair lice showed the closest similarity to clinical scrapie. The unilateral deficiency of the cerebral nerves has potential as an clinical exclusion criterion for scrapie. However, the laboratory confirmation--or exclusion--of scrapie remains important. It thus needs to be realized that a consistent and thorough examination of neurologically diseased small ruminants (including fallen stock) is the backbone of a good surveillance system for these diseases. This should be a motivation for submitting adult sheep and goats for neuropathological examination.
Klein, Tilmann A.; Ullsperger, Markus; Danielmeier, Claudia
Becoming aware of errors that one has committed might be crucial for strategic behavioral and neuronal adjustments to avoid similar errors in the future. This review addresses conscious error perception (“error awareness”) in healthy subjects as well as the relationship between error awareness and neurological and psychiatric diseases. We first discuss the main findings on error awareness in healthy subjects. A brain region, that appears consistently involved in error awareness processes, is the insula, which also provides a link to the clinical conditions reviewed here. Then we focus on a neurological condition whose core element is an impaired awareness for neurological consequences of a disease: anosognosia for hemiplegia (AHP). The insular cortex has been implicated in both error awareness and AHP, with anterior insular regions being involved in conscious error processing and more posterior areas being related to AHP. In addition to cytoarchitectonic and connectivity data, this reflects a functional and structural gradient within the insula from anterior to posterior. Furthermore, studies dealing with error awareness and lack of insight in a number of psychiatric diseases are reported. Especially in schizophrenia, attention-deficit hyperactivity disorder, (ADHD) and autism spectrum disorders (ASD) the performance monitoring system seems impaired, thus conscious error perception might be altered. PMID:23382714
Barthélemy, Ernest Joseph; Benjamin, Ernest; Edouard Jean-Pierre, Marie Yolaine; Poitevien, Geneviève; Ernst, Silvia; Osborn, Irene; Germano, Isabelle M
To perform the first prospective survey of neurologic and neurosurgical emergency department (ED) admissions in Haiti. Data of all ED admissions at 3 Haitian hospitals for 90 consecutive days per site were collected prospectively. Patients who were given a diagnosis of a neurologic or neurosurgical disorder by the ED physician were entered in a deidentified database including demographics, presenting symptoms, brain imaging (when available), requests for neurosurgical consultation, and outcome. Of the 7628 patients admitted to the ED during this study, 1243 patients had a neurologic disorder, yielding an ED-based neurologic disease prevalence of 16%. The 3 most common neurologic diseases were cerebrovascular disease (31%), neurotrauma (28%), and altered mental status (12%). Neurosurgical pathologies represented 19% of all neurologic admissions with a combined ED-based disease prevalence of 3%. Mortality rate was 9%. The most common neurosurgical disease was neurotrauma (87%), caused by motor vehicle accidents (59%), falls (20%), and assault (17%). Neurosurgical procedures were performed in 14 of 208 patients with a mortality rate of 33%. This prospective survey represents the first study of neurosurgical or neurologic disease patterns in Haiti. The results suggest specific disease priorities for this population that can guide efforts to improve Haitian health care and conduct more comprehensive epidemiologic studies in Haiti. Copyright © 2014 Elsevier Inc. All rights reserved.
Xu, Xiaohua; Warrington, Arthur E; Bieber, Allan J; Rodriguez, Moses
Repair of the central nervous system (CNS) constitutes an integral part of treating neurological disease and plays a crucial role in restoring CNS architecture and function. Distinct strategies have been developed to reconstruct the damaged neural tissue, with many tested preclinically in animal models. We review cell replacement-based repair strategies. By taking spinal cord injury, cerebral ischaemia and degenerative CNS disorders as examples for CNS repair, we discuss progress and potential problems in utilizing embryonic stem cells and adult neural/non-neural stem cells to repair cell loss in the CNS. Nevertheless, CNS repair is not simply a matter of cell transplantation. The major challenge is to induce regenerating neural cells to integrate into the neural network and compensate for damaged neural function. The neural cells confront an environment very different from that of the developmental stage in which these cells differentiate to form interwoven networks. During the repair process, one of the challenges is neurodegeneration, which can develop from interrupted innervations to/from the targets, chronic inflammation, ischaemia, aging or idiopathic neural toxicity. Neurodegeneration, which occurs on the basis of a characteristic vascular and neural web, usually presents as a chronically progressive process with unknown aetiology. Currently, there is no effective treatment to stop or slow down neurodegeneration. Pathological changes from patients with Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis indicate a broken homeostasis in the CNS. We discuss how the blood-brain barrier and neural networks are formed to maintain CNS homeostasis and their contribution to neurodegeneration in diseased conditions. Another challenge is that some inhibitors produced by CNS injury do not facilitate the regenerating neural cells to incorporate into a pre-existing network. We review glial responses to CNS injury. Of note, the reactive astrocytes
Venneti, Sriram; Wang, Guoji; Nguyen, Jason; Wiley, Clayton A.
Chronic microglial activation is an important component of many neurological disorders, and imaging activated microglia in vivo will enable the detection and improved treatment of neuroinflammation. 1-(2-Chlorphenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline-carbox-amide (PK11195), a peripheral benzodiazepine receptor ligand, has been used to image neuroinflammation, but the extent to which PK11195 binding distinguishes activated microglia and reactive astrocytes is unclear. Moreover, PK11195 may lack sufficient sensitivity for detecting mild neuroinflammation. We hypothesized that N-(2,5-dimethoxybenzyl)-N-(4-fluoro-2-phenoxyphenyl) acetamide (DAA1106), a new ligand that binds specifically to peripheral benzodiazepine receptor, binds to activated microglia in human neurological diseases with higher affinity than does PK11195. We therefore compared the pharmacological binding properties of [3H](R)-PK11195 and [3H]DAA1106 in postmortem tissues from patients with cerebral infarcts, amyotrophic lateral sclerosis, Alzheimer disease, frontotemporal dementia, and multiple sclerosis (n = 10 each). In all diseases, [3H]DAA1106 showed a higher binding affinity as reflected by lower dissociation constant (KD) values than that of [3H](R)-PK11195. Moreover, specific binding of both ligands correlated with the presence of activated microglia identified by immunohistochemistry in situ. We conclude that 1) ligands that bind peripheral benzodiazepine receptor mainly label activated microglia in human neurological disorders and that 2) DAA1106 may possess binding characteristics superior to those of PK11195, which may be beneficial for in vivo positron emission tomography imaging. PMID:18800007
Malinovsky, Jean-Marc; Hamidi, Armine; Lelarge, Chantal; Boulay-Malinovsky, Catherine
Anaesthesia of patients with neurological disease is feasible but each specific disease requires specific adjustments accordingly. A preoperative evaluation of neurological status is required and patients should be informed of the potential harms in the perioperative period. Regional anaesthesia is commonly considered as contraindicated in these patients although it is commonly not. General anaesthesia has not been demonstrated to worsen cognitive dysfunction in patients suffering from Alzheimer's disease but these dysfunctions may disturb postoperative rehabilitation. Regional anaesthesia has no special benefit in these patients. In patients with Parkinson's disease, inability to use the oral route in the postoperative period may impair the administration of the treatment. Multiple sclerosis is not a contraindication of epidural anaesthesia especially in obstetrics, since there is no evidence that it may trigger relapse of the disease especially in the postpartum period. Regional anaesthesia is doable in patients with a dysimmune demyelinated lesions out of the regeneration phase of the disease. In peripheral hereditary or acquired neuropathies regional anaesthesia is also feasible. Epilepsy, spina bifida and traumatic pathologies of the spine are not contraindications to regional anaesthesia but the latter require technical adjustment. Copyright © 2014 Elsevier Masson SAS. All rights reserved.
Vance, David E; Dodson, Joan E; Watkins, Jason; Kennedy, Bridgett H; Keltner, Norman L
To successfully negotiate and interact with one's environment, optimal cognitive functioning is needed. Unfortunately, many neurological and psychiatric diseases impede certain cognitive abilities such as executive functioning or speed of processing; this can produce a poor fit between the patient and the cognitive demands of his or her environment. Such nondementia diseases include bipolar disorder, schizophrenia, post-traumatic stress syndrome, depression, and anxiety disorders, just to name a few. Each of these diseases negatively affects particular areas of the brain, resulting in distinct cognitive profiles (e.g., deficits in executive functioning but normal speed of processing as seen in schizophrenia). In fact, it is from these cognitive deficits in which such behavioral and emotional symptoms may manifest (e.g., delusions, paranoia). This article highlights the distinct cognitive profiles of such common neurological and psychiatric diseases. An understanding of such disease-specific cognitive profiles can assist nurses in providing care to patients by knowing what cognitive deficits are associated with each disease and how these cognitive deficits impact everyday functioning and social interactions. Implications for nursing practice and research are posited within the framework of cognitive reserve and neuroplasticity.
Jagannathan, Jay; Li, Jie; Szerlip, Nicholas; Vortmeyer, Alexander O.; Lonser, Russell R.; Oldfield, Edward H.; Zhuang, Zhengping
OBJECTIVE Proteins are the primary components of cells and are vital constituents of any living organism. The proteins that make up an organism (proteome) are constantly changing and are intricately linked to neurological disease processes. The study of proteins, or proteomics, is a relatively new but rapidly expanding field with increasing relevance to neurosurgery. METHODS We present a review of the state-of-the-art proteomic technology and its applications in central nervous system diseases. RESULTS The technique of “selective microdissection” allows an investigator to selectively isolate and study a pathological tissue of interest. By evaluating protein expression in a variety of central nervous system disorders, it is clear that proteins are differentially expressed across disease states, and protein expression changes markedly during disease progression. CONCLUSION Understanding the patterns of protein expression in the nervous system has critical implications for the diagnosis and treatment of neurological disease. As gatekeepers in the diagnosis, evaluation, and treatment of central nervous system diseases, it is important for neurosurgeons to develop an appreciation for proteomic techniques and their utility. PMID:19145153
Tiedeken, Jessica A; Ramsdell, John S
The harmful alga Pseudo-nitzschia sp. is the cause of human amnesic shellfish poisoning and the stranding of thousands of sea lions with seizures as a hallmark symptom. A human case study and epidemiological report of hundreds of stranded sea lions found individuals presenting months after recovery with a neurological disease similar to temporal lobe epilepsy. A rat model developed to establish and better predict how epileptic disease results from domoic acid poisoning demonstrated that a single episode of status epilepticus (SE), after a latent period, leads to a progressive state of spontaneous recurrent seizure (SRS) and expression of atypical aggressive behaviors. Structural damage associated with domoic acid-induced SE is prominent in olfactory pathways. Here, we examine structural damage in seven rats that progressed to epileptic disease. Diseased animals show progressive neuronal loss in the piriform cortex and degeneration of terminal fields in these layers and the posteromedial cortical amygdaloid nucleus. Animals that display aggressive behavior had additional neuronal damage to the anterior olfactory cortex. This study provides insight into the structural basis for the progression of domoic acid epileptic disease and relates to the California sea lion, where poisoned animals progress to a disease characterized by SRS and aggressive behaviors.
Mengnjo, Michel K; Kamtchum-Tatuene, Joseph; Nicastro, Nicolas; Noubiap, Jean Jacques N
Introduction Sickle cell disease (SCD) is highly prevalent in Africa. Considered as a public health problem, it is associated with high morbidity and mortality. Neurological complications of SCD can cause significant disability with important socioeconomic and psychological impact on the patients and their families, and can even lead to death if not properly managed. There are important knowledge gaps regarding the burden of neurological complications of SCD in African populations. We propose to conduct the first systematic review to summarise the epidemiological data available on neurological complications of SCD in Africa. Methods and analysis We will search PubMed, MEDLINE, EMBASE and the African Index Medicus from 1 January 1950 to 31 May 2016 for studies of neurological complications of SCD in Africa. After study selection, full-text paper acquisition, data extraction and synthesis, we will assess all studies for quality, risk of bias and heterogeneity. Appropriate methods of meta-analysis will be used to pool prevalence estimates from studies with similar features, globally and in major subgroups. This protocol complies with the 2015 Preferred Reporting Items for Systematic reviews and Meta-Analysis protocols (PRISMA-P) guidelines. Ethics and dissemination The proposed study will use published data. Therefore, there is no requirement for ethical approval. This review is expected to provide relevant data to help quantify the burden of neurological complications of SCD in African populations, inform policymakers and identify further research topics. The final report of the systematic review will be published in a peer-reviewed journal and presented at conferences. Review registration number CRD42016039574. PMID:27798028
Hoang, Ha Thi; Schlager, Max A; Carter, Andrew P; Bullock, Simon L
Mutations in the human DYNC1H1 gene are associated with neurological diseases. DYNC1H1 encodes the heavy chain of cytoplasmic dynein-1, a 1.4-MDa motor complex that traffics organelles, vesicles, and macromolecules toward microtubule minus ends. The effects of the DYNC1H1 mutations on dynein motility, and consequently their links to neuropathology, are not understood. Here, we address this issue using a recombinant expression system for human dynein coupled to single-molecule resolution in vitro motility assays. We functionally characterize 14 DYNC1H1 mutations identified in humans diagnosed with malformations in cortical development (MCD) or spinal muscular atrophy with lower extremity predominance (SMALED), as well as three mutations that cause motor and sensory defects in mice. Two of the human mutations, R1962C and H3822P, strongly interfere with dynein's core mechanochemical properties. The remaining mutations selectively compromise the processive mode of dynein movement that is activated by binding to the accessory complex dynactin and the cargo adaptor Bicaudal-D2 (BICD2). Mutations with the strongest effects on dynein motility in vitro are associated with MCD. The vast majority of mutations do not affect binding of dynein to dynactin and BICD2 and are therefore expected to result in linkage of cargos to dynein-dynactin complexes that have defective long-range motility. This observation offers an explanation for the dominant effects of DYNC1H1 mutations in vivo. Collectively, our results suggest that compromised processivity of cargo-motor assemblies contributes to human neurological disease and provide insight into the influence of different regions of the heavy chain on dynein motility.
Hoang, Ha Thi; Schlager, Max A.; Carter, Andrew P.
Mutations in the human DYNC1H1 gene are associated with neurological diseases. DYNC1H1 encodes the heavy chain of cytoplasmic dynein-1, a 1.4-MDa motor complex that traffics organelles, vesicles, and macromolecules toward microtubule minus ends. The effects of the DYNC1H1 mutations on dynein motility, and consequently their links to neuropathology, are not understood. Here, we address this issue using a recombinant expression system for human dynein coupled to single-molecule resolution in vitro motility assays. We functionally characterize 14 DYNC1H1 mutations identified in humans diagnosed with malformations in cortical development (MCD) or spinal muscular atrophy with lower extremity predominance (SMALED), as well as three mutations that cause motor and sensory defects in mice. Two of the human mutations, R1962C and H3822P, strongly interfere with dynein’s core mechanochemical properties. The remaining mutations selectively compromise the processive mode of dynein movement that is activated by binding to the accessory complex dynactin and the cargo adaptor Bicaudal-D2 (BICD2). Mutations with the strongest effects on dynein motility in vitro are associated with MCD. The vast majority of mutations do not affect binding of dynein to dynactin and BICD2 and are therefore expected to result in linkage of cargos to dynein–dynactin complexes that have defective long-range motility. This observation offers an explanation for the dominant effects of DYNC1H1 mutations in vivo. Collectively, our results suggest that compromised processivity of cargo–motor assemblies contributes to human neurological disease and provide insight into the influence of different regions of the heavy chain on dynein motility. PMID:28196890
Hirano, Minato; Muto, Memi; Sakai, Mizuki; Kondo, Hirofumi; Kobayashi, Shintaro; Kariwa, Hiroaki; Yoshii, Kentaro
Neurological diseases caused by encephalitic flaviviruses are severe and associated with high levels of mortality. However, little is known about the detailed mechanisms of viral replication and pathogenicity in the brain. Previously, we reported that the genomic RNA of tick-borne encephalitis virus (TBEV), a member of the genus Flavivirus, is transported and replicated in the dendrites of neurons. In the present study, we analyzed the transport mechanism of the viral genome to dendrites. We identified specific sequences of the 5' untranslated region of TBEV genomic RNA that act as a cis-acting element for RNA transport. Mutated TBEV with impaired RNA transport in dendrites caused a reduction in neurological symptoms in infected mice. We show that neuronal granules, which regulate the transport and local translation of dendritic mRNAs, are involved in TBEV genomic RNA transport. TBEV genomic RNA bound an RNA-binding protein of neuronal granules and disturbed the transport of dendritic mRNAs. These results demonstrated a neuropathogenic virus hijacking the neuronal granule system for the transport of viral genomic RNA in dendrites, resulting in severe neurological disease.
Yan, Xiao-Xin; Ma, Chao; Gai, Wei-Ping; Cai, Huaibin; Luo, Xue-Gang
β-Secretase-1 (BACE1) is the rate-limiting enzyme for the genesis of amyloid-β (Aβ) peptides, the main constituents of the amyloid plaques in the brains of Alzheimer’s disease (AD) patients. BACE1 is being evaluated as an anti-Aβ target for AD therapy. Recent studies indicate that BACE1 elevation is associated with axonal and presynaptic pathology during plaque development. Evidence also points to a biological role for BACE1 in axonal outgrowth and synapse formation during development. Axonal, including presynaptic, pathology exists in AD as well as many other neurological disorders such as Parkinson’s disease, epilepsy, stroke, and trauma. In this review, we discuss pharmaceutical BACE1 inhibition as a therapeutic option for axonal pathogenesis, in addition to amyloid pathology. We first introduce the amyloidogenic processing of amyloid-β protein precursor and describe the normal expression pattern of the amyloidogenic proteins in the brain, with an emphasis on BACE1. We then address BACE1 elevation relative to amyloid plaque development, followed by updating recent understanding of a neurotrophic role of BACE1 in axon and synapse development. We further elaborate the occurrence of axonal pathology in some other neurological conditions. Finally, we propose pharmacological inhibition of excessive BACE1 activity as an option to mitigate early axonal pathology occurring in AD and other neurological disorders. PMID:24081378
Loschiavo, C; Grecò, M; Polo, A; Del Colle, R
The use of plasmapheresis in neurological diseases with immune-mediated pathogenesis is widely certified. In recent years, the technological evolution of the dialysis membranes allowed to accompany the classical plasma exchange (PEX) treatment of apheresis by means of selective adsorption (IA). It has proved to be of equal therapeutic efficacy and, at the same time, devoid of most of the PEX side effects. The recent guidelines of the American Society for Apheresis (ASFA) and, later, the American Academy of Neurology, outlined directions and diagrams for the application of the method that has found wide use in many neurological diseases on the basis of auto-antibodies; in particular in Myasthenia Gravis, Guillain-Barre Syndrome, Multiple Sclerosis and Chronic Demyelinating Polyradiculoneuropathy. We add our experience in the treatment of 13 patients suffering from Myasthenia Gravis, treated over a four years period with filters containing tryptophan immunoadsorption in polyvinyl alcohol gel. The results confirm the achievement of a rapid regression of clinical symptoms, together with the rapid fall in the levels of antibody against acetylcholine-receptor. Therefore, the method of AI is to be considered of equal therapeutic efficacy of PEX, providing greater security in its use.
Manto, Mario-Ubaldo; Laute, Marie-Aline; Aguera, Michèle; Rogemond, Véronique; Pandolfo, Massimo; Honnorat, Jérome
Glutamic acid decarboxylase (GAD) catalyzes the conversion of glutamic acid into GABA. GAD autoantibodies (GAD-Ab) have been described in diabetes mellitus and in diseases involving the central nervous system such as stiff-person syndrome and cerebellar ataxia. However, the pathogenic role of GAD-Ab in neurological diseases remains a matter of debate. Using neurophysiological and neurochemical methods, we analyzed the effects of intracerebellar and paraspinal administration of GAD-Ab in rats. Intracerebellar administration of IgG from patients with GAD-Ab and neurological involvement (IgG-GAD) blocked the potentiation of the corticomotor response normally associated with trains of repetitive peripheral nerve stimulation. When injected in the lumbar paraspinal region, IgG-GAD induced continuous motor activity with repetitive discharges, abnormal exteroceptive reflexes, and increased excitability of anterior horn neurons, as assessed by F/M ratios. Furthermore, IgG-GAD significantly reduced the N-methyl-D-aspartate-mediated production of nitric oxide in cerebellar nuclei and impaired the synaptic regulation of glutamate after N-methyl-D-aspartate administration. These effects were not observed after administration of IgG from the following groups: (1) patients with GAD-Ab, diabetes mellitus, and without neurological complications; and (2) control patients. These results indicate that stiff-person syndrome and cerebellar ataxia are the direct consequence of antibody-mediated neuronal dysfunction.
Souza, Anselmo; Carvalho, Natália; Neves, Yuri; Braga Santos, Silvane; Bastos, Maria de Lourdes; Arruda, Sérgio; Netto, Eduardo Martins; Glesby, Marshall J; Carvalho, Edgar
The human T cell lymphotropic virus type 1 (HTLV-1) is the etiologic agent of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-1 infected individuals have increased susceptibility to Mycobacterium tuberculosis infection but the influence of tuberculosis (TB) on the course of HTLV-1 infection is unknown. The aim of this study was to evaluate the influence of TB on immunological, virologic, and neurologic features of HTLV-1 infection. This is a retrospective analysis of individuals enrolled in a cohort study from an HTLV-1 clinic who were evaluated for past or latent tuberculosis (LTB) and classified clinically as HTLV-1 carriers, probable HAM/TSP and definite HAM/TSP. Spontaneous cytokine production (interferon-gamma [IFN-γ], tumor necrosis factor [TNF], and interleukin[IL]-10), serum chemokines (CXCL9 and CXCL10) and HTLV-1 proviral load were evaluated. Of 172 participants, 64 did not have histories of TB (TB- group), 81 had LTB and 27 had TB in the past (TB+ group). In the TB+ group, there was a higher frequency of HAM/TSP patients (35%) than in HTLV-1 carriers (10%) (OR = 3.8, p = .0001). HAM/TSP patients with histories of TB had higher IFN-γ/IL-10 and TNF/IL-10 ratios when compared with HAM/TSP patients without histories of TB. There were no differences in serum chemokine production and proviral load across TB groups stratified on HTLV-1 clinical status. In conclusion, TB may influence the development of HAM/TSP, and patients with these two diseases have an impairment in the modulation of immune response.
Brennan, Greg; Podell, Michael D.; Wack, Raymund; Kraft, Susan; Troyer, Jennifer L.; Bielefeldt-Ohmann, Helle; VandeWoude, Sue
Lion lentivirus (LLV; also known as feline immunodeficiency virus of lion, Panthera leo [FIVPle]) is present in free-ranging and captive lion populations at a seroprevalence of up to 100%; however, clinical signs are rarely reported. LLV displays up to 25% interclade sequence diversity, suggesting that it has been in the lion population for some time and may be significantly host adapted. Three captive lions diagnosed with LLV infection displayed lymphocyte subset alterations and progressive behavioral, locomotor, and neuroanatomic abnormalities. No evidence of infection with other potential neuropathogens was found. Antemortem electrodiagnostics and radiologic imaging indicated a diagnosis consistent with lentiviral neuropathy. PCR was used to determine a partial lentiviral genomic sequence and to quantify the proviral burden in eight postmortem tissue specimens. Phylogenetic analysis demonstrated that the virus was consistent with the LLV detected in other captive and free-ranging lions. Despite progressive neurologic signs, the proviral load in tissues, including several regions of the brain, was low; furthermore, gross and histopathologic changes in the brain were minimal. These findings suggest that the symptoms in these animals resulted from nonspecific encephalopathy, similar to human immunodeficiency virus, FIV, and simian immunodeficiency virus (SIV) neuropathies, rather than a direct effect of active viral replication. The association of neuropathy and lymphocyte subset alterations with chronic LLV infection suggests that long-term LLV infection can have detrimental effects for the host, including death. This is similar to reports of aged sootey mangabeys dying from diseases typically associated with end-stage SIV infection and indicates areas for further research of lentiviral infections of seemingly adapted natural hosts, including mechanisms of host control and viral adaptation. PMID:17005739
Brennan, Greg; Podell, Michael D; Wack, Raymund; Kraft, Susan; Troyer, Jennifer L; Bielefeldt-Ohmann, Helle; VandeWoude, Sue
Lion lentivirus (LLV; also known as feline immunodeficiency virus of lion, Panthera leo [FIVPle]) is present in free-ranging and captive lion populations at a seroprevalence of up to 100%; however, clinical signs are rarely reported. LLV displays up to 25% interclade sequence diversity, suggesting that it has been in the lion population for some time and may be significantly host adapted. Three captive lions diagnosed with LLV infection displayed lymphocyte subset alterations and progressive behavioral, locomotor, and neuroanatomic abnormalities. No evidence of infection with other potential neuropathogens was found. Antemortem electrodiagnostics and radiologic imaging indicated a diagnosis consistent with lentiviral neuropathy. PCR was used to determine a partial lentiviral genomic sequence and to quantify the proviral burden in eight postmortem tissue specimens. Phylogenetic analysis demonstrated that the virus was consistent with the LLV detected in other captive and free-ranging lions. Despite progressive neurologic signs, the proviral load in tissues, including several regions of the brain, was low; furthermore, gross and histopathologic changes in the brain were minimal. These findings suggest that the symptoms in these animals resulted from nonspecific encephalopathy, similar to human immunodeficiency virus, FIV, and simian immunodeficiency virus (SIV) neuropathies, rather than a direct effect of active viral replication. The association of neuropathy and lymphocyte subset alterations with chronic LLV infection suggests that long-term LLV infection can have detrimental effects for the host, including death. This is similar to reports of aged sootey mangabeys dying from diseases typically associated with end-stage SIV infection and indicates areas for further research of lentiviral infections of seemingly adapted natural hosts, including mechanisms of host control and viral adaptation.
Diaz-Figueroa, Orlando; Smith, Mary O
Neurology represents an important specialty within ferret clinical medicine. Veterinarians should become familiar with the unique anatomic and physiologic differences between ferrets to improve their management of theses cases. In addition, veterinarians should use available diagnostic tests to confirm the presence of neurologic diseases. Recent advances in ferret medicine and veterinary neurology offer new capabilities to investigate and treat neurological disease in ferrets.
Schneider, Ruth B; Biglan, Kevin M
Disparities in access to health care, particularly specialist care, exist worldwide. As the prevalence of chronic neurological disorders increases with ageing populations, access to neurologist care is likely to worsen in many regions if there are no changes to models of care. Telemedicine-defined here as the use of real-time, synchronous videoconferencing to deliver medical care-could be used to improve access to neurologist care for patients with a range of chronic neurological disorders. In Parkinson's disease, several studies have shown the feasibility and potential benefits of telemedicine-delivered care. Further research is needed to establish whether telemedicine can deliver on the promise of improved access to neurologist care and whether telemedicine-delivered care is comparable to in-person care in terms of clinical outcomes. Many barriers to widespread implementation of telemedicine services remain to be addressed, including reimbursement, legal considerations, and technological issues. Copyright © 2017 Elsevier Ltd. All rights reserved.
In this paper we study the epidemiological criteria and those of etiological investigation which should be considered when analysing and investigating problems with health due to exposure to occupational hazards, with special attention to neurological damage due to chemical or physical contamination or to the ergonometric requirements of the task. We define the part played by occupational hazards in causing disease both professional and related to other occupations. The different preventive models used in the history of prevention of professional hazards are analysed. Particular attention is paid to the so-called socio-technical model which considers illness as dysfunction of the relation man/work. The neurological risk factors are analysed separately; therefore we emphasize the different neurotoxic chemicals, physical and ergonomic agents (the latter may be considered a pandemic in the workplace), and we establish the relationships with the main clinical and functional disorders of the central and peripheral nervous systems and the musculoskeletal system.
Uchino, M; Tanaka, Y; Ando, Y; Yonehara, T; Hara, A; Mishima, I; Okajima, T; Ando, M
To elucidate the neurologic features of chronic Minamata disease, and the incidence of complications with aging, we studied 80 patients with documented Minamata disease (organic mercury poisoning) from 1986 to 1994 (mean age: 63 years). Of the cardinal neurologic findings, sensory impairment was seen with highest frequency in 98.8% of patients limited to the extremities in 86.3%. Impairment of lower extremity coordination was observed in 60%, constriction of the visual field in 51.9%, and retrocochlear hearing loss in 41%. To assess age-related complications, patients were separated into three groups by age: Group I (10 to 39 years); Group II (40 to 69 years); Group III (> or = 70 years). The incidences of hypertension and cerebrovascular diseases, organic ophthalmologic disorders (including cataracts), presbyacusis, and cervical spondylosis deformans increased significantly with age. Compared with a preceding survey (1981 to 1985, 171 patients, mean age: 63.5 years), the incidences of complicated hypertension and cataracts had decreased, whereas those of cerebrovascular disease and retinitis pigmentosa remained unchanged. The incidences of abnormal brain computed tomography (CT), presbyacusis, cervical spondylosis deformans, and positive tests for urine sugar also increased. The incidences of these complications other than retinitis pigmentosa were similar to those in the general population. These results accurately reflect the recent epidemiological disease tendencies in Japan toward a decreased incidence of hypertension and an increased incidence of diabetes.
Sundquist, J; Forsling, M L; Olsson, J E; Akerlund, M
Arginine vasopressin (AVP) was determined in plasma and lumbar CSF from 46 patients with Parkinson's disease, dementia, cerebrovascular disease, multiple sclerosis and other, mostly peripheral neurological disorders. The mean plasma concentration of AVP was 1.62 microU/ml, the CSF concentration 1.14 microU/ml and the gradient CSF/plasma 0.72. There was a good correlation between the plasma and the CSF values in most patients. No sex difference could be found. A slight decrease of the CSF values could be found with increasing age. Significantly higher CSF-AVP values were found in patients with cerebrovascular disease, whereas lower CSF values were found in patients with dementia and Parkinson's disease. However there were decreased CSF/plasma gradients in patients with dementia and Parkinson's disease to about 0.30 compared to 0.98 in patients with peripheral neurological disorders. Patients with multiple sclerosis had an increased IgG index indicating an intrathecal IgG production but there was no obvious correlation between this and the AVP concentrations in plasma and CSF, nor with the total CSF protein content, nor with the albumin and IgG concentrations in plasma and CSF. PMID:6842195
Ribes, Julie A.; Vanover-Sams, Carolyn L.; Baker, Doris J.
The Zygomycetes represent relatively uncommon isolates in the clinical laboratory, reflecting either environmental contaminants or, less commonly, a clinical disease called zygomycosis. There are two orders of Zygomycetes containing organisms that cause human disease, the Mucorales and the Entomophthorales. The majority of human illness is caused by the Mucorales. While disease is most commonly linked to Rhizopus spp., other organisms are also associated with human infection, including Mucor, Rhizomucor, Absidia, Apophysomyces, Saksenaea, Cunninghamella, Cokeromyces, and Syncephalastrum spp. Although Mortierella spp. do cause disease in animals, there is no longer sufficient evidence to suggest that they are true human pathogens. The spores from these molds are transmitted by inhalation, via a variety of percutaneous routes, or by ingestion of spores. Human zygomycosis caused by the Mucorales generally occurs in immunocompromised hosts as opportunistic infections. Host risk factors include diabetes mellitus, neutropenia, sustained immunosuppressive therapy, chronic prednisone use, iron chelation therapy, broad-spectrum antibiotic use, severe malnutrition, and primary breakdown in the integrity of the cutaneous barrier such as trauma, surgical wounds, needle sticks, or burns. Zygomycosis occurs only rarely in immunocompetent hosts. The disease manifestations reflect the mode of transmission, with rhinocerebral and pulmonary diseases being the most common manifestations. Cutaneous, gastrointestinal, and allergic diseases are also seen. The Mucorales are associated with angioinvasive disease, often leading to thrombosis, infarction of involved tissues, and tissue destruction mediated by a number of fungal proteases, lipases, and mycotoxins. If the diagnosis is not made early, dissemination often occurs. Therapy, if it is to be effective, must be started early and requires combinations of antifungal drugs, surgical intervention, and reversal of the underlying risk
Rosa, Roberta; Costa, Erica Azevedo; Marques, Rafael Elias; Oliveira, Taismara Simas; Furtini, Ronaldo; Bomfim, Maria Rosa Quaresma; Teixeira, Mauro Martins; Paixão, Tatiane Alves; Santos, Renato Lima
St. Louis encephalitis virus (SLEV) is a causative agent of encephalitis in humans in the Western hemisphere. SLEV is a positive-sense RNA virus that belongs to the Flavivirus genus, which includes West Nile encephalitis virus, Japanese encephalitis virus, Dengue virus and other medically important viruses. Recently, we isolated a SLEV strain from the brain of a horse with neurological signs in the countryside of Minas Gerais, Brazil. The SLEV isolation was confirmed by reverse-transcription RT-PCR and sequencing of the E protein gene. Virus identity was also confirmed by indirect immunofluorescence using commercial antibodies against SLEV. To characterize this newly isolated strain in vivo, serial passages in newborn mice were performed and led to hemorrhagic manifestations associated with recruitment of inflammatory cells into the central nervous system of newborns. In summary this is the first isolation of SLEV from a horse with neurological signs in Brazil. PMID:24278489
Grell, Kathrine; Meersohn, Andrea; Schüz, Joachim; Johansen, Christoffer
Several studies suggest a link between electric injuries and neurological diseases, where electric shocks may explain elevated risks for neuronal degeneration and, subsequently, neurological diseases. We conducted a retrospective cohort study on the risk of neurological diseases among people in Denmark who had survived an electric accident in 1968-2008. The cohort included 3,133 people and occurrences of neurological diseases were determined by linkage to the nationwide population-based Danish National Register of Patients. The numbers of cases observed at first hospital contact in the cohort were compared with the respective rates of first hospital contacts for neurological diseases in the general population. We observed significantly increased risks for peripheral nerve diseases (standardized hospitalization ratio (SHR), 1.66; 95% confidence interval (CI), 1.22-2.22), for migraine (SHR, 1.80; 95% CI, 1.23-2.54), for vertigo (SHR, 1.60; 95% CI, 1.22-2.05), and for epilepsy (SHR, 1.45; 95% CI, 1.11-1.85). Only small numbers of cases of other neurological diseases were found, making the risk estimates unstable. These findings suggest an association between a single electric shock and increased risks for peripheral nerve diseases, migraines, vertigo, and epilepsy, but confirmation of these observations is needed.
Sena, Emily S.; Aretouli, Eleni; Evangelou, Evangelos; Howells, David W.; Salman, Rustam Al-Shahi; Macleod, Malcolm R.; Ioannidis, John P. A.
Animal studies generate valuable hypotheses that lead to the conduct of preventive or therapeutic clinical trials. We assessed whether there is evidence for excess statistical significance in results of animal studies on neurological disorders, suggesting biases. We used data from meta-analyses of interventions deposited in Collaborative Approach to Meta-Analysis and Review of Animal Data in Experimental Studies (CAMARADES). The number of observed studies with statistically significant results (O) was compared with the expected number (E), based on the statistical power of each study under different assumptions for the plausible effect size. We assessed 4,445 datasets synthesized in 160 meta-analyses on Alzheimer disease (n = 2), experimental autoimmune encephalomyelitis (n = 34), focal ischemia (n = 16), intracerebral hemorrhage (n = 61), Parkinson disease (n = 45), and spinal cord injury (n = 2). 112 meta-analyses (70%) found nominally (p≤0.05) statistically significant summary fixed effects. Assuming the effect size in the most precise study to be a plausible effect, 919 out of 4,445 nominally significant results were expected versus 1,719 observed (p<10−9). Excess significance was present across all neurological disorders, in all subgroups defined by methodological characteristics, and also according to alternative plausible effects. Asymmetry tests also showed evidence of small-study effects in 74 (46%) meta-analyses. Significantly effective interventions with more than 500 animals, and no hints of bias were seen in eight (5%) meta-analyses. Overall, there are too many animal studies with statistically significant results in the literature of neurological disorders. This observation suggests strong biases, with selective analysis and outcome reporting biases being plausible explanations, and provides novel evidence on how these biases might influence the whole research domain of neurological animal literature. PMID:23874156
Marinho-Buzelli, Andresa R; Bonnyman, Alison M; Verrier, Mary C
To summarize evidence on the effects of aquatic therapy on mobility in individuals with neurological diseases. MEDLINE, EMBASE, PsycInfo, CENTRAL, CINAHL, SPORTDiscus, PEDro, PsycBITE and OT Seeker were searched from inception to 15 September 2014. Hand-searching of reference lists was performed in the selected studies. The search included randomized controlled trials and quasi-experimental studies that investigated the use of aquatic therapy and its effect on mobility of adults with neurological diseases. One reviewer screened titles and abstracts of retrieved studies from the search strategy. Two reviewers independently examined the full texts and conducted the study selection, data extraction and quality assessment. A narrative synthesis of data was applied to summarize information from included studies. The Downs and Black Scale was used to assess methodological quality. A total of 116 articles were obtained for full text eligibility. Twenty studies met the specified inclusion criteria: four Randomized Controlled Trials (RCTs), four non-randomized studies and 12 before-and-after tests. Two RCTs (30 patients with stroke in the aquatic therapy groups), three non-randomized studies and three before-and-after studies showed "fair" evidence that aquatic therapy increases dynamic balance in participants with some neurological disorders. One RCT (seven patients with stroke in the aquatic therapy group) and two before-and-after tests (20 patients with multiple sclerosis) demonstrated "fair" evidence on improvement of gait speed after aquatic therapy. Our synthesis showed "fair" evidence supporting the use of aquatic therapy to improve dynamic balance and gait speed in adults with certain neurological conditions. © The Author(s) 2014.
Since the incidental discovery in 1981 that intravenous immunoglobulins (IVIg) are immunomodulatory, they have been investigated in a large number of putative autoimmune diseases. This has led to licensing for idiopathic thrombocytopenic purpura, Kawasaki disease, and in neurological disorders for Guillain-Barré syndrome (GBS). Although not licensed, randomized controlled trials have also shown IVIg efficacy in other neuroimmunological diseases such as multifocal motor neuropathy (MMN), chronic inflammatory demyelinating neuropathy (CIDP), myasthenia gravis, dermatomyositis, and stiff-person syndrome. However, other indications are currently being explored including Alzheimer's disease, postpolio syndrome, and narcolepsy. There are even reports from experimental studies in stroke. The results of recently published clinical trials in both the classical neuroimmunological disorders as well as for new indications are reported and their role in clinical practice is discussed. PMID:21180569
Candler, P; Hart, P; Barnett, M; Weil, R; Rees, J
Objectives: To examine the range of clinical phenotypes, tumour associations, relevant investigations, response to therapy and outcome in a large series of non-selected patients with paraneoplastic neurological disease (PND) affecting the central nervous system (CNS) in the United Kingdom. Methods: Data were obtained on patients either through direct referral or through the British Neurological Surveillance Unit (BNSU) from February 2000 to January 2001. Physicians were asked to supply information about age and sex of patients, presenting neurological syndromes, the basis of the diagnosis of PND, any associated malignancy, and treatment. Case notes were reviewed and follow up data obtained where possible one year after notification. Results: A total of 63 patients (48 females, 15 males) were identified, 48 through the BNSU and 15 through direct referral. Of these 52 were diagnosed as having definite PND, 10 probable PND, and 1 possible PND. The median age of onset of PND was 66 years (range 30–80 years) and only 7 patients (11%) were less than 50 years at presentation. In 53 patients (84%) the PND preceded the diagnosis of cancer. Paraneoplastic sensory neuronopathy, paraneoplastic encephalomyelitis, and paraneoplastic cerebellar degeneration (PCD) were the most common syndromes reported. The benefit of magnetic resonance imaging in the diagnosis of the disease was limited, while fluorodeoxyglucose positron emission tomography was shown to be useful for the detection of an occult malignancy in 10 out of 14 patients. Antineuronal antibodies were positive in 44/57 (77%) of cases. The following tumours were diagnosed: small cell lung cancer (30%), breast cancer (14%), ovarian cancer (8%), non-small cell lung cancer (8%), Hodgkin's lymphoma (6%), other (16%). With the exception of PCD associated with mesothelioma all other tumours diagnosed in these patients had been previously documented as being associated with PND. Only treatment of the tumour was found to be
Ochalek, Anna; Szczesna, Karolina; Petazzi, Paolo; Kobolak, Julianna
The cellular and molecular bases of neurological diseases have been studied for decades; however, the underlying mechanisms are not yet fully elucidated. Compared with other disorders, diseases of the nervous system have been very difficult to study mainly due to the inaccessibility of the human brain and live neurons in vivo or in vitro and difficulties in examination of human postmortem brain tissue. Despite the availability of various genetically engineered animal models, these systems are still not adequate enough due to species variation and differences in genetic background. Human induced pluripotent stem cells (hiPSCs) reprogrammed from patient somatic cells possess the potential to differentiate into any cell type, including neural progenitor cells and postmitotic neurons; thus, they open a new area to in vitro modeling of neurological diseases and their potential treatment. Currently, many protocols for generation of various neuronal subtypes are being developed; however, most of them still require further optimization. Here, we highlight accomplishments made in the generation of dopaminergic and cholinergic neurons, the two subtypes most affected in Alzheimer's and Parkinson's diseases and indirectly affected in Huntington's disease. Furthermore, we discuss the potential role of hiPSC-derived neurons in the modeling and treatment of neurological diseases related to dopaminergic and cholinergic system dysfunction. PMID:28105055
Liu, Ching Ming; Chang, Fang Chia
This study was conducted to evaluate new acupuncture protocols for the clinical treatment of cervical spinal cord diseases in 19 dogs. Three treatment options containing Jing-jiaji (cervical jiaji) were developed to treat neck pain, hemiparesis, and tetraparesis depending on the severity. The interval between the neurological disease onset and treatment (duration of signs), time to improvement after treatment, and recovery time were compared in dogs by body weight, age, and dry needle acupuncture (AP) with or without electro-AP (EAP). The duration of signs was longer in dogs weighing greater than 10 kg than in those weighing less than 10 kg (p < 0.05). Improvement and recovery times did not vary by body weight. Additionally, improvement and recovery times did not vary by age. The improvement and recovery times were longer in the AP+EAP group than the AP group (p < 0.05). Acupuncture with Jing-jiaji was effective in cervical spinal cord diseases in different sized dogs and in middle-aged and senior dogs. This report standardized AP treatment containing Jing-jiaji for canine cervical problems and evaluated its effects. The newly standardized AP methodology offers clinical practitioners an effective way to improve the outcomes of cervical neurological diseases in dogs. PMID:26645331
Hurtt, A E; Smith, M O
To examine the effects that iatrogenic blood contamination would have on total protein concentration and nucleated cell count in CSF from clinically normal dogs and dogs with neurologic disease. Case-control study. 53 dogs confirmed to have neurologic disease and 21 clinically normal dogs. CSF samples were obtained from the cerebellomedullary cistern or the lumbar portion of the subarachnoid space. Red blood and nucleated cell counts were determined, and protein concentration was measured. RBC count was not significantly correlated with nucleated cell count or protein concentration in clinically normal dogs or dogs with neurologic disease. High CSF nucleated cell counts and protein concentrations are indicative of neurologic disease, even if samples contain moderate amounts of blood contamination.
Brewer, George J; Askari, Fred; Lorincz, Matthew T; Carlson, Martha; Schilsky, Michael; Kluin, Karen J; Hedera, Peter; Moretti, Paolo; Fink, John K; Tankanow, Roberta; Dick, Robert B; Sitterly, Julia
To compare tetrathiomolybdate and trientine in treating patients with the neurologic presentation of Wilson disease for the frequency of neurologic worsening, adverse effects, and degree of neurologic recovery. A randomized, double-blind, controlled, 2-arm study of 48 patients with the neurologic presentation of Wilson disease. Patients either received 500 mg of trientine hydrochloride 2 times per day or 20 mg of tetrathiomolybdate 3 times per day with meals and 20 mg 3 times per day between meals for 8 weeks. All patients received 50 mg of zinc 2 times per day. Patients were hospitalized for 8 weeks, with neurologic and speech function assessed weekly; discharged taking 50 mg of zinc 3 times per day, and returned annually for follow-up. A university hospital referral setting. Primarily newly diagnosed patients with Wilson disease presenting with neurologic symptoms who had not been treated longer than 4 weeks with an anticopper drug. Treatment with either trientine plus zinc or tetrathiomolybdate plus zinc. Neurologic function was assessed by semiquantitative neurologic and speech examinations. Drug adverse events were evaluated by blood cell counts and biochemical measures. Six of 23 patients in the trientine arm and 1 of 25 patients in the tetrathiomolybdate arm underwent neurologic deterioration (P<.05). Three patients receiving tetrathiomolybdate had adverse effects of anemia and/or leukopenia, and 4 had further transaminase elevations. One patient receiving trientine had an adverse effect of anemia. Four patients receiving trientine died during follow-up, 3 having shown initial neurologic deterioration. Neurologic and speech recovery during a 3-year follow-up period were quite good. Tetrathiomolybdate is a better choice than trientine for preserving neurologic function in patients who present with neurologic disease.
Crino, Peter B
Defining the multiple roles of the mechanistic (formerly 'mammalian') target of rapamycin (mTOR) signalling pathway in neurological diseases has been an exciting and rapidly evolving story of bench-to-bedside translational research that has spanned gene mutation discovery, functional experimental validation of mutations, pharmacological pathway manipulation, and clinical trials. Alterations in the dual contributions of mTOR - regulation of cell growth and proliferation, as well as autophagy and cell death - have been found in developmental brain malformations, epilepsy, autism and intellectual disability, hypoxic-ischaemic and traumatic brain injuries, brain tumours, and neurodegenerative disorders. mTOR integrates a variety of cues, such as growth factor levels, oxygen levels, and nutrient and energy availability, to regulate protein synthesis and cell growth. In line with the positioning of mTOR as a pivotal cell signalling node, altered mTOR activation has been associated with a group of phenotypically diverse neurological disorders. To understand how altered mTOR signalling leads to such divergent phenotypes, we need insight into the differential effects of enhanced or diminished mTOR activation, the developmental context of these changes, and the cell type affected by altered signalling. A particularly exciting feature of the tale of mTOR discovery is that pharmacological mTOR inhibitors have shown clinical benefits in some neurological disorders, such as tuberous sclerosis complex, and are being considered for clinical trials in epilepsy, autism, dementia, traumatic brain injury, and stroke.
Diez-Roux, Graciana; Ballabio, Andrea
Sulfatases are a highly conserved family of proteins that cleave sulfate esters from a wide range of substrates. The importance of sulfatases in human metabolism is underscored by the presence of at least eight human monogenic diseases caused by the deficiency of individual sulfatases. Sulfatase activity requires a unique posttranslational modification, which is impaired in patients with multiple sulfatase deficiency (MSD) due to a mutation of the sulfatase modifying factor 1 (SUMF1). Here we review current knowledge and future perspectives on the evolution of the sulfatase gene family, on the role of these enzymes in human metabolism, and on new developments in the therapy of sulfatase deficiencies.
Leite, Ângela; Leite, Fernanda; Dinis, Maria Alzira P
This study addresses the objective knowledge about the disease of subjects at risk for 3 genetic late-onset neurological diseases (LOND): familial amyloid polyneuropathy (FAP) TTR V30M, Huntington disease (HD), and Machado-Joseph disease (MJD). Subjects at risk for FAP, HD, and MJD submitted to genetic counseling to know their status (carrier or non-carrier) and subjects at risk for hereditary hemochromatosis (HH), the control group, completed a sociodemographic questionnaire and answered the open-ended question: "What do you know about this disease?." From 10 categories of answers, references to the disease, quantitative answers, references to the family, and metaphors stood out. References to the disease, references to the family, and metaphors were mentioned more often by subjects at risk for LOND than by subjects at risk for HH (control group). The disease itself and its meaning as well as sick relatives play a key role in the objective knowledge about LOND. Thus, genetic counseling protocols of subjects at risk for LOND should include questions concerning family knowledge and disease experience. © 2017 S. Karger AG, Basel.
Foureur, N; Descamps, V; Lebrun-Vignes, B; Picard-Dahan, C; Grossin, M; Belaich, S; Crickx, B
We report a typical case of bullous pemphigoid (BP) associated with a neurological disorder and study a possible link between neurological disorders and BP. An 84-year-old hemiplegic woman presented with unilateral BP on the hemiparetic side. BP was confirmed by histological and immunofluorescence data. The medical records of the previous 46 consecutive patients with BP were retrospectively analyzed (average age: 79; median age: 85). Thirty of the 46 patients with BP had neurological disorders. These disorders included dementia, epilepsy, multiple sclerosis, cerebral stroke, Parkinson's disease, gonadotropic adenoma, trembling, dyskinesia, lumbar spinal stenosis. In a control group of the 46 consecutive oldest patients (older than 71; average age: 82,5; median age: 80) with another skin disease referred during the previous two-year-period to our one-day-unit only, 13 patients had a neurological disorder. This study demonstrates that there is a high prevalence of neurological disorders in patients with BP (p = 0.0004). A prospective case control study with neurological examination and psychometrical evaluation is warranted to confirm these data. We speculate that neuroautoimmunity associated with the aging process or neurological disorders may be involved in pemphigoid development via an autoimmune response against dystonin which shares homology with bullous pemphigoid antigen 1. Bullous pemphigoid could be considered to be a marker of neurological disorder.
Barthel, Henryk; Hermann, Wieland; Kluge, Regine; Hesse, Swen; Collingridge, David R; Wagner, Armin; Sabri, Osama
Although previous brain imaging studies of Wilson disease (WD) focused on the dopaminergic system, correlational data on the integrity of the pre- and postsynaptic compartments are lacking. The present study was initiated to intra-individually determine the integrity of these compartments in patients with WD. A total of 46 patients with WD and 10 matched control subjects underwent [(123)I]2beta-carbomethoxy-3beta-(4[(123)I]iodophenyl)tropane ([(123)I]beta-CIT) and [(123)I]iodobenzamide ([(123)I]IBZM) single photon emission CT (SPECT). For both radiotracers, specific striatal binding ratios (with the cerebellum as the reference region) were calculated after a standardized region-of-interest technique was applied. In addition, the severity of putative neurologic symptoms was evaluated by using a linear scoring system. In patients without neurologic symptoms, striatal binding ratios of both radiotracers did not differ from those of the control group (13.8 +/- 3.1 vs 12.0 +/- 3.4 and 2.00 +/- 0.19 vs 1.90 +/- 0.27; n.s.). In symptomatic patients, however, striatal binding ratios for both [(123)I]beta-CIT and [(123)I]IBZM were significantly reduced (9.1 +/- 2.3 and 1.64 +/- 0.18; P <.001). In all patients with WD, the [(123)I]beta-CIT and [(123)I]IBZM binding ratios were significantly correlated (r = 0.65, P <.001), as were SPECT parameters and the severity of the neurologic symptoms (r = -0.60 and -0.62; P <.001). These findings of a concordant bicompartmental dopaminergic deficit in neurologic WD provide in vivo evidence for assigning WD to the group of secondary Parkinsonian syndromes. These results could be relevant in therapeutic decision making in patients with this copper deposition disorder.
Kanitz, Fábio A; Cargnelutti, Juliana F; Anziliero, Deniz; Gonçalves, Kelley V; Masuda, Eduardo K; Weiblen, Rudi; Flores, Eduardo F
Equid herpesvirus type 1 (EHV-1) is an important pathogen of horses worldwide, associated with respiratory, reproductive and/or neurological disease. A mouse model for EHV-1 infection has been established but fails to reproduce some important aspects of the viral pathogenesis. Then, we investigated the susceptibility of rabbits to EHV-1 aiming at proposing this species as an alternative model for EHV-1 infection. Weanling rabbits inoculated intranasal with EHV-1 Kentucky D (10(7) TCID50/animal) shed virus in nasal secretions up to day 8-10 post-inoculation (pi), presented viremia up to day 14 pi and seroconverted to EHV-1 (virus neutralizing titers 4 to 64). Most rabbits (75%) developed respiratory disease, characterized by serous to hemorrhagic nasal discharge and mild to severe dyspnea. Some animals (20%) presented neurological signs as circling, bruxism and opisthotonus. Six animals died during acute disease (days 3-6); infectious virus and/or viral DNA were detected in the lungs, trigeminal ganglia (TG), olfactory bulbs (OBs) and cerebral cortex/brain (CC). Histological examination showed necrohemorrhagic, multifocal to coalescent bronchointerstitial pneumonia and diffuse alveolar edema. In two rabbits euthanized at day 50 pi, latent EHV-1 DNA was detected in the OBs. Dexamethasone administration at day 50 pi resulted in virus reactivation, demonstrated by virus shedding, viremia, clinical signs, and increase in VN titers and/or by detection of virus DNA in lungs, OBs, TGs and/or CC. These results demonstrate that rabbits are susceptible to EHV-1 infection and develop respiratory and neurological signs upon experimental inoculation. Thus, rabbits may be used to study selected aspects of EHV-1 biology and pathogenesis, extending and complementing the mouse model.
Dumas-Mallet, Estelle; Button, Katherine; Boraud, Thomas; Munafo, Marcus; Gonon, François
Context There are growing concerns about effect size inflation and replication validity of association studies, but few observational investigations have explored the extent of these problems. Objective Using meta-analyses to measure the reliability of initial studies and explore whether this varies across biomedical domains and study types (cognitive/behavioral, brain imaging, genetic and “others”). Methods We analyzed 663 meta-analyses describing associations between markers or risk factors and 12 pathologies within three biomedical domains (psychiatry, neurology and four somatic diseases). We collected the effect size, sample size, publication year and Impact Factor of initial studies, largest studies (i.e., with the largest sample size) and the corresponding meta-analyses. Initial studies were considered as replicated if they were in nominal agreement with meta-analyses and if their effect size inflation was below 100%. Results Nominal agreement between initial studies and meta-analyses regarding the presence of a significant effect was not better than chance in psychiatry, whereas it was somewhat better in neurology and somatic diseases. Whereas effect sizes reported by largest studies and meta-analyses were similar, most of those reported by initial studies were inflated. Among the 256 initial studies reporting a significant effect (p<0.05) and paired with significant meta-analyses, 97 effect sizes were inflated by more than 100%. Nominal agreement and effect size inflation varied with the biomedical domain and study type. Indeed, the replication rate of initial studies reporting a significant effect ranged from 6.3% for genetic studies in psychiatry to 86.4% for cognitive/behavioral studies. Comparison between eight subgroups shows that replication rate decreases with sample size and “true” effect size. We observed no evidence of association between replication rate and publication year or Impact Factor. Conclusion The differences in reliability
Dumas-Mallet, Estelle; Button, Katherine; Boraud, Thomas; Munafo, Marcus; Gonon, François
There are growing concerns about effect size inflation and replication validity of association studies, but few observational investigations have explored the extent of these problems. Using meta-analyses to measure the reliability of initial studies and explore whether this varies across biomedical domains and study types (cognitive/behavioral, brain imaging, genetic and "others"). We analyzed 663 meta-analyses describing associations between markers or risk factors and 12 pathologies within three biomedical domains (psychiatry, neurology and four somatic diseases). We collected the effect size, sample size, publication year and Impact Factor of initial studies, largest studies (i.e., with the largest sample size) and the corresponding meta-analyses. Initial studies were considered as replicated if they were in nominal agreement with meta-analyses and if their effect size inflation was below 100%. Nominal agreement between initial studies and meta-analyses regarding the presence of a significant effect was not better than chance in psychiatry, whereas it was somewhat better in neurology and somatic diseases. Whereas effect sizes reported by largest studies and meta-analyses were similar, most of those reported by initial studies were inflated. Among the 256 initial studies reporting a significant effect (p<0.05) and paired with significant meta-analyses, 97 effect sizes were inflated by more than 100%. Nominal agreement and effect size inflation varied with the biomedical domain and study type. Indeed, the replication rate of initial studies reporting a significant effect ranged from 6.3% for genetic studies in psychiatry to 86.4% for cognitive/behavioral studies. Comparison between eight subgroups shows that replication rate decreases with sample size and "true" effect size. We observed no evidence of association between replication rate and publication year or Impact Factor. The differences in reliability between biological psychiatry, neurology and somatic
Lee, Sang Min; Dunnavant, Floyd D; Jang, Haeman; Zunt, Joseph; Levin, Michael C
As a model for molecular mimicry in neurological disease, we study people infected with human T-lymphotropic virus type 1 (HTLV-1) who develop HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP), an immune-mediated disease of the central nervous system (CNS). In HAM/TSP, data suggests molecular mimicry is the result of cross-reactive antibodies between HTLV-1-tax and heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1), a protein over-expressed in human CNS neurons. The hnRNP A1 epitope recognized by autoantibodies was unknown. In this study, we hypothesized that antibodies purified from HAM/TSP patients would react with functionally significant domains of hnRNP A1. Western blotting of functionally significant deletion mutants and overlapping fusion proteins using HAM/TSP IgG revealed two core epitopes within the C-terminal region of hnRNP A1. The first (aminoacids 191-SSQRGRSGSGNF-202), overlapped the RGG domain and the second (aminoacids 293-GQYFAKPRNQGG-304), with the M9 shuttling sequence, two functionally important regions of hnRNP A1. Monoclonal antibodies to HTLV-1-tax also reacted with the epitopes. These data fulfill an important criterion of molecular mimicry, namely that mimicking epitopes are not random, but include biologically significant regions of target proteins. This suggests an important role for the cross-reactive immune response between HTLV-1 and hnRNP A1 in the pathogenesis of immune-mediated neurological diseases via molecular mimicry.
It is inevitable for patients at home with neurological intractable diseases to prepare against natural disasters, such as severe earthquakes or power failures, because they need not only daily physical care but also extensive medical supports. Administrative organs have to support those patients in case of disasters, and they have to make up countermeasures in advance for their refuge in safety. For this purpose, we published a guideline in 2008 for administration to make support plans for those patients. To plan countermeasures against calamities according to this guideline is an urgent issue especially for those who need extensive supports at home.
Boxall, Ruth; Porteous, David J.; Thomson, Pippa A.
We re-annotated the interacting partners of the neuronal scaffold protein DISC1 using a knowledge-based approach that incorporated recent protein interaction data and published literature to. This revealed two highly connected networks. These networks feature cellular function and maintenance, and cell signaling. Of potentially greatest interest was the novel finding of a high degree of connectivity between the DISC1 scaffold protein, linked to psychiatric illness, and huntingtin, the protein which is mutated in Huntington's disease. The potential link between DISC1, huntingtin and their interacting partners may open new areas of research into the effects of pathway dysregulation in severe neurological disorders. PMID:21298101
Background Neurologic disorders are not uncommon at in patient departments of different hospitals. We have conducted the study to see the pattern and burden of neurologic disorders at different inpatient departments of a tertiary care centre. Methodology This retrospective observational study was carried out from the records and referral notes of neurology department of Dhaka Medical College Hospital (DMCH) from July 2011 to June 2012. A total 335 patients were evaluated by consultant neurologists during this period. Result Majority of the patients (59.7%) presented after the age of forty years. The mean age at presentation was 45.11 ± 17.3 years with a male predominance (63.3%). Stroke was the most common condition (47.5%) observed at referral, followed by seizure (9.3%), disease of spinal cord (7.8%) and encephalopathy (6.3%). Even after consultation, 30 patients remained undiagnosed and 6 were diagnosed as functional disorder. Department of Medicine (231, 69%) and Cardiology (61, 18.2%) made most of the calls. More than half (56%) of the stroke patients were referred from medicine and one third (35.2%) from cardiology. Seizure (67.7%), problem in spinal cord (92.3%), coma (50%), encephalopathy (57.1%), motor neuron disease (MND) (72.7%) were common reasons for referral from department of Medicine. Whereas patients with cord disease (7.3%), CNS tumor (40%), seizure disorder (6.5%) and stroke (3.8%) were referred from surgery. Department of Obstetrics and Gynecology sought help for stroke (2.5%), seizure (12.9%), MND (27.3%), coma (16.7%) and encephalopathy (9.5%). Hypertension, diabetes, ischemic heart disease, dyslipidaemia and respiratory problem were significantly associated co-morbid conditions in stroke patients (at 95% CI, p value is <0.001, <0.01, <0.001, <0.05, <0.05 respectively). Hematological disorders were common association among patients with cord problem (<0.05). Conclusion Wide ranges of neurological problems are often managed by physicians
Villoslada, Pablo; Steinman, Lawrence; Baranzini, Sergio E
Recent advances in molecular biology, neurobiology, genetics, and imaging have demonstrated important insights about the nature of neurological diseases. However, a comprehensive understanding of their pathogenesis is still lacking. Although reductionism has been successful in enumerating and characterizing the components of most living organisms, it has failed to generate knowledge on how these components interact in complex arrangements to allow and sustain two of the most fundamental properties of the organism as a whole: its fitness, also termed its robustness, and its capacity to evolve. Systems biology complements the classic reductionist approaches in the biomedical sciences by enabling integration of available molecular, physiological, and clinical information in the context of a quantitative framework typically used by engineers. Systems biology employs tools developed in physics and mathematics such as nonlinear dynamics, control theory, and modeling of dynamic systems. The main goal of a systems approach to biology is to solve questions related to the complexity of living systems such as the brain, which cannot be reconciled solely with the currently available tools of molecular biology and genomics. As an example of the utility of this systems biological approach, network-based analyses of genes involved in hereditary ataxias have demonstrated a set of pathways related to RNA splicing, a novel pathogenic mechanism for these diseases. Network-based analysis is also challenging the current nosology of neurological diseases. This new knowledge will contribute to the development of patient-specific therapeutic approaches, bringing the paradigm of personalized medicine one step closer to reality.
Norflus, F; Tifft, C J; McDonald, M P; Goldstein, G; Crawley, J N; Hoffmann, A; Sandhoff, K; Suzuki, K; Proia, R L
The GM2 gangliosidoses are a group of severe, neurodegenerative conditions that include Tay-Sachs disease, Sandhoff disease, and the GM2 activator deficiency. Bone marrow transplantation (BMT) was examined as a potential treatment for these disorders using a Sandhoff disease mouse model. BMT extended the life span of these mice from approximately 4.5 mo to up to 8 mo and slowed their neurologic deterioration. BMT also corrected biochemical deficiencies in somatic tissues as indicated by decreased excretion of urinary oligosaccharides, and lower glycolipid storage and increased levels of beta-hexosaminidase activity in visceral organs. Even with neurologic improvement, neither clear reduction of brain glycolipid storage nor improvement in neuronal pathology could be detected, suggesting a complex pathogenic mechanism. Histological analysis revealed beta-hexosaminidase-positive cells in the central nervous system and visceral organs with a concomitant reduction of colloidal iron-positive macrophages. These results may be important for the design of treatment approaches for the GM2 gangliosidoses. PMID:9576752
Dominiak, Agnieszka; Wilkaniec, Anna; Wroczyńsk, Piotr; Adamczyk, Agata
Selenium (34Se), an antioxidant trace element, is an important regulator of brain function. These beneficial properties that Se possesses are attributed to its ability to be incorporated into selenoproteins as an amino acid. Several selenoproteins are expressed in the brain, in which some of them, e.g. glutathione peroxidases (GPxs), thioredoxin reductases (TrxRs) or selenoprotein P (SelP), are strongly involved in antioxidant defence and in maintaining intercellular reducing conditions. Since increased oxidative stress has been implicated in neurological disorders, including Parkinson’s disease, Alzheimer’s disease, stroke, epilepsy and others, a growing body of evidence suggests that Se depletion followed by decreased activity of Se-dependent enzymes may be important factors connected with those pathologies. Undoubtedly, the remarkable progress that has been made in understanding the biological function of Se in the brain has opened up new potential possibilities for the treatment of neurological diseases by using Se as a potential drug. However, further research in the search for optimal Se donors is necessary in order to achieve an effective and safe therapeutic income. PMID:26549649
Hypophosphatemia (HP) with or without intracellular depletion of inorganic phosphate (Pi) and adenosine triphosphate has been associated with central and peripheral nervous system complications and can be observed in various diseases and conditions related to respiratory alkalosis, alcoholism (alcohol withdrawal), diabetic ketoacidosis, malnutrition, obesity, and parenteral and enteral nutrition. In addition, HP may explain serious muscular, neurological, and haematological disorders and may cause peripheral neuropathy with paresthesias and metabolic encephalopathy, resulting in confusion and seizures. The neuropathy may be improved quickly after proper phosphate replacement. Phosphate depletion has been corrected using potassium-phosphate infusion, a treatment that can restore consciousness. In severe ataxia and tetra paresis, complete recovery can occur after adequate replacement of phosphate. Patients with multiple risk factors, often with a chronic disease and severe HP that contribute to phosphate depletion, are at risk for neurologic alterations. To predict both risk and optimal phosphate replenishment requires assessing the nutritional status and risk for re-feeding hypophosphatemia. The strategy for correcting HP depends on the severity of the underlying disease and the goal for re-establishing a phosphate balance to limit the consequences of phosphate depletion.
Presecki, Paola; Mimica, Ninoslav
Involuntary emotional expression disorder (IEED) is underrecognized by clinicians, misdiagnosed as depression or bipolar disorder and undertreated, because clinicians are unfamiliar with the disorder. An important clinical consideration for IEED is that of distinguishing mood from affect. IEED describes a syndrome of relatively stereotypical episodes of uncontrollable crying and/or laughing, resulting from lesions of multiple types, in multiple brain regions, without an apparent stimulus to trigger such responses. This syndrome is common among a number of neurological diseases like patients with a stroke or traumatic brain injury (TBI), patients with amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), as well as dementias such as Alzheimer;s disease (AD), and motor disorders such as Parkinson;s disease (PD). The neuropathological cause and neurochemistry of the disorder remains unclear. There is general agreement that IEED is the result of an injury to the neurological pathways that control the expression of emotions. Adequate treatment can reduce the frequency and improve the quality of life of patients and caregivers.
Lovelace, Michael D; Varney, Bianca; Sundaram, Gayathri; Lennon, Matthew J; Lim, Chai K; Jacobs, Kelly; Guillemin, Gilles J; Brew, Bruce J
The kynurenine pathway (KP) of tryptophan metabolism has emerged in recent years as a key regulator of the production of both neuroprotective (e.g. kynurenic and picolinic acid, and the essential cofactor NAD+) and neurotoxic metabolites (e.g. quinolinic acid, 3-hydroxykynurenine). The balance between the production of the two types of metabolites is controlled by key rate-limiting enzymes such as indoleamine-2,3-dioxygenase (IDO-1), and in turn, molecular signals such as interferon-γ (IFN-γ), which activate the KP metabolism of tryptophan by this enzyme, as opposed to alternative pathways for serotonin and melatonin production. Dysregulated KP metabolism has been strongly associated with neurological diseases in recent years, and is the subject of increasing efforts to understand how the metabolites are causative of disease pathology. Concurrent with these endeavours are drug development initiatives to use inhibitors to block certain enzymes in the pathway, resulting in reduced levels of neurotoxic metabolites (e.g. quinolinic acid, an excitotoxin and N-Methyl-d-Aspartate (NMDA) receptor agonist), while in turn enhancing the bioavailability of the neuroprotective metabolites such as kynurenic acid. Neurodegenerative diseases often have a substantial autoimmune or inflammatory component; hence a greater understanding of how KP metabolites influence the inflammatory cascade is required. Additionally, challenges exist in diseases like multiple sclerosis (MS) and motor neurone disease (MND), which do not have reliable biomarkers. Clinical diagnosis can often be prolonged in order to exclude other diseases, and often diagnosis occurs at an advanced state of disease pathology, which does not allow a lengthy time for patient assessment and intervention therapies. This review considers the current evidence for involvement of the KP in several neurological diseases, in biomarkers of disease and also the parallels that exist in KP metabolism with what is known in other
Kaper, Tasso J.; Kramer, Mark A.; Rotstein, Horacio G.
Rhythmic neuronal oscillations across a broad range of frequencies, as well as spatiotemporal phenomena, such as waves and bumps, have been observed in various areas of the brain and proposed as critical to brain function. While there is a long and distinguished history of studying rhythms in nerve cells and neuronal networks in healthy organisms, the association and analysis of rhythms to diseases are more recent developments. Indeed, it is now thought that certain aspects of diseases of the nervous system, such as epilepsy, schizophrenia, Parkinson's, and sleep disorders, are associated with transitions or disruptions of neurological rhythms. This focus issue brings together articles presenting modeling, computational, analytical, and experimental perspectives about rhythms and dynamic transitions between them that are associated to various diseases.
Kaper, Tasso J. Kramer, Mark A.; Rotstein, Horacio G.
Rhythmic neuronal oscillations across a broad range of frequencies, as well as spatiotemporal phenomena, such as waves and bumps, have been observed in various areas of the brain and proposed as critical to brain function. While there is a long and distinguished history of studying rhythms in nerve cells and neuronal networks in healthy organisms, the association and analysis of rhythms to diseases are more recent developments. Indeed, it is now thought that certain aspects of diseases of the nervous system, such as epilepsy, schizophrenia, Parkinson's, and sleep disorders, are associated with transitions or disruptions of neurological rhythms. This focus issue brings together articles presenting modeling, computational, analytical, and experimental perspectives about rhythms and dynamic transitions between them that are associated to various diseases.
Rima, Bertus K; Duprex, W Paul
Morbilliviruses are a group of viruses that belong to the family Paramyxoviridae. The most instantly recognizable member is measles virus (MV) and individuals acutely infected with the virus exhibit a wide range of clinical symptoms ranging from a characteristic mild self-limiting infection to death. Canine distemper virus (CDV) and rinderpest virus (RPV) cause a similar but distinctive pathology in dogs and cattle, respectively, and these, alongside experimental MV infection of primates, have been useful models for MV pathogenesis. Traditionally, viruses were identified because a distinctive disease was observed in man or animals; an infectious agent was subsequently isolated, cultured, and this could be used to recapitulate the disease in an experimentally infected host. Thus, satisfying Koch's postulates has been the norm. More recently, particularly due to the advent of exceedingly sensitive molecular biological assays, many researchers have looked for infectious agents in disease conditions for which a viral aetiology has not been previously established. For these cases, the modified Koch's postulates of Bradford Hill have been developed as criteria to link a virus to a specific disease. Only in a few cases have these conditions been fulfilled. Therefore, many viruses have over the years been definitely and tentatively linked to human diseases and in this respect the morbilliviruses are no different. In this review, human diseases associated with morbillivirus infection have been grouped into three broad categories: (1) those which are definitely caused by the infection; (2) those which may be exacerbated or facilitated by an infection; and (3) those which currently have limited, weak, unsubstantiated or no credible scientific evidence to support any link to a morbillivirus. Thus, an attempt has been made to clarify the published data and separate human diseases actually linked to morbilliviruses from those that are merely anecdotally associated.
Innis, Sheila M
Maternal nutrition has little or no effect on many nutrients in human milk; for others, human milk may not be designed as a primary nutritional source for the infant; and for a few, maternal nutrition can lead to substantial variations in human milk quality. Human milk fatty acids are among the nutrients that show extreme sensitivity to maternal nutrition and are implicated in neurological development. Extensive development occurs in the infant brain, with growth from ∼ 350 g at birth to 925 g at 1 y, with this growth including extensive dendritic and axonal arborization. Transfer of n-6 (omega-6) and n-3 (omega-3) fatty acids from the maternal diet into human milk occurs with little interconversion of 18:2n-6 to 20:4n-6 or 18:3n-3 to docosahexaenoic acid (DHA) and little evidence of mammary gland regulation to maintain individual fatty acids constant with varying maternal fatty acid nutrition. DHA has gained attention because of its high concentrations and roles in the brain and retina. Studies addressing DHA intakes by lactating women or human milk amounts of DHA at levels above those typical in the United States and Canada on infant outcomes are inconsistent. However, separating effects of the fatty acid supply in gestation or in the weaning diet from effects on neurodevelopment solely due to human milk fatty acids is complex, particularly when neurodevelopment is assessed after the period of exclusive human milk feeding. Information on infant fatty acid intakes, including milk volume consumed and energy density, will aid in understanding of the human milk fatty acids that best support neurological development.
Fox, Michael D.; Buckner, Randy L.; Liu, Hesheng; Chakravarty, M. Mallar; Lozano, Andres M.; Pascual-Leone, Alvaro
Brain stimulation, a therapy increasingly used for neurological and psychiatric disease, traditionally is divided into invasive approaches, such as deep brain stimulation (DBS), and noninvasive approaches, such as transcranial magnetic stimulation. The relationship between these approaches is unknown, therapeutic mechanisms remain unclear, and the ideal stimulation site for a given technique is often ambiguous, limiting optimization of the stimulation and its application in further disorders. In this article, we identify diseases treated with both types of stimulation, list the stimulation sites thought to be most effective in each disease, and test the hypothesis that these sites are different nodes within the same brain network as defined by resting-state functional-connectivity MRI. Sites where DBS was effective were functionally connected to sites where noninvasive brain stimulation was effective across diseases including depression, Parkinson's disease, obsessive-compulsive disorder, essential tremor, addiction, pain, minimally conscious states, and Alzheimer’s disease. A lack of functional connectivity identified sites where stimulation was ineffective, and the sign of the correlation related to whether excitatory or inhibitory noninvasive stimulation was found clinically effective. These results suggest that resting-state functional connectivity may be useful for translating therapy between stimulation modalities, optimizing treatment, and identifying new stimulation targets. More broadly, this work supports a network perspective toward understanding and treating neuropsychiatric disease, highlighting the therapeutic potential of targeted brain network modulation. PMID:25267639
Stegelmeier, B L; James, L F; Hall, J O; Mattix, M T
About 200/2500 Spanish goats foraging on mountain rangelands of western Montana developed neurologic disease with severe rear limb weakness, knuckling of the rear fetlocks, and a hopping gait. Sick goats were of all ages and in good flesh, though they often had dull, shaggy coats. Some mildly affected animals recovered after being moved to feed lots, but others progressed to recumbency, seizures and death. At necropsy both moribund and clinically affected animals had few gross lesions; 1 animal had contusions and puncture wounds on rear legs and perineum, suggestive of predator bites. Histologic lesions included mild vacuolation of neurons and visceral epithelial cells, mild diffuse cerebral edema with minimal neuronal pyknosis, and random, multifocal Wallarian degeneration of spinal cord axons. Affected animals had elevated serum sodium, potassium and chloride levels; other mineral analyses and serum biochemistries were within normal limits. Locoweed-induced depression and inhibition of neuromuscular function coupled with water deprivation due to predation pressure allowed development of neurologic disease and hypernatremia.
Lara, Elvira; Garin, Noé; Ferrari, Alize J; Tyrovolas, Stefanos; Olaya, Beatriz; Sànchez-Riera, Lidia; Whiteford, Harvey A; Haro, Josep Maria
We used data from the Global Burden of Disease, Injuries, and Risk Factors Study 2010 to report on the burden of neuropsychiatric disorders in Spain. The summary measure of burden used in the study was the disability-adjusted life-year (DALY), which sums of the years of life lost due to premature mortality (YLLs) and the years lived with disability (YLDs). DALYs were adjusted for comorbidity and estimated with 95% uncertainty intervals. The burden of neuropsychiatric disorders accounted for 18.4% of total all-cause DALYs generated in Spain for 2010. Within this group, the top five leading causes of DALYs were: depressive disorders, Alzheimer's disease, migraine, substance-use disorders, and anxiety disorder, which accounted for 70.9% of all DALYs due to neuropsychiatric disorders. Neurological disorders represented 5.03% of total all cause YLLs, whereas mental and substance-use disorders accounted for 0.8%. Mental and substance-use disorders accounted for 22.4% of total YLDs, with depression being the most disabling disorder. Neurological disorders represented 8.3% of total YLDs. Neuropsychiatric disorders were one of the leading causes of disability in 2010. This finding contributes to our understanding of the burden of neuropsychiatric disorders in the Spanish population and highlights the importance of prioritising neuropsychiatric disorders in the Spanish public health system. Copyright © 2014 SEP y SEPB. Published by Elsevier España. All rights reserved.
Lance, Eboni I; Casella, James F; Everett, Allen D; Barron-Casella, Emily
Biomarker analysis and proteomic discovery in pediatric sickle cell disease has the potential to lead to important discoveries and improve care. The aim of this review article is to describe proteomic and biomarker articles involving neurological and developmental complications in this population. A systematic review was conducted to identify relevant research publications. Articles were selected for children under the age of 21 years with the most common subtypes of sickle cell disease. Included articles focused on growth factors (platelet-derived growth factor), intra and extracellular brain proteins (glial fibrillary acidic protein, brain-derived neurotrophic factor), and inflammatory and coagulation markers (interleukin-1β, l-selectin, thrombospondin-1, erythrocyte, and platelet-derived microparticles). Positive findings include increases in plasma brain-derived neurotrophic factor and platelet-derived growth factor with elevated transcranial Dopplers velocities, increases in platelet-derived growth factor isoform AA with overt stroke, and increases in glial fibrillary acidic protein with acute brain injury. These promising potential neuro-biomarkers provide insight into pathophysiologic processes and clinical events, but their clinical utility is yet to be established. Additional proteomics research is needed, including broad-based proteomic discovery of plasma constituents and blood cell proteins, as well as urine and cerebrospinal fluid components, before, during and after neurological and developmental complications. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Koprowski, Hilary; Zheng, Yong Mu; Heber-Katz, Ellen; Fraser, Nigel; Rorke, Lucy; Fu, Zhen Fang; Hanlon, Cathleen; Dietzschold, Bernhard
The purpose of this study was to investigate the induction of inducible nitric oxide synthase (iNOS) mRNA in the brain tissue of rats and mice under the following experimental conditions: in rats infected with borna disease virus and rabies virus, in mice infected with herpes simplex virus, and in rats after the induction of experimental allergic encephalitis. The results showed that iNOS mRNA, normally nondetectable in the brain, was present in animals after viral infection or after induction of experimental allergic encephalitis. The induction of iNOS mRNA coincided with the severity of clinical signs and in some cases with the presence of inflammatory cells in the brain. The results indicate that nitric oxide produced by cells induced by iNOS may be the toxic factor accounting for cell damage and this may open the door to approaches to the study of the pathogenesis of neurological diseases.
Nzwalo, Hipólito; Cliff, Julie
Konzo is a distinct neurological entity with selective upper motor neuron damage, characterized by an abrupt onset of an irreversible, non-progressive, and symmetrical spastic para/tetraparesis. Despite its severity, konzo remains a neglected disease. The disease is associated with high dietary cyanogen consumption from insufficiently processed roots of bitter cassava combined with a protein-deficient diet. Epidemics occur when these conditions coincide at times of severe food shortage. Up to 1993, outbreaks in poor rural areas in Africa contributed to more than 3,700 cases of konzo. The number of affected people is underestimated. From unofficial reports, the number of cases was estimated to be at least 100,000 in 2000, in contrast to the 6,788 cases reported up to 2009 from published papers. PMID:21738800
Johnson, M.A,; Pennock, J.M.; Bydder, G.M.; Steiner, R.E.; Thomas, D.J.; Hayward, R.; Bryant, D.R.T.; Payne, J.A.; Levene, M.I.; Whitelaw, A.; Dubowitz, L.M.S.; Dubowitz, V.
The results of initial clinical nuclear magnetic resonance imaging of the brain in eight normal and 52 children with a wide variety of neurologic diseases were reviewed. The high level of gray-white matter contrast available with inversion-recovery sequences provided a basis for visualizing normal myelination as well as delays or deficits in this process. The appearances seen in cases of parenchymal hemorrhage, cerebral infarction, and proencephalic cysts are described. Ventricular enlargement was readily identified and marginal edema was demonstrated with spin-echo sequences. Abnormalities were seen in cerebral palsy, congenital malformations, Hallervorden-Spatz disease, aminoaciduria, and meningitis. Space-occupying lesions were identified by virtue of their increased relaxation times and mass effects. Nuclear magnetic resonance imaging has considerable potential in pediatric neuroradiologic practice, in some conditions supplying information not available by computed tomography or sonography.
Ehmann, W.D.; Vance, D.E.; Khare, S.S.; Kasarskis, E.J.; Markesbery, W.R.
Evidence has been presented in the literature to implicate trace elements in the etiology of several age-related neurological diseases. Most of these studies are based on brain analyses. Using instrumental neutron activation analysis (INAA), we have observed trace element imbalances in brains of patients with Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and Picks's disease. The most prevalent elemental imbalances found in the brain were for bromine, mercury, and the alkali metals. In this study the authors report INAA studies of trace elements in nonneural tissues from Alzheimer's disease and ALS patients. Samples from household relatives were collected for use as controls wherever possible. Hair samples were washed according to the International Atomic Energy Agency recommended procedure. Fingernail samples were scraped with a quartz knife prior to washing by the same procedure. For ALS patients, blood samples were also collected. These data indicate that elemental imbalances in Alzheimer's disease and ALS are not restricted to the brain. Many elements perturbed in the brain are also altered in the several nonneural tissues examined to date. The imbalances in different tissues, however, are not always in the same direction. The changes observed may represent causes, effects, or simply epiphenomena. Longitudinal studies of nonneural tissues and blood, as well as tissue microprobe analyses at the cellular and subcellular level, will be required in order to better assess the role of trace elements in the etiology of these diseases.
Jorgensen, N; Cabañas, M; Oliva, J; Rejas, J; León, T
The aim of the present work is to review the Spanish literature on informal care cost in patients with a high prevalence of incapacitating neurological diseases. Stroke, dementia (including Alzheimer's disease), Parkinson's disease and multiple sclerosis were distinguished in this group. The different methods of evaluation of the informal care were also reviewed prior to analyzing the national literature on the topic. A systematical search was done in MEDLINE, ECONLIT, ABI-INFORM, CSIC data bases, IME (Index Medicus) and ISOC databases. Google was also used for searching
Dangor, Ziyaad; Lala, Sanjay G.; Cutland, Clare L.; Koen, Anthonet; Jose, Lisa; Nakwa, Firdose; Ramdin, Tanusha; Fredericks, Joy; Wadula, Jeannette; Madhi, Shabir A.
Introduction Group B Streptococcus (GBS) is a leading cause of neonatal sepsis and meningitis. We aimed to evaluate the burden of invasive early-onset (0–6 days of life, EOD) and late-onset (7–89 days, LOD) GBS disease and subsequent neurological sequelae in infants from a setting with a high prevalence (29.5%) of HIV among pregnant women. Methods A case-control study was undertaken at three secondary-tertiary care public hospitals in Johannesburg. Invasive cases in infants <3 months age were identified by surveillance of laboratories from November 2012 to February 2014. Neurodevelopmental screening was done in surviving cases and controls at 3 and 6 months of age. Results We identified 122 cases of invasive GBS disease over a 12 month period. Although the incidence (per 1,000 live births) of EOD was similar between HIV-exposed and HIV-unexposed infants (1.13 vs. 1.46; p = 0.487), there was a 4.67-fold (95%CI: 2.24–9.74) greater risk for LOD in HIV-exposed infants (2.27 vs. 0.49; p<0.001). Overall, serotypes Ia, Ib and III constituted 75.8% and 92.5% of EOD and LOD, respectively. Risk factors for EOD included offensive draining liquor (adjusted Odds Ratio: 27.37; 95%CI: 1.94–386.50) and maternal GBS bacteriuria (aOR: 8.41; 95%CI: 1.44–49.15), which was also a risk-factor for LOD (aOR: 3.49; 95%CI: 1.17–10.40). The overall case fatality rate among cases was 18.0%. The adjusted odds for neurological sequelae at 6 months age was 13.18-fold (95%CI: 1.44–120.95) greater in cases (13.2%) than controls (0.4%). Discussion The high burden of invasive GBS disease in South Africa, which is also associated with high case fatality rates and significant neurological sequelae among survivors, is partly due to the heightened risk for LOD in infants born to HIV-infected women. An effective trivalent GBS conjugate vaccine targeted at pregnant women could prevent invasive GBS disease in this setting. PMID:25849416
Pascual, J M
To expand the -supposedly- narrow relationships that exist between genes and clinical syndromes by reflecting on several illustrative examples that disturb current simplistic genotype: phenotype correlations, and to explore a variety of biological mechanisms that account for this emerging phenomenon. Because it is well known that mutations in a single gene can give rise to numerous phenotypes, it would appear, at least intuitively, that the converse relationship might also hold true: that different genotypes may converge on just one single phenotype. Several examples taken from the study of selected neurological diseases illustrate that the latter principle indeed occurs in nature because disparate human genetic anomalies manifest similarly by exhibiting only a relatively limited phenotypic repertoire. This interesting biological phenomenon and vexing clinical problem is best described as phenocopying. Conditions such as spinal muscular atrophy, congenital glycosylation disorders, and mitochondrial diseases are but a few notorious examples of phenocopying. The nervous system is endowed with a limited number of genes and of types of molecules and, especially during development, its functional repertoire, at least from an observable point of view, is also limited. Therefore, ample genotyping capabilities are necessary to avoid erring in the process of diagnostic attribution because of phenocopying.
Grabrucker, Andreas M.; Rowan, Magali; Garner, Craig C.
Homeostasis of metal ions such as Zn2+ is essential for proper brain function. Moreover, the list of psychiatric and neurodegenerative disorders involving a dysregulation of brain Zn2+-levels is long and steadily growing, including Parkinson’s and Alzheimer’s disease as well as schizophrenia, attention deficit and hyperactivity disorder, depression, amyotrophic lateral sclerosis, Down's syndrome, multiple sclerosis, Wilson’s disease and Pick’s disease. Furthermore, alterations in Zn2+-levels are seen in transient forebrain ischemia, seizures, traumatic brain injury and alcoholism. Thus, the possibility of altering Zn2+-levels within the brain is emerging as a new target for the prevention and treatment of psychiatric and neurological diseases. Although the role of Zn2+ in the brain has been extensively studied over the past decades, methods for controlled regulation and manipulation of Zn2+ concentrations within the brain are still in their infancy. Since the use of dietary Zn2+ supplementation and restriction has major limitations, new methods and alternative approaches are currently under investigation, such as the use of intracranial infusion of Zn2+ chelators or nanoparticle technologies to elevate or decrease intracellular Zn2+ levels. Therefore, this review briefly summarizes the role of Zn2+ in psychiatric and neurodegenerative diseases and highlights key findings and impediments of brain Zn2+-level manipulation. Furthermore, some methods and compounds, such as metal ion chelation, redistribution and supplementation that are used to control brain Zn2+-levels in order to treat brain disorders are evaluated. PMID:22102982
Varadan, Vijay K.
controlled manipulation of individual molecules and atoms that can interact with the human body at sub-cellular level. The recent progress in microelectronics and nanosensors crates very powerful tools for the early detection and diagnosis. The nanowire integrated potassium and dopamine sensors are ideal for the monitoring and control of many cardiovascular diseases and neurological disorders. Selected movies illustrating the applications of nanodevices to patients will be shown at the talk.
Poletaev, A. B.; Abrosimova, A. A.; Sokolov, M. A.; Gekht, A. B.; Alferova, V. V.; Gusev, E. I.; Nikolaeva, T. Ya.; Selmi, C.
The role of natural idiotypic (Id-Abs) and anti-idiotypic (AId-Abs) autoantibodies against neuro-antigens observed in different neurological disorders is not fully understood. In particular, limited experimental evidence has been provided concerning the qualitative and quantitative serological response after acute injuries of the central nervous system or during chronic mental diseases. In this study, we analyzed the specific Id-Abs and AId-Abs serological reactivities against 4 neuro-antigens in a large population of patients with ischemic stroke, schizophrenia, as well as healthy individuals. Patients with ischemic stroke were tested at different time points following the acute stroke episode and a correlation was attempted between autoantibodies response and different patterns of functional recovery. Results showed variable and detectable Id-Abs and AId-Abs in different proportions of all three populations of subjects. Among patients with different functional recovery after ischemic stroke, a difference in time-related trends of Id-Abs and AId-Abs was encountered. Our observations suggest that changes in the production of natural neurotropic Abs may engender a positive homeostatic, beside a possible pathogenic effect, in specific neurological disorders. PMID:15330451
Peng, Liang; Parpura, Vladimir; Verkhratsky, Alexei
Neuroglia of the central nervous system (CNS), represented by cells of neural (astrocytes, oligodendrocytes and NG2 glial cells) and myeloid (microglia) origins are fundamental for homeostasis of the nervous tissue. Astrocytes are critical for the development of the CNS, they are indispensable for synaptogenesis, and they define structural organisation of the nervous tissue, as well as the generation and maintenance of CNS-blood and cerebrospinal fluid-blood barriers. Astroglial cells control homeostasis of ions and neurotransmitters and provide neurones with metabolic support. Oligodendrocytes, through the process of myelination, as well as by homoeostatic support of axons provide for interneuronal connectivity. The NG2 cells receive direct synaptic inputs, and might be important elements of adult remyelination. Microglial cells, which originate from foetal macrophages invading the brain early in embryogenesis, shape the synaptic connections through removing of redundant synapses and phagocyting apoptotic neurones. Neuroglia also form the defensive system of the CNS through complex and context-specific programmes of activation, known as reactive gliosis. Many neurological diseases are associated with neurogliopathologies represented by asthenic and atrophic changes in glial cells that, through the loss or diminution of their homeostatic and defensive functions, assist evolution of pathology. Conceptually, neurological and psychiatric disorders can be regarded as failures of neuroglial homeostatic/ defensive responses, and, hence, glia represent a (much underappreciated) target for therapeutic intervention. PMID:25342938
Rice, Gillian I; Kitabayashi, Naoki; Barth, Magalie; Briggs, Tracy A; Burton, Annabel C E; Carpanelli, Maria Luisa; Cerisola, Alfredo M; Colson, Cindy; Dale, Russell C; Danti, Federica Rachele; Darin, Niklas; De Azua, Begoña; De Giorgis, Valentina; De Goede, Christian G L; Desguerre, Isabelle; De Laet, Corinne; Eslahi, Atieh; Fahey, Michael C; Fallon, Penny; Fay, Alex; Fazzi, Elisa; Gorman, Mark P; Gowrinathan, Nirmala Rani; Hully, Marie; Kurian, Manju A; Leboucq, Nicolas; Lin, Jean-Pierre S-M; Lines, Matthew A; Mar, Soe S; Maroofian, Reza; Martí-Sanchez, Laura; McCullagh, Gary; Mojarrad, Majid; Narayanan, Vinodh; Orcesi, Simona; Ortigoza-Escobar, Juan Dario; Pérez-Dueñas, Belén; Petit, Florence; Ramsey, Keri M; Rasmussen, Magnhild; Rivier, François; Rodríguez-Pombo, Pilar; Roubertie, Agathe; Stödberg, Tommy I; Toosi, Mehran Beiraghi; Toutain, Annick; Uettwiller, Florence; Ulrick, Nicole; Vanderver, Adeline; Waldman, Amy; Livingston, John H; Crow, Yanick J
We investigated the genetic, phenotypic, and interferon status of 46 patients from 37 families with neurological disease due to mutations in ADAR1. The clinicoradiological phenotype encompassed a spectrum of Aicardi-Goutières syndrome, isolated bilateral striatal necrosis, spastic paraparesis with normal neuroimaging, a progressive spastic dystonic motor disorder, and adult-onset psychological difficulties with intracranial calcification. Homozygous missense mutations were recorded in five families. We observed a p.Pro193Ala variant in the heterozygous state in 22 of 23 families with compound heterozygous mutations. We also ascertained 11 cases from nine families with a p.Gly1007Arg dominant-negative mutation, which occurred de novo in four patients, and was inherited in three families in association with marked phenotypic variability. In 50 of 52 samples from 34 patients, we identified a marked upregulation of type I interferon-stimulated gene transcripts in peripheral blood, with a median interferon score of 16.99 (interquartile range [IQR]: 10.64-25.71) compared with controls (median: 0.93, IQR: 0.57-1.30). Thus, mutations in ADAR1 are associated with a variety of clinically distinct neurological phenotypes presenting from early infancy to adulthood, inherited either as an autosomal recessive or dominant trait. Testing for an interferon signature in blood represents a useful biomarker in this context.
Arguedas, Deborah; Stewart, Jeanette; Hodgkinson, Suzanne; Batchelor, Jennifer
Wilson's Disease (WD) (also known as hepatolenticular degeneration) is a rare inherited autosomal recessive disorder of abnormal copper metabolism, with an estimated prevalence of approximately 1 in 30,000. The clinical features associated with WD are highly varied. However, subtypes generally reflect neurological, hepatic, and psychiatric symptoms. The present case study reports two brothers with a recent diagnosis of WD. Neurological symptoms and cognitive deficits were exhibited in one brother (BL) in the form of extrapyramidal features, while the other brother (AL) only exhibited hepatic symptoms. Extensive neuropsychological testing was conducted on both siblings to compare cognitive profiles. Results for BL indicated significantly impaired motor functioning and information processing speed, which impacted him significantly at school. Aspects of executive dysfunction were also apparent in addition to reduced visual and verbal memory, working memory, and attention. Results for AL revealed evidence of verbal memory difficulties and aspects of executive dysfunction. Comparison is made of the distinct and common cognitive characteristics of the cases presented in terms of implications for early intervention and management of cognitive difficulties.
Colaci, Michele; Cassone, Giulia; Manfredi, Andreina; Sebastiani, Marco; Giuggioli, Dilia; Ferri, Clodoveo
Objectives. Sjögren's syndrome (SS) may be complicated by some neurological manifestations, generally sensory polyneuropathy. Furthermore, involvement of cranial nerves was described as rare complications of SS. Methods. We reported 2 cases: the first one was a 40-year-old woman who developed neuritis of the left optic nerve as presenting symptom few years before the diagnosis of SS; the second was a 54-year-old woman who presented a paralysis of the right phrenic nerve 7 years after the SS onset. An exhaustive review of the literature on patients with cranial or phrenic nerve involvements was also carried out. Results. To the best of our knowledge, our second case represents the first observation of SS-associated phrenic nerve mononeuritis, while optic neuritis represents the most frequent cranial nerve involvement detectable in this connective tissue disease. Trigeminal neuropathy is also frequently reported, whereas neuritis involving the other cranial nerves is quite rare. Conclusions. Cranial nerve injury is a harmful complication of SS, even if less commonly recorded compared to peripheral neuropathy. Neurological manifestations may precede the clinical onset of SS; therefore, in patients with apparently isolated cranial nerve involvement, a correct diagnosis of the underlying SS is often delayed or overlooked entirely; in these instances, standard clinicoserological assessment is recommendable. PMID:25161786
Sato, Hiroshi; Matsuo, Kayoko; Osanai, Arihiro; Kamiya, Haruo; Akao, Nobuaki; Owaki, Shigeo; Furuoka, Hidefumi
Raccoon roundworms (Baylisascaris procyonis) and other Baylisascaris species cause patent or latent larva migrans (LM) in a variety of mammals and birds, including humans. It is not clear whether LM by Baylisascaris transfuga, roundworms of bears, is associated with clinical neurological disorders. To clarify this issue, ICR and BALB/c mice as well as Mongolian jirds (Meriones unguiculatus) were orally inoculated with 2,000-5,000 embryonated eggs of B. transfuga. In mice, the ascarid caused symptomatic LM of limited extent and duration, whereas the infection was fatal in jirds; i.e., they exhibited general signs such as severe depression and emaciation on days 8-11 postinfection (PI) and died, or they developed progressive and fatal neurological disorders after day 14 PI. Histological examination showed B. transfuga larvae in the brain of all mice and jirds examined, and the larvae collected from them developed to a size comparable with that of B. procyonis. There existed, however, critical differences in host reactions against larvae localized in the brain of mice and jirds; B. transfuga larvae found in mice were surrounded by granulomatous reactions and immobilized, whereas larvae found in jirds were free from any host reaction and mobile, causing extensive malacia.
Orrù, Graziella; Pettersson-Yeo, William; Marquand, Andre F; Sartori, Giuseppe; Mechelli, Andrea
Standard univariate analysis of neuroimaging data has revealed a host of neuroanatomical and functional differences between healthy individuals and patients suffering a wide range of neurological and psychiatric disorders. Significant only at group level however these findings have had limited clinical translation, and recent attention has turned toward alternative forms of analysis, including Support-Vector-Machine (SVM). A type of machine learning, SVM allows categorisation of an individual's previously unseen data into a predefined group using a classification algorithm, developed on a training data set. In recent years, SVM has been successfully applied in the context of disease diagnosis, transition prediction and treatment prognosis, using both structural and functional neuroimaging data. Here we provide a brief overview of the method and review those studies that applied it to the investigation of Alzheimer's disease, schizophrenia, major depression, bipolar disorder, presymptomatic Huntington's disease, Parkinson's disease and autistic spectrum disorder. We conclude by discussing the main theoretical and practical challenges associated with the implementation of this method into the clinic and possible future directions.
Uchino, Haruto; Nakayama, Naoki; Kazumata, Ken; Kuroda, Satoshi; Houkin, Kiyohiro
Postoperative hyperperfusion-related transient neurological deficits (TNDs) are frequently observed in adult patients with moyamoya disease who undergo direct bypass procedures. The present study evaluated the effect of the free radical scavenger edaravone on postoperative hyperperfusion in adult moyamoya disease. This study included 92 hemispheres in 72 adult patients who underwent direct bypass for moyamoya disease. Serial measurements of cerebral blood flow were conducted immediately after surgery and on postoperative days 2 and 7. In 40 hemispheres for 36 patients, edaravone (60 mg/d) was administered from the day of surgery to postsurgical day 7. The incidence of postoperative hyperperfusion and associated TNDs were compared with a control group that included 52 hemispheres in 36 patients. Radiological hyperperfusion was observed in 28 of 40 (70.0%) and 39 of 52 (75.0%) hemispheres in the edaravone and control groups, respectively (P=0.30). Hyperperfusion-related TND incidences were significantly lower in the edaravone group compared with the control group (12.5% versus 32.7%; P=0.024). Multivariate analysis demonstrated that edaravone administration (P=0.009) and left-sided surgery (P=0.037) were significantly correlated with hyperperfusion-related TNDs (odds ratios, 0.3 and 4.2, respectively). Perioperative administration of edaravone reduced the incidence of hyperperfusion-related TNDs after direct bypass procedures in adult patients with moyamoya disease. © 2016 American Heart Association, Inc.
Rosales-Reynoso, M A; Ochoa-Hernández, A B; Juárez-Vázquez, C I; Barros-Núñez, P
Today, scientists accept that the central nervous system of an adult possesses considerable morphological and functional flexibility, allowing it to perform structural remodelling processes even after the individual is fully developed and mature. In addition to the vast number of genes participating in the development of memory, different known epigenetic mechanisms are involved in normal and pathological modifications to neurons and therefore also affect the mechanisms of memory development. This study entailed a systematic review of biomedical article databases in search of genetic and epigenetic factors that participate in synaptic function and memory. The activation of gene expression in response to external stimuli also occurs in differentiated nerve cells. Neural activity induces specific forms of synaptic plasticity that permit the creation and storage of long-term memory. Epigenetic mechanisms play a key role in synaptic modification processes and in the creation and development of memory. Changes in these mechanisms result in the cognitive and memory impairment seen in neurodegenerative diseases (Alzheimer disease, Huntington disease) and in neurodevelopmental disorders (Rett syndrome, fragile X, and schizophrenia). Nevertheless, results obtained from different models are promising and point to potential treatments for some of these diseases. Copyright © 2013 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.
Rosin, A J
Mechanical deformity associated, with neurological disease is commonly encountered in the form of contractures, or pre-existing arthritis. Less common is the occurrence of ectopic calcification around the joints of a paralysed limb. Two forms of this are presented in a series of twenty patients. Para-articular calcification with the appearance of myositis ossificans around large joints of the affected limbs occurred most often. The interior of the joints was not affected, nor was there evidence of bony injury. In some cases, however, the excessive outgrowth of bone around the joint eventually resulted in a functional ankylosis by a uniting bar of bone outside the joint. The second form of calcification was periosteal, which unlike the first type was resorbed and left an area of cortical bony thickening. Images PMID:1221938
Fazzi, Elisa; Cattalini, Marco; Orcesi, Simona; Tincani, Angela; Andreoli, L; Balottin, U; De Simone, M; Fredi, M; Facchetti, F; Galli, J; Giliani, S; Izzotti, A; Meini, A; Olivieri, I; Plebani, A
Aicardi-Goutieres syndrome (AGS), described by J. Aicardi and F. Goutieres in 1984, is a rare neurological disease with onset in infancy. It is often misdiagnosed as a sequela of congenital infection or recognized later. Nowadays almost 200 cases are reported all over the world, most of them collected by the International Aicardi-Goutieres Syndrome Association (IAGSA), founded in Pavia (Italy) in 2000. AGS (MIM 225750) is a genetically-determined encephalopathy characterized by severe neurological dysfunction, acquired microcephaly associated with severe prognosis quoad valetudinem, and less frequently also quoad vitam. Some AGS children also develop some symptoms overlapping with systemic lupus erythematosus (SLE). Intracranial calcification, white matter involvement and brain atrophy revealed on MRI, lymphocytosis and elevated levels of interferon alpha (IFN-α) in the cerebrospinal fluid (CSF) are features of both AGS and congenital viral infection. No evidence of congenital infection at serological exams has ever been found. A genetic etiology was hypothesized since the first descriptions, because of the recurrence in families, and demonstrated some years ago. Nowadays five genes (AGS1-5), if mutated, can be responsible for 90% of the cases. The transmission is autosomal recessive but there are also rare "de novo" autosomal dominant cases. Even if pathogenesis is still almost unknown, it seems that responsible genes are involved in nucleic acid reparation mechanisms and consequently in a secondary activation of innate autoimmunity. The relative lack of precise information on pathogenesis and on the evolution of the disease over time has not yet allowed the creation of codified diagnostic and therapeutic models and programs.
Giraldo, Pilar; Capablo, José Luis; Alfonso, Pilar; Latre, Paz; García, Beatriz; Pocoví, Miguel
Gaucher disease (GD) is characterized by a wide spectrum of manifestations. Previous reports indicate that GD relatives could develop neurological abnormalities more frequently than the general population. We aimed to know the presence of neurological symptoms (NS) in GD patients and their relatives. From January to December 2006 we performed a postal survey contacting 42 physicians and 92 families to evaluate NS and correlate them with genetic characteristics. Statistical analysis using descriptive parameters, ANOVA, t-test and a correlation study including Pearson coefficient were performed. Information from 72 families (78.3% responses) including 99 patients and 266 relatives was obtained. Thirty type 1 GD (32.6%) reported NS: tremor 8 (8.7%), uncoordinated movements 9 (9.8%), concentration defects 11 (11.9%), strabism 7 (7.6%), deafness 8 (8.7%), Parkinson disease (PD) 7 (7.6%) and peripheral neuropathy 10 (10.9%). Thirty-six (13.5%) first or second degrees relatives presented the following NS: PD 14 (4.9%), epilepsy 8 (3.0%), tremor 7 (2.6%), deafness 2 (0.7%) and others 5 (1.9%). 17.3% of carriers had NS versus 5.7% in non-carriers (p = 0.0096). Patients with PD had mutations in S364R, D409H, L444P, [IVS4-2a ==> g; c.(-203)A ==> G], c.500insT and L336P. In relatives with PD a wide spectrum of mutations was observed: L444P, N370S, V398I, G202R, c.1439-1445del7, [E326K; N188S] and c.953delT. In other NS, predominant mutations were D409H, G195W, R120W, R147X, L336P and G377S. A higher incidence than expected of PD and other NS in GD type 1 patients and relatives was observed. These manifestations appear frequently in L444P or rare mutations carriers. It is important to perform a systematic neurological exam in type 1 GD patients and carriers with risk mutations.
Whiteford, Harvey A.; Ferrari, Alize J.; Degenhardt, Louisa; Feigin, Valery; Vos, Theo
Background The Global Burden of Disease Study 2010 (GBD 2010), estimated that a substantial proportion of the world’s disease burden came from mental, neurological and substance use disorders. In this paper, we used GBD 2010 data to investigate time, year, region and age specific trends in burden due to mental, neurological and substance use disorders. Method For each disorder, prevalence data were assembled from systematic literature reviews. DisMod-MR, a Bayesian meta-regression tool, was used to model prevalence by country, region, age, sex and year. Prevalence data were combined with disability weights derived from survey data to estimate years lived with disability (YLDs). Years lost to premature mortality (YLLs) were estimated by multiplying deaths occurring as a result of a given disorder by the reference standard life expectancy at the age death occurred. Disability-adjusted life years (DALYs) were computed as the sum of YLDs and YLLs. Results In 2010, mental, neurological and substance use disorders accounted for 10.4% of global DALYs, 2.3% of global YLLs and, 28.5% of global YLDs, making them the leading cause of YLDs. Mental disorders accounted for the largest proportion of DALYs (56.7%), followed by neurological disorders (28.6%) and substance use disorders (14.7%). DALYs peaked in early adulthood for mental and substance use disorders but were more consistent across age for neurological disorders. Females accounted for more DALYs in all mental and neurological disorders, except for mental disorders occurring in childhood, schizophrenia, substance use disorders, Parkinson’s disease and epilepsy where males accounted for more DALYs. Overall DALYs were highest in Eastern Europe/Central Asia and lowest in East Asia/the Pacific. Conclusion Mental, neurological and substance use disorders contribute to a significant proportion of disease burden. Health systems can respond by implementing established, cost effective interventions, or by supporting the
Selimovic-Hamza, Senija; Boujon, Céline L; Hilbe, Monika; Oevermann, Anna; Seuberlich, Torsten
Next-generation sequencing (NGS) has opened up the possibility of detecting new viruses in unresolved diseases. Recently, astrovirus brain infections have been identified in neurologically diseased humans and animals by NGS, among them bovine astrovirus (BoAstV) CH13/NeuroS1, which has been found in brain tissues of cattle with non-suppurative encephalitis. Only a few studies are available on neurotropic astroviruses and a causal relationship between BoAstV CH13/NeuroS1 infections and neurological disease has been postulated, but remains unproven. Aiming at making a step forward towards assessing the causality, we collected brain samples of 97 cases of cattle diagnosed with unresolved non-suppurative encephalitis, and analyzed them by in situ hybridization and immunohistochemistry, to determine the frequency and neuropathological distribution of the BoAstV CH13/NeuroS1 and its topographical correlation to the pathology. We detected BoAstV CH13/NeuroS1 RNA or proteins in neurons throughout all parts of the central nervous system (CNS) in 34% of all cases, but none were detected in cattle of the control group. In general, brain lesions had a high correlation with the presence of the virus. These findings show that a substantial proportion of cattle with non-suppurative encephalitis are infected with BoAstV CH13/NeuroS1 and further substantiate the causal relationship between neurological disease and astrovirus infections.
Selimovic-Hamza, Senija; Boujon, Céline L.; Hilbe, Monika; Oevermann, Anna; Seuberlich, Torsten
Next-generation sequencing (NGS) has opened up the possibility of detecting new viruses in unresolved diseases. Recently, astrovirus brain infections have been identified in neurologically diseased humans and animals by NGS, among them bovine astrovirus (BoAstV) CH13/NeuroS1, which has been found in brain tissues of cattle with non-suppurative encephalitis. Only a few studies are available on neurotropic astroviruses and a causal relationship between BoAstV CH13/NeuroS1 infections and neurological disease has been postulated, but remains unproven. Aiming at making a step forward towards assessing the causality, we collected brain samples of 97 cases of cattle diagnosed with unresolved non-suppurative encephalitis, and analyzed them by in situ hybridization and immunohistochemistry, to determine the frequency and neuropathological distribution of the BoAstV CH13/NeuroS1 and its topographical correlation to the pathology. We detected BoAstV CH13/NeuroS1 RNA or proteins in neurons throughout all parts of the central nervous system (CNS) in 34% of all cases, but none were detected in cattle of the control group. In general, brain lesions had a high correlation with the presence of the virus. These findings show that a substantial proportion of cattle with non-suppurative encephalitis are infected with BoAstV CH13/NeuroS1 and further substantiate the causal relationship between neurological disease and astrovirus infections. PMID:28106800
Chtarto, Abdelwahed; Bockstael, Olivier; Tshibangu, Terence; Dewitte, Olivier; Levivier, Marc; Tenenbaum, Liliane
Recombinant adeno-associated virus (rAAV) vectors mediating long term transgene expression are excellent gene therapy tools for chronic neurological diseases. While rAAV2 was the first serotype tested in the clinics, more efficient vectors derived from the rh10 serotype are currently being evaluated and other serotypes are likely to be tested in the near future. In addition, aside from the currently used stereotaxy-guided intraparenchymal delivery, new techniques for global brain transduction (by intravenous or intra-cerebrospinal injections) are very promising. Various strategies for therapeutic gene delivery to the central nervous system have been explored in human clinical trials in the past decade. Canavan disease, a genetic disease caused by an enzymatic deficiency, was the first to be approved. Three gene transfer paradigms for Parkinson's disease have been explored: converting L-dopa into dopamine through AADC gene delivery in the putamen; synthesizing GABA through GAD gene delivery in the overactive subthalamic nucleus and providing neurotrophic support through neurturin gene delivery in the nigro-striatal pathway. These pioneer clinical trials demonstrated the safety and tolerability of rAAV delivery in the human brain at moderate doses. Therapeutic effects however, were modest, emphasizing the need for higher doses of the therapeutic transgene product which could be achieved using more efficient vectors or expression cassettes. This will require re-addressing pharmacological aspects, with attention to which cases require either localized and cell-type specific expression or efficient brain-wide transgene expression, and when it is necessary to modulate or terminate the administration of transgene product. The ongoing development of targeted and regulated rAAV vectors is described. PMID:23331189
Zanin, M P; Pettingill, L N; Harvey, A R; Emerich, D F; Thanos, C G; Shepherd, R K
Cell encapsulation therapies involve the implantation of cells that secrete a therapeutic factor to provide clinical benefits. The transplanted cells are protected from immunorejection via encapsulation in a semipermeable membrane. This treatment strategy was originally investigated as a method for protecting pancreatic islets from immunorejection, thus allowing them to secrete insulin as a chronic treatment for diabetes. Since then a significant body of work has been conducted in developing cell encapsulation therapies to treat a variety of different diseases. Many of these conditions involve neurodegeneration, such as Alzheimer's and Parkinson's disease, as cell encapsulation therapies have proven to be particularly suitable for delivering therapeutics to the central nervous system. This is mainly because they offer chronic delivery of a therapeutic and can be implanted proximal to the affected tissue, bypassing the blood brain barrier, which is impermeable to many agents. Whilst these therapies are not yet widely available in the clinic, promising results have been obtained in several advanced clinical trials and further developmental work is currently underway. This review specifically examines the development of encapsulated cell therapies as treatments for neurological and sensory diseases and evaluates the challenges that are yet to be overcome before they can be made available for clinical use.
García-Albea, E; Pérez Trullen, J M
The object of this review is to recapitulate historical events tied to the discovery of Alzheimer's disease and to narrate the contribution by two graduates of the Spanish School of Neurology, N. Achúcarro and G. Lafora, who went on to describe the first cases in North America. Both Achúcarro and Lafora had studied with Alois Alzheimer at his Nervenklinik in Munich, Germany. Subsequently, their scientific skills were put to work at the neuropathology laboratory at the Government Hospital for the Insane in Washington, D.C. Achúcarro described the first American case of this disease in a 77-year-old patients in 1910. All the descriptions were accompanied by new findings, such as granular degeneration. This was the sixth case recorded in the literature worldwide. One year later, in 1911, Lafora presented a third case, a 62-year-old Civil War veteran, and subsequently a fifth case, a 50-year-old woman, in 1914. In this case Lafora observed histological structures similar to Lewy bodies. These original contributions have not been sufficiently mentioned in writings dealing with the history of Alzheimer's disease.
It is the case of the great difficulties for patients living with neurological intractable diseases to visit outpatient when the diseases are in the progressive stage. The national nursing care insurance was matured and the revised medical insurance system led to open the local supportive clinic for home care in 2006. It has set easier access to medical care at home. This is encouraging for patients who wish to continue to live with their families at their long time home. The medical care at home is where the attending physician has to demonstrate the expertise of how to assemble in- and out- interdisciplinary medical team. Moving a hospital room simply into at home does not made a medical care at home. You have to begin recognizing what gaps needed to fill in between a hospital room and at home. This is the area beyond what a family doctor single-handedly deals with due to the nature of the diseases. The dual attending physician set-up is desirable including a family doctor and a specialist.
Bowman, Michelle; Racke, Michael; Kissel, John; Imitola, Jaime
"Stem cell tourism" is a rising Internet-based industry that aims to offer unproven procedures to patients with incurable diseases. This unregulated activity is reaching the neurologist's office as well as across the world, as patients request information or clearance for such procedures. Herein, we posit the need for medical societies and licensing boards to bring this issue to the forefront of neurology because it has the potential to affect patient care with risk of morbidity and mortality, as well as to undermine public confidence in legitimate stem cell research for incurable neurological diseases such as multiple sclerosis and amyotrophic lateral sclerosis.
Khan, U; Mason, J M; Mecci, M; Yiannakou, Y
This study assessed the effectiveness of temporary sacral nerve stimulation (SNS) in patients with constipation associated with neurological disease using an off-on-off design, and evaluated the long-term response in patients undergoing permanent SNS. Patients with chronic constipation associated with neurological disease receiving specialist clinic care at the University Hospital North Durham over a 2-year period were recruited to a trial of SNS. Recordings of bowel function were made for 6 weeks (baseline) and a temporary electrode was then inserted and recordings were made for the next 3 weeks (stimulation). The electrodes were then removed and assessment was continued for a further 3 weeks (posttreatment). Patient-completed questionnaires were used to determine the severity of constipation (Global Assessment of Symptoms, Constipation, GA Constipation), symptoms (Patient Assessment of Constipation Symptoms score, PAC-SYM) and quality-of-life (Patient Assessment of Constipation-Quality Of Life score, PAC-QOL; European Quality of Life-Five-Domain score; European Quality of Life-Visual Analogue Score). Information was obtained on bowel function and medication. Physiological data were also available for transit and laser Doppler flow cytometry to measure mucosal blood flow. Twenty-two patients were recruited, of whom 18 completed the trial. GA Constipation reduced significantly during temporary SNS: -1.09 (95% CI -1.59 to -0.59; P = 0.0003). PAC-SYM and PAC-QOL scores showed similar improvements. There was also a significant fall in the time spent in the toilet (P = 0.04) and a decrease in laxative use (P = 0.03). Twelve (67%) patients responded to temporary SNS and received a permanent implant with long-term success in 50%. Sacral nerve stimulation can be effective in treating some patients with refractory severe neuroconstipation. A response to temporary SNS may predict long-term benefit in only half the patients undergoing permanent SNS. Colorectal
Ismail, Alaa M; Dubrey, Simon W; Patel, Maneesh C
A 48-year-old black male, of Nigerian heritage, presented with a 24-hour history of frontal headache of gradual onset. The headache characteristic was migranous, being described as throbbing in nature and located to the right frontal area with associated blurring of vision. Although similar to prior frequent headaches, there was now increasing unsteadiness on walking. Diagnosed 10 years earlier with Behçet's disease, the initial presentation was with oral and genital ulceration. Recurrent episodes of headache caused by neurological flare-ups resulted in a stroke at the age of 46 years. This previous stroke was ischaemic in character with involvement of the brainstem, pons, midbrain and right cerebral peduncle with extension into the right internal capsule. Surveillance brain imaging (computed tomographic and magnetic resonance imaging with venography) 10 months earlier showed brainstem disease activity (Figure 1a) with disease quiescence a month later (Figure 1b) following an escalation of immunosuppressant therapy. Regular medications comprised prednisolone 10 mg (however, regular recurrences had resulted in him taking doses of between 20 and 30 mg/day of prednisolone for most of the past 24 months) and azathioprine 150 mg daily, aspirin 75 mg daily, one adcal D3 twice daily with weekly alendronic acid, and omeprazole 20 mg daily. For headache he took topiramate 25 mg daily and for depression mirtazepine 15 mg daily. The patient was also addicted to a high level of cannabis use which he was reluctant to stop as he felt it helped his symptoms. On examination he was apyrexial and cardiovascularly stable. Neurological examination revealed a residual horizontal nystagmus to the right on lateral gaze, mild left hemiparesis with moderate spasticity, in addition to dysarthria and dysphonia from his prior stroke. A new feature was an exacerbation of gait unsteadiness. Blood tests were unremarkable and specifically the erythrocyte sedimentation rate was normal at 2 mm
Probasco, John; Sahin, Bogachan; Tran, Tung; Chung, Tae Hwan; Rosenthal, Liana Shapiro; Mari, Zoltan; Levy, Michael
Neurological diseases are prevalent in the general population, and the neurohospitalist has an important role to play in the preoperative planning for patients with and at risk for developing neurological disease. The neurohospitalist can provide patients and their families as well as anesthesiologists, surgeons, hospitalists, and other providers guidance in particular to the patient’s neurological disease and those he or she is at risk for. Here we present considerations and guidance for the neurohospitalist providing preoperative consultation for the neurological patient with or at risk of disturbances of consciousness, cerebrovascular and carotid disease, epilepsy, neuromuscular disease, and Parkinson disease. PMID:24198903
López Bravo, Alba; Parra Soto, Carlos; Bellosta Diago, Elena; Cecilio Irazola, Álvaro; Santos-Lasaosa, Sonia
Neurological involvement in Behçet's disease is rare, especially at the onset. It can present in the form of parenchymal changes or as damage to the vascular structures in its nonparenchymal form. The coexistence of both kinds of manifestations in the same patient is exceptional. We report the case of a 32-year-old patient with a history of deep venous thrombosis, who was being treated for holocranial headache, apathy, and oral and genital ulcers. Brain magnetic resonance imaging showed hyperintense lesions in the basal ganglia and white matter, and the vascular study evidenced venous thrombosis of the left transverse sinus. After confirming the diagnosis of Behçet's disease with parenchymal and nonparenchymal cerebral involvement, immunosuppressive and corticosteroid therapy was started, resulting in the remission of the symptoms. Copyright © 2017 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.
Fuenzalida, Marco; Pérez, Miguel Ángel; Arias, Hugo R
The cholinergic activity in the brain is fundamental for cognitive functions. The modulatory activity of the neurotransmitter acetylcholine (ACh) is mediated by activating a variety of nicotinic acetylcholine receptors (nAChR) and muscarinic acetylcholine receptors (mAChR). Accumulating evidence indicates that both nAChR and mAChRs can modulate the release of several other neurotransmitters, modify the threshold of long-term plasticity, finally improving learning and memory processes. Importantly, the expression, distribution, and/or function of these systems are altered in several neurological diseases. The aim of this review is to discuss our current knowledge on cholinergic receptors and their regulating synaptic functions and neuronal network activities as well as their use as targets for the development of new and clinically useful cholinergic ligands. These new therapies involve the development of novel and more selective cholinergic agonists and allosteric modulators as well as selective cholinesterase inhibitors, which may improve cognitive and behavioral symptoms, and also provide neuroprotection in several brain diseases. The review will focus on two nAChR receptor subtypes found in the mammalian brain and the most commonly targeted in drug discovery programs for neuropsychiatric disorder, the ligands of α4β2 nAChR and α7 nAChRs.
Mehler, Mark F; Mattick, John S
The progressive maturation and functional plasticity of the nervous system in health and disease involve a dynamic interplay between the transcriptome and the environment. There is a growing awareness that the previously unexplored molecular and functional interface mediating these complex gene-environmental interactions, particularly in brain, may encompass a sophisticated RNA regulatory network involving the twin processes of RNA editing and multifaceted actions of numerous subclasses of non-protein-coding RNAs. The mature nervous system encompasses a wide range of cell types and interconnections. Long-term changes in the strength of synaptic connections are thought to underlie memory retrieval, formation, stabilization, and effector functions. The evolving nervous system involves numerous developmental transitions, such as neurulation, neural tube patterning, neural stem cell expansion and maintenance, lineage elaboration, differentiation, axonal path finding, and synaptogenesis. Although the molecular bases for these processes are largely unknown, RNA-based epigenetic mechanisms appear to be essential for orchestrating these precise and versatile biological phenomena and in defining the etiology of a spectrum of neurological diseases. The concerted modulation of RNA editing and the selective expression of non-protein-coding RNAs during seminal as well as continuous state transitions may comprise the plastic molecular code needed to couple the intrinsic malleability of neural network connections to evolving environmental influences to establish diverse forms of short- and long-term memory, context-specific behavioral responses, and sophisticated cognitive capacities.
Yedavalli, Vivek; Nyberg, Eric M; Chow, Daniel S; Thaker, Ashesh A
Given the rapid evolution and technological advances in the diagnosis and treatment of acute ischaemic stroke (AIS), including the proliferation of comprehensive stroke centres and increasing emphasis on interventional stroke therapies, the need for prompt recognition of stroke due to acute large vessel occlusion has received significant attention in the recent literature. Diffusion-weighted imaging (DWI) is the gold standard for the diagnosis of acute ischaemic stroke, as images appear positive within minutes of ischaemic injury, and a high signal-to-noise ratio enables even punctate infarcts to be readily detected. DWI lesions resulting from a single arterial embolic occlusion or steno-occlusive lesion classically lateralise and conform to a specific arterial territory. When there is a central embolic source (e.g. left atrial thrombus), embolic infarcts are often found in multiple vascular territories. However, ischaemic disease arising from aetiologies other than arterial occlusion will often not conform to an arterial territory. Furthermore, there are several important entities unrelated to ischaemic disease that can present with abnormal DWI and which should not be confused with infarct. This pictorial review explores the scope and typical DWI findings of select neurologic conditions beyond acute arterial occlusion, which should not be missed or misinterpreted. • DWI abnormalities due to acute arterial occlusion must be promptly identified. • DWI abnormalities not due to arterial occlusion will often not conform to an arterial territory. • Several important non-ischaemic entities can present on DWI and should not be confused with infarct.
Ouyang, Qing; Nakayama, Tojo; Baytas, Ozan; Davidson, Shawn M.; Yang, Chendong; Schmidt, Michael; Lizarraga, Sofia B.; Mishra, Sasmita; EI-Quessny, Malak; Niaz, Saima; Gul Butt, Mirrat; Imran Murtaza, Syed; Javed, Afzal; Chaudhry, Haroon Rashid; Vaughan, Dylan J.; Hill, R. Sean; Partlow, Jennifer N.; Yoo, Seung-Yun; Lam, Anh-Thu N.; Nasir, Ramzi; Al-Saffar, Muna; Barkovich, A. James; Schwede, Matthew; Nagpal, Shailender; Rajab, Anna; DeBerardinis, Ralph J.; Housman, David E.; Mochida, Ganeshwaran H.; Morrow, Eric M.
Mutations that cause neurological phenotypes are highly informative with regard to mechanisms governing human brain function and disease. We report autosomal recessive mutations in the enzyme glutamate pyruvate transaminase 2 (GPT2) in large kindreds initially ascertained for intellectual and developmental disability (IDD). GPT2 [also known as alanine transaminase 2 (ALT2)] is one of two related transaminases that catalyze the reversible addition of an amino group from glutamate to pyruvate, yielding alanine and α-ketoglutarate. In addition to IDD, all affected individuals show postnatal microcephaly and ∼80% of those followed over time show progressive motor symptoms, a spastic paraplegia. Homozygous nonsense p.Arg404* and missense p.Pro272Leu mutations are shown biochemically to be loss of function. The GPT2 gene demonstrates increasing expression in brain in the early postnatal period, and GPT2 protein localizes to mitochondria. Akin to the human phenotype, Gpt2-null mice exhibit reduced brain growth. Through metabolomics and direct isotope tracing experiments, we find a number of metabolic abnormalities associated with loss of Gpt2. These include defects in amino acid metabolism such as low alanine levels and elevated essential amino acids. Also, we find defects in anaplerosis, the metabolic process involved in replenishing TCA cycle intermediates. Finally, mutant brains demonstrate misregulated metabolites in pathways implicated in neuroprotective mechanisms previously associated with neurodegenerative disorders. Overall, our data reveal an important role for the GPT2 enzyme in mitochondrial metabolism with relevance to developmental as well as potentially to neurodegenerative mechanisms. PMID:27601654
Kim, Joong-Seok; Park, In-Seok; Park, Hyung-Eun; Kim, Su-Young; Yun, Jung A; Jung, Chan Kwon; Sung, Hye-Young; Lee, Jin-Kwon; Kang, Won-Kyung
Extranigral non-motor signs precede the first motor manifestations of Parkinson's disease by many years in some patients. The presence of α-synuclein deposition within colon tissues in patients with Parkinson's disease can aid in identifying early neuropathological changes prior to disease onset. In the present study, we evaluated the roles of non-motor symptoms and signs and imaging biomarkers of nigral neuronal changes and α-synuclein accumulation in the colon. Twelve subjects undergoing colectomy for primary colon cancer were recruited for this study. Immunohistochemical staining for α-synuclein in normal and phosphorylated forms was performed in normally appearing colonic tissue. We evaluated 16 candidate premotor risk factors in this study cohort. Among them, ten subjects showed positive immunostaining with normal- and phosphorylated-α-synuclein. An accumulation of premotor markers in each subject was accompanied with positive normal- and phosphorylated-α-synuclein immunostaining, ranging from 2 to 7 markers per subject, whereas the absence of Lewy bodies in the colon was associated with relative low numbers of premotor signs. A principal component analysis and a cluster analysis of these premotor markers suggest that urinary symptoms were commonly clustered with deposition of peripheral phosphorylated-α-synuclein. Among other premotor marker, color vision abnormalities were related to non-smoking. This mathematical approach confirmed the clustering of premotor markers in preclinical stage of Parkinson's disease. This is the first report showing that α-synuclein in the colon and other premotor markers are related to each other in neurologically normal subjects.
Several systemic and neurological complications can occur with Plasmodium falciparum malaria, of which cerebral malaria is well known and is the most serious. Rarely, patients may suffer a neurological disorder that occurs after complete recovery from P. falciparum infection, an entity known as post-malaria neurological syndrome (PMNS). It is a rare and transient clinical syndrome in which patients with symptomatic malaria infection, after parasitic clearance from the peripheral blood, develop neurological symptoms within 2 months of recovery. We report a case of PMNS manifesting as bilateral common peroneal nerve palsy leading to foot drop.
Gaud, S; Sauvée, M; Debouverie, M
There is, to our knowledge, no study reporting the demand for health care related to neurological diseases in rural tropical areas of developing countries. Neurology is nonetheless more or less closely related to the priority health issues in these countries. Over a 6-week period, 626 patients were seen at the primary health center in the town of Madirovalo, Madagascar. Neurological disorders accounted for 11.1% of the consultations. The neurological disorders most frequently leading to consultations were headaches (42.7%), with primary headaches accounting for 16%; next came leprosy neuropathy (14.7%), with a worrisome total of 8 new cases; other peripheral neuropathies (13.3%), and epilepsy (12%). The relatively low share of the latter seems likely related to families' frequent use of traditional healers rather than Western medicine. Neurological diseases appears to represent a significant part of the health-care demand of people living in rural tropical areas of developing countries, and specific support in this specialization is essential.
Mouridsen, Svend Erik; Rich, Bente; Isager, Torben
In order to study the broader phenotype of infantile autism (IA) we compared the rates and types of epilepsy and other neurological diseases in the parents of 111 consecutively admitted patients with IA with a matched control group of parents of 330 children from the general population. All participants were screened through the nationwide Danish…
Mouridsen, Svend Erik; Rich, Bente; Isager, Torben
In order to study the broader phenotype of infantile autism (IA) we compared the rates and types of epilepsy and other neurological diseases in the parents of 111 consecutively admitted patients with IA with a matched control group of parents of 330 children from the general population. All participants were screened through the nationwide Danish…
Leite, H P; Fantozzi, G
To report on acquired experience of metabolic support for children with acute neurological diseases, emphasizing enteral tube feeding usage and metabolic assessment, and also to recommend policies aimed towards improving its implementation. Retrospective analysis. Pediatric Intensive Care Unit of Hospital do Servidor Público Estadual de São Paulo. 44 patients consecutively admitted to the Pediatric ICU over a period of 3 years who were given nutrition and metabolic support for at least 72 hours. Head trauma, CNS infections and craniotomy post-operative period following tumor exeresis were the main diagnoses. Records of protein-energy intake, nutrient supply route, nitrogen balance and length of therapy. From a total of 527 days of therapy, single parenteral nutrition was utilized for 34.3% and single enteral tube feeding for 79.1% of that period. 61.4% of the children were fed exclusively via enteral tube feeding, 9.1% via parenteral and 39.5% by both routes. The enteral tube feeding was introduced upon admission and transpyloric placement was successful in 90% of the cases. Feeding was started 48 hours after ICU admission. The caloric goal was achieved on the 7th day after admission, and thereafter parenteral nutrition was interrupted. The maximum energy supply was 104.2 +/- 23.15 kcal/kg. The median length of therapy was 11 days (range 4-38). None of the patients on tube feeding developed GI tract bleeding, pneumonia or bronchoaspiration episodes and, of the 4 patients who were given exclusive TPN, 2 developed peptic ulcer. The initial urinary urea nitrogen was 7.11 g/m2 and at discharge 6.44 g/m2. The protein supply increased from 1.49 g/kg to 3.65 g/kg (p < 0.01). The nitrogen balance increased from--7.05 to 2.2 g (p < 0.01). Children with acute neurological diseases are hypercatabolic and have high urinary nitrogen losses. The initial negative nitrogen balance can be increased by more aggressive feeding regimes than the usual ones. Early tube feeding was
Ecevit, Ciğdem; Ozgenç, Funda; Gökçay, Figen; Celebisoy, Neşe; Baran, Maşallah; Yağci, Raşit Vural
Wilson's disease (WD) is a progressive degeneration of hepatolenticular tissue caused by excessive tissue-damaging copper accumulation and in which liver involvement most frequently presents in childhood. Neurological signs also accompany liver disease with time. However, subclinical neurological involvement may occur earlier and diagnostic methods that reveal this subclinical involvement are not well established. The aim of the current study is to assess the subclinical neurological involvement by using multimodality evoked potential (EP) measurements and to explore the relationship between neurological disease and the severity of liver damage. The patient group included 28 children (mean age 11.8 ± 2.9 years, range 5.5-17) diagnosed with WD and a control group included 24 age-matched healthy children. Multimodality EP tests (Nihon Kohden Neuropack 8 4200K) of both groups were performed at the Department of Neurology Electrophysiology Laboratory of Ege University. At least one abnormal EP value was observed in 53.5% of the children in the patient group. At least on one side, there were abnormal values for visual evoked potential (VEP) P100, brainstem auditory evoked potential (BAEP) and somatosensory evoked potential (SEP), where the ratios were 25, 28.5, and 11%, respectively. Absolute latency values of patients with right-side VEP P100 and left-side BAEP I, and the interpeak latency values of right-side BAEP I-III were significantly high. The difference in right-side BAEP I-III interpeak latency between cirrhotic and noncirrhotic groups was found to be statistically significant (P<0.05). The EP examinations can be an indicator of subclinical brain damage in non-neurological WD; however, cirrhosis because of WD does not cause an increase in the EP values. Detection of changes in the EP values periodically, especially at the time of diagnosis and during the treatment follow-up, may be valuable for revealing subclinical impairment.
Allen, Mariet; Lincoln, Sarah J.; Corda, Morgane; Watzlawik, Jens O.; Carrasquillo, Minerva M.; Reddy, Joseph S.; Burgess, Jeremy D.; Nguyen, Thuy; Malphrus, Kimberly; Petersen, Ronald C.; Graff-Radford, Neill R.; Dickson, Dennis W.
Objective: To investigate and characterize putative “loss-of-function” (LOF) adenosine triphosphate–binding cassette, subfamily A member 7 (ABCA7) mutations reported to associate with Alzheimer disease (AD) risk. Methods: We genotyped 6 previously reported ABCA7 putative LOF variants in 1,465 participants with AD, 381 participants with other neuropathologies (non-AD), and 1,043 controls and assessed the overall mutational burden for association with different diagnosis groups. We measured brain ABCA7 protein and messenger RNA (mRNA) levels using Western blot and quantitative PCR, respectively, in 11 carriers of the 3 most common variants, and sequenced all 47 ABCA7 exons in these participants to screen for other coding variants. Results: At least one of the investigated variants was identified in 45 participants with late-onset Alzheimer disease, 12 participants with other neuropathologies, and 11 elderly controls. Association analysis revealed a significantly higher burden of these variants in participants with AD (p = 5.00E-04) and those with other neuropathologies (p = 8.60E-03) when compared with controls. Concurrent analysis of brain ABCA7 mRNA and protein revealed lower protein but not mRNA in p.L1403fs carriers, lower mRNA but not protein in p.E709fs carriers, and additional deleterious mutations in some c.5570+5G>C carriers. Conclusions: Our results suggest that LOF may not be a common mechanism for these ABCA7 variants and expand the list of neurologic diseases enriched for them. PMID:28097223
Allen, Mariet; Lincoln, Sarah J; Corda, Morgane; Watzlawik, Jens O; Carrasquillo, Minerva M; Reddy, Joseph S; Burgess, Jeremy D; Nguyen, Thuy; Malphrus, Kimberly; Petersen, Ronald C; Graff-Radford, Neill R; Dickson, Dennis W; Ertekin-Taner, Nilüfer
To investigate and characterize putative "loss-of-function" (LOF) adenosine triphosphate-binding cassette, subfamily A member 7 (ABCA7) mutations reported to associate with Alzheimer disease (AD) risk. We genotyped 6 previously reported ABCA7 putative LOF variants in 1,465 participants with AD, 381 participants with other neuropathologies (non-AD), and 1,043 controls and assessed the overall mutational burden for association with different diagnosis groups. We measured brain ABCA7 protein and messenger RNA (mRNA) levels using Western blot and quantitative PCR, respectively, in 11 carriers of the 3 most common variants, and sequenced all 47 ABCA7 exons in these participants to screen for other coding variants. At least one of the investigated variants was identified in 45 participants with late-onset Alzheimer disease, 12 participants with other neuropathologies, and 11 elderly controls. Association analysis revealed a significantly higher burden of these variants in participants with AD (p = 5.00E-04) and those with other neuropathologies (p = 8.60E-03) when compared with controls. Concurrent analysis of brain ABCA7 mRNA and protein revealed lower protein but not mRNA in p.L1403fs carriers, lower mRNA but not protein in p.E709fs carriers, and additional deleterious mutations in some c.5570+5G>C carriers. Our results suggest that LOF may not be a common mechanism for these ABCA7 variants and expand the list of neurologic diseases enriched for them.
Singhal, B S; Khadilkar, Satish V
The social and economic impact of neurologic disorders is being increasingly recognized in the developing world. Demographic transition, especially in large Asian populations, has resulted in a significant increase in the elderly population, bringing to the fore neurologic illnesses such as strokes, Alzheimer's disease, and Parkinson's disease. CNS infections such as retroviral diseases, tuberculosis, and malaria still account for high mortality and morbidity. Traumatic brain injury due to traffic accidents takes a high toll of life. Epilepsy continues to be a major health concern with large segments of the developing world's population receiving no treatment. A significant mismatch between the provision of specialized neurologic services and the requirement for them exists, especially in rural areas. Also, health insurance is not available for the majority, with patients having bear the costs themselves, thus limiting the procurement of available healthcare facilities. Neurologic training centers are few and the availability of laboratory facilities and equipment is largely limited to the metropolitan areas. Cultural practices, superstitious beliefs, ignorance, and social stigma may also impede the delivery of neurologic care. Optimizing available human resources, integrating primary, secondary, and tertiary healthcare tiers and making medical treatment more affordable will improve the neurologic care in the developing world. © 2014 Elsevier B.V. All rights reserved.
Jiang, Ping; Chiba, Ryosuke; Takakusaki, Kaoru; Ota, Jun
The development of a physiologically plausible computational model of a neural controller that can realize a human-like biped stance is important for a large number of potential applications, such as assisting device development and designing robotic control systems. In this paper, we develop a computational model of a neural controller that can maintain a musculoskeletal model in a standing position, while incorporating a 120-ms neurological time delay. Unlike previous studies that have used an inverted pendulum model, a musculoskeletal model with seven joints and 70 muscular-tendon actuators is adopted to represent the human anatomy. Our proposed neural controller is composed of both feed-forward and feedback controls. The feed-forward control corresponds to the constant activation input necessary for the musculoskeletal model to maintain a standing posture. This compensates for gravity and regulates stiffness. The developed neural controller model can replicate two salient features of the human biped stance: (1) physiologically plausible muscle activations for quiet standing; and (2) selection of a low active stiffness for low energy consumption. PMID:27655271
Tanaka, Keiko; Sekijima, Yoshiki; Yoshida, Kunihiro; Mizuuchi, Asako; Yamashita, Hiromi; Tamai, Mariko; Ikeda, Shu-ichi; Fukushima, Yoshimitsu
The current status of predictive genetic testing for late-onset hereditary neurological diseases in Japan is largely unknown. In this study, we analyzed data from 73 clients who visited the Division of Clinical and Molecular Genetics, Shinshu University Hospital, for the purpose of predictive genetic testing. The clients consisted of individuals with family histories of familial amyloid polyneuropathy (FAP; n=30), Huntington's disease (HD; n=16), spinocerebellar degeneration (SCD; n=14), myotonic dystrophy type 1 (DM1; n=9), familial amyotrophic lateral sclerosis type 1 (ALS1; n=3), and Alzheimer's disease (AD; n=1). Forty-nine of the 73 (67.1%) clients were in their twenties or thirties. Twenty-seven of the 73 (37.0%) clients visited a medical institution within 3 months after becoming aware of predictive genetic testing. The most common reason for requesting predictive genetic testing was a need for certainty or to reduce uncertainty and anxiety. The decision-making about marriage and having a child was also a main reason in clients in the twenties and thirties. The numbers of clients who actually underwent predictive genetic testing was 22 of 30 (73.3%) in FAP, 3 of 16 (18.8%) in HD, 6 of 10 (60.0%) in SCD, 7 of 9 (77.8%) in DM1, and 0 of 3 (0%) in ALS1 (responsible gene of the disease was unknown in 4 SCD patients and an AD patient). The percentage of test usage was lower in untreatable diseases such as HD and SCD than that in FAP, suggesting that many clients changed their way of thinking on the significance of testing through multiple genetic counseling sessions. In addition, it was obvious that existence of disease-modifying therapy promoted usage of predictive genetic testing in FAP. Improvement of genetic counseling system to manage predictive genetic testing is necessary, as consultation concerning predictive genetic testing is the main motivation to visit genetic counseling clinic in many at-risk clients.
García-Merino, A; Fernández, O; Montalbán, X; de Andrés, C; Oreja-Guevara, C; Rodríguez-Antigüedad, A; Arbizu, T
Treatments for multiple sclerosis therapy are rapidly evolving. It is believed that new drugs will be approved in the near future, thereby changing current indications for treatment. In this context, the Spanish Society of Neurology's study group on demyelinating diseases, which evaluates medication use in MS, has decided to draw up a consensus statement on the current indications and guidelines for multiple sclerosis treatment. Copyright © 2013 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.
Karaca, Ender; Harel, Tamar; Pehlivan, Davut; Jhangiani, Shalini N.; Gambin, Tomasz; Akdemir, Zeynep Coban; Gonzaga-Jauregui, Claudia; Erdin, Serkan; Bayram, Yavuz; Campbell, Ian M.; Hunter, Jill V.; Atik, Mehmed M.; Van Esch, Hilde; Yuan, Bo; Wiszniewski, Wojciech; Isikay, Sedat; Yesil, Gozde; Yuregir, Ozge O.; Bozdogan, Sevcan Tug; Aslan, Huseyin; Aydin, Hatip; Tos, Tulay; Aksoy, Ayse; De Vivo, Darryl C.; Jain, Preti; Geckinli, B. Bilge; Sezer, Ozlem; Gul, Davut; Durmaz, Burak; Cogulu, Ozgur; Ozkinay, Ferda; Topcu, Vehap; Candan, Sukru; Cebi, Alper Han; Ikbal, Mevlit; Gulec, Elif Yilmaz; Gezdirici, Alper; Koparir, Erkan; Ekici, Fatma; Coskun, Salih; Cicek, Salih; Karaer, Kadri; Koparir, Asuman; Duz, Mehmet Bugrahan; Kirat, Emre; Fenercioglu, Elif; Ulucan, Hakan; Seven, Mehmet; Guran, Tulay; Elcioglu, Nursel; Yildirim, Mahmut Selman; Aktas, Dilek; Alikaşifoğlu, Mehmet; Ture, Mehmet; Yakut, Tahsin; Overton, John D.; Yuksel, Adnan; Ozen, Mustafa; Muzny, Donna M.; Adams, David R.; Boerwinkle, Eric; Chung, Wendy K.; Gibbs, Richard A.; Lupski, James R
Development of the human nervous system involves complex interactions between fundamental cellular processes and requires a multitude of genes, many of which remain to be associated with human disease. We applied whole exome sequencing to 128 mostly consanguineous families with neurogenetic disorders that often included brain malformations. Rare variant analyses for both single nucleotide variant (SNV) and copy number variant (CNV) alleles allowed for identification of 45 novel variants in 43 known disease genes, 41 candidate genes, and CNVs in 10 families, with an overall potential molecular cause identified in >85% of families studied. Among the candidate genes identified, we found PRUNE, VARS, and DHX37 in multiple families, and homozygous loss of function variants in AGBL2, SLC18A2, SMARCA1, UBQLN1, and CPLX1. Neuroimaging and in silico analysis of functional and expression proximity between candidate and known disease genes allowed for further understanding of genetic networks underlying specific types of brain malformations. PMID:26539891
Coggrave, Maureen; Norton, Christine
People with central neurological disease or injury have a much higher risk of both faecal incontinence and constipation than the general population. There is often a fine line between the two symptoms, with any management intended to ameliorate one risking precipitating the other. Bowel problems are observed to be the cause of much anxiety and may reduce quality of life in these people. Current bowel management is largely empirical, with a limited research base. This is an update of a Cochrane review first published in 2001 and subsequently updated in 2003 and 2006. The review is relevant to individuals with any disease directly and chronically affecting the central nervous system (post-traumatic, degenerative, ischaemic or neoplastic), such as multiple sclerosis, spinal cord injury, cerebrovascular disease, Parkinson's disease and Alzheimer's disease. To determine the effects of management strategies for faecal incontinence and constipation in people with a neurological disease or injury affecting the central nervous system. We searched the Cochrane Incontinence Group Trials Register (searched 8 June 2012), which includes searches of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and MEDLINE In-Process as well as handsearching of journals and conference proceedings; and all reference lists of relevant articles. Randomised and quasi-randomised trials evaluating any type of conservative or surgical intervention for the management of faecal incontinence and constipation in people with central neurological disease or injury were selected. Specific therapies for the treatment of neurological diseases that indirectly affect bowel dysfunction were also considered. Two review authors independently assessed the risk of bias of eligible trials and independently extracted data from the included trials using a range of pre-specified outcome measures. Twenty trials involving 902 people were included.Oral medicationsThere was evidence from individual
Coggrave, Maureen; Norton, Christine; Cody, June D
People with central neurological disease or injury have a much higher risk of both faecal incontinence and constipation than the general population. There is often a fine line between the two symptoms, with any management intended to ameliorate one risking precipitating the other. Bowel problems are observed to be the cause of much anxiety and may reduce quality of life in these people. Current bowel management is largely empirical, with a limited research base. This is an update of a Cochrane review first published in 2001 and subsequently updated in 2003 and 2006. The review is relevant to individuals with any disease directly and chronically affecting the central nervous system (post-traumatic, degenerative, ischaemic or neoplastic), such as multiple sclerosis, spinal cord injury, cerebrovascular disease, Parkinson's disease and Alzheimer's disease. To determine the effects of management strategies for faecal incontinence and constipation in people with a neurological disease or injury affecting the central nervous system. We searched the Cochrane Incontinence Group Trials Register (searched 8 June 2012), which includes searches of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and MEDLINE In-Process as well as handsearching of journals and conference proceedings; and all reference lists of relevant articles. Randomised and quasi-randomised trials evaluating any type of conservative or surgical intervention for the management of faecal incontinence and constipation in people with central neurological disease or injury were selected. Specific therapies for the treatment of neurological diseases that indirectly affect bowel dysfunction were also considered. At least two review authors independently assessed the risk of bias of eligible trials and independently extracted data from the included trials using a range of pre-specified outcome measures. Twenty trials involving 902 people were included. Oral medications There was evidence from
Grishaber, J E; Cunningham, M C; Rohret, P A; Strauss, R G
We retrospectively analyzed our 2-year experience with venous access for 363 therapeutic plasma exchanges in 46 patients with neurological disease, including acute Guillain-Barré syndrome (N = 20), myasthenia gravis (N = 17), and chronic inflammatory demyelinating polyneuropathy (N = 9). Twenty-three patients (50%) completed the planned course of therapy using only peripheral venous access, and 28 central venous catheters were placed in the remaining 23 patients. Patients utilizing central venous access did not undergo a greater number of procedures, but they were more likely to have acute Guillain-Barré syndrome (P < 0.02) or to be hospitalized in a medical intensive care unit (P < 0.01). Three types of central catheters were used, and although our experience was predominantly with 1 type, differences were noted. Only 3% of procedures (3 of 96) done with a Quinton-Mahurkar catheter were associated with a catheter failure, compared to 27% (4 of 15, P < 0.01) with a Hickman catheter and 67% (2 of 3) with a triple-lumen catheter. Life-threatening complications occurred with 3 of 28 (11%) central catheters. To optimize the success of therapeutic plasma exchange using central access, it is critical that hemapheresis personnel advise each patient's primary physician regarding the type of central venous catheter required. Currently, we recommend use of a Quinton-Mahurkar or other dual-lumen hemodialysis catheter.
Yu, Seong Hun; Park, Seong Doo; Sim, Ki Chel
[Purpose] This study examined the effect of