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Sample records for human neurological disease

  1. Ionotropic GABA and Glutamate Receptor Mutations and Human Neurologic Diseases

    PubMed Central

    Yuan, Hongjie; Low, Chian-Ming; Moody, Olivia A.; Jenkins, Andrew

    2015-01-01

    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

  2. Human gene therapy and imaging in neurological diseases

    PubMed Central

    Jacobs, Andreas H.; Winkler, Alexandra; Castro, Maria G.; Lowenstein, Pedro

    2010-01-01

    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

  3. [Depression and neurological diseases].

    PubMed

    Piber, D; Hinkelmann, K; Gold, S M; Heesen, C; Spitzer, C; Endres, M; Otte, C

    2012-11-01

    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.

  4. Measles, mumps, rubella, and human parvovirus B19 infections and neurologic disease.

    PubMed

    Bale, James F

    2014-01-01

    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.

  5. Transcriptome sequencing of neurologic diseases associated genes in HHV-6A infected human astrocyte

    PubMed Central

    Tang, Junwei; Lu, Shuai; Feng, Dongju; Cheng, Ci; Qing, Lanqun; Yao, Kun; Chen, Yun

    2016-01-01

    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

  6. The Application of Human iPSCs in Neurological Diseases: From Bench to Bedside

    PubMed Central

    Xie, Nina; Tang, Beisha

    2016-01-01

    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

  7. Neurological diseases and pain

    PubMed Central

    2012-01-01

    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

  8. A novel porcine model of ataxia telangiectasia reproduces neurological features and motor deficits of human disease

    PubMed Central

    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.

    2015-01-01

    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

  9. Neurological Disease Rises from Ocean to Bring Model for Human Epilepsy to Life

    PubMed Central

    Ramsdell, John S.

    2010-01-01

    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

  10. Neurological disease rises from ocean to bring model for human epilepsy to life.

    PubMed

    Ramsdell, John S

    2010-07-01

    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.

  11. Genetically-modified human pluripotent stem cells: new hopes for the understanding and the treatment of neurological diseases?

    PubMed

    Nedelec, Stéphane; Onteniente, Brigitte; Peschanski, Marc; Martinat, Cécile

    2013-04-01

    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.

  12. Mouse models for neurological disease.

    PubMed

    Hafezparast, Majid; Ahmad-Annuar, Azlina; Wood, Nicholas W; Tabrizi, Sarah J; Fisher, Elizabeth M C

    2002-08-01

    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.

  13. Neurological complications of coeliac disease

    PubMed Central

    Pengiran, T; Wills, A; Holmes, G

    2002-01-01

    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

  14. Modeling Human Neurological and Neurodegenerative Diseases: From Induced Pluripotent Stem Cells to Neuronal Differentiation and Its Applications in Neurotrauma

    PubMed Central

    Bahmad, Hisham; Hadadeh, Ola; Chamaa, Farah; Cheaito, Katia; Darwish, Batoul; Makkawi, Ahmad-Kareem; Abou-Kheir, Wassim

    2017-01-01

    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

  15. Neurological diseases in famous painters.

    PubMed

    Piechowski-Jozwiak, Bartlomiej; Bogousslavsky, Julien

    2013-01-01

    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.

  16. Genomic medicine and neurological disease.

    PubMed

    Boone, Philip M; Wiszniewski, Wojciech; Lupski, James R

    2011-07-01

    "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.

  17. Progressive neurologic and somatic disease in a novel mouse model of human mucopolysaccharidosis type IIIC

    PubMed Central

    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

    2016-01-01

    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

  18. [Gene therapy of neurological diseases].

    PubMed

    Kahn, A; Haase, G; Akli, S; Guidotti, J E

    1996-01-01

    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

  19. Neurologic Diseases in Special Care Patients.

    PubMed

    Robbins, Miriam R

    2016-07-01

    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.

  20. Dysexecutive syndromes in neurologic disease.

    PubMed

    Hanna-Pladdy, B

    2007-09-01

    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.

  1. Human Embryonic Stem Cells: A Model for the Study of Neural Development and Neurological Diseases

    PubMed Central

    Prajumwongs, Piya; Weeranantanapan, Oratai; Jaroonwitchawan, Thiranut; Noisa, Parinya

    2016-01-01

    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

  2. Bioactivation of cyanide to cyanate in sulfur amino acid deficiency: relevance to neurological disease in humans subsisting on cassava.

    PubMed

    Tor-Agbidye, J; Palmer, V S; Lasarev, M R; Craig, A M; Blythe, L L; Sabri, M I; Spencer, P S

    1999-08-01

    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.

  3. [Neurological disease and facial recognition].

    PubMed

    Kawamura, Mitsuru; Sugimoto, Azusa; Kobayakawa, Mutsutaka; Tsuruya, Natsuko

    2012-07-01

    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.

  4. Motor unit number estimation in human neurological diseases and animal models.

    PubMed

    Shefner, J M

    2001-06-01

    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.

  5. Human Neurological Development: Past, Present and Future

    NASA Technical Reports Server (NTRS)

    Pelligra, R. (Editor)

    1978-01-01

    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.

  6. Neurological Complications of Lyme Disease

    MedlinePlus

    ... after a tick bite, include decreased concentration, irritability, memory and sleep disorders, and nerve damage in the arms and legs. × Definition Lyme disease is caused by a bacterial organism that is transmitted to humans via the bite of an infected tick. Most ...

  7. NEURON SPECIFIC α-ADRENERGIC RECEPTOR EXPRESSION IN HUMAN CEREBELLUM: IMPLICATIONS FOR EMERGING CEREBELLAR ROLES IN NEUROLOGIC DISEASE

    PubMed Central

    SCHAMBRA, U. B.; MACKENSEN, G. B.; STAFFORD-SMITH, M.; HAINES, D. E.; SCHWINN, D. A.

    2008-01-01

    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

  8. [Neurological diseases in the aged].

    PubMed

    Kameyama, M

    1990-12-01

    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.

  9. The neurogenomics view of neurological diseases.

    PubMed

    Tsuji, Shoji

    2013-06-01

    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.

  10. Molecular imaging in traditional Chinese medicine therapy for neurological diseases.

    PubMed

    Wang, Zefeng; Wan, Haitong; Li, Jinhui; Zhang, Hong; Tian, Mei

    2013-01-01

    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.

  11. Molecular Imaging in Traditional Chinese Medicine Therapy for Neurological Diseases

    PubMed Central

    Wan, Haitong; Li, Jinhui; Zhang, Hong; Tian, Mei

    2013-01-01

    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

  12. Identification of a Common Epitope between Enterovirus 71 and Human MED25 Proteins Which May Explain Virus-Associated Neurological Disease

    PubMed Central

    Fan, Peihu; Li, Xiaojun; Sun, Shiyang; Su, Weiheng; An, Dong; Gao, Feng; Kong, Wei; Jiang, Chunlai

    2015-01-01

    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

  13. Dysfunctional HCN ion channels in neurological diseases.

    PubMed

    DiFrancesco, Jacopo C; DiFrancesco, Dario

    2015-01-01

    Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are expressed as four different isoforms (HCN1-4) in the heart and in the central and peripheral nervous systems. HCN channels are activated by membrane hyperpolarization at voltages close to resting membrane potentials and carry the hyperpolarization-activated current, dubbed If (funny current) in heart and Ih in neurons. HCN channels contribute in several ways to neuronal activity and are responsible for many important cellular functions, including cellular excitability, generation, and modulation of rhythmic activity, dendritic integration, transmission of synaptic potentials, and plasticity phenomena. Because of their role, defective HCN channels are natural candidates in the search for potential causes of neurological disorders in humans. Several data, including growing evidence that some forms of epilepsy are associated with HCN mutations, support the notion of an involvement of dysfunctional HCN channels in different experimental models of the disease. Additionally, some anti-epileptic drugs are known to modify the activity of the Ih current. HCN channels are widely expressed in the peripheral nervous system and recent evidence has highlighted the importance of the HCN2 isoform in the transmission of pain. HCN channels are also present in the midbrain system, where they finely regulate the activity of dopaminergic neurons, and a potential role of these channels in the pathogenesis of Parkinson's disease has recently emerged. The function of HCN channels is regulated by specific accessory proteins, which control the correct expression and modulation of the neuronal Ih current. Alteration of these proteins can severely interfere with the physiological channel function, potentially predisposing to pathological conditions. In this review we address the present knowledge of the association between HCN dysfunctions and neurological diseases, including clinical, genetic, and physiopathological

  14. Toward precision medicine in neurological diseases.

    PubMed

    Tan, Lin; Jiang, Teng; Tan, Lan; Yu, Jin-Tai

    2016-03-01

    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.

  15. Mitochondrial Biology and Neurological Diseases

    PubMed Central

    Arun, Siddharth; Liu, Lei; Donmez, Gizem

    2016-01-01

    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 [1], while mutations in APP, PSEN1 and PSEN2 have been implicated in a variety of clinical symptoms of AD [5]. Mutant htt protein is known to cause HD [2]. 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

  16. Metabolic Disturbances in Diseases with Neurological Involvement

    PubMed Central

    Duarte, João M. N.; Schuck, Patrícia F.; Wenk, Gary L.; Ferreira, Gustavo C.

    2014-01-01

    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

  17. Neurological complications in chronic kidney disease

    PubMed Central

    Arnold, Ria; Issar, Tushar; Krishnan, Arun V

    2016-01-01

    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

  18. Astaxanthin as a Potential Neuroprotective Agent for Neurological Diseases

    PubMed Central

    Wu, Haijian; Niu, Huanjiang; Shao, Anwen; Wu, Cheng; Dixon, Brandon J.; Zhang, Jianmin; Yang, Shuxu; Wang, Yirong

    2015-01-01

    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

  19. Inhibition of human glutamine synthetase by L-methionine-S,R-sulfoximine-relevance to the treatment of neurological diseases.

    PubMed

    Jeitner, Thomas M; Cooper, Arthur J L

    2014-12-01

    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.

  20. The Neurologic Manifestations of Mitochondrial Disease

    ERIC Educational Resources Information Center

    Parikh, Sumit

    2010-01-01

    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…

  1. Sleep disorders in children with neurologic diseases.

    PubMed

    Zucconi, M; Bruni, O

    2001-12-01

    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.

  2. Management of oral secretions in neurological disease.

    PubMed

    McGeachan, Alexander J; Mcdermott, Christopher J

    2017-04-01

    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.

  3. Neurological disorders and inflammatory bowel diseases

    PubMed Central

    Casella, Giovanni; Tontini, Gian Eugenio; Bassotti, Gabrio; Pastorelli, Luca; Villanacci, Vincenzo; Spina, Luisa; Baldini, Vittorio; Vecchi, Maurizio

    2014-01-01

    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

  4. [Nutritional and metabolic aspects of neurological diseases].

    PubMed

    Planas Vilà, Mercè

    2014-01-01

    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

  5. Toward precision medicine in neurological diseases

    PubMed Central

    Tan, Lin; Jiang, Teng

    2016-01-01

    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

  6. Epigenetic mechanisms in neurological and neurodegenerative diseases

    PubMed Central

    Landgrave-Gómez, Jorge; Mercado-Gómez, Octavio; Guevara-Guzmán, Rosalinda

    2015-01-01

    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

  7. Wilson's disease and other neurological copper disorders.

    PubMed

    Bandmann, Oliver; Weiss, Karl Heinz; Kaler, Stephen G

    2015-01-01

    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.

  8. Neurologic complications of valvular heart disease.

    PubMed

    Cruz-Flores, Salvador

    2014-01-01

    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.

  9. Brain biopsy in benign neurological disease.

    PubMed

    Gilkes, C E; Love, S; Hardie, R J; Edwards, R J; Scolding, N J; Rice, C M

    2012-05-01

    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.

  10. Therapies for neurological disease in the mucopolysaccharidoses.

    PubMed

    Anson, Donald S; McIntyre, Chantelle; Byers, Sharon

    2011-04-01

    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.

  11. Trends in Mitochondrial Therapeutics for Neurological Disease.

    PubMed

    Leitão-Rocha, Ana; Guedes-Dias, Pedro; Pinho, Brígida R; Oliveira, Jorge M A

    2015-01-01

    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.

  12. Progress in stem cell therapy for major human neurological disorders.

    PubMed

    Martínez-Morales, P L; Revilla, A; Ocaña, I; González, C; Sainz, P; McGuire, D; Liste, I

    2013-10-01

    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.

  13. A mouse model for fucosidosis recapitulates storage pathology and neurological features of the milder form of the human disease

    PubMed Central

    Wolf, Heike; Stroobants, Stijn; D'Hooge, Rudi; Hermans-Borgmeyer, Irm; Lüllmann-Rauch, Renate; Dierks, Thomas; Lübke, Torben

    2016-01-01

    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

  14. The role of RNA metabolism in neurological diseases

    PubMed Central

    Abou Al-Shaar, H; Shariff, RK; Albakr, A

    2015-01-01

    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

  15. Chromogranin A immunoreactivity in human cerebrospinal fluid: properties, relationship to noradrenergic neuronal activity, and variation in neurologic disease.

    PubMed

    O'Connor, D T; Cervenka, J H; Stone, R A; Parmer, R J; Franco-Bourland, R E; Madrazo, I; Langlais, P J

    1993-10-01

    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)

  16. Managing Pain Caused By Neurological Disease

    PubMed Central

    Tunks, Eldon

    1985-01-01

    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

  17. Modeling human neurological disorders with induced pluripotent stem cells.

    PubMed

    Imaizumi, Yoichi; Okano, Hideyuki

    2014-05-01

    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

  18. Neurologic complications of sickle cell disease.

    PubMed

    Venkataraman, Akila; Adams, Robert J

    2014-01-01

    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.

  19. Cell therapy: the final frontier for treatment of neurological diseases.

    PubMed

    Dutta, Susmita; Singh, Gurbind; Sreejith, Sailaja; Mamidi, Murali Krishna; Husin, Juani Mazmin; Datta, Indrani; Pal, Rajarshi; Das, Anjan Kumar

    2013-01-01

    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.

  20. Wilson's disease and other neurological copper disorders.

    PubMed Central

    Bandmann, Oliver; Weiss, Karl Heinz; Kaler, Stephen G.

    2015-01-01

    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

  1. The mitochondrial permeability transition in neurologic disease.

    PubMed

    Norenberg, M D; Rao, K V Rama

    2007-06-01

    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.

  2. BKCa channel dysfunction in neurological diseases

    PubMed Central

    N'Gouemo, Prosper

    2014-01-01

    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

  3. Immune aging, dysmetabolism, and inflammation in neurological diseases

    PubMed Central

    Deleidi, Michela; Jäggle, Madeline; Rubino, Graziella

    2015-01-01

    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

  4. NEUROLOGICAL ASPECTS OF HUMAN GLYCOSYLATION DISORDERS

    PubMed Central

    Freeze, Hudson H.; Eklund, Erik A.; Ng, Bobby G.; Patterson, Marc C.

    2016-01-01

    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

  5. Ethical considerations in paediatric neurology: neuromuscular disease and epilepsy.

    PubMed

    Bodensteiner, John B; Ng, Yu-Tze

    2011-09-01

    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.

  6. Neurological Manifestations of Renal Diseases in Children in Qazvin/ Iran

    PubMed Central

    DALIRANI, Reza; MAHYAR, Abolfazl; AYAZI, Parviz; AHMADI, Ghazaleh

    2016-01-01

    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

  7. MicroRNA therapeutics in neurological disease.

    PubMed

    Greenberg, David S; Soreq, Hermona

    2014-01-01

    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

  8. Astrocytes: The missing link in neurological disease?

    PubMed Central

    Lin, Chia-Ching John; Deneen, Benjamin

    2013-01-01

    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

  9. Induced pluripotent stem cells and neurological disease models.

    PubMed

    Cai, Sa; Chan, Ying-Shing; Shum, Daisy Kwok-Yan

    2014-02-25

    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.

  10. Remote Physical Activity Monitoring in Neurological Disease: A Systematic Review

    PubMed Central

    Block, Valerie A. J.; Pitsch, Erica; Tahir, Peggy; Cree, Bruce A. C.; Allen, Diane D.; Gelfand, Jeffrey M.

    2016-01-01

    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

  11. Polynucleotide Kinase-Phosphatase (PNKP) Mutations and Neurologic Disease

    PubMed Central

    Dumitrache, Lavinia C.; McKinnon, Peter J.

    2016-01-01

    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

  12. Bovine diseases causing neurological signs and death in Mexican feedlots.

    PubMed

    Ramírez-Romero, Rafael; Ramírez-Hernández, Cecilia; García-Márquez, Luis Jorge; Macedo-Barragán, Rafael Julio; Martínez-Burnes, Julio; López-Mayagoitia, Alfonso

    2014-06-01

    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.

  13. Therapeutic translation of iPSCs for treating neurological disease.

    PubMed

    Yu, Diana X; Marchetto, Maria C; Gage, Fred H

    2013-06-06

    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.

  14. Preservation of glial cytoarchitecture from ex vivo human tumor and non-tumor cerebral cortical explants: A human model to study neurological diseases.

    PubMed

    Chaichana, Kaisorn L; Capilla-Gonzalez, Vivian; Gonzalez-Perez, Oscar; Pradilla, Gustavo; Han, James; Olivi, Alessandro; Brem, Henry; Garcia-Verdugo, Jose Manuel; Quiñones-Hinojosa, Alfredo

    2007-08-30

    For the human brain, in vitro models that accurately represent what occurs in vivo are lacking. Organotypic models may be the closest parallel to human brain tissue outside of a live patient. However, this model has been limited primarily to rodent-derived tissue. We present an organotypic model to maintain intraoperatively collected human tumor and non-tumor explants ex vivo for a prolonged period of time ( approximately 11 days) without any significant changes to the tissue cytoarchitecture as evidenced through immunohistochemistry and electron microscopy analyses. The ability to establish and reliably predict the cytoarchitectural changes that occur with time in an organotypic model of tumor and non-tumor human brain tissue has several potential applications including the study of cell migration on actual tissue matrix, drug toxicity on neural tissue and pharmacological treatment for brain cancers, among others.

  15. Inflammatory bowel disease: An increased risk factor for neurologic complications

    PubMed Central

    Morís, Germán

    2014-01-01

    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

  16. Recent advances in metabolomics in neurological disease, and future perspectives.

    PubMed

    Zhang, Ai-hua; Sun, Hui; Wang, Xi-jun

    2013-10-01

    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.

  17. Childhood organic neurological disease presenting as psychiatric disorder.

    PubMed Central

    Rivinus, T M; Jamison, D L; Graham, P J

    1975-01-01

    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

  18. Fertility treatment in spinal cord injury and other neurologic disease

    PubMed Central

    Trofimenko, Vera

    2016-01-01

    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

  19. Fertility treatment in spinal cord injury and other neurologic disease.

    PubMed

    Trofimenko, Vera; Hotaling, James M

    2016-02-01

    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).

  20. Molecular mimicry in autoimmune neurological disease after viral infection.

    PubMed

    Roep, Bart O

    2003-10-01

    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

  1. Parkinson's disease between internal medicine and neurology.

    PubMed

    Csoti, Ilona; Jost, Wolfgang H; Reichmann, Heinz

    2016-01-01

    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.

  2. Ketogenic diets, mitochondria, and neurological diseases

    PubMed Central

    Gano, Lindsey B.; Patel, Manisha; Rho, Jong M.

    2014-01-01

    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

  3. Ketogenic diets, mitochondria, and neurological diseases.

    PubMed

    Gano, Lindsey B; Patel, Manisha; Rho, Jong M

    2014-11-01

    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.

  4. The role of cannabinoids and leptin in neurological diseases.

    PubMed

    Agar, E

    2015-12-01

    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.

  5. Epigenetics and Triplet-Repeat Neurological Diseases.

    PubMed

    Nageshwaran, Sathiji; Festenstein, Richard

    2015-01-01

    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.

  6. Lyme disease: neurology, neurobiology, and behavior.

    PubMed

    Halperin, John J

    2014-05-01

    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.

  7. Dynamic diseases in neurology and psychiatry

    NASA Astrophysics Data System (ADS)

    Milton, John; Black, Deborah

    1995-03-01

    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.

  8. Systems biological approach on neurological disorders: a novel molecular connectivity to aging and psychiatric diseases

    PubMed Central

    2011-01-01

    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

  9. The Unstable Repeats - Three Evolving Faces of Neurological Disease

    PubMed Central

    Nelson, David L.; Orr, Harry T.; Warren, Stephen T.

    2013-01-01

    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

  10. Bullous pemphigoid and neurological disease: statistics from a dermatology service*

    PubMed Central

    Tarazona, Monica Jidid Mateus; Mota, Amanda Nascimento Cavalleiro de Macedo; Gripp, Alexandre Carlos; Unterstell, Natasha; Bressan, Aline Lopes

    2015-01-01

    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

  11. Node of Ranvier disruption as a cause of neurological diseases

    PubMed Central

    Susuki, Keiichiro

    2013-01-01

    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

  12. Induced pluripotent stem cells in the study of neurological diseases

    PubMed Central

    2011-01-01

    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

  13. Epigenetics and Triplet-Repeat Neurological Diseases

    PubMed Central

    Nageshwaran, Sathiji; Festenstein, Richard

    2015-01-01

    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

  14. Neurological aspects of neglected tropical diseases: an unrecognized burden.

    PubMed

    Jannin, Jean; Gabrielli, Albis Francesco

    2013-01-01

    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.

  15. Neurological diseases associated with viral and Mycoplasma pneumoniae infections

    PubMed Central

    Assaad, F.; Gispen, R.; Kleemola, M.; Syrůček, L.; Esteves, K.

    1980-01-01

    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

  16. [Cortical spreading depolarization: a new pathophysiological mechanism in neurological diseases].

    PubMed

    Sánchez-Porras, Renán; Robles-Cabrera, Adriana; Santos, Edgar

    2014-05-20

    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.

  17. Olfaction in Neurologic and Neurodegenerative Diseases: A Literature Review

    PubMed Central

    Godoy, Maria Dantas Costa Lima; Voegels, Richard Louis; Pinna, Fábio de Rezende; Imamura, Rui; Farfel, José Marcelo

    2014-01-01

    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

  18. Insomnia in central neurologic diseases--occurrence and management.

    PubMed

    Mayer, Geert; Jennum, Poul; Riemann, Dieter; Dauvilliers, Yves

    2011-12-01

    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.

  19. Translational neurophysiology in sheep: measuring sleep and neurological dysfunction in CLN5 Batten disease affected sheep

    PubMed Central

    Perentos, Nicholas; Martins, Amadeu Q.; Watson, Thomas C.; Bartsch, Ullrich; Mitchell, Nadia L.; Palmer, David N.; Jones, Matthew W.

    2015-01-01

    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

  20. Stem cell transplantation in neurological diseases: improving effectiveness in animal models

    PubMed Central

    Adami, Raffaella; Scesa, Giuseppe; Bottai, Daniele

    2014-01-01

    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

  1. Dysprosody nonassociated with neurological diseases--a case report.

    PubMed

    Pinto, José Antonio; Corso, Renato José; Guilherme, Ana Cláudia Rocha; Pinho, Sílvia Rebelo; Nóbrega, Monica de Oliveira

    2004-03-01

    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.

  2. Ultrasound treatment of neurological diseases--current and emerging applications.

    PubMed

    Leinenga, Gerhard; Langton, Christian; Nisbet, Rebecca; Götz, Jürgen

    2016-03-01

    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.

  3. Neurologic and psychiatric manifestations of celiac disease and gluten sensitivity.

    PubMed

    Jackson, Jessica R; Eaton, William W; Cascella, Nicola G; Fasano, Alessio; Kelly, Deanna L

    2012-03-01

    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.

  4. Neurologic involvement in patients with atypical Chediak-Higashi disease

    PubMed Central

    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

    2016-01-01

    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

  5. K-Cl cotransporters, cell volume homeostasis, and neurological disease

    PubMed Central

    Kahle, Kristopher T.; Khanna, Arjun R.; Alper, Seth L.; Adragna, Norma C.; Lauf, Peter K.; Sun, Dandan; Delpire, Eric

    2016-01-01

    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

  6. Antibodies to chondroitin sulfates A, B, and C: clinico-pathological correlates in neurological diseases.

    PubMed

    Briani, C; Santoro, M; Latov, N

    2000-08-01

    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.

  7. Nutritional Alterations Associated with Neurological and Neurosurgical Diseases

    PubMed Central

    Dionyssiotis, Yannis; Papachristos, Aris; Petropoulou, Konstantina; Papathanasiou, Jannis; Papagelopoulos, Panayiotis

    2016-01-01

    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

  8. Unintended Effects of Orphan Product Designation for Rare Neurological Diseases

    PubMed Central

    Murphy, Sinéad M; Puwanant, Araya; Griggs, Robert C.

    2012-01-01

    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

  9. Unintended effects of orphan product designation for rare neurological diseases.

    PubMed

    Murphy, Sinéad M; Puwanant, Araya; Griggs, Robert C

    2012-10-01

    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.

  10. Toxicities of Immunosuppressive Treatment of Autoimmune Neurologic Diseases

    PubMed Central

    Lallana, Enrico C; Fadul, Camilo E

    2011-01-01

    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

  11. Understanding neurological disease mechanisms in the era of epigenetics.

    PubMed

    Qureshi, Irfan A; Mehler, Mark F

    2013-06-01

    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.

  12. Could a neurological disease be a part of Mozart's pathography?

    PubMed

    Ivkić, Goran; Erdeljić, Viktorija

    2011-01-01

    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.

  13. Cerebrospinal fluid biomarkers of neurodegeneration in chronic neurological diseases.

    PubMed

    Tumani, Hayrettin; Teunissen, Charlotte; Süssmuth, Sigurd; Otto, Markus; Ludolph, Albert C; Brettschneider, Johannes

    2008-07-01

    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.

  14. Visual evoked potential findings in Behcet's disease without neurological manifestations.

    PubMed

    Anlar, Omer; Akdeniz, Necmettin; Tombul, Temel; Calka, Omer; Bilgili, Serap G

    2006-03-01

    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).

  15. Human T cell leukemia virus type I and neurologic disease: events in bone marrow, peripheral blood, and central nervous system during normal immune surveillance and neuroinflammation.

    PubMed

    Grant, Christian; Barmak, Kate; Alefantis, Timothy; Yao, Jing; Jacobson, Steven; Wigdahl, Brian

    2002-02-01

    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

  16. Texas Occurrence of Lyme Disease and Its Neurological Manifestations.

    PubMed

    Dandashi, Jad A; Nizamutdinov, Damir; Dayawansa, Samantha; Fonkem, Ekokobe; Huang, Jason H

    2016-06-01

    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.

  17. NLRP3 Inflammasome in Neurological Diseases, from Functions to Therapies

    PubMed Central

    Song, Limin; Pei, Lei; Yao, Shanglong; Wu, Yan; Shang, You

    2017-01-01

    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

  18. Preclinical Assessment of Stem Cell Therapies for Neurological Diseases

    PubMed Central

    Joers, Valerie L.; Emborg, Marina E.

    2010-01-01

    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

  19. Emerging links between homeostatic synaptic plasticity and neurological disease.

    PubMed

    Wondolowski, Joyce; Dickman, Dion

    2013-11-21

    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.

  20. Genomic Discoveries and Personalized Medicine in Neurological Diseases.

    PubMed

    Zhang, Li; Hong, Huixiao

    2015-12-07

    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.

  1. Transgenic Monkey Model of the Polyglutamine Diseases Recapitulating Progressive Neurological Symptoms

    PubMed Central

    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

    2017-01-01

    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

  2. tDCS-enhanced motor and cognitive function in neurological diseases.

    PubMed

    Flöel, Agnes

    2014-01-15

    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.

  3. Frontiers in therapeutic development of allopregnanolone for Alzheimer’s disease and other neurological disorders

    PubMed Central

    Irwin, Ronald W.; Solinsky, Christine M.; Brinton, Roberta Diaz

    2014-01-01

    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

  4. Stem and progenitor cell-derived astroglia therapies for neurological diseases

    PubMed Central

    Chen, Chen; Chan, Albert; Wen, Han; Chung, Seung-Hyuk; Deng, Wenbin; Jiang, Peng

    2015-01-01

    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

  5. Recombinant human erythropoietin improves neurological outcomes in very preterm infants

    PubMed Central

    Song, Juan; Sun, Huiqing; Xu, Falin; Kang, Wenqing; Gao, Liang; Guo, Jiajia; Zhang, Yanhua; Xia, Lei; Wang, Xiaoyang

    2016-01-01

    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

  6. Novel test of motor and other dysfunctions in mouse neurological disease models

    PubMed Central

    Barth, Albert M.I.; Mody, Istvan

    2013-01-01

    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

  7. PPAR agonists as therapeutics for CNS trauma and neurological diseases

    PubMed Central

    Mandrekar-Colucci, Shweta; Sauerbeck, Andrew; Popovich, Phillip G.; McTigue, Dana M.

    2013-01-01

    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

  8. Therapeutic Apheresis in Immunologic Renal and Neurological Diseases.

    PubMed

    Bambauer, Rolf; Latza, Reinhard; Burgard, Daniel; Schiel, Ralf

    2017-02-01

    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.

  9. Neurological images and the predictors for neurological sequelae of epidemic herpangina/hand-foot-mouth disease with encephalomyelitis.

    PubMed

    Tsai, Jeng-Dau; Kuo, Hung-Tsung; Chen, Shan-Ming; Lue, Ko-Huang; Sheu, Ji-Nan

    2014-04-01

    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.

  10. Shiga Toxin Mediated Neurologic Changes in Murine Model of Disease

    PubMed Central

    Pradhan, Suman; Pellino, Christine; MacMaster, Kayleigh; Coyle, Dennis; Weiss, Alison A.

    2016-01-01

    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

  11. Neurological Disease Produced by Varicella Zoster Virus Reactivation Without Rash

    PubMed Central

    Gilden, Don; Cohrs, Randall J.; Mahalingam, Ravi; Nagel, Maria A.

    2010-01-01

    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

  12. [Neurological diseases after lightning strike : Lightning strikes twice].

    PubMed

    Gruhn, K M; Knossalla, Frauke; Schwenkreis, Peter; Hamsen, Uwe; Schildhauer, Thomas A; Tegenthoff, Martin; Sczesny-Kaiser, Matthias

    2016-06-01

    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.

  13. Samuel Alexander Kinnier Wilson. Wilson's disease, Queen Square and neurology.

    PubMed

    Broussolle, E; Trocello, J-M; Woimant, F; Lachaux, A; Quinn, N

    2013-12-01

    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

  14. Psychiatric manifestations of neurologic disease: where are we headed?

    PubMed Central

    Lyketsos, Constantin G.; Kozauer, Nicholas; Rabins, Peter V.

    2007-01-01

    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

  15. Focused Ultrasound: An Emerging Therapeutic Modality for Neurologic Disease.

    PubMed

    Fishman, Paul S; Frenkel, Victor

    2017-02-27

    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.

  16. Neurological Complications Following Endoluminal Repair of Thoracic Aortic Disease

    SciTech Connect

    Morales, J. P.; Taylor, P. R.; Bell, R. E.; Chan, Y. C.; Sabharwal, T.; Carrell, T. W. G.; Reidy, J. F.

    2007-09-15

    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.

  17. Yellow fever vaccine-associated neurological disease, a suspicious case.

    PubMed

    Beirão, Pedro; Pereira, Patrícia; Nunes, Andreia; Antunes, Pedro

    2017-03-02

    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.

  18. HTLV-I/II seroindeterminate Western blot reactivity in a cohort of patients with neurological disease.

    PubMed

    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

    1999-09-01

    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.

  19. Exposure to lipophilic chemicals as a cause of neurological impairments, neurodevelopmental disorders and neurodegenerative diseases.

    PubMed

    Zeliger, Harold I

    2013-09-01

    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.

  20. Exposure to lipophilic chemicals as a cause of neurological impairments, neurodevelopmental disorders and neurodegenerative diseases

    PubMed Central

    2013-01-01

    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

  1. Iron as a risk factor in neurological diseases

    NASA Astrophysics Data System (ADS)

    Galazka-Friedman, Jolanta

    2008-02-01

    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).

  2. CD133-Positive Membrane Particles in Cerebrospinal Fluid of Patients with Inflammatory and Degenerative Neurological Diseases

    PubMed Central

    Bobinger, Tobias; May, Lisa; Lücking, Hannes; Kloska, Stephan P.; Burkardt, Petra; Spitzer, Philipp; Maler, Juan M.; Corbeil, Denis; Huttner, Hagen B.

    2017-01-01

    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.

  3. Genetically modified pig models for human diseases.

    PubMed

    Fan, Nana; Lai, Liangxue

    2013-02-20

    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.

  4. Rescue of Adult Hippocampal Neurogenesis in a Mouse Model of HIV Neurologic Disease

    PubMed Central

    Lee, Myoung-Hwa; Wang, Tongguang; Jang, Mi-Hyeon; Steiner, Joseph; Haughey, Norman; Ming, Guo-li; Song, Hongjun; Nath, Avindra; Venkatesan, Arun

    2011-01-01

    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

  5. Focal neurological disease in patients with acquired immunodeficiency syndrome.

    PubMed

    Skiest, Daniel J

    2002-01-01

    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.

  6. Chloride extrusion enhancers as novel therapeutics for neurological diseases.

    PubMed

    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

    2013-11-01

    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.

  7. Sindbis and Middelburg Old World Alphaviruses Associated with Neurologic Disease in Horses, South Africa

    PubMed Central

    van Niekerk, Stephanie; Human, Stacey; Williams, June; van Wilpe, Erna; Pretorius, Marthi; Swanepoel, Robert

    2015-01-01

    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

  8. Neurological Diseases, Disorders and Injuries in Canada: Highlights of a National Study.

    PubMed

    Bray, Garth M; Huggett, Deanna L

    2016-01-01

    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.

  9. Ultrasonic investigations of brain in infants with some neurological diseases

    NASA Astrophysics Data System (ADS)

    Ulezko, E. A.; Shan'ko, G. G.

    1996-05-01

    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.

  10. Functional Neurons Generated from T Cell-Derived Induced Pluripotent Stem Cells for Neurological Disease Modeling

    PubMed Central

    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

    2016-01-01

    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

  11. Structural basis for early-onset neurological disorders caused by mutations in human selenocysteine synthase

    PubMed Central

    Puppala, Anupama K.; French, Rachel L.; Matthies, Doreen; Baxa, Ulrich; Subramaniam, Sriram; Simonović, Miljan

    2016-01-01

    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

  12. Acute aseptic meningitis and diffuse myelitis as the presenting features of neurological Behcet disease.

    PubMed

    Mullins, G M; Elamin, M; Saidha, S; Ali, E; Jennings, L; Counihan, T J; Hennessy, M

    2009-12-01

    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.

  13. Noise-Induced Sensitization of Human Brain: Toward the Neurological Application of Stochastic Resonance

    NASA Astrophysics Data System (ADS)

    Yamamoto, Yoshiharu; Soma, Rika; Hidaka, Ichiro; Nozaki, Daichi; Iso-o, Noriko; Kwak, Shin

    2003-05-01

    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.

  14. The Protective and Therapeutic Function of Small Heat Shock Proteins in Neurological Diseases

    PubMed Central

    Brownell, Sara E.; Becker, Rachel A.; Steinman, Lawrence

    2012-01-01

    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

  15. The neurotechnological revolution: unlocking the brain's secrets to develop innovative technologies as well as treatments for neurological diseases.

    PubMed

    Banks, Jim

    2015-01-01

    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.

  16. Brain Dynamics: Methodological Issues and Applications in Psychiatric and Neurologic Diseases

    NASA Astrophysics Data System (ADS)

    Pezard, Laurent

    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.

  17. Therapeutic potential of human adipose-derived stem cells in neurological disorders.

    PubMed

    Chang, Keun-A; Lee, Jun-Ho; Suh, Yoo-Hun

    2014-01-01

    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.

  18. Scavenger receptor b2 as a receptor for hand, foot, and mouth disease and severe neurological diseases.

    PubMed

    Yamayoshi, Seiya; Fujii, Ken; Koike, Satoshi

    2012-01-01

    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.

  19. Maternal stress induces epigenetic signatures of psychiatric and neurological diseases in the offspring.

    PubMed

    Zucchi, Fabiola C R; Yao, Youli; Ward, Isaac D; Ilnytskyy, Yaroslav; Olson, David M; Benzies, Karen; Kovalchuk, Igor; Kovalchuk, Olga; Metz, Gerlinde A S

    2013-01-01

    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.

  20. Maternal Stress Induces Epigenetic Signatures of Psychiatric and Neurological Diseases in the Offspring

    PubMed Central

    Zucchi, Fabiola C. R.; Yao, Youli; Ward, Isaac D.; Ilnytskyy, Yaroslav; Olson, David M.; Benzies, Karen; Kovalchuk, Igor; Kovalchuk, Olga; Metz, Gerlinde A. S.

    2013-01-01

    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

  1. Intravenous immunoglobulin in neurological disease: a specialist review

    PubMed Central

    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

    2002-01-01

    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

  2. Neurological manifestations of connective tissue diseases mimicking multiple sclerosis.

    PubMed

    Pelidou, Sigliti-Henrietta; Giannopoulos, Sotiris; Tzavidi, Sotiria; Tsifetaki, Niki; Kitsos, Georgios; Stefanou, Dimitrios; Kostadima, Vassiliki; Drosos, Alexandros A; Kyritsis, Athanassios P

    2007-11-01

    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.

  3. Acute neurologic disease in Porcine rubulavirus experimentally infected piglets.

    PubMed

    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

    2017-02-15

    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

  4. New Insights into the Crosstalk between NMDARs and Iron: Implications for Understanding Pathology of Neurological Diseases

    PubMed Central

    Xu, Huamin; Jiang, Hong; Xie, Junxia

    2017-01-01

    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

  5. Histone turnover and chromatin accessibility: Critical mediators of neurological development, plasticity, and disease

    PubMed Central

    Wenderski, Wendy; Maze, Ian

    2016-01-01

    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

  6. Adaptive preconditioning in neurological diseases – therapeutic insights from proteostatic perturbations

    PubMed Central

    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.

    2016-01-01

    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

  7. Astrocyte Differentiation of Human Pluripotent Stem Cells: New Tools for Neurological Disorder Research

    PubMed Central

    Chandrasekaran, Abinaya; Avci, Hasan X.; Leist, Marcel; Kobolák, Julianna; Dinnyés, Andras

    2016-01-01

    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

  8. Health implications of creatine: can oral creatine supplementation protect against neurological and atherosclerotic disease?

    PubMed

    Wyss, Markus; Schulze, Andreas

    2002-01-01

    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

  9. Reaction time of patients with Parkinson's disease, with reference to asymmetry of neurological signs.

    PubMed

    Yokochi, F; Nakamura, R; Narabayashi, H

    1985-07-01

    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.

  10. Iatrogenic neurology.

    PubMed

    Sposato, Luciano A; Fustinoni, Osvaldo

    2014-01-01

    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.

  11. Current neurology

    SciTech Connect

    Appel, S.H. )

    1988-01-01

    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.

  12. [Biotidinase deficiency: a disease with neurologic and cutaneous expression susceptible to biotin].

    PubMed

    de Parscau, L; Beaufrère, B; Vianey-Liaud, C; Rolland, M O; Langue, J; Divry, P; Guibaud, P

    1989-01-01

    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.

  13. Systems-level thinking for nanoparticle-mediated therapeutic delivery to neurological diseases.

    PubMed

    Curtis, Chad; Zhang, Mengying; Liao, Rick; Wood, Thomas; Nance, Elizabeth

    2017-03-01

    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.

  14. Infection of immunodeficient horses with Sarcocystis neurona does not result in neurologic disease.

    PubMed

    Sellon, Debra C; Knowles, Donald P; Greiner, Ellis C; Long, Maureen T; Hines, Melissa T; Hochstatter, Tressa; Tibary, Ahmed; Dame, John B

    2004-11-01

    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.

  15. [Results and outlooks of using cell technologies in the treatment of neurological diseases].

    PubMed

    Ugriumov, M V; Konovalov, A N; Gusev, E I

    2004-01-01

    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

  16. Recent achievements in restorative neurology: Progressive neuromuscular diseases

    SciTech Connect

    Dimitrijevic, M.R.; Kakulas, B.A.; Vrbova, G.

    1986-01-01

    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.

  17. The Social Context Network Model in Psychiatric and Neurological Diseases.

    PubMed

    Baez, Sandra; García, Adolfo M; Ibanez, Agustín

    2017-01-01

    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.

  18. Blood-brain interfaces and bilirubin-induced neurological diseases.

    PubMed

    Ghersi-Egea, J F; Gazzin, S; Strazielle, N

    2009-01-01

    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.

  19. Glyphosate, pathways to modern diseases III: Manganese, neurological diseases, and associated pathologies

    PubMed Central

    Samsel, Anthony; Seneff, Stephanie

    2015-01-01

    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

  20. Glyphosate, pathways to modern diseases III: Manganese, neurological diseases, and associated pathologies.

    PubMed

    Samsel, Anthony; Seneff, Stephanie

    2015-01-01

    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.

  1. Translational research on cognitive and behavioural disorders in neurological and psychiatric diseases.

    PubMed

    Corvol, Jean-Christophe; Goni, Sylvia; Bordet, Régis

    2016-02-01

    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.

  2. Sustained normalization of neurological disease after intracranial gene therapy in a feline model**

    PubMed Central

    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.

    2015-01-01

    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

  3. Utility of Induced Pluripotent Stem Cells for the Study and Treatment of Genetic Diseases: Focus on Childhood Neurological Disorders

    PubMed Central

    Barral, Serena; Kurian, Manju A.

    2016-01-01

    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

  4. Next generation sequencing for neurological diseases: New hope or new hype?

    PubMed Central

    Keogh, M.J.; Chinnery, P.F.

    2013-01-01

    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

  5. Disregard of neurological impairments associated with neglected tropical diseases in Africa.

    PubMed

    Quansah, Emmanuel; Sarpong, Esther; Karikari, Thomas K

    2016-06-01

    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.

  6. Human retroviruses and neoplastic disease.

    PubMed

    Kaplan, M H

    1993-11-01

    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.

  7. Looks can be deceiving: three cases of neurological diseases mimicking Guillain-Barrè syndrome.

    PubMed

    Sciacca, G; Nicoletti, A; Fermo, S Lo; Mostile, G; Giliberto, C; Zappia, Mario

    2016-04-01

    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.

  8. Induced pluripotent stem cells (iPSCs) and neurological disease modeling: progress and promises

    PubMed Central

    Marchetto, Maria C.; Brennand, Kristen J.; Boyer, Leah F.; Gage, Fred H.

    2011-01-01

    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

  9. Seizure control and improvement of neurological dysfunction in Lafora disease with perampanel

    PubMed Central

    Dirani, Maya; Nasreddine, Wassim; Abdulla, Fatima; Beydoun, Ahmad

    2014-01-01

    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

  10. Developing retinal biomarkers of neurological disease: an analytical perspective.

    PubMed

    MacCormick, Ian J C; Czanner, Gabriela; Faragher, Brian

    2015-01-01

    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.

  11. Developing retinal biomarkers of neurological disease: an analytical perspective

    PubMed Central

    MacCormick, Ian JC; Czanner, Gabriela; Faragher, Brian

    2015-01-01

    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

  12. Systemic oxidative stress associated with the neurological diseases of aging.

    PubMed

    Serra, Jorge A; Domínguez, Raúl O; Marschoff, Enrique R; Guareschi, Eduardo M; Famulari, Arturo L; Boveris, Alberto

    2009-12-01

    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.

  13. 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.

    PubMed Central

    1996-01-01

    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

  14. Revisiting Mitochondrial Function and Metabolism in Pluripotent Stem Cells: Where Do We Stand in Neurological Diseases?

    PubMed

    Lopes, Carla; Rego, A Cristina

    2017-04-01

    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.

  15. Calcium channels, neuromuscular synaptic transmission and neurological diseases.

    PubMed

    Urbano, Francisco J; Pagani, Mario R; Uchitel, Osvaldo D

    2008-09-15

    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.

  16. Simultaneous expression of Borrelia OspA and OspC and IgM response in cerebrospinal fluid in early neurologic Lyme disease.

    PubMed Central

    Schutzer, S E; Coyle, P K; Krupp, L B; Deng, Z; Belman, A L; Dattwyler, R; Luft, B J

    1997-01-01

    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

  17. The use of complementary and alternative medicine in children with common neurologic diseases

    PubMed Central

    Yeon, Gyu-Min

    2016-01-01

    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

  18. The genetics of Parkinson disease: Implications for neurological care.

    PubMed

    Klein, Christine; Schlossmacher, Michael G

    2006-03-01

    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!').

  19. Predicting targets of compounds against neurological diseases using cheminformatic methodology

    NASA Astrophysics Data System (ADS)

    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.

    2015-02-01

    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).

  20. Efficient and versatile CRISPR engineering of human neurons in culture to model neurological disorders.

    PubMed

    Shah, Ruth R; Cholewa-Waclaw, Justyna; Davies, Faith C J; Paton, Katie M; Chaligne, Ronan; Heard, Edith; Abbott, Catherine M; Bird, Adrian P

    2016-11-15

    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.

  1. Efficient and versatile CRISPR engineering of human neurons in culture to model neurological disorders

    PubMed Central

    2016-01-01

    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

  2. 76 FR 36993 - Medical Devices; Neurological Devices; Clarification of Classification for Human Dura Mater...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-06-24

    ... 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 AGENCY: Food and Drug Administration, HHS. ACTION: Final rule; technical amendment. SUMMARY: The Food...

  3. Cutaneous and neurologic disease associated with HTLV-I infection.

    PubMed

    Sharata, H H; Colvin, J H; Fujiwara, K; Goldman, B; Hashimoto, K

    1997-05-01

    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.

  4. 123I-Meta-iodobenzylguanidine Sympathetic Imaging: Standardization and Application to Neurological Diseases

    PubMed Central

    Yamada, Masahito

    2016-01-01

    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

  5. MicroRNAs: Key Regulators in the Central Nervous System and Their Implication in Neurological Diseases

    PubMed Central

    Cao, Dan-Dan; Li, Lu; Chan, Wai-Yee

    2016-01-01

    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

  6. Adhesive arachnoiditis in mixed connective tissue disease: a rare neurological manifestation.

    PubMed

    Khan, Maria Usman; Devlin, James Anthony Joseph; Fraser, Alexander

    2016-12-16

    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.

  7. Adhesive arachnoiditis in mixed connective tissue disease: a rare neurological manifestation

    PubMed Central

    Devlin, James Anthony Joseph; Fraser, Alexander

    2016-01-01

    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

  8. Clinical and immunological relevance of anti-neuronal antibodies in celiac disease with neurological manifestations

    PubMed Central

    Caio, Giacomo; Giorgio, Roberto De; Venturi, Alessandro; Giancola, Fiorella; Latorre, Rocco; Boschetti, Elisa; Serra, Mauro; Ruggeri, Eugenio; Volta, Umberto

    2015-01-01

    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

  9. A hypothetical neurological association between dehumanization and human rights abuses.

    PubMed

    Murrow, Gail B; Murrow, Richard

    2015-07-01

    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.

  10. RNA structures as mediators of neurological diseases and as drug targets

    PubMed Central

    Bernat, Viachaslau; Disney, Matthew D.

    2015-01-01

    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

  11. An update of neurological manifestations of vasculitides and connective tissue diseases: a literature review

    PubMed Central

    Bougea, Anastasia; Anagnostou, Evangelos; Spandideas, Nikolaos; Triantafyllou, Nikolaos; Kararizou, Evangelia

    2015-01-01

    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

  12. RNA Structures as Mediators of Neurological Diseases and as Drug Targets.

    PubMed

    Bernat, Viachaslau; Disney, Matthew D

    2015-07-01

    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.

  13. AMPA receptors as drug targets in neurological disease--advantages, caveats, and future outlook.

    PubMed

    Chang, Philip K-Y; Verbich, David; McKinney, R Anne

    2012-06-01

    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.

  14. The crystal structure of human GlnRS provides basis for the development of neurological disorders

    PubMed Central

    Ognjenović, Jana; Wu, Jiang; Matthies, Doreen; Baxa, Ulrich; Subramaniam, Sriram; Ling, Jiqiang; Simonović, Miljan

    2016-01-01

    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

  15. The crystal structure of human GlnRS provides basis for the development of neurological disorders

    DOE PAGES

    Ognjenovic, Jana; Wu, Jiang; Matthies, Doreen; ...

    2016-02-10

    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

  16. The crystal structure of human GlnRS provides basis for the development of neurological disorders

    SciTech Connect

    Ognjenovic, Jana; Wu, Jiang; Matthies, Doreen; Baxa, Ulrich; Subramaniam, Sriram; Ling, Jiqiang; Simonovic, Miljan

    2016-02-10

    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

  17. A hypothetical neurological association between dehumanization and human rights abuses

    PubMed Central

    Murrow, Gail B.; Murrow, Richard

    2015-01-01

    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

  18. Traumatic brain injury is associated with subsequent neurologic and psychiatric disease: a meta-analysis

    PubMed Central

    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.

    2016-01-01

    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

  19. Neurologic Diseases

    MedlinePlus

    ... brain, spinal cord, and nerves make up the nervous system. Together they control all the workings of the ... something goes wrong with a part of your nervous system, you can have trouble moving, speaking, swallowing, breathing, ...

  20. Behcet's Disease

    MedlinePlus

    ... 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 ...

  1. 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.

    PubMed

    Ren, Wuze; Mumbauer, Alexandra; Gettie, Agegnehu; Seaman, Michael S; Russell-Lodrigue, Kasi; Blanchard, James; Westmoreland, Susan; Cheng-Mayer, Cecilia

    2013-06-01

    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.

  2. Depressive symptoms in Parkinson’s disease and in non-neurological medical illnesses

    PubMed Central

    Assogna, Francesca; Fagioli, Sabrina; Cravello, Luca; Meco, Giuseppe; Pierantozzi, Mariangela; Stefani, Alessandro; Imperiale, Francesca; Caltagirone, Carlo; Pontieri, Francesco E; Spalletta, Gianfranco

    2013-01-01

    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

  3. Barriers to care for patients with neurologic disease in rural Zambia.

    PubMed

    Birbeck, G L

    2000-03-01

    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

  4. Overstimulation of the inhibitory nervous system plays a role in the pathogenesis of neuromuscular and neurological diseases: a novel hypothesis

    PubMed Central

    Tuk, Bert

    2016-01-01

    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

  5. Neurologic disease induced in transgenic mice by cerebral overexpression of interleukin 6.

    PubMed Central

    Campbell, I L; Abraham, C R; Masliah, E; Kemper, P; Inglis, J D; Oldstone, M B; Mucke, L

    1993-01-01

    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

  6. Zebrafish: An in vivo model for the study of neurological diseases

    PubMed Central

    Best, J D; Alderton, Wendy K

    2008-01-01

    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

  7. Newer insights to the neurological diseases among biblical characters of old testament

    PubMed Central

    Mathew, Stephen K.; Pandian, Jeyaraj D.

    2010-01-01

    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

  8. Translational Meta-analytical Methods to Localize the Regulatory Patterns of Neurological Disorders in the Human Brain

    PubMed Central

    Sochat, Vanessa; David, Maude; Wall, Dennis P

    2015-01-01

    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

  9. Stem Cells in Large Animal Models of Retinal and Neurological Disease

    DTIC Science & Technology

    2012-01-01

    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

  10. Physiochemical basis of human degenerative disease

    PubMed Central

    Lipinski, Boguslaw

    2015-01-01

    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

  11. Recent evidence for an expanded role of the kynurenine pathway of tryptophan metabolism in neurological diseases.

    PubMed

    Lovelace, Michael D; Varney, Bianca; Sundaram, Gayathri; Lennon, Matthew J; Lim, Chai K; Jacobs, Kelly; Guillemin, Gilles J; Brew, Bruce J

    2017-01-01

    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

  12. Management of disease-modifying treatments in neurological autoimmune diseases of the central nervous system

    PubMed Central

    Salmen, A; Gold, R; Chan, A

    2014-01-01

    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

  13. [Swiss scrapie surveillance. I. Clinical aspects of neurological diseases in sheep and goats].

    PubMed

    Maurer, E; Botteron, C; Ehrensperger, F; Fatzer, R; Jaggy, A; Kolly, C; Meylan, M; Zurbriggen, A; Doherr, M G

    2005-10-01

    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.

  14. Approach to Neurometabolic Diseases from a Pediatric Neurological Point of View

    PubMed Central

    KARIMZADEH, Parvaneh

    2015-01-01

    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

  15. Error awareness and the insula: links to neurological and psychiatric diseases

    PubMed Central

    Klein, Tilmann A.; Ullsperger, Markus; Danielmeier, Claudia

    2013-01-01

    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

  16. Enhancing CNS repair in neurological disease: challenges arising from neurodegeneration and rewiring of the network.

    PubMed

    Xu, Xiaohua; Warrington, Arthur E; Bieber, Allan J; Rodriguez, Moses

    2011-07-01

    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

  17. Persistent neurological damage associated with spontaneous recurrent seizures and atypical aggressive behavior of domoic acid epileptic disease.

    PubMed

    Tiedeken, Jessica A; Ramsdell, John S

    2013-05-01

    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.

  18. Neurological complications of sickle cell disease in Africa: protocol for a systematic review

    PubMed Central

    Mengnjo, Michel K; Kamtchum-Tatuene, Joseph; Nicastro, Nicolas; Noubiap, Jean Jacques N

    2016-01-01

    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

  19. DYNC1H1 mutations associated with neurological diseases compromise processivity of dynein–dynactin–cargo adaptor complexes

    PubMed Central

    Hoang, Ha Thi; Schlager, Max A.; Carter, Andrew P.

    2017-01-01

    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

  20. DYNC1H1 mutations associated with neurological diseases compromise processivity of dynein-dynactin-cargo adaptor complexes.

    PubMed

    Hoang, Ha Thi; Schlager, Max A; Carter, Andrew P; Bullock, Simon L

    2017-02-28

    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.

  1. Can BACE1 Inhibition Mitigate Early Axonal Pathology in Neurological Diseases?

    PubMed Central

    Yan, Xiao-Xin; Ma, Chao; Gai, Wei-Ping; Cai, Huaibin; Luo, Xue-Gang

    2014-01-01

    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

  2. Neurologic Disease in Captive Lions (Panthera leo) with Low-Titer Lion Lentivirus Infection▿

    PubMed Central

    Brennan, Greg; Podell, Michael D.; Wack, Raymund; Kraft, Susan; Troyer, Jennifer L.; Bielefeldt-Ohmann, Helle; VandeWoude, Sue

    2006-01-01

    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

  3. Neurologic disease in captive lions (Panthera leo) with low-titer lion lentivirus infection.

    PubMed

    Brennan, Greg; Podell, Michael D; Wack, Raymund; Kraft, Susan; Troyer, Jennifer L; Bielefeldt-Ohmann, Helle; VandeWoude, Sue

    2006-12-01

    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.

  4. Risk of neurological diseases among survivors of electric shocks: a nationwide cohort study, Denmark, 1968-2008.

    PubMed

    Grell, Kathrine; Meersohn, Andrea; Schüz, Joachim; Johansen, Christoffer

    2012-09-01

    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.

  5. Cerebrospinal fluid arginine vasopressin in degenerative disorders and other neurological diseases.

    PubMed Central

    Sundquist, J; Forsling, M L; Olsson, J E; Akerlund, M

    1983-01-01

    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

  6. Neurologic features of chronic minamata disease (organic mercury poisoning) and incidence of complications with aging.

    PubMed

    Uchino, M; Tanaka, Y; Ando, Y; Yonehara, T; Hara, A; Mishima, I; Okajima, T; Ando, M

    1995-09-01

    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.

  7. Zygomycetes in Human Disease

    PubMed Central

    Ribes, Julie A.; Vanover-Sams, Carolyn L.; Baker, Doris J.

    2000-01-01

    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

  8. Retrospective study of the clinical effects of acupuncture on cervical neurological diseases in dogs

    PubMed Central

    Liu, Ching Ming; Chang, Fang Chia

    2016-01-01

    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

  9. Generation of Cholinergic and Dopaminergic Interneurons from Human Pluripotent Stem Cells as a Relevant Tool for In Vitro Modeling of Neurological Disorders Pathology and Therapy

    PubMed Central

    Ochalek, Anna; Szczesna, Karolina; Petazzi, Paolo; Kobolak, Julianna

    2016-01-01

    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

  10. The mTOR signalling cascade: paving new roads to cure neurological disease.

    PubMed

    Crino, Peter B

    2016-07-01

    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.

  11. Bullous pemphigoid in a leg affected with hemiparesia: a possible relation of neurological diseases with bullous pemphigoid?

    PubMed

    Foureur, N; Descamps, V; Lebrun-Vignes, B; Picard-Dahan, C; Grossin, M; Belaich, S; Crickx, B

    2001-01-01

    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.

  12. Replication Validity of Initial Association Studies: A Comparison between Psychiatry, Neurology and Four Somatic Diseases

    PubMed Central

    Dumas-Mallet, Estelle; Button, Katherine; Boraud, Thomas; Munafo, Marcus; Gonon, François

    2016-01-01

    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

  13. Respiratory and neurological disease in rabbits experimentally infected with equid herpesvirus 1.

    PubMed

    Kanitz, Fábio A; Cargnelutti, Juliana F; Anziliero, Deniz; Gonçalves, Kelley V; Masuda, Eduardo K; Weiblen, Rudi; Flores, Eduardo F

    2015-10-01

    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.

  14. DISC1 and Huntington's Disease – Overlapping Pathways of Vulnerability to Neurological Disorder?

    PubMed Central

    Boxall, Ruth; Porteous, David J.; Thomson, Pippa A.

    2011-01-01

    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

  15. Pattern of neurological disease seen among patients admitted in tertiary care hospital

    PubMed Central

    2014-01-01

    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

  16. Systems biology and its application to the understanding of neurological diseases.

    PubMed

    Villoslada, Pablo; Steinman, Lawrence; Baranzini, Sergio E

    2009-02-01

    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.

  17. Bone marrow transplantation prolongs life span and ameliorates neurologic manifestations in Sandhoff disease mice.

    PubMed Central

    Norflus, F; Tifft, C J; McDonald, M P; Goldstein, G; Crawley, J N; Hoffmann, A; Sandhoff, K; Suzuki, K; Proia, R L

    1998-01-01

    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

  18. Selenium in the Therapy of Neurological Diseases. Where is it Going?

    PubMed Central

    Dominiak, Agnieszka; Wilkaniec, Anna; Wroczyńsk, Piotr; Adamczyk, Agata

    2016-01-01

    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

  19. Using phosphate supplementation to reverse hypophosphatemia and phosphate depletion in neurological disease and disturbance.

    PubMed

    Håglin, Lena

    2016-06-01

    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.

  20. Involuntary emotional expression disorder - new/old disease in psychiatry and neurology.

    PubMed

    Presecki, Paola; Mimica, Ninoslav

    2007-09-01

    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.

  1. Introduction to Focus Issue: Rhythms and Dynamic Transitions in Neurological Disease: Modeling, Computation, and Experiment

    NASA Astrophysics Data System (ADS)

    Kaper, Tasso J.; Kramer, Mark A.; Rotstein, Horacio G.

    2013-12-01

    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.

  2. Introduction to Focus Issue: Rhythms and Dynamic Transitions in Neurological Disease: Modeling, Computation, and Experiment

    SciTech Connect

    Kaper, Tasso J. Kramer, Mark A.; Rotstein, Horacio G.

    2013-12-15

    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.

  3. Sulfatases and human disease.

    PubMed

    Diez-Roux, Graciana; Ballabio, Andrea

    2005-01-01

    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.

  4. Morbilliviruses and human disease.

    PubMed

    Rima, Bertus K; Duprex, W Paul

    2006-01-01

    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.

  5. Neurologic disease in range goats associated with Oxytropis sericea (Locoweed) poisoning and water deprivation.

    PubMed

    Stegelmeier, B L; James, L F; Hall, J O; Mattix, M T

    2001-10-01

    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.

  6. Clinical NMR imaging of the brain in children: normal and neurologic disease

    SciTech Connect

    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.

    1983-11-01

    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.

  7. In vivo Expression of Inducible Nitric Oxide Synthase in Experimentally Induced Neurologic Diseases

    NASA Astrophysics Data System (ADS)

    Koprowski, Hilary; Zheng, Yong Mu; Heber-Katz, Ellen; Fraser, Nigel; Rorke, Lucy; Fu, Zhen Fang; Hanlon, Cathleen; Dietzschold, Bernhard

    1993-04-01

    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.

  8. Studies of generalized elemental imbalances in neurological disease patients using INAA (instrumental neutron activation analysis)

    SciTech Connect

    Ehmann, W.D.; Vance, D.E.; Khare, S.S.; Kasarskis, E.J.; Markesbery, W.R.

    1988-01-01

    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.

  9. Impact of maternal diet on human milk composition and neurological development of infants.

    PubMed

    Innis, Sheila M

    2014-03-01

    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.

  10. Brain-Delivery of Zinc-Ions as Potential Treatment for Neurological Diseases: Mini Review

    PubMed Central

    Grabrucker, Andreas M.; Rowan, Magali; Garner, Craig C.

    2011-01-01

    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

  11. The role of nanotechnology and nano and micro-electronics in monitoring and control of cardiovascular diseases and neurological disorders

    NASA Astrophysics Data System (ADS)

    Varadan, Vijay K.

    2007-04-01

    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.

  12. Dialectics and Implications of Natural Neurotropic Autoantibodies in Neurological Disease and Rehabilitation

    PubMed Central

    Poletaev, A. B.; Abrosimova, A. A.; Sokolov, M. A.; Gekht, A. B.; Alferova, V. V.; Gusev, E. I.; Nikolaeva, T. Ya.; Selmi, C.

    2004-01-01

    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

  13. Neurologic Complications Associated with Sjögren's Disease: Case Reports and Modern Pathogenic Dilemma

    PubMed Central

    Colaci, Michele; Cassone, Giulia; Manfredi, Andreina; Sebastiani, Marco; Giuggioli, Dilia; Ferri, Clodoveo

    2014-01-01

    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

  14. Using Support Vector Machine to identify imaging biomarkers of neurological and psychiatric disease: a critical review.

    PubMed

    Orrù, Graziella; Pettersson-Yeo, William; Marquand, Andre F; Sartori, Giuseppe; Mechelli, Andrea

    2012-04-01

    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.

  15. Frequency and Pathological Phenotype of Bovine Astrovirus CH13/NeuroS1 Infection in Neurologically-Diseased Cattle: Towards Assessment of Causality

    PubMed Central

    Selimovic-Hamza, Senija; Boujon, Céline L.; Hilbe, Monika; Oevermann, Anna; Seuberlich, Torsten

    2017-01-01

    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

  16. Aicardi-Goutieres syndrome, a rare neurological disease in children: a new autoimmune disorder?

    PubMed

    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

    2013-02-01

    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.

  17. A next step in adeno-associated virus-mediated gene therapy for neurological diseases: regulation and targeting

    PubMed Central

    Chtarto, Abdelwahed; Bockstael, Olivier; Tshibangu, Terence; Dewitte, Olivier; Levivier, Marc; Tenenbaum, Liliane

    2013-01-01

    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

  18. [Delivery of medical care to the neurological intractable diseases at home].

    PubMed

    Ogino, Mieko

    2009-11-01

    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.

  19. The development of encapsulated cell technologies as therapies for neurological and sensory diseases.

    PubMed

    Zanin, M P; Pettingill, L N; Harvey, A R; Emerich, D F; Thanos, C G; Shepherd, R K

    2012-05-30

    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.

  20. The Spanish school of neurology and the first American cases of Alzheimer's disease.

    PubMed

    García-Albea, E; Pérez Trullen, J M

    2003-12-01

    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.

  1. The Preoperative Neurological Evaluation

    PubMed Central

    Probasco, John; Sahin, Bogachan; Tran, Tung; Chung, Tae Hwan; Rosenthal, Liana Shapiro; Mari, Zoltan; Levy, Michael

    2013-01-01

    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

  2. Recurrent headaches: a case of neurological Behçet's disease.

    PubMed

    Ismail, Alaa M; Dubrey, Simon W; Patel, Maneesh C

    2013-10-01

    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

  3. Noncoding RNAs and RNA editing in brain development, functional diversification, and neurological disease.

    PubMed

    Mehler, Mark F; Mattick, John S

    2007-07-01

    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.

  4. Mutations in mitochondrial enzyme GPT2 cause metabolic dysfunction and neurological disease with developmental and progressive features

    PubMed Central

    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.

    2016-01-01

    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

  5. α-Synuclein in the colon and premotor markers of Parkinson disease in neurologically normal subjects.

    PubMed

    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

    2017-01-01

    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.

  6. [Neurologic diseases in a rural tropical area: experience at a primary health care center in the Boeny region of Madagascar].

    PubMed

    Gaud, S; Sauvée, M; Debouverie, M

    2014-01-01

    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.

  7. Consensus Statement on medication use in multiple sclerosis by the Spanish Society of Neurology's study group for demyelinating diseases.

    PubMed

    García-Merino, A; Fernández, O; Montalbán, X; de Andrés, C; Oreja-Guevara, C; Rodríguez-Antigüedad, A; Arbizu, T

    2013-01-01

    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.

  8. Epilepsy and Other Neurological Diseases in the Parents of Children with Infantile Autism. A Case Control Study

    ERIC Educational Resources Information Center

    Mouridsen, Svend Erik; Rich, Bente; Isager, Torben

    2008-01-01

    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…

  9. Neurology in the developing world.

    PubMed

    Singhal, B S; Khadilkar, Satish V

    2014-01-01

    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.

  10. ABCA7 loss-of-function variants, expression, and neurologic disease risk

    PubMed Central

    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.

    2017-01-01

    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

  11. [Current status of the predictive genetic testing for hereditary neurological diseases in Shinshu University Hospital].

    PubMed

    Tanaka, Keiko; Sekijima, Yoshiki; Yoshida, Kunihiro; Mizuuchi, Asako; Yamashita, Hiromi; Tamai, Mariko; Ikeda, Shu-ichi; Fukushima, Yoshimitsu

    2013-01-01

    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.

  12. Genes that affect brain structure and function identified by rare variant analyses of Mendelian neurologic disease

    PubMed Central

    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

    2015-01-01

    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

  13. Acid-sensing ion channels (ASICs): therapeutic targets for neurological diseases and their regulation.

    PubMed

    Kweon, Hae-Jin; Suh, Byung-Chang

    2013-06-01

    Extracellular acidification occurs not only in pathological conditions such as inflammation and brain ischemia, but also in normal physiological conditions such as synaptic transmission. Acid-sensing ion channels (ASICs) can detect a broad range of physiological pH changes during pathological and synaptic cellular activities. ASICs are voltage-independent, proton-gated cation channels widely expressed throughout the central and peripheral nervous system. Activation of ASICs is involved in pain perception, synaptic plasticity, learning and memory, fear, ischemic neuronal injury, seizure termination, neuronal degeneration, and mechanosensation. Therefore, ASICs emerge as potential therapeutic targets for manipulating pain and neurological diseases. The activity of these channels can be regulated by many factors such as lactate, Zn(2+), and Phe-Met-Arg-Phe amide (FMRFamide)-like neuropeptides by interacting with the channel's large extracellular loop. ASICs are also modulated by G protein-coupled receptors such as CB1 cannabinoid receptors and 5-HT2. This review focuses on the physiological roles of ASICs and the molecular mechanisms by which these channels are regulated.

  14. The Effect of tDCS on Cognition and Neurologic Recovery of Rats with Alzheimer's Disease.

    PubMed

    Yu, Seong Hun; Park, Seong Doo; Sim, Ki Chel

    2014-02-01

    [Purpose] This study examined the effect of the application of transcranial direct current stimulation (tDCS) on neurologic recovery and cognitive function of rats with Alzheimer-like dementia induced by scopolamine injections. [Subjects] To create a cognition dysfunction model, intraperitoneal injection of scopolamine was given to Sprague-Dawley rats that subsequently received tDCS for 4 weeks. [Methods] Changes in motor behavior were evaluated by conducting an open field test. Acetylcholine content in the cerebral cortex and hippocampus was examined for a biochemical assessment. [Results] With respect to changes in motor behavior, group II showed the most meaningful difference after scopolamine injection, followed by group III. In the biochemical assessment, the results of the examination of acetylcholine content in the tissue of the cerebral cortex and the hippocampus on the 14th and 28th days, respectively, showed the most significant increase in group II, followed by group III. [Conclusion] The above findings confirm that tDCS application after the onset of cognitive dysfunction caused by Alzheimer's disease leads to a positive effect on motor behavior and biochemical changes, and this effect is maintained over a specific period of time.

  15. Analysis of venous access for therapeutic plasma exchange in patients with neurological disease.

    PubMed

    Grishaber, J E; Cunningham, M C; Rohret, P A; Strauss, R G

    1992-01-01

    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.

  16. Generation of the Human Biped Stance by a Neural Controller Able to Compensate Neurological Time Delay

    PubMed Central

    Jiang, Ping; Chiba, Ryosuke; Takakusaki, Kaoru; Ota, Jun

    2016-01-01

    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

  17. Neurological, psychological, and cognitive disorders in patients with chronic kidney disease on conservative and replacement therapy

    PubMed Central

    Lai, Silvia; Mecarelli, Oriano; Pulitano, Patrizia; Romanello, Roberto; Davi, Leonardo; Zarabla, Alessia; Mariotti, Amalia; Carta, Maria; Tasso, Giorgia; Poli, Luca; Mitterhofer, Anna Paola; Testorio, Massimo; Frassetti, Nicla; Aceto, Paola; Galani, Alessandro; Lai, Carlo

    2016-01-01

    Abstract Chronic kidney disease (CKD) is a highly prevalent condition in the world. Neurological, psychological, and cognitive disorders, related to CKD, could contribute to the morbidity, mortality, and poor quality of life of these patients. The aim of this study was to assess the neurological, psychological, and cognitive imbalance in patients with CKD on conservative and replacement therapy. Seventy-four clinically stable patients affected by CKD on conservative therapy, replacement therapy (hemodialysis (HD), peritoneal dialysis (PD)), or with kidney transplantation (KT) and 25 healthy controls (HC), matched for age and sex were enrolled. Clinical, laboratory, and instrumental examinations, as renal function, inflammation and mineral metabolism indexes, electroencephalogram (EEG), psychological (MMPI-2, Sat P), and cognitive tests (neuropsychological tests, NPZ5) were carried out. The results showed a significant differences in the absolute and relative power of delta band and relative power of theta band of EEG (P = 0.008, P < 0.001, P = 0.051), a positive correlation between relative power of delta band and C-reactive protein (CRP) (P < 0.001) and a negative correlation between estimated glomerular filtration rate (eGFR) (P < 0.001) and 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) (P < 0.001), in all the samples. Qualitative analysis of EEG showed alterations of Grade 2 (according to Parsons–Smith classification) in patients on conservative therapy, and Grade 2–3 in KT patients. The scales of MMPI-2 hysteria and paranoia, are significantly correlated with creatinine, eGFR, serum nitrogen, CRP, 1,25-(OH)2D3, intact parathyroid hormone (iPTH), phosphorus, and cynical and hysterical personality, are correlated with higher relative power of delta (P = 0.016) and theta band (P = 0.016). Moreover, all NPZ5 scores showed a significant difference between the means of nephropathic patients and the means of the HC, and a positive

  18. Neurological, psychological, and cognitive disorders in patients with chronic kidney disease on conservative and replacement therapy.

    PubMed

    Lai, Silvia; Mecarelli, Oriano; Pulitano, Patrizia; Romanello, Roberto; Davi, Leonardo; Zarabla, Alessia; Mariotti, Amalia; Carta, Maria; Tasso, Giorgia; Poli, Luca; Mitterhofer, Anna Paola; Testorio, Massimo; Frassetti, Nicla; Aceto, Paola; Galani, Alessandro; Lai, Carlo

    2016-11-01

    Chronic kidney disease (CKD) is a highly prevalent condition in the world. Neurological, psychological, and cognitive disorders, related to CKD, could contribute to the morbidity, mortality, and poor quality of life of these patients. The aim of this study was to assess the neurological, psychological, and cognitive imbalance in patients with CKD on conservative and replacement therapy.Seventy-four clinically stable patients affected by CKD on conservative therapy, replacement therapy (hemodialysis (HD), peritoneal dialysis (PD)), or with kidney transplantation (KT) and 25 healthy controls (HC), matched for age and sex were enrolled. Clinical, laboratory, and instrumental examinations, as renal function, inflammation and mineral metabolism indexes, electroencephalogram (EEG), psychological (MMPI-2, Sat P), and cognitive tests (neuropsychological tests, NPZ5) were carried out.The results showed a significant differences in the absolute and relative power of delta band and relative power of theta band of EEG (P = 0.008, P < 0.001, P = 0.051), a positive correlation between relative power of delta band and C-reactive protein (CRP) (P < 0.001) and a negative correlation between estimated glomerular filtration rate (eGFR) (P < 0.001) and 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) (P < 0.001), in all the samples. Qualitative analysis of EEG showed alterations of Grade 2 (according to Parsons-Smith classification) in patients on conservative therapy, and Grade 2-3 in KT patients. The scales of MMPI-2 hysteria and paranoia, are significantly correlated with creatinine, eGFR, serum nitrogen, CRP, 1,25-(OH)2D3, intact parathyroid hormone (iPTH), phosphorus, and cynical and hysterical personality, are correlated with higher relative power of delta (P = 0.016) and theta band (P = 0.016). Moreover, all NPZ5 scores showed a significant difference between the means of nephropathic patients and the means of the HC, and a positive correlation with e

  19. “Curcumin, the King of Spices”: Epigenetic Regulatory Mechanisms in the Prevention of Cancer, Neurological, and Inflammatory Diseases

    PubMed Central

    Boyanapalli, Sarandeep S. S.

    2015-01-01

    Curcumin (diferuloylmethane), a polyphenolic compound, is a component of Curcuma longa, commonly known as turmeric. It is a well-known anti-inflammatory, anti-oxidative, and anti-lipidemic agent and has recently been shown to modulate several diseases via epigenetic regulation. Many recent studies have demonstrated the role of epigenetic inactivation of pivotal genes that regulate human pathologies, such as neurocognitive disorders, inflammation, obesity, and cancers. Epigenetic changes involve changes in DNA methylation, histone modifications, or altered microRNA expression patterns which are known to be interconnected and play a key role in tumor progression and failure of conventional chemotherapy. The majority of epigenetic changes are influenced by lifestyle and diets. In this regard, dietary phytochemicals as dietary supplements have emerged as a promising source that are able to reverse these epigenetic alterations, to actively regulate gene expression and molecular targets that are known to promote tumorigenesis, and also to prevent age-related diseases through epigenetic modifications. There have been several studies which reported the role of curcumin as an epigenetic regulator in neurological disorders, inflammation, and in diabetes apart from cancers. The epigenetic regulatory roles of curcumin include (1) inhibition of DNA methyltransferases (DNMTs), which has been well defined from the recent studies on its function as a DNA hypomethylating agent; (2) regulation of histone modifications via regulation of histone acetyltransferases (HATs) and histone deacetylases (HDACs); and (3) regulation of micro RNAs (miRNA). This review summarizes the current knowledge on the effect of curcumin in the treatment and/or prevention of inflammation, neurodegenerative diseases, and cancers by regulating histone deacetylases, histone acetyltransferases, and DNA methyltransferases. PMID:26457241

  20. Age-Dependent Myeloid Dendritic Cell Responses Mediate Resistance to La Crosse Virus-Induced Neurological Disease

    PubMed Central

    Taylor, Katherine G.; Woods, Tyson A.; Winkler, Clayton W.; Carmody, Aaron B.

    2014-01-01

    ABSTRACT La Crosse virus (LACV) is the major cause of pediatric viral encephalitis in the United States; however, the mechanisms responsible for age-related susceptibility in the pediatric population are not well understood. Our current studies in a mouse model of LACV infection indicated that differences in myeloid dendritic cell (mDC) responses between weanling and adult mice accounted for susceptibility to LACV-induced neurological disease. We found that type I interferon (IFN) responses were significantly stronger in adult than in weanling mice. Production of these IFNs required both endosomal Toll-like receptors (TLRs) and cytoplasmic RIG-I-like receptors (RLRs). Surprisingly, IFN expression was not dependent on plasmacytoid DCs (pDCs) but rather was dependent on mDCs, which were found in greater number and induced stronger IFN responses in adults than in weanlings. Inhibition of these IFN responses in adults resulted in susceptibility to LACV-induced neurological disease, whereas postinfection treatment with type I IFN provided protection in young mice. These studies provide a definitive mechanism for age-related susceptibility to LACV encephalitis, where mDCs in young mice are insufficiently activated to control peripheral virus replication, thereby allowing virus to persist and eventually cause central nervous system (CNS) disease. IMPORTANCE La Crosse virus (LACV) is the primary cause of pediatric viral encephalitis in the United States. Although the virus infects both adults and children, over 80% of the reported neurological disease cases are in children. To understand why LACV causes neurological disease primarily in young animals, we used a mouse model where weanling mice, but not adult mice, develop neurological disease following virus infection. We found that an early immune response cell type, myeloid dendritic cells, was critical for protection in adult animals and that these cells were reduced in young animals. Activation of these cells during

  1. Hippocrates: the forefather of neurology.

    PubMed

    Breitenfeld, T; Jurasic, M J; Breitenfeld, D

    2014-09-01

    Hippocrates is one of the most influential medical doctors of all times. He started observing and experimenting in times of mysticism and magic. He carried a holistic and humanitarian approach to the patient with examination as the principal approach-inspection, palpation and auscultation are still the most important tools in diagnosing algorithms of today. He had immense experience with the human body most likely due to numerous wound treatments he had performed; some even believe he performed autopsies despite the negative trend at the time. Hippocrates identified the brain as the analyst of the outside world, the interpreter of consciousness and the center of intelligence and willpower. Interestingly, Hippocrates was aware of many valid concepts in neurology; his treatise On the Sacred Disease was the most important for understanding neurology and epilepsy. His other ideas pioneered modern day neurology mentioning neurological diseases like apoplexy, spondylitis, hemiplegia, and paraplegia. Today, 10 % of neurological Pubmed and 7 % of neuroscience Scopus reviews mention Corpus Hippocraticum as one of the sources. Therefore, Hippocrates may be considered as the forefather of neurology.

  2. Congenital and inherited neurologic diseases in dogs and cats: Legislation and its effect on purchase in Italy.

    PubMed

    Passantino, Annamaria; Masucci, Marisa

    2016-05-01

    Many of the congenital neurologic diseases can result in incapacity or death of the animal. Some of them, such as idiopathic epilepsy and hydrocephalus, exhibit breed or familial predisposition and a genetic basis was proved or suggested. Some diseases can be presumptively diagnosed after a detailed signalment (breed predisposition), history (e.g. family history because many of these defects have familial tendencies), and through physical exam; other diagnostic methods (radiography, computed tomography, magnetic resonance, electrophysiologic tests, etc.) can provide supportive evidence for the congenital defect and help to confirm the diagnosis. Some cases can lead to civil law-suits when the lesions are congenital, but not easily recognizable, or when the lesions are hereditary but tend to became manifest only after some time (more than 12 months after the date of purchase, e.g., after the vice-free guarantee period has expired). Moreover, quite frequently an early diagnosis is not made because there are delays in consulting the veterinarian or the general practitioner veterinarian does not perceive subtle signs. This study was designed to focus on the medico-legal aspects concerning the buying and selling in Italy of dogs and cats affected by congenital and hereditary neurologic diseases that could constitute vice in these animals. While adequate provisions to regulate in detail the various aspects of pet sale have still to be drawn up by legislators, it may be helpful to involve breeders, by obliging them by contract to extend guarantees in the case of hereditary lesions, including neurologic diseases.

  3. Mitochondrial dysfunction in psychiatric and neurological diseases: cause(s), consequence(s), and implications of antioxidant therapy.

    PubMed

    Kasote, Deepak M; Hegde, Mahabaleshwar V; Katyare, Surendra S

    2013-01-01

    Mitochondrial dysfunction is at the base of development and progression of several psychiatric and neurologic diseases with different etiologies. MtDNA/nDNA mutational damage, failure of endogenous antioxidant defenses, hormonal malfunction, altered membrane permeability, metabolic dysregulation, disruption of calcium buffering capacity and ageing have been found to be the root causes of mitochondrial dysfunction in psychatric and neurodegenerative diseases. However, the overall consequences of mitochondrial dysfunction are only limited to increase in oxidative/nitrosative stress and cellular energy crises. Thus far, extensive efforts have been made to improve mitochondrial function through specific cause-dependent antioxidant therapy. However, owing to complex genetic and interlinked causes of mitochondrial dysfunction, it has not been possible to achieve any common, unique supportive antioxidant therapeutic strategy for the treatment of psychiatric and neurologic diseases. Hence, we propose an antioxidant therapeutic strategy for management of consequences of mitochondrial dysfunction in psychiatric and neurologic diseases. It is expected that this will not only reduces oxidative stress, but also promote anaerobic energy production.

  4. Genome-Wide Approaches to Dissect the Roles of RNA Binding Proteins in Translational Control: Implications for Neurological Diseases

    PubMed Central

    Kapeli, Katannya; Yeo, Gene W.

    2012-01-01

    Translational control of messenger RNAs (mRNAs) is a key aspect of neurobiology, defects of which can lead to neurological diseases. In response to stimuli, local translation of mRNAs is activated at synapses to facilitate long-lasting forms of synaptic plasticity, the cellular basis for learning, and memory formation. Translation, as well as all other aspects of RNA metabolism, is controlled in part by RNA binding proteins (RBPs) that directly interact with mRNAs to form mRNA-protein complexes. Disruption of RBP function is becoming widely recognized as a major cause of neurological diseases. Thus understanding the mechanisms that govern the interplay between translation control and RBP regulation in both normal and diseased neurons will provide new opportunities for novel diagnostics and therapeutic intervention. As a means of studying translational control, genome-wide methods are emerging as powerful tools that have already begun to unveil mechanisms that are missed by single-gene studies. Here, we describe the roles of RBPs in translational control, review genome-wide approaches to examine translational control, and discuss how the application of these approaches may provide mechanistic insight into the pathogenic underpinnings of RBPs in neurological diseases. PMID:23060744

  5. Inositol polyphosphate phosphatases in human disease.

    PubMed

    Hakim, Sandra; Bertucci, Micka C; Conduit, Sarah E; Vuong, David L; Mitchell, Christina A

    2012-01-01

    Phosphoinositide signalling molecules interact with a plethora of effector proteins to regulate cell proliferation and survival, vesicular trafficking, metabolism, actin dynamics and many other cellular functions. The generation of specific phosphoinositide species is achieved by the activity of phosphoinositide kinases and phosphatases, which phosphorylate and dephosphorylate, respectively, the inositol headgroup of phosphoinositide molecules. The phosphoinositide phosphatases can be classified as 3-, 4- and 5-phosphatases based on their specificity for dephosphorylating phosphates from specific positions on the inositol head group. The SAC phosphatases show less specificity for the position of the phosphate on the inositol ring. The phosphoinositide phosphatases regulate PI3K/Akt signalling, insulin signalling, endocytosis, vesicle trafficking, cell migration, proliferation and apoptosis. Mouse knockout models of several of the phosphoinositide phosphatases have revealed significant physiological roles for these enzymes, including the regulation of embryonic development, fertility, neurological function, the immune system and insulin sensitivity. Importantly, several phosphoinositide phosphatases have been directly associated with a range of human diseases. Genetic mutations in the 5-phosphatase INPP5E are causative of the ciliopathy syndromes Joubert and MORM, and mutations in the 5-phosphatase OCRL result in Lowe's syndrome and Dent 2 disease. Additionally, polymorphisms in the 5-phosphatase SHIP2 confer diabetes susceptibility in specific populations, whereas reduced protein expression of SHIP1 is reported in several human leukaemias. The 4-phosphatase, INPP4B, has recently been identified as a tumour suppressor in human breast and prostate cancer. Mutations in one SAC phosphatase, SAC3/FIG4, results in the degenerative neuropathy, Charcot-Marie-Tooth disease. Indeed, an understanding of the precise functions of phosphoinositide phosphatases is not only

  6. Analysis of Preplate Splitting and Early Cortical Development Illuminates the Biology of Neurological Disease

    PubMed Central

    Olson, Eric C.

    2014-01-01

    The development of the layered cerebral cortex starts with a process called preplate splitting. Preplate splitting involves the establishment of prospective cortical layer 6 (L6) neurons within a plexus of pioneer neurons called the preplate. The forming layer 6 splits the preplate into a superficial layer of pioneer neurons called the marginal zone and a deeper layer of pioneer neurons called the subplate. Disruptions of this early developmental event by toxin exposure or mutation are associated with neurological disease including severe intellectual disability. This review explores recent findings that reveal the dynamism of gene expression and morphological differentiation during this early developmental period. Over 1000 genes show expression increases of ≥2-fold during this period in differentiating mouse L6 neurons. Surprisingly, 88% of previously identified non-syndromic intellectual-disability (NS-ID) genes are expressed at this time and show an average expression increase of 1.6-fold in these differentiating L6 neurons. This changing genetic program must, in part, support the dramatic cellular reorganizations that occur during preplate splitting. While different models have been proposed for the formation of a layer of L6 cortical neurons within the preplate, original histological studies and more recent work exploiting transgenic mice suggest that the process is largely driven by the coordinated polarization and coalescence of L6 neurons rather than by cellular translocation or migration. The observation that genes associated with forms of NS-ID are expressed during very early cortical development raises the possibility of studying the relevant biological events at a time point when the cortex is small, contains relatively few cell types, and few functional circuits. This review then outlines how explant models may prove particularly useful in studying the consequence of toxin and mutation on the etiology of some forms of NS-ID. PMID:25426475

  7. Depletion of GSH in glial cells induces neurotoxicity: relevance to aging and degenerative neurological diseases.

    PubMed

    Lee, Moonhee; Cho, Taesup; Jantaratnotai, Nattinee; Wang, Yu Tian; McGeer, Edith; McGeer, Patrick L

    2010-07-01

    Oxidative stress induced by inhibition of glutathione (GSH) biosynthesis with D,L-buthionine-S,R-sulfoximine (BSO) causes human microglia, human astrocytes, THP-1 cells, and U373 cells to secrete materials toxic to human neuroblastoma SH-SY5Y cells and stimulates them to release TNF-alpha, IL-6, and nitrite ions. The effect is correlated with activation of the inflammatory pathways P38 MAP- kinase, Jun-N-terminal kinase, and NF-kappaB. The effect is reduced by adding to the medium GSH or clotrimazole (CTM), an inhibitor of Ca(2+)-influx through TRPM2 channels. It is also produced by inhibiting TRPM2 protein expression in microglia and astrocytes through introduction of its small inhibitory RNA (siRNA). TRPM2 mRNA is expressed by glial cells but not by SH-SY5Y cells. BSO in the culture medium causes an almost 3-fold increase in [Ca(2+)](i) in microglia and astrocytes over a 24-h period, which is reduced to half by the addition of CTM. The data strongly suggest that inhibiting intracellular GSH synthesis induces a neuroinflammatory response in human microglia and astrocytes, which is linked to Ca(2+) influx through TRPM2 channels. It represents a new model for inducing neuroinflammation and suggests that increasing GSH levels in glial cells may confer neuroprotection in neurodegenerative diseases, such as Alzheimer disease, which have a prominent neuroinflammatory component.

  8. Bravo! Neurology at the opera.

    PubMed

    Matthews, Brandy R

    2010-01-01

    Opera is a complex musical form that reflects the complexity of the human condition and the human brain. This article presents an introduction to the portrayal of medical professionals in opera, including one neurologist, as well as two characters in whom neurological disease contributes to the action of the musical drama. Consideration is also given to the neuroanatomy and neuropathology of opera singers with further speculation regarding the neural underpinnings of the passion of opera's audience.

  9. Social support associated with quality of life in home care patients with intractable neurological disease in Japan.

    PubMed

    Nishida, Tomoko; Ando, Eriko; Sakakibara, Hisataka

    2012-01-01

    The aim of the present study was to investigate what kinds of social supports contribute to the higher quality of life (QOL) of home care patients with intractable neurological disease. We investigated the World Health Organization Quality of Life-BREF (WHOQOL-BREF) and social supports to 74 patients with intractable neurological disease in a city of the Aichi prefecture, Japan. Association between WHOQOL and social supports was examined using multiple logistic regression analyses adjusting activities of daily living (ADL). High WHOQOL scores were associated with "attending patient gatherings held by the public health center," "having someone who will listen empathically to anxieties or troubles," and ADL. Physical health was associated with ADL, while psychological well-being was related to "having a hobby," "having someone who will listen," and "having a hospital for admission in emergencies." Patients not having someone who will listen were more likely to participate in the gatherings. The present findings suggest that having someone who will provide emotional support is important for home care patients with neurological diseases. Patient gatherings held by the public health center were expected to provide patients with emotional support.

  10. Age-related brain atrophy may be mitigated by internal jugular vein enlargement in male individuals without neurologic disease.

    PubMed

    Belov, Pavel; Magnano, Christopher; Krawiecki, Jacqueline; Hagemeier, Jesper; Bergsland, Niels; Beggs, Clive; Zivadinov, Robert

    2017-03-01

    Objectives To assess the relationship between cross-sectional area of internal jugular veins and brain volumes in healthy individuals without neurologic disease. Methods A total of 193 healthy individuals without neurologic disease (63 male and 130 female; age > 20 to < 70 years) received magnetic resonance venography and structural brain magnetic resonance imaging at 3T. The internal jugular vein cross-sectional area was assessed at C2-C3, C4, C5-C6, and C7-T1. Normalized whole brain volume was assessed. Partial correlation analyses were used to determine associations. Results There was an inverse relationship between normalized whole brain volume and total internal jugular vein cross-sectional area (C7-T1: males r = -0.346, p = 0.029; females r = -0.301, p = 0.002). After age adjustment, association of normalized whole brain volume and normalized gray matter volume with internal jugular vein cross-sectional area became positive in males (normalized whole brain volume and right internal jugular vein cross-sectional area (C2-C3) changed from r = -0.163 to r = 0.384, p = 0.002), but not in the females. Conclusion Sex differences exist in the relationship between brain volume and internal jugular vein cross-sectional area in healthy individuals without neurologic disease.

  11. Clinical research into anesthetic neurotoxicity: does anesthesia cause neurological abnormalities in humans?

    PubMed

    Lei, Susan Y; Hache, Manon; Loepke, Andreas W

    2014-10-01

    General anesthetics mitigate distress and exaggerated hemodynamic responses to pain and stressful stimulation, allowing surgery and diagnostic procedures to be performed worldwide in millions of children every year. Emerging studies, mainly carried out in early postnatal laboratory animals, demonstrate widespread neuronal elimination, alteration in neuronal circuitry, and long-term neurological disabilities following exposure to all commonly used sedatives and anesthetics. These findings have raised concerns among parents, anesthesiologists, neuroscientists, and government regulators about the safety of anesthetic drugs in children, especially infants. Accumulating evidence from epidemiological studies suggests an association between surgery with anesthesia in early childhood and subsequent behavioral and cognitive abnormalities. During the Fourth Pediatric Anesthesia NeuroDevelopmental Assessment (PANDA) symposium, a meeting attended by many stakeholders, the most recent findings in the field were presented and discussed. This review summarizes the current state of clinical research into the effects of anesthetic exposure in human brain development, addresses some of the difficulties in examining the phenomenon, and introduces the most recent clinical findings presented at the PANDA symposium. The unanimous consensus among participants was that additional preclinical and clinical research efforts are urgently required to address this important concern for child health.

  12. Familial infantile convulsions and paroxysmal choreoathetosis: a new neurological syndrome linked to the pericentromeric region of human chromosome 16.

    PubMed Central

    Szepetowski, P; Rochette, J; Berquin, P; Piussan, C; Lathrop, G M; Monaco, A P

    1997-01-01

    Benign infantile familial convulsions is an autosomal dominant disorder characterized by nonfebrile seizures, with the first attack occurring at age 3-12 mo. It is one of the rare forms of epilepsy that are inherited as monogenic Mendelian traits, thus providing a powerful tool for mapping genes involved in epileptic syndromes. Paroxysmal choreoathetosis is an involuntary-movement disorder characterized by attacks that occur spontaneously or are induced by a variety of stimuli. Classification is still elusive, and the epileptic nature of this movement disorder has long been discussed and remains controversial. We have studied four families from northwestern France in which benign infantile convulsions was inherited as an autosomal dominant trait together with variably expressed paroxysmal choreoathetosis. The human genome was screened with microsatellite markers regularly spaced, and strong evidence of linkage for the disease gene was obtained in the pericentromeric region of chromosome 16, with a maximum two-point LOD score, for D16S3133, of 6.76 at a recombination fraction of 0. Critical recombinants narrowed the region of interest to a 10-cM interval around the centromere. Our study provides the first genetic evidence for a common basis of convulsive and choreoathetotic disorders and will help in the understanding and classification of paroxysmal neurological syndromes. PMID:9382100

  13. MOG cell-based assay detects non-MS patients with inflammatory neurologic disease

    PubMed Central

    Woodhall, Mark; O'Connor, Kevin C.; Reindl, Markus; Lang, Bethan; Sato, Douglas K.; Juryńczyk, Maciej; Tackley, George; Rocha, Joao; Takahashi, Toshiyuki; Misu, Tatsuro; Nakashima, Ichiro; Palace, Jacqueline; Fujihara, Kazuo; Leite, M. Isabel; Vincent, Angela

    2015-01-01

    Objective: To optimize sensitivity and disease specificity of a myelin oligodendrocyte glycoprotein (MOG) antibody assay. Methods: Consecutive sera (n = 1,109) sent for aquaporin-4 (AQP4) antibody testing were screened for MOG antibodies (Abs) by cell-based assays using either full-length human MOG (FL-MOG) or the short-length form (SL-MOG). The Abs were initially detected by Alexa Fluor goat anti-human IgG (H + L) and subsequently by Alexa Fluor mouse antibodies to human IgG1. Results: When tested at 1:20 dilution, 40/1,109 sera were positive for AQP4-Abs, 21 for SL-MOG, and 180 for FL-MOG. Only one of the 40 AQP4-Ab–positive sera was positive for SL-MOG-Abs, but 10 (25%) were positive for FL-MOG-Abs (p = 0.0069). Of equal concern, 48% (42/88) of sera from controls (patients with epilepsy) were positive by FL-MOG assay. However, using an IgG1-specific secondary antibody, only 65/1,109 (5.8%) sera were positive on FL-MOG, and AQP4-Ab– positive and control sera were negative. IgM reactivity accounted for the remaining anti-human IgG (H + L) positivity toward FL-MOG. The clinical diagnoses were obtained in 33 FL-MOG–positive patients, blinded to the antibody data. IgG1-Abs to FL-MOG were associated with optic neuritis (n = 11), AQP4-seronegative neuromyelitis optica spectrum disorder (n = 4), and acute disseminated encephalomyelitis (n = 1). All 7 patients with probable multiple sclerosis (MS) were MOG-IgG1 negative. Conclusions: The limited disease specificity of FL-MOG-Abs identified using Alexa Fluor goat anti-human IgG (H + L) is due in part to detection of IgM-Abs. Use of the FL-MOG and restricting to IgG1-Abs substantially improves specificity for non-MS demyelinating diseases. Classification of evidence: This study provides Class II evidence that the presence of serum IgG1- MOG-Abs in AQP4-Ab–negative patients distinguishes non-MS CNS demyelinating disorders from MS (sensitivity 24%, 95% confidence interval [CI] 9%–45%; specificity 100%, 95% CI 88%

  14. Early Diagnosis of Cerebral X-linked Adrenoleukodystrophy in Boys with Addison’s Disease Improves Survival and Neurological Outcomes

    PubMed Central

    Polgreen, LE; Chahla, S; Miller, W; Rothman, S.; Tolar, J; Kivisto, T; Nascene, D.; Orchard, PJ; Petryk, A

    2011-01-01

    Approximately one-third of boys with X-linked adrenoleukodystophy (X-ALD) develop an acute, progressive inflammatory process of the central nervous system, resulting in rapid neurologic deterioration and death. Hematopoietic cell transplantation (HCT) can halt the progression of neurologic disease if performed early in the course of the cerebral form of X-ALD. We describe a retrospective cohort study of 90 boys with X-ALD evaluated at our institution between 2000 and 2009, to determine if early diagnosis of X-ALD following the diagnosis of unexplained adrenal insufficiency (AI) improves outcomes. We describe 7 cases with a delay in the diagnosis of X-ALD, and compare their outcomes to 10 controls with the diagnosis of ALD made within 12 months following diagnosis of AI. At the time of evaluation for HCT, boys with a delay in the diagnosis of X-ALD had more extensive cerebral involvement and more limited functioning. These boys also were 3.9 times more likely to die, and had significant advancement of cerebral disease after HCT, compared to boys with a timely diagnosis of X-ALD. Conclusion Early diagnosis of cerebral X-ALD following the diagnosis of unexplained AI, and subsequent treatment with HCT, improves both neurological outcomes and survival in boys with cerebral X-ALD. PMID:21279382

  15. [Service portfolio in neurology].

    PubMed

    Jiménez, M D

    2003-12-01

    The specialist health assistance service book (SB) is the development of a clinical health product directed to the general population. The main objectives are: the offer of a clinical health product or to look for new offers, the evaluation or accreditation of neurological departments, the management of neurological departments, the SB presentation to main skateholder (patients, doctors, managers) and finally to inform patients of the neurological products through health resources map, that allowed them to use it. The SB includes emergency, inpatient and outpatient neurological services, and also specific diagnostic and treatment neurological procedures. In a few departments there will be also clinical units directed to specific neurological diseases or processes. It is important to develop the neurological SB in every department because it can satisfy the patients needs, and allow us to adapt quickly to our changing health reality.

  16. [Inflammasomes in human diseases].

    PubMed

    Jamilloux, Y; Sève, P; Henry, T

    2014-11-01

    The understanding of the innate immunity, the first line of the host defence, was significantly modified following the sequential discovery of innate immune receptors such as the Toll-like receptors (TLRs) and the NOD-like receptors (NLRs). In response to recognition of microbial patterns or danger signals, some NLRs assemble a multimolecular platform termed as the inflammasome. Inflammasome assembly leads to the activation of the proinflammatory caspase-1. Consequently, an inflammatory immune response is mounted along with a programmed cell death, called pyroptosis. This review summarizes recent advances in the knowledge of the inflammasome and its role in auto-inflammatory diseases, autoimmune diseases, and most common metabolic, cardiovascular or rheumatic diseases.

  17. Human astrocytes in the diseased brain.

    PubMed

    Dossi, Elena; Vasile, Flora; Rouach, Nathalie

    2017-02-13

    Astrocytes are key active elements of the brain that contribute to information processing. They not only provide neurons with metabolic and structural support, but also regulate neurogenesis and brain wiring. Furthermore, astrocytes modulate synaptic activity and plasticity in part by controlling the extracellular space volume, as well as ion and neurotransmitter homeostasis. These findings, together with the discovery that human astrocytes display contrasting characteristics with their rodent counterparts, point to a role for astrocytes in higher cognitive functions. Dysfunction of astrocytes can thereby induce major alterations in neuronal functions, contributing to the pathogenesis of several brain disorders. In this review we summarize the current knowledge on the structural and functional alterations occurring in astrocytes from the human brain in pathological conditions such as epilepsy, primary tumours, Alzheimer's disease, major depressive disorder and Down syndrome. Compelling evidence thus shows that dysregulations of astrocyte functions and interplay with neurons contribute to the development and progression of various neurological diseases. Targeting astrocytes is thus a promising alternative approach that could contribute to the development of novel and effective therapies to treat brain disorders.

  18. [Circular RNA in human disease and their potential clinic significance].

    PubMed

    Chen, Yonghua; Li, Cheng; Tan, Chunlu; Mai, Gang; Liu, Xubao

    2017-02-10

    Circular RNAs (circ RNAs) are a novel type of RNA that, unlike linear RNAs, form a covalently closed continuous loop and are highly represented in the eukaryotic transcriptome. They share a stable structure, high expression and often exhibit tissue/developmental-stage-specific expression. Emerging evidence indicates that circRNAs might play important roles in human disease, such as cancer, neurological disorders and atherosclerotic vascular disease risk. The huge potentials of circRNAs are recently being discovered from the laboratory to the clinic. CircRNAs might be developed as a potential novel and stable biomarker and potential drugs used in disease diagnosis and treatment. Here, we review the current understanding of the roles of circRNAs in human disease and their potential clinic significance in disease.

  19. Risk of psychiatric and neurological diseases in patients with workplace mobbing experience in Germany: a retrospective database analysis

    PubMed Central

    Kostev, Karel; Rex, Juliana; Waehlert, Lilia; Hog, Daniela; Heilmaier, Christina

    2014-01-01

    Introduction: The number of mobbing experiences recorded has increased during recent years and it has now been established as global phenomenon among the working population. The goal of our study was to analyze the incidence of certain neurologic and psychiatric diseases as a consequence of mobbing as compared with a control group and to examine the possible influence of previous diseases that occurred within one year before the first mobbing documentation on the incidence of mobbing. Material & methods: We used a large database (IMS® Disease Analyzer, Germany) to collect data from general practitioners in Germany from 01/2003 until 12/2012. Based on age, gender, and health insurance, patients with experience of mobbing were matched with a control group of patients who had not reported workplace mobbing and who were being treated by the same physicians. At first, diseases that occurred within one year before the bullying experience took place (“index date”) were noted and compared to a control group of similar composition in terms of gender, age, and health insurance. Subsequently, the prevalence of depression, anxiety, somatoform disorders, and sleep disorders following experiences of mobbing were determined. After adjustment to take into account the odds of bullying, the ratios of these diseases were assessed using a logistic regression model. Results: The study population consisted of n=2,625 patients and n=2,625 controls, of which 33% were men. The number of cases of bullying documented rose continuously from 2003 to 2011 and remained high in 2012. Those who would later become victims of mobbing demonstrated a considerably higher prevalence of diseases in general – these diseases were not confined to the neurologic-psychiatric spectrum. Following experiences of bullying, depression, anxiety, somatoform disorders, and sleep disorders were significantly more prevalent than in the control group (for all, p<0.05). Similarly, odds ratios (OR) representing the

  20. Effects of miglustat on stabilization of neurological disorder in niemann-pick disease type C: Iranian pediatric case series.

    PubMed

    Karimzadeh, Parvaneh; Tonekaboni, Seyed Hassan; Ashrafi, Mahmoud Reza; Shafeghati, Yousef; Rezayi, Alireza; Salehpour, Shadab; Ghofrani, Mohammad; Taghdiri, Mohammad Mehdi; Rahmanifar, Ali; Zaman, Talieh; Aryani, Omid; Shoar, Babak Najaf; Shiva, Farideh; Tavasoli, Alireza; Houshmand, Massoud

    2013-12-01

    Niemann-Pick disease type C is a rare neurodegenerative disorder with autosomal recessive inheritance that can be broadly categorized into different forms dependent on age at disease onset: pre-/perinatal, early infantile, late infantile, juvenile, and adolescent/adult. This study was conducted to define the age at onset, clinical manifestations, neuroimaging findings and response to treatment in 21 patients diagnosed with Niemann-Pick disease type C and managed in the neurology departments of hospitals in Tehran, Iran. The effects of miglustat on patient ambulation, fine and gross motor function, swallowing, hearing, speech, seizures, psychomotor development, and ocular movements were evaluated for up to 26 months of treatment. Ambulation, fine and gross motor movements, swallowing, speech, and supranuclear gaze palsy were generally stabilized during therapy, and psychomotor delay appeared to be improved in early- and late-infantile onset patients. However, miglustat had no effect on organomegaly or other systemic manifestations of the disease. Miglustat was well tolerated.

  1. Congenital and inherited neurologic diseases in dogs and cats: Legislation and its effect on purchase in Italy

    PubMed Central

    Passantino, Annamaria; Masucci, Marisa

    2016-01-01

    Many of the congenital neurologic diseases can result in incapacity or death of the animal. Some of them, such as idiopathic epilepsy and hydrocephalus, exhibit breed or familial predisposition and a genetic basis was proved or suggested. Some diseases can be presumptively diagnosed after a detailed signalment (breed predisposition), history (e.g. family history because many of these defects have familial tendencies), and through physical exam; other diagnostic methods (radiography, computed tomography, magnetic resonance, electrophysiologic tests, etc.) can provide supportive evidence for the congenital defect and help to confirm the diagnosis. Some cases can lead to civil law-suits when the lesions are congenital, but not easily recognizable, or when the lesions are hereditary but tend to became manifest only after some time (more than 12 months after the date of purchase, e.g., after the vice-free guarantee period has expired). Moreover, quite frequently an early diagnosis is not made because there are delays in consulting the veterinarian or the general practitioner veterinarian does not perceive subtle signs. This study was designed to focus on the medico-legal aspects concerning the buying and selling in Italy of dogs and cats affected by congenital and hereditary neurologic diseases that could constitute vice in these animals. While adequate provisions to regulate in detail the various aspects of pet sale have still to be drawn up by legislators, it may be helpful to involve breeders, by obliging them by contract to extend guarantees in the case of hereditary lesions, including neurologic diseases. PMID:27284217

  2. Modeling oscillatory dynamics in brain microcircuits as a way to help uncover neurological disease mechanisms: A proposal

    SciTech Connect

    Skinner, F. K.; Ferguson, K. A.

    2013-12-15

    There is an undisputed need and requirement for theoretical and computational studies in Neuroscience today. Furthermore, it is clear that oscillatory dynamical output from brain networks is representative of various behavioural states, and it is becoming clear that one could consider these outputs as measures of normal and pathological brain states. Although mathematical modeling of oscillatory dynamics in the context of neurological disease exists, it is a highly challenging endeavour because of the many levels of organization in the nervous system. This challenge is coupled with the increasing knowledge of cellular specificity and network dysfunction that is associated with disease. Recently, whole hippocampus in vitro preparations from control animals have been shown to spontaneously express oscillatory activities. In addition, when using preparations derived from animal models of disease, these activities show particular alterations. These preparations present an opportunity to address challenges involved with using models to gain insight because of easier access to simultaneous cellular and network measurements, and pharmacological modulations. We propose that by developing and using models with direct links to experiment at multiple levels, which at least include cellular and microcircuit, a cycling can be set up and used to help us determine critical mechanisms underlying neurological disease. We illustrate our proposal using our previously developed inhibitory network models in the context of these whole hippocampus preparations and show the importance of having direct links at multiple levels.

  3. The Crossroads of Synaptic Growth Signaling, Membrane Traffic and Neurological Disease: Insights from Drosophila.

    PubMed

    Deshpande, Mugdha; Rodal, Avital A

    2016-02-01

    Neurons require target-derived autocrine and paracrine growth factors to maintain proper identity, innervation, homeostasis and survival. Neuronal growth factor signaling is highly dependent on membrane traffic, both for the packaging and release of the growth factors themselves, and for regulation of intracellular signaling by their transmembrane receptors. Here, we review recent findings from the Drosophila larval neuromuscular junction (NMJ) that illustrate how specific steps of intracellular traffic and inter-organelle interactions impinge on signaling, particularly in the bone morphogenic protein, Wingless and c-Jun-activated kinase pathways, regulating elaboration and stability of NMJ arbors, construction of synapses and synaptic transmission and homeostasis. These membrane trafficking and signaling pathways have been implicated in human motor neuron diseases including amyotrophic lateral sclerosis and hereditary spastic paraplegia, highlighting their importance for neuronal health and survival.

  4. Neurology and neurologic practice in China.

    PubMed

    Shi, Fu-Dong; Jia, Jian-Ping

    2011-11-29

    In the wake of dramatic economic success during the past 2 decades, the specialized field of neurology has undergone a significant transformation in China. With an increase in life expectancy, the problems of aging and cognition have grown. Lifestyle alterations have been associated with an epidemiologic transition both in the incidence and etiology of stroke. These changes, together with an array of social issues and institution of health care reform, are creating challenges for practicing neurologists throughout China. Notable problems include overcrowded, decrepit facilities, overloaded physician schedules, deteriorating physician-patient relationships, and an insufficient infrastructure to accommodate patients who need specialized neurologic care. Conversely, with the creation of large and sophisticated neurology centers in many cities across the country, tremendous opportunities exist. Developments in neurologic subspecialties enable delivery of high-quality care. Clinical and translational research based on large patient populations as well as highly sophisticated technologies are emerging in many neurologic centers and pharmaceutical companies. Child neurology and neurorehabilitation will be fast-developing subdisciplines. Given China's extensive population, the growth and progress of its neurology complex, and its ever-improving quality control, it is reasonable to anticipate that Chinese neurologists will contribute notably to unraveling the pathogenic factors causing neurologic diseases and to providing new therapeutic solutions.

  5. [Tree shrews under the spot light: emerging model of human diseases].

    PubMed

    Xu, Lin; Zhang, Yun; Liang, Bin; Lü, Long-Bao; Chen, Ce-Shi; Chen, Yong-Bin; Zhou, Ju-Min; Yao, Yong-Gang

    2013-04-01

    Animal models are indispensible in biomedical research and have made tremendous contributions to answer fundamental questions on human biology, disease mechanisms, and to the development of new drugs and diagnostic tools. Due to the limitations of rodent models in translational medicine, tree shrews (Tupaia belangeri chinensis), the closest relative of primates, have attracted increasing attention in modeling human diseases and therapeutic responses. Here we discuss the recent progress in tree shrew biology and the development of tree shrews as human disease models including infectious diseases, metabolic diseases, neurological and psychiatric diseases, and cancers. Meanwhile, the current problems and future perspectives of the tree shrew model are explored.

  6. Mouse models of human disease

    PubMed Central

    Perlman, Robert L.

    2016-01-01

    The use of mice as model organisms to study human biology is predicated on the genetic and physiological similarities between the species. Nonetheless, mice and humans have evolved in and become adapted to different environments and so, despite their phylogenetic relatedness, they have become very different organisms. Mice often respond to experimental interventions in ways that differ strikingly from humans. Mice are invaluable for studying biological processes that have been conserved during the evolution of the rodent and primate lineages and for investigating the developmental mechanisms by which the conserved mammalian genome gives rise to a variety of different species. Mice are less reliable as models of human disease, however, because the networks linking genes to disease are likely to differ between the two species. The use of mice in biomedical research needs to take account of the evolved differences as well as the similarities between mice and humans. PMID:27121451

  7. Neurological complications and risk factors of cardiopulmonary failure of EV-A71-related hand, foot and mouth disease.

    PubMed

    Long, Lili; Xu, Lin; Xiao, Zhenghui; Hu, Shixiong; Luo, Ruping; Wang, Hua; Lu, Xiulan; Xu, Zhiyue; Yao, Xu; Zhou, Luo; Long, Hongyu; Gong, Jiaoe; Song, Yanmin; Zhao, Li; Luo, Kaiwei; Zhang, Mengqi; Feng, Li; Yang, Liming; Sheng, Xiaoqi; Fan, Xuegong; Xiao, Bo

    2016-03-22

    From 2010 to 2012, large outbreaks of EV-A71-related- hand foot and mouth disease (HFMD) occurred annually in China. Some cases had neurological complications and were closely associated with fatal cardiopulmonary collapse, but not all children with central nervous system (CNS) involvement demonstrated a poor prognosis. To identify which patients and which neurological complications are more likely to progress to cardiopulmonary failure, we retrospectively studied 1,125 paediatric inpatients diagnosed with EV-A71-related HFMD in Hunan province, including 1,017 cases with CNS involvement. These patients were divided into cardiopulmonary failure (976 people) group and group without cardiopulmonary failure (149 people). A logistic regression analysis was used to compare the clinical symptoms, laboratory test results, and neurological complications between these two groups. The most significant risk factors included young age, fever duration ≥3 days, coma, limb weakness, drowsiness and ANS involvement. Patients with brainstem encephalitis and more CNS-involved regions were more likely to progress to cardiopulmonary failure. These findings can help front-line clinicians rapidly and accurately determine patient prognosis, thus rationally distributing the limited medical resources and implementing interventions as early as possible.

  8. Neurological complications and risk factors of cardiopulmonary failure of EV-A71-related hand, foot and mouth disease

    PubMed Central

    Long, Lili; Xu, Lin; Xiao, Zhenghui; Hu, Shixiong; Luo, Ruping; Wang, Hua; Lu, Xiulan; Xu, Zhiyue; Yao, Xu; Zhou, Luo; Long, Hongyu; Gong, Jiaoe; Song, Yanmin; Zhao, Li; Luo, Kaiwei; Zhang, Mengqi; Feng, Li; Yang, Liming; Sheng, Xiaoqi; Fan, Xuegong; Xiao, Bo

    2016-01-01

    From 2010 to 2012, large outbreaks of EV-A71-related- hand foot and mouth disease (HFMD) occurred annually in China. Some cases had neurological complications and were closely associated with fatal cardiopulmonary collapse, but not all children with central nervous system (CNS) involvement demonstrated a poor prognosis. To identify which patients and which neurological complications are more likely to progress to cardiopulmonary failure, we retrospectively studied 1,125 paediatric inpatients diagnosed with EV-A71-related HFMD in Hunan province, including 1,017 cases with CNS involvement. These patients were divided into cardiopulmonary failure (976 people) group and group without cardiopulmonary failure (149 people). A logistic regression analysis was used to compare the clinical symptoms, laboratory test results, and neurological complications between these two groups. The most significant risk factors included young age, fever duration ≥3 days, coma, limb weakness, drowsiness and ANS involvement. Patients with brainstem encephalitis and more CNS-involved regions were more likely to progress to cardiopulmonary failure. These findings can help front-line clinicians rapidly and accurately determine patient prognosis, thus rationally distributing the limited medical resources and implementing interventions as early as possible. PMID:27001010

  9. MicroRNAs in Human Diseases: From Autoimmune Diseases to Skin, Psychiatric and Neurodegenerative Diseases

    PubMed Central

    2011-01-01

    MicroRNAs (miRNAs) are small noncoding RNA molecules that negatively regulate gene expression via degradation or translational repression of their target messenger RNAs (mRNAs). Recent studies have clearly demonstrated that miRNAs play critical roles in several biologic processes, including cell cycle, differentiation, cell development, cell growth, and apoptosis and that miRNAs are highly expressed in regulatory T (Treg) cells and a wide range of miRNAs are involved in the regulation of immunity and in the prevention of autoimmunity. It has been increasingly reported that miRNAs are associated with various human diseases like autoimmune disease, skin disease, neurological disease and psychiatric disease. Recently, the identification of mi- RNAs in skin has added a new dimension in the regulatory network and attracted significant interest in this novel layer of gene regulation. Although miRNA research in the field of dermatology is still relatively new, miRNAs have been the subject of much dermatological interest in skin morphogenesis and in regulating angiogenesis. In addition, miRNAs are moving rapidly onto center stage as key regulators of neuronal development and function in addition to important contributions to neurodegenerative disorder. Moreover, there is now compelling evidence that dysregulation of miRNA networks is implicated in the development and onset of human neruodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Tourette's syndrome, Down syndrome, depression and schizophrenia. In this review, I briefly summarize the current studies about the roles of miRNAs in various autoimmune diseases, skin diseases, psychoneurological disorders and mental stress. PMID:22194706

  10. Neurological mechanisms of green tea polyphenols in Alzheimer's and Parkinson's diseases.

    PubMed

    Weinreb, Orly; Mandel, Silvia; Amit, Tamar; Youdim, Moussa B H

    2004-09-01

    Tea consumption is varying its status from a mere ancient beverage and a lifestyle habit, to a nutrient endowed with possible prospective neurobiological-pharmacological actions beneficial to human health. Accumulating evidence suggest that oxidative stress resulting in reactive oxygen species generation and inflammation play a pivotal role in neurodegenerative diseases, supporting the implementation of radical scavengers, transition metal (e.g., iron and copper) chelators, and nonvitamin natural antioxidant polyphenols in the clinic. These observations are in line with the current view that polyphenolic dietary supplementation may have an impact on cognitive deficits in individuals of advanced age. As a consequence, green tea polyphenols are now being considered as therapeutic agents in well controlled epidemiological studies, aimed to alter brain aging processes and to serve as possible neuroprotective agents in progressive neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. In particular, literature on the putative novel neuroprotective mechanism of the major green tea polyphenol, (-)-epigallocatechin-3-gallate, are examined and discussed in this review.

  11. Reflections: Neurology and The Humanities. The case of the locked house. The finished mystery.

    PubMed

    Joynt, Robert J; Kempster, Peter A; Lee, Andrew J

    2014-08-12

    After the death in 2012 of Dr. Robert Joynt, who served Neurology® as CPC Section Editor, an unfinished manuscript was found on his computer. It would have been his sixth Sherlock Holmes pastiche. Intrigued by the story but deflated at the lack of an ending, the editors published the case in the September 10, 2013, issue of Neurology and requested that readers finish it. A panel of editors reviewed over 30 submissions and the top 4 were posted online and on the iPad. Readers voted online, on the iPad, and during the 2014 American Academy of Neurology Annual Meeting in Philadelphia. The winning coauthors are Peter A. Kempster, from Melbourne, and Andrew J. Lees, from London. The runners-up are Anonymous (ending 1), Gerald Honch (ending 2), and Clifton Gooch (ending 4). The editors thank all participants and voters. The rule on page 662 indicates where the winning ending begins.

  12. Biochemical and toxicological evidence of neurological effects of pesticides: the example of Parkinson's disease.

    PubMed

    Moretto, A; Colosio, C

    2011-08-01

    Parkinson's disease (PD) is frequently reported to be associated with pesticide exposure but the issue has not yet been solved because the data are inconsistent and the studies suffer from several biases and limitations. The aim of this article is to summarise available biochemical and toxicological data on some pesticides, particularly on paraquat, that might help in the evaluation of epidemiological data. The nigrostriatal system appears to be particularly sensitive to oxidative damage caused by different mechanisms and agents, thus supporting the epidemiological evidence that Parkinson's disease is in fact an environmental disease. In available experimental studies, animals have been treated with a high single or a few doses of pesticide, and have been followed up for a few days or weeks after treatment. Moreover, experimental data indicate additive/synergistic effects of different pesticides that act on different targets within the dopaminergic system. In these conditions and to a different extent, pesticides such as paraquat, maneb and other dithiocarbamates, pyrethroids, rotenone, and dieldrin cause neurotoxic effects that may suggest a possible role in the development of a PD-like syndrome in animals. Although, all the characteristics of PD cannot be reproduced by any single chemical, these data can be of help for understanding the role of pesticide exposure in human PD development. On the other hand farmers are exposed for days or weeks during several years to much lower doses than those used in experimental studies. Therefore, a firm conclusion on the role of pesticide exposure on the increased risk of developing PD cannot be drawn. However, it is suggested that close follow up of survivors of acute poisonings by these pesticides, or identification in epidemiological studies of such subjects or of those reporting episodes of accidentally high exposure will certainly provide information useful for the understanding of the relevance of actual human exposure

  13. Mutations of EXOSC3/Rrp40p associated with neurological diseases impact ribosomal RNA processing functions of the exosome in S. cerevisiae.

    PubMed

    Gillespie, Abby; Gabunilas, Jason; Jen, Joanna C; Chanfreau, Guillaume F

    2017-04-01

    The RNA exosome is a conserved multiprotein complex that achieves a large number of processive and degradative functions in eukaryotic cells. Recently, mutations have been mapped to the gene encoding one of the subunits of the exosome, EXOSC3 (yeast Rrp40p), which results in pontocerebellar hypoplasia with motor neuron degeneration in human patients. However, the molecular impact of these mutations in the pathology of these diseases is not well understood. To investigate the molecular consequences of mutations in EXOSC3 that lead to neurological diseases, we analyzed the effect of three of the mutations that affect conserved residues of EXOSC3/Rrp40p (G31A, G191C, and W238R; G8A, G148C, and W195R, respectively, in human and yeast) in S. cerevisiae We show that the severity of the phenotypes of these mutations in yeast correlate with that of the disease in human patients, with the W195R mutant showing the strongest growth and RNA processing phenotypes. Furthermore, we show that these mutations affect more severely pre-ribosomal RNA processing functions of the exosome rather than other nuclear processing or surveillance functions. These results suggest that delayed or defective pre-rRNA processing might be the primary defect responsible for the pathologies detected in patients with mutations affecting EXOSC3 function in residues conserved throughout eukaryotes.

  14. Mutations of EXOSC3/Rrp40p associated with neurological diseases impact ribosomal RNA processing functions of the exosome in S. cerevisiae

    PubMed Central

    Gillespie, Abby; Gabunilas, Jason; Jen, Joanna C.; Chanfreau, Guillaume F.

    2017-01-01

    The RNA exosome is a conserved multiprotein complex that achieves a large number of processive and degradative functions in eukaryotic cells. Recently, mutations have been mapped to the gene encoding one of the subunits of the exosome, EXOSC3 (yeast Rrp40p), which results in pontocerebellar hypoplasia with motor neuron degeneration in human patients. However, the molecular impact of these mutations in the pathology of these diseases is not well understood. To investigate the molecular consequences of mutations in EXOSC3 that lead to neurological diseases, we analyzed the effect of three of the mutations that affect conserved residues of EXOSC3/Rrp40p (G31A, G191C, and W238R; G8A, G148C, and W195R, respectively, in human and yeast) in S. cerevisiae. We show that the severity of the phenotypes of these mutations in yeast correlate with that of the disease in human patients, with the W195R mutant showing the strongest growth and RNA processing phenotypes. Furthermore, we show that these mutations affect more severely pre-ribosomal RNA processing functions of the exosome rather than other nuclear processing or surveillance functions. These results suggest that delayed or defective pre-rRNA processing might be the primary defect responsible for the pathologies detected in patients with mutations affecting EXOSC3 function in residues conserved throughout eukaryotes. PMID:28053271

  15. Barefoot Plantar Pressure Indicates Progressive Neurological Damage in Patients with Human T-Cell Lymphotropic Virus Type 1 Infection

    PubMed Central

    Vasconcelos, Beatriz Helena B.; Souza, Givago S.; Barroso, Tatiana G. C. P.; Silveira, Luiz Carlos L.; Sousa, Rita Catarina M.; Callegari, Bianca; Xavier, Marília B.

    2016-01-01

    Background The human T-Cell Lymphotropic Virus Type 1 (HTLV-1) is a retrovirus associated with neurological alterations; individuals with HTLV-1 infection may develop HTLV-1 associated myelopathy / tropical spastic paraparesis (HAM/TSP). Frequent neurological complaints include foot numbness and leg weakness. In this study, we compared the distribution of the body weight on different areas of the foot in HTLV-1 patients with HAM/TSP, asymptomatic HTLV-1 patients, and healthy individuals. Methodology We studied 36 HTLV-1 infected patients, who were divided in two groups of 18 patients each based on whether or not they had been diagnosed with HAM/TSP, and 17 control subjects. The evaluation included an interview on the patient’s clinical history and examinations of the patient’s reflexes, foot skin tactile sensitivity, and risk of falling. The pressure distribution on different areas of the foot was measured with baropodometry, using a pressure platform, while the patients had their eyes open or closed. Main Findings The prevalence of neurological disturbances—altered reflexes and skin tactile sensitivity and increased risk of falling—was higher in HTLV-1 HAM/TSP patients than in HTLV-1 asymptomatic patients. The medium and maximum pressure values were higher in the forefoot than in the midfoot and hindfoot in both HTLV-1 groups. In addition, the pressure on the hindfoot was lower in HAM/TSP patients compared to control subjects. Conclusions The neurological disturbances associated with HTLV-1 infection gradually worsened from HTLV-1 asymptomatic patients to HAM/TSP patients. Baropodometry is a valuable tool to establish the extent of neurological damage in patients suffering from HTLV-1 infection. PMID:26998608

  16. Early neurologic abnormalities associated with human T-cell lymphotropic virus type 1 infection in a cohort of Peruvian children

    PubMed Central

    Kendall, Emily A.; González, Elsa; Espinoza, Iván; Tipismana, Martín; Verdonck, Kristien; Clark, Daniel; Vermund, Sten H.; Gotuzzo, Eduardo

    2009-01-01

    Objective Because human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) may occur in some children infected with HTLV-1-infected, we sought to determine the prevalence of neurologic abnormalities and any associations with infective dermatitis in these children. Study design We enrolled 58 children infected with HTLV-1 and 42 uninfected children (ages 3-17) of mothers infected with HTLV-1 in a family study in Lima, Peru. We obtained medical and developmental histories, surveyed current neurologic symptoms, and conducted a standardized neurologic examination without prior knowledge of HTLV-1 status. Results HTLV-1 infection was associated with reported symptoms of lower extremity weakness/fatigue (OR=6.1, CI:0.7–281), lumbar pain (odds ratio [OR] = 1.7, 95% confidence interval [CI]:0.4–8), and paresthesia/dysesthesia (OR=2.6, CI:0.6–15.8). HTLV-1 infection was associated with lower-extremity hyperreflexia (OR=3.1, CI:0.8–14.2), ankle clonus (OR=5.0, CI:1.0–48.3), and extensor plantar reflex (OR undefined; p = 0.2). Among children infected HTLV-1, a history of infective dermatitis was associated with weakness (OR=2.7, CI:0.3–33), lumbar pain (OR=1.3, CI:0.2–8), paresthesia/dysesthesia (OR=2.9, CI:0.5–20), and urinary disturbances (OR=5.7, CI:0.5–290). Conclusions Abnormal neurologic findings were common in Peruvian children infected with HTLV-1, and several findings were co-prevalent with infective dermatitis. Pediatricians should monitor children infected with HTLV-1 for neurologic abnormalities. PMID:19628219

  17. Follow-up nationwide survey on predictive genetic testing for late-onset hereditary neurological diseases in Japan.

    PubMed

    Tanaka, Keiko; Sekijima, Yoshiki; Yoshida, Kunihiro; Tamai, Mariko; Kosho, Tomoki; Sakurai, Akihiro; Wakui, Keiko; Ikeda, Shu-ichi; Fukushima, Yoshimitsu

    2013-08-01

    A follow-up nationwide survey on predictive genetic testing for late-onset neurological diseases in Japan was conducted. A questionnaire was sent to 89 institutional members of the Japan's National Liaison Council for Clinical Sections of Medical Genetics, and was returned by 60 (67.4%). A total of 301 clients with an interest in predictive testing were accumulated from April 2006 to March 2011. The greatest interest was shown for spinocerebellar degeneration (SCD, n=110), followed by myotonic dystrophy type 1 (DM1, n=69), Huntington's disease (HD, n=52) and familial amyloid polyneuropathy (FAP, n=35). The ratios of clients who actually underwent predictive testing were: SCD, 21.8%; DM1, 39.1%; HD, 26.9%; and FAP, 74.3%, indicating that predictive testing was conducted very cautiously for untreatable neurological diseases in Japan. Clinical geneticists were predominantly involved in genetic counseling, whereas the participation of non-medical doctor (non-MD) staff, including nurses, clinical psychologists and genetic counselors, was not common. Lack of non-MD counseling staff was one of the most serious issues in conducting predictive testing, which has not been improved since the previous survey performed in 2006. Institutional arrangements, such as revision of medical insurance system regarding genetic testing and counseling, might be necessary to resolve this issue.

  18. G4-associated human diseases

    PubMed Central

    Maizels, Nancy

    2015-01-01

    Recent research has established clear connections between G-quadruplexes and human disease. Features of quadruplex structures that promote genomic instability have been determined. Quadruplexes have been identified as transcriptional, translational and epigenetic regulatory targets of factors associated with human genetic disease. An expandable GGGGCC motif that can adopt a G4 structure, located in the previously obscure C9ORF72 locus, has been shown to contribute to two well-recognized neurodegenerative diseases, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This review focuses on these advances, which further dispel the view that genomic biology is limited to the confines of the canonical B-form DNA duplex, and show how quadruplexes contribute spatial and temporal dimensionalities to linear sequence information. This recent progress also has clear practical ramifications, as prevention, diagnosis, and treatment of disease depend on understanding the underlying mechanisms. PMID:26150098

  19. Large animal models of neurological disorders for gene therapy.

    PubMed

    Gagliardi, Christine; Bunnell, Bruce A

    2009-01-01

    he development of therapeutic interventions for genetic disorders and diseases that affect the central nervous system (CNS) has proven challenging. There has been significant progress in the development of gene therapy strategies in murine models of human disease, but gene therapy outcomes in these models do not always translate to the human setting. Therefore, large animal models are crucial to the development of diagnostics, treatments, and eventual cures for debilitating neurological disorders. This review focuses on the description of large animal models of neurological diseases such as lysosomal storage diseases, Parkinsons disease, Huntingtons disease, and neuroAIDS. The review also describes the contributions of these models to progress in gene therapy research.

  20. Identification and validation of clinical predictors for the risk of neurological involvement in children with hand, foot, and mouth disease in Sarawak

    PubMed Central

    2009-01-01

    Background Human enterovirus 71 (HEV71) can cause Hand, foot, and mouth disease (HFMD) with neurological complications, which may rapidly progress to fulminant cardiorespiratory failure, and death. Early recognition of children at risk is the key to reduce acute mortality and morbidity. Methods We examined data collected through a prospective clinical study of HFMD conducted between 2000 and 2006 that included 3 distinct outbreaks of HEV71 to identify risk factors associated with neurological involvement in children with HFMD. Results Total duration of fever ≥ 3 days, peak temperature ≥ 38.5°C and history of lethargy were identified as independent risk factors for neurological involvement (evident by CSF pleocytosis) in the analysis of 725 children admitted during the first phase of the study. When they were validated in the second phase of the study, two or more (≥ 2) risk factors were present in 162 (65%) of 250 children with CSF pleocytosis compared with 56 (30%) of 186 children with no CSF pleocytosis (OR 4.27, 95% CI2.79–6.56, p < 0.0001). The usefulness of the three risk factors in identifying children with CSF pleocytosis on hospital admission during the second phase of the study was also tested. Peak temperature ≥ 38.5°C and history of lethargy had the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 28%(48/174), 89%(125/140), 76%(48/63) and 50%(125/251), respectively in predicting CSF pleocytosis in children that were seen within the first 2 days of febrile illness. For those presented on the 3rd or later day of febrile illness, the sensitivity, specificity, PPV and NPV of ≥ 2 risk factors predictive of CSF pleocytosis were 75%(57/76), 59%(27/46), 75%(57/76) and 59%(27/46), respectively. Conclusion Three readily elicited clinical risk factors were identified to help detect children at risk of neurological involvement. These risk factors may serve as a guide to clinicians to decide the need for

  1. A new clinical tool for assessing numerical abilities in neurological diseases: numerical activities of daily living

    PubMed Central

    Semenza, Carlo; Meneghello, Francesca; Arcara, Giorgio; Burgio, Francesca; Gnoato, Francesca; Facchini, Silvia; Benavides-Varela, Silvia; Clementi, Maurizio; Butterworth, Brian

    2014-01-01

    The aim of this study was to build an instrument, the numerical activities of daily living (NADL), designed to identify the specific impairments in numerical functions that may cause problems in everyday life. These impairments go beyond what can be inferred from the available scales evaluating activities of daily living in general, and are not adequately captured by measures of the general deterioration of cognitive functions as assessed by standard clinical instruments like the MMSE and MoCA. We assessed a control group (n = 148) and a patient group affected by a wide variety of neurological conditions (n = 175), with NADL along with IADL, MMSE, and MoCA. The NADL battery was found to have satisfactory construct validity and reliability, across a wide age range. This enabled us to calculate appropriate criteria for impairment that took into account age and education. It was found that neurological patients tended to overestimate their abilities as compared to the judgment made by their caregivers, assessed with objective tests of numerical abilities. PMID:25126077

  2. An eye-tracking controlled neuropsychological battery for cognitive assessment in neurological diseases.

    PubMed

    Poletti, Barbara; Carelli, Laura; Solca, Federica; Lafronza, Annalisa; Pedroli, Elisa; Faini, Andrea; Zago, Stefano; Ticozzi, Nicola; Ciammola, Andrea; Morelli, Claudia; Meriggi, Paolo; Cipresso, Pietro; Lulé, Dorothée; Ludolph, Albert C; Riva, Giuseppe; Silani, Vincenzo

    2017-04-01

    Traditional cognitive assessment in neurological conditions involving physical disability is often prevented by the presence of verbal-motor impairment; to date, an extensive motor-verbal-free neuropsychological battery is not available for such purposes. We adapted a set of neuropsychological tests, assessing language, attentional abilities, executive functions and social cognition, for eye-tracking (ET) control, and explored its feasibility in a sample of healthy participants. Thirty healthy subjects performed a neuropsychological assessment, using an ET-based neuropsychological battery, together with standard "paper and pencil" cognitive measures for frontal (Frontal Assessment Battery-FAB) and working memory abilities (Digit Sequencing Task) and for global cognitive efficiency (Montreal Cognitive Assessment-MoCA). Psychological measures of anxiety (State-Trait Anxiety Inventory-Y-STAI-Y) and depression (Beck Depression Inventory-BDI) were also collected, and a usability questionnaire was administered. Significant correlations were observed between the "paper and pencil" screening of working memory abilities and the ET-based neuropsychological measures. The ET-based battery also correlated with the MoCA, while poor correlations were observed with the FAB. Usability aspects were found to be influenced by both working memory abilities and psychological components. The ET-based neuropsychological battery developed could provide an extensive assessment of cognitive functions, allowing participants to perform tasks independently from the integrity of motor or verbal channels. Further studies will be aimed at investigating validity and usability components in neurological populations with motor-verbal impairments.

  3. [Palliative care in neurology].

    PubMed

    Provinciali, Leandro; Tarquini, Daniela; De Falco, Fabrizio A; Carlini, Giulia; Zappia, Mario; Toni, Danilo

    2015-07-01

    Palliative care in neurology is characterized by the need of taking into account some distinguishing features which supplement and often differ from the general palliative approach to cancer or to severe organ failures. Such position is emphasized by a new concept of palliative assistance which is not limited to the "end of life" stage, as it was the traditional one, but is applied along the entire course of progressive, life-limiting, and disabling conditions. There are various reasons accounting for a differentiation of palliative care in neurology and for the development of specific expertise; the long duration of the advanced stages of many neurological diseases and the distinguishing features of some clinical problems (cognitive disorders, psychic disorders, etc.), in addition to the deterioration of some general aspects (nutrition, etc.), make the general criteria adopted for cancer, severe respiratory, hepatic or renal failures and heart failure inadequate. The neurological diseases which could benefit from the development of a specific palliative approach are dementia, cerebrovascular diseases, movement disorders, neuromuscular diseases, severe traumatic brain injury, brain cancers and multiple sclerosis, as well as less frequent conditions. The growing literature on palliative care in neurology provides evidence of the neurological community's increasing interest in taking care of the advanced and terminal stages of nervous system diseases, thus encouraging research, training and updating in such direction. This document aims to underline the specific neurological requirements concerning the palliative assistance.

  4. Neurologic complications of vaccinations.

    PubMed

    Miravalle, Augusto A; Schreiner, Teri

    2014-01-01

    This chapter reviews the most common neurologic disorders associated with common vaccines, evaluates the data linking the disorder with the vaccine, and discusses the potential mechanism of disease. A literature search was conducted in PubMed using a combination of the following terms: vaccines, vaccination, immunization, and neurologic complications. Data were also gathered from publications of the American Academy of Pediatrics Committee on Infectious Diseases, the World Health Organization, the US Centers for Disease Control and Prevention, and the Vaccine Adverse Event Reporting System. Neurologic complications of vaccination are rare. Many associations have been asserted without objective data to support a causal relationship. Rarely, patients with a neurologic complication will have a poor outcome. However, most patients recover fully from the neurologic complication. Vaccinations have altered the landscape of infectious disease. However, perception of risk associated with vaccinations has limited the success of disease eradication measures. Neurologic complications can be severe, and can provoke fear in potential vaccines. Evaluating whether there is causal link between neurologic disorders and vaccinations, not just temporal association, is critical to addressing public misperception of risk of vaccination. Among the vaccines available today, the cost-benefit analysis of vaccinations and complications strongly argues in favor of vaccination.

  5. Full genome sequence of a novel coxsackievirus B5 strain isolated from neurological hand, foot, and mouth disease patients in China.

    PubMed

    Hu, Y F; Zhao, R; Xue, Y; Yang, Fan; Jin, Q

    2012-10-01

    Coxsackievirus B5 (CVB5) belongs to the human enterovirus B species within the family Picornaviridae. We report the complete genome sequence of a novel CVB5 strain, CVB5/SD/09, that is associated with neurological hand, foot, and mouth disease in China. The complete genome consists of 7,399 nucleotides, excluding the 3' poly(A) tail, and has an open reading frame that maps between nucleotide positions 744 and 7301 and encodes a 2,185-amino-acid polyprotein. Phylogenetic analysis based on different genome region regions reveals that CVB5/SD/09 belongs to a novel CVB5 lineage, and similarity plotting and bootscanning analysis based on the whole genome of CVB5 in the present study and those available in GenBank indicate that the genome of CVB5/SD/09 has a mosaic-like structure, suggesting that recombination between different CVB5 strains may occur.

  6. Vanishing bone disease of chest wall and spine with kyphoscoliosis and neurological deficit: A case report and review of literature

    PubMed Central

    Srivastava, Sudhir Kumar; Aggarwal, Rishi Anil; Nemade, Pradip Sharad; Bhoale, Sunil Krishna

    2017-01-01

    Vanishing bone disease is an extremely rare disorder of unknown etiology characterized by idiopathic osteolysis of bone. We describe a case of vanishing bone disease of chest wall and spine with kyphoscoliosis and neurological deficit. A 17-year-old male presented with gradually progressive deformity of back and dorsal compressive myelopathy with nonambulatory power in lower limbs. Radiographs revealed absent 4th–7th ribs on the right side with dorsal kyphoscoliosis and severe canal narrowing at the apex. The patient was given localized radiotherapy and started on a monthly infusion of 4 mg zoledronic acid. Posterior instrumented fusion with anterior reconstruction via posterolateral approach was performed. The patient had a complete neurological recovery at 5 weeks following surgery. At 1 year, anterior nonunion was noted for which transthoracic tricortical bone grafting was done. Bone graft from the patient's mother was used both times. At 7 months following anterior grafting, the alignment was maintained and the patient was asymptomatic; however, fusion at graft-host interface was not achieved. Bisphosphonates and radiotherapy were successful in halting the progress of osteolysis. PMID:28216760

  7. Rodent models for human diseases.

    PubMed

    Vandamme, Thierry F

    2015-07-15

    One of the factors limiting the translation of knowledge from preclinical studies to the clinic has been the limitations of in vivo diseases models. Except in the case of highly controlled and regulated clinical trials, geneticists and scientists do not use humans for their experimental investigations because of the obvious risk to life. Instead, they use various animal, fungal, bacterial, and plant species as model organisms for their studies. Amongst these model organisms, rodent models are the most used due to the easiness for the experiments and the possibility to modify genetically these model animals. Nevertheless, due to the fact that animal models typically do not contract the same genetic diseases as people, so scientists must alter their genomes to induce human disease states and to know what kind of mutation causes the disease. In this brief review, we will discuss the interests of rodent models that have been developed to simulate human pathologies, focusing in models that employ xenografts and genetic modification. Within the framework of genetically engineered mouse (GEM) models, we will review some of the current genetic strategies for modeling diseases.

  8. Physical activity behavior change in persons with neurologic disorders: overview and examples from Parkinson disease and multiple sclerosis.

    PubMed

    Ellis, Terry; Motl, Robert W

    2013-06-01

    Persons with chronic progressive neurologic diseases such as Parkinson disease (PD) and multiple sclerosis (MS) face significant declines in mobility and activities of daily living, resulting in a loss of independence and compromised health-related quality of life over the course of the disease. Such undesirable outcomes can be attenuated through participation in exercise and physical activity, yet there is profound and prevalent physical inactivity in persons with PD and MS that may initiate a cycle of deconditioning and worsening of disease consequences, independent of latent disease processes. This Special Interest article highlights the accruing evidence revealing the largely sedentary behaviors common among persons living with physically disabling conditions and summarizes the evidence on the benefits of physical activity in persons with PD and MS. We then examine the social cognitive theory as an approach to identifying the primary active ingredients for behavioral change and, hence, the targets of interventions for increasing physical activity levels. The design and efficacies of interventions based on the social cognitive theory for increasing physical activity in persons with PD and MS are discussed. Finally, a rationale for adopting a secondary prevention approach to delivering physical therapy services is presented, with an emphasis on the integration of physical activity behavior change interventions into the care of persons with chronic, progressive disabilities over the course of the disease.Video Abstract available (see Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A42) for more insights from the authors.

  9. Human endogenous retroviruses: nature, occurrence, and clinical implications in human disease.

    PubMed Central

    Urnovitz, H B; Murphy, W H

    1996-01-01

    Retroviral diagnostics have become standard in human laboratory medicine. While current emphasis is placed on the human exogenous viruses (human immunodeficiency virus and human T-cell leukemia virus), evidence implicating human endogenous retroviruses (HERVs) in various human disease entities continues to mount. Literature on the occurrence of HERVs in human tissues and cells was analyzed. Substantial evidence documents that retrovirus particles were clearly demonstrable in various tissues and cells in both health and disease and were abundant in the placenta and that their occurrence could be implicated in some of the reproductive diseases. The characteristics of HERVs are summarized, mechanisms of replication and regulation are outlined, and the consistent hormonal responsiveness of HERVs is noted. Clear evidence implicating HERV gene products as participants in glomerulonephritis in some cases of systemic lupus erythematosus is adduced. Data implicating HERVs as etiologic factors in reproductive diseases, in some of the autoimmune diseases, in some forms of rheumatoid arthritis and connective tissue disease, in psoriasis, and in some of the inflammatory neurologic diseases are reviewed. The current major needs are to improve methods for HERV detection, to identify the most appropriate HERV prototypes, and to develop diagnostic reagents so that the putative biologic and pathologic roles of HERVs can be better evaluated. PMID:8665478

  10. Asymptomatic carotid disease--a new tool for assessing neurological risk.

    PubMed

    Pedro, Luís M; Sanches, J Miguel; Seabra, José; Suri, Jasjit S; Fernandes E Fernandes, José

    2014-03-01

    Active carotid plaques are associated with atheroembolism and neurological events; its identification is crucial for stroke prevention. High-definition ultrasound (HDU) can be used to recognize plaque structure in carotid bifurcation stenosis associated with plaque vulnerability and occurrence of brain ischemic events. A new computer-assisted HDU method to study the echomorphology of the carotid plaque and to determine a risk score for developing appropriate symptoms is proposed in this study. Plaque echomorphology characteristics such as presence of ulceration at the plaque surface, juxta-luminal location of echolucent areas, echoheterogeneity were obtained from B-mode ultrasound scans using several image processing algorithms and were combined with measurement of severity of stenosis to obtain a clinical score--enhanced activity index (EAI)--which was correlated with the presence or absence of ipsilateral appropriate ischemic symptoms. An optimal cutoff value of EAI was determined to obtain the best separation between symptomatic (active) from asymptomatic (inactive) plaques and its diagnostic yield was compared to other 2 reference methods by means of receiver-operating characteristic (ROC) analysis. Classification performance was evaluated by leave-one-patient-out cross-validation applied to a cohort of 146 carotid plaques from 99 patients. The proposed method was benchmarked against (a) degree of stenosis criteria and (b) earlier proposed activity index (AI) and demonstrated that EAI yielded the highest accuracy up to an accuracy of 77% to predict asymptomatic plaques that developed symptoms in a prospective cross-sectional study. Enhanced activity index is a noninvasive, easy to obtain parameter, which provided accurate estimation of neurological risk of carotid plaques.

  11. Neurological Outcomes after Human Umbilical Cord Patch for In Utero Spina Bifida Repair in a Sheep Model

    PubMed Central

    Papanna, Ramesha; Mann, Lovepreet K.; Snowise, Saul; Morales, Yisel; Prabhu, Sanjay P.; Tseng, Scheffer C. G.; Grill, Raymond; Fletcher, Stephen; Moise, Kenneth J.

    2016-01-01

    Objectives The objective of our study was to test the hypothesis that in utero repair of surgically created spina bifida in a sheep model using cryopreserved human umbilical cord (HUC) patch improves neurological outcome. Methods Spina bifida with myelotomy was surgically created in timed pregnant ewes at gestational day (GD) 75. The fetuses were randomly assigned to unrepaired versus HUC and treated at GD 95 and then delivered at GD 140. Neurological evaluation was performed using the Texas Spinal Cord Injury Scale (TSCIS), bladder control using ultrasound, and the hindbrain herniation. Results Three lambs without the spina bifida creation served as controls. There were four lambs with spina bifida: two were unrepaired and two underwent HUC repair. The control lambs had normal function. Both unrepaired lambs had nonhealed skin lesions with leakage of cerebrospinal fluid, a 0/20 TSCIS score, no bladder control, and the hindbrain herniation. In contrast, both HUC lambs had a completely healed skin defect and survived to day 2 of life, a 3/20 and 4/20 TSCIS score (nociception), partial bladder control, and normal hindbrain anatomy. Conclusions Cryopreserved HUC patch appears to improve survival and neurological outcome in this severe form of the ovine model of spina bifida. PMID:27621952

  12. The PRRT2 knockout mouse recapitulates the neurological diseases associated with PRRT2 mutations.

    PubMed

    Michetti, Caterina; Castroflorio, Enrico; Marchionni, Ivan; Forte, Nicola; Sterlini, Bruno; Binda, Francesca; Fruscione, Floriana; Baldelli, Pietro; Valtorta, Flavia; Zara, Federico; Corradi, Anna; Benfenati, Fabio

    2017-03-01

    Heterozygous and rare homozygous mutations in PRoline-Rich Transmembrane protein 2 (PRRT2) underlie a group of paroxysmal disorders including epilepsy, kinesigenic dyskinesia episodic ataxia and migraine. Most of the mutations lead to impaired PRRT2 expression and/or function. Recently, an important role for PRTT2 in the neurotransmitter release machinery, brain development and synapse formation has been uncovered. In this work, we have characterized the phenotype of a mouse in which the PRRT2 gene has been constitutively inactivated (PRRT2 KO). β-galactosidase staining allowed to map the regional expression of PRRT2 that was more intense in the cerebellum, hindbrain and spinal cord, while it was localized to restricted areas in the forebrain. PRRT2 KO mice are normal at birth, but display paroxysmal movements at the onset of locomotion that persist in the adulthood. In addition, adult PRRT2 KO mice present abnormal motor behaviors characterized by wild running and jumping in response to audiogenic stimuli that are ineffective in wild type mice and an increased sensitivity to the convulsive effects of pentylentetrazol. Patch-clamp electrophysiology in hippocampal and cerebellar slices revealed specific effects in the cerebellum, where PRRT2 is highly expressed, consisting in a higher excitatory strength at parallel fiber-Purkinje cell synapses during high frequency stimulation. The results show that the PRRT2 KO mouse reproduces the motor paroxysms present in the human PRRT2-linked pathology and can be proposed as an experimental model for the study of the pathogenesis of the disease as well as for testing personalized therapeutic approaches.

  13. Avian vacuolar myelinopathy: a newly recognized fatal neurologic disease of eagles, waterfowl, and other birds

    USGS Publications Warehouse

    Fischer, John R.; Lewis, L.A.; Augspurger, T.; Rocke, T.E.

    2002-01-01

    Wildlife biologists and health specialists have been frustrated by a long list of negative findings in their AVM investigations, however studies continue to provide pieces of information to aid the determination of the cause and its source. Available data indicated that AVM may have been present since at least 1990, occurs in at least five states, has been documented during October through April at sites of wintering populations of birds where the exposure apparently occurs, and has killed at least 90 bald eagles. Birds with AVM have difficulty or inability to fly, swim, walk, or perch, but there has been resolution of clinical signs in some affected coots. The list of affected species continues to grow, but remains confined to wild avians, including bald eagle, American coot, great horned owl, killdeer, Canada goose, mallard, ring-necked duck and bufflehead. The effects of the AVM agent on mammals, including human beings, are unknown. A neurotoxicant of manmade or natural origin is the suspected cause of AVM because no infectious disease agents, such as viruses, bacteria, parasites and prions, have been found, and the lesion and epizootiology of AVM resemble those of toxicoses. Additionally it is documented, experimentally, that exposure to raptors can occur through ingestion of infected coots. Collaborative studies will continue in the effort to identify the cause of AVM, its geographic distribution, and the range of species susceptibility. Hopefully, this information can be used to identify measures that might be taken to reduce the impact of AVM on the wildlife resource. Multiple agencies, institutions, and individuals must rely on each other's expertise in the multidisciplinary approach to this problem, persevere in their efforts and take advantage of serendipity that presents itself during investigations of this newly recognized cause of wild bird mortality.

  14. Cardiomyopathy in neurological disorders.

    PubMed

    Finsterer, Josef; Stöllberger, Claudia; Wahbi, Karim

    2013-01-01

    According to the American Heart Association, cardiomyopathies are classified as primary (solely or predominantly confined to heart muscle), secondary (those showing pathological myocardial involvement as part of a neuromuscular disorder) and those in which cardiomyopathy is the first/predominant manifestation of a neuromuscular disorder. Cardiomyopathies may be further classified as hypertrophic cardiomyopathy, dilated cardiomyopathy, restrictive cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, or unclassified cardiomyopathy (noncompaction, Takotsubo-cardiomyopathy). This review focuses on secondary cardiomyopathies and those in which cardiomyopathy is the predominant manifestation of a myopathy. Any of them may cause neurological disease, and any of them may be a manifestation of a neurological disorder. Neurological disease most frequently caused by cardiomyopathies is ischemic stroke, followed by transitory ischemic attack, syncope, or vertigo. Neurological disease, which most frequently manifests with cardiomyopathies are the neuromuscular disorders. Most commonly associated with cardiomyopathies are muscular dystrophies, myofibrillar myopathies, congenital myopathies and metabolic myopathies. Management of neurological disease caused by cardiomyopathies is not at variance from the same neurological disorders due to other causes. Management of secondary cardiomyopathies is not different from that of cardiomyopathies due to other causes either. Patients with neuromuscular disorders require early cardiologic investigations and close follow-ups, patients with cardiomyopathies require neurological investigation and avoidance of muscle toxic medication if a neuromuscular disorder is diagnosed. Which patients with cardiomyopathy profit most from primary stroke prevention is unsolved and requires further investigations.

  15. Proteins aggregation and human diseases

    NASA Astrophysics Data System (ADS)

    Hu, Chin-Kun

    2015-04-01

    Many human diseases and the death of most supercentenarians are related to protein aggregation. Neurodegenerative diseases include Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), frontotemporallobar degeneration, etc. Such diseases are due to progressive loss of structure or function of neurons caused by protein aggregation. For example, AD is considered to be related to aggregation of Aβ40 (peptide with 40 amino acids) and Aβ42 (peptide with 42 amino acids) and HD is considered to be related to aggregation of polyQ (polyglutamine) peptides. In this paper, we briefly review our recent discovery of key factors for protein aggregation. We used a lattice model to study the aggregation rates of proteins and found that the probability for a protein sequence to appear in the conformation of the aggregated state can be used to determine the temperature at which proteins can aggregate most quickly. We used molecular dynamics and simple models of polymer chains to study relaxation and aggregation of proteins under various conditions and found that when the bending-angle dependent and torsion-angle dependent interactions are zero or very small, then protein chains tend to aggregate at lower temperatures. All atom models were used to identify a key peptide chain for the aggregation of insulin chains and to find that two polyQ chains prefer anti-parallel conformation. It is pointed out that in many cases, protein aggregation does not result from protein mis-folding. A potential drug from Chinese medicine was found for Alzheimer's disease.

  16. Cerebrospinal fluid and serum cytokine profiling to detect immune control of infectious and inflammatory neurological and psychiatric diseases.

    PubMed

    Maxeiner, Horst-Guenter; Marion Schneider, E; Kurfiss, Sina-Tatjana; Brettschneider, Johannes; Tumani, Hayrettin; Bechter, Karl

    2014-09-01

    The present study aimed at profiling inflammatory cytokines for neurological and psychiatric diseases. A total of 86 patients with meningitis, multiple sclerosis, tension-type headache, idiopathic facial nerve palsy (IFNP), affective and schizophrenic disorders were tested for both, serum and cerebrospinal fluid (CSF) using a multiplexed cytokine ELISA for IFN-γ, TNF-α, IL-1β, IL-2, IL-4, IL-5, IL-8/CXCL8, IL-10, IL12p70, IL-13 and IL-17. Cases with viral and bacterial meningitis had unequivocally higher cytokine concentrations in the CSF when compared with serum. Bacterial meningitis was unique by extremely elevated IL-17, TNF-α and IL-1β, indicating a plethora of inflammatory pathways, selectively activated in the CSF. In relapsing multiple sclerosis, IFN-γ and IL-10 were elevated in both, serum and CSF, but IL-12p70, IL-5, IL-13, and TNF-α were more prominent in serum than in CSF. Qualitatively similar biomarker patterns were detected in patients with idiopathic facial nerve palsy and tension-type cephalgia. Affective and schizophrenic disorders clearly present with an inflammatory phenotype in the CSF and also serum, the cytokines determined were in general higher in schizophrenia. Except IFN-γ, schizophrenic patients had higher IL-12p70 and a trend of higher IL-10 and IL-13 in serum suggesting a more prominent TH2-type counter regulatory immune response than in affective disorders. These differences were also mirrored in the CSF. Elevated IL-8 appears to be the most sensitive marker for inflammation in the CSF of all diseases studied, whereas TNF-α was restricted to peripheral blood. With the exception of IL-8, all but viral and bacterial meningitis, studied, displayed higher means of elevated lymphokine concentrations in the serum than in the CSF. This observation supports the concept of immunological crosstalk between periphery and intrathecal immunity in neurological and psychiatric diseases.

  17. REM Sleep Behavior Disorder and REM Sleep Without Atonia as an Early Manifestation of Degenerative Neurological Disease

    PubMed Central

    McCarter, Stuart J.; St Louis, Erik K.

    2013-01-01

    Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by repeated episodes of dream enactment behavior and REM sleep without atonia (RSWA) during polysomnography recording. RSWA is characterized by increased phasic or tonic muscle activity seen on polysomnographic electromyogram channels. RSWA is a requisite diagnostic feature of RBD, but may also be seen in patients without clinical symptoms or signs of dream enactment as an incidental finding in neurologically normal individuals, especially in patients receiving antidepressant therapy. RBD may be idiopathic or symptomatic. Patients with idiopathic RBD often later develop other neurological features including parkinsonism, orthostatic hypotension, anosmia, or cognitive impairment. RSWA without clinical symptoms as well as clinically overt RBD also often occurs concomitantly with the α-synucleinopathy family of neurodegenerative disorders, which includes idiopathic Parkinson disease, Lewy body dementia, and multiple system atrophy. This review article considers the epidemiology of RBD, clinical and polysomnographic diagnostic standards for both RBD and RSWA, previously reported associations of RSWA and RBD with neurodegenerative disorders and other potential causes, the pathophysiology of which brain structures and networks mediate dysregulation of REM sleep muscle atonia, and considerations for the effective and safe management of RBD. PMID:22328094

  18. Virtual reality interface devices in the reorganization of neural networks in the brain of patients with neurological diseases.

    PubMed

    Gatica-Rojas, Valeska; Méndez-Rebolledo, Guillermo

    2014-04-15

    Two key characteristics of all virtual reality applications are interaction and immersion. Systemic interaction is achieved through a variety of multisensory channels (hearing, sight, touch, and smell), permitting the user to interact with the virtual world in real time. Immersion is the degree to which a person can feel wrapped in the virtual world through a defined interface. Virtual reality interface devices such as the Nintendo® Wii and its peripheral nunchuks-balance board, head mounted displays and joystick allow interaction and immersion in unreal environments created from computer software. Virtual environments are highly interactive, generating great activation of visual, vestibular and proprioceptive systems during the execution of a video game. In addition, they are entertaining and safe for the user. Recently, incorporating therapeutic purposes in virtual reality interface devices has allowed them to be used for the rehabilitation of neurological patients, e.g., balance training in older adults and dynamic stability in healthy participants. The improvements observed in neurological diseases (chronic stroke and cerebral palsy) have been shown by changes in the reorganization of neural networks in patients' brain, along with better hand function and other skills, contributing to their quality of life. The data generated by such studies could substantially contribute to physical rehabilitation strategies.

  19. Virtual reality interface devices in the reorganization of neural networks in the brain of patients with neurological diseases

    PubMed Central

    Gatica-Rojas, Valeska; Méndez-Rebolledo, Guillermo

    2014-01-01

    Two key characteristics of all virtual reality applications are interaction and immersion. Systemic interaction is achieved through a variety of multisensory channels (hearing, sight, touch, and smell), permitting the user to interact with the virtual world in real time. Immersion is the degree to which a person can feel wrapped in the virtual world through a defined interface. Virtual reality interface devices such as the Nintendo® Wii and its peripheral nunchuks-balance board, head mounted displays and joystick allow interaction and immersion in unreal environments created from computer software. Virtual environments are highly interactive, generating great activation of visual, vestibular and proprioceptive systems during the execution of a video game. In addition, they are entertaining and safe for the user. Recently, incorporating therapeutic purposes in virtual reality interface devices has allowed them to be used for the rehabilitation of neurological patients, e.g., balance training in older adults and dynamic stability in healthy participants. The improvements observed in neurological diseases (chronic stroke and cerebral palsy) have been shown by changes in the reorganization of neural networks in patients’ brain, along with better hand function and other skills, contributing to their quality of life. The data generated by such studies could substantially contribute to physical rehabilitation strategies. PMID:25206907

  20. REM sleep behavior disorder and REM sleep without atonia as an early manifestation of degenerative neurological disease.

    PubMed

    McCarter, Stuart J; St Louis, Erik K; Boeve, Bradley F

    2012-04-01

    Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by repeated episodes of dream enactment behavior and REM sleep without atonia (RSWA) during polysomnography recording. RSWA is characterized by increased phasic or tonic muscle activity seen on polysomnographic electromyogram channels. RSWA is a requisite diagnostic feature of RBD, but may also be seen in patients without clinical symptoms or signs of dream enactment as an incidental finding in neurologically normal individuals, especially in patients receiving antidepressant therapy. RBD may be idiopathic or symptomatic. Patients with idiopathic RBD often later develop other neurological features including parkinsonism, orthostatic hypotension, anosmia, or cognitive impairment. RSWA without clinical symptoms as well as clinically overt RBD also often occurs concomitantly with the α-synucleinopathy family of neurodegenerative disorders, which includes idiopathic Parkinson disease, Lewy body dementia, and multiple system atrophy. This review article considers the epidemiology of RBD, clinical and polysomnographic diagnostic standards for both RBD and RSWA, previously reported associations of RSWA and RBD with neurodegenerative disorders and other potential causes, the pathophysiology of which brain structures and networks mediate dysregulation of REM sleep muscle atonia, and considerations for the effective and safe management of RBD.

  1. An Acoustic Study of the Relationships among Neurologic Disease, Dysarthria Type, and Severity of Dysarthria

    ERIC Educational Resources Information Center

    Kim, Yunjung; Kent, Raymond D.; Weismer, Gary

    2011-01-01

    Purpose: This study examined acoustic predictors of speech intelligibility in speakers with several types of dysarthria secondary to different diseases and conducted classification analysis solely by acoustic measures according to 3 variables (disease, speech severity, and dysarthria type). Method: Speech recordings from 107 speakers with…

  2. Favipiravir (T-705) protects against peracute Rift Valley fever virus infection and reduces delayed-onset neurologic disease observed with ribavirin treatment

    PubMed Central

    Scharton, Dionna; Bailey, Kevin W.; Vest, Zachary; Westover, Jonna B.; Kumaki, Yohichi; Van Wettere, Arnaud; Furuta, Yousuke; Gowen, Brian B.

    2014-01-01

    Rift Valley Fever is a zoonotic, arthropod-borne disease that affects livestock and humans. The etiologic agent, Rift Valley fever virus (RVFV; Bunyaviridae, Phlebovirus) is primarily transmitted through mosquito bites, but can also be transmitted by exposure to infectious aerosols. There are presently no licensed vaccines or therapeutics to prevent or treat severe RVFV infection in humans. We have previously reported on the activity of favipiravir (T-705) against the MP-12 vaccine strain of RVFV and other bunyaviruses in cell culture. In addition, efficacy has also been documented in mouse and hamster models of infection with the related Punta Toro virus. Here, we challenged hamsters with the highly pathogenic ZH501 strain of RVFV to evaluate the activity of favipiravir against lethal infection. Subcutaneous RVFV challenge resulted in substantial serum and tissue viral loads and caused severe disease and mortality within 2–3 days after infection. Oral favipiravir (200 mg/kg/day) prevented mortality in 60% or greater in hamsters challenged with RVFV when administered within 1 or 6 h post-exposure and reduced RVFV titers in serum and tissues relative to the time of treatment initiation. In contrast, although ribavirin (75 mg/kg/day) was effective at protecting animals from the peracute RVFV disease, most ultimately succumbed from a delayed-onset neurologic disease associated with high RVFV burden in the brain observed in moribund animals. When combined, T-705 and ribavirin treatment started 24 h post-infection significantly improved survival outcome and reduced serum and tissue virus titers compared to monotherapy. Our findings demonstrate significant post-RVFV exposure efficacy with favipiravir against both peracute disease and delayed-onset neuroinvasion, and suggest added benefit when combined with ribavirin. PMID:24486952

  3. Favipiravir (T-705) protects against peracute Rift Valley fever virus infection and reduces delayed-onset neurologic disease observed with ribavirin treatment.

    PubMed

    Scharton, Dionna; Bailey, Kevin W; Vest, Zachary; Westover, Jonna B; Kumaki, Yohichi; Van Wettere, Arnaud; Furuta, Yousuke; Gowen, Brian B

    2014-04-01

    Rift Valley fever is a zoonotic, arthropod-borne disease that affects livestock and humans. The etiologic agent, Rift Valley fever virus (RVFV; Bunyaviridae, Phlebovirus) is primarily transmitted through mosquito bites, but can also be transmitted by exposure to infectious aerosols. There are presently no licensed vaccines or therapeutics to prevent or treat severe RVFV infection in humans. We have previously reported on the activity of favipiravir (T-705) against the MP-12 vaccine strain of RVFV and other bunyaviruses in cell culture. In addition, efficacy has also been documented in mouse and hamster models of infection with the related Punta Toro virus. Here, hamsters challenged with the highly pathogenic ZH501 strain of RVFV were used to evaluate the activity of favipiravir against lethal infection. Subcutaneous RVFV challenge resulted in substantial serum and tissue viral loads and caused severe disease and mortality within 2-3 days of infection. Oral favipiravir (200 mg/kg/day) prevented mortality in 60% or greater of hamsters challenged with RVFV when administered within 1 or 6h post-exposure and reduced RVFV titers in serum and tissues relative to the time of treatment initiation. In contrast, although ribavirin (75 mg/kg/day) was effective at protecting animals from the peracute RVFV disease, most ultimately succumbed from a delayed-onset neurologic disease associated with high RVFV burden observed in the brain in moribund animals. When combined, T-705 and ribavirin treatment started 24 h post-infection significantly improved survival outcome and reduced serum and tissue virus titers compared to monotherapy. Our findings demonstrate significant post-RVFV exposure efficacy with favipiravir against both peracute disease and delayed-onset neuroinvasion, and suggest added benefit when combined with ribavirin.

  4. Molecular underpinnings of Aprataxin RNA/DNA deadenylase function and dysfunction in neurological disease.

    PubMed

    Schellenberg, Matthew J; Tumbale, Percy P; Williams, R Scott

    2015-03-01

    Eukaryotic DNA ligases seal DNA breaks in the final step of DNA replication and repair transactions via a three-step reaction mechanism that can abort if DNA ligases encounter modified DNA termini, such as the products and repair intermediates of DNA oxidation, alkylation, or the aberrant incorporation of ribonucleotides into genomic DNA. Such abortive DNA ligation reactions act as molecular checkpoint for DNA damage and create 5'-adenylated nucleic acid termini in the context of DNA and RNA-DNA substrates in DNA single strand break repair (SSBR) and ribonucleotide excision repair (RER). Aprataxin (APTX), a protein altered in the heritable neurological disorder Ataxia with Oculomotor Apraxia 1 (AOA1), acts as a DNA ligase "proofreader" to directly reverse AMP-modified nucleic acid termini in DNA- and RNA-DNA damage responses. Herein, we survey APTX function and the emerging cell biological, structural and biochemical data that has established a molecular foundation for understanding the APTX mediated deadenylation reaction, and is providing insights into the molecular bases of APTX deficiency in AOA1.

  5. Molecular Underpinnings of Aprataxin RNA/DNA Deadenylase Function and Dysfunction in Neurological Disease

    PubMed Central

    Williams, R. Scott

    2015-01-01

    Eukaryotic DNA ligases seal DNA breaks in the final step of DNA replication and repair transactions via a three-step reaction mechanism that can abort if DNA ligases encounter modified DNA termini, such as the products and repair intermediates of DNA oxidation, alkylation, or the aberrant incorporation of ribonucleotides into genomic DNA. Such abortive DNA ligation reactions create 5’–adenylated nucleic acid termini in the context of DNA and RNA-DNA substrates in DNA base excision repair (BER), double strand break repair (DSBR) and ribonucleotide excision repair (RER). Aprataxin (APTX), a protein altered in the heritable neurological disorder Ataxia with Oculomotor Apraxia 1 (AOA1), acts as a DNA ligase “proofreader” to directly reverse AMP-modified nucleic acid termini in DNA- and RNA-DNA damage responses. Herein, we survey APTX function and the emerging cell biological, structural and biochemical data that has established a molecular foundation for understanding the APTX mediated deadenylation reaction, and is providing insights into the molecular bases of APTX deficiency in AOA1. PMID:25637650

  6. Mycoplasmas in diseases of humans.

    PubMed Central

    Embree, J E; Embil, J A

    1980-01-01

    The roles of Mycoplasma pneumoniae, M. hominis and Ureaplasma urealyticum in diseases of humans are currently under investigation. M. pneumoniae, which causes primary atypical pneumonia, is a well established pathogen of the respiratory tract. Complications of infection by this organism are also being recognized; they include disorders of the hematopoietic, cardiovascular, central nervous, musculoskeletal, cutaneous and gastrointestinal systems. The roles of the genital mycoplasmas M. hominis and U. urealyticum are controversial but may include infections of the genitourinary tract and in pregnancy as well as diseases of the newborn, such as neonatal pneumonia and meningitis. In this review atypical pneumonia due to M. pneumoniae is described and the role of mycoplasmas in other diseases is discussed. Images FIG. 1A FIG. 1B FIG. 2 PMID:6790148

  7. Do all of the neurologic diseases in patients with DNA repair gene mutations result from the accumulation of DNA damage?

    PubMed

    Brooks, P J; Cheng, Tsu-Fan; Cooper, Lori

    2008-06-01

    The classic model for neurodegeneration due to mutations in DNA repair genes holds that DNA damage accumulates in the absence of repair, resulting in the death of neurons. This model was originally put forth to explain the dramatic loss of neurons observed in patients with xeroderma pigmentosum neurologic disease, and is likely to be valid for other neurodegenerative diseases due to mutations in DNA repair genes. However, in trichiothiodystrophy (TTD), Aicardi-Goutières syndrome (AGS), and Cockayne syndrome (CS), abnormal myelin is the most prominent neuropathological feature. Myelin is synthesized by specific types of glial cells called oligodendrocytes. In this review, we focus on new studies that illustrate two disease mechanisms for myelin defects resulting from mutations in DNA repair genes, both of which are fundamentally different than the classic model described above. First, studies using the TTD mouse model indicate that TFIIH acts as a co-activator for thyroid hormone-dependent gene expression in the brain, and that a causative XPD mutation in TTD results in reduction of this co-activator function and a dysregulation of myelin-related gene expression. Second, in AGS, which is caused by mutations in either TREX1 or RNASEH2, recent evidence indicates that failure to degrade nucleic acids produced during S-phase triggers activation of the innate immune system, resulting in myelin defects and calcification of the brain. Strikingly, both myelin defects and brain calcification are both prominent features of CS neurologic disease. The similar neuropathology in CS and AGS seems unlikely to be due to the loss of a common DNA repair function, and based on the evidence in the literature, we propose that vascular abnormalities may be part of the mechanism that is common to both diseases. In summary, while the classic DNA damage accumulation model is applicable to the neuronal death due to defective DNA repair, the myelination defects and brain calcification seem to

  8. New Perspectives on Oxidized Genome Damage and Repair Inhibition by Pro-Oxidant Metals in Neurological Diseases

    PubMed Central

    Mitra, Joy; Guerrero, Erika N.; Hegde, Pavana M.; Wang, Haibo; Boldogh, Istvan; Rao, Kosagi Sharaf; Mitra, Sankar; Hegde, Muralidhar L.

    2014-01-01

    The primary cause(s) of neuronal death in most cases of neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease, are still unknown. However, the association of certain etiological factors, e.g., oxidative stress, protein misfolding/aggregation, redox metal accumulation and various types of damage to the genome, to pathological changes in the affected brain region(s) have been consistently observed. While redox metal toxicity received major attention in the last decade, its potential as a therapeutic target is still at a cross-roads, mostly because of the lack of mechanistic understanding of metal dyshomeostasis in affected neurons. Furthermore, previous studies have established the role of metals in causing genome damage, both directly and via the generation of reactive oxygen species (ROS), but little was known about their impact on genome repair. Our recent studies demonstrated that excess levels of iron and copper observed in neurodegenerative disease-affected brain neurons could not only induce genome damage in neurons, but also affect their repair by oxidatively inhibiting NEIL DNA glycosylases, which initiate the repair of oxidized DNA bases. The inhibitory effect was reversed by a combination of metal chelators and reducing agents, which underscore the need for elucidating the molecular basis for the neuronal toxicity of metals in order to develop effective therapeutic approaches. In this review, we have focused on the oxidative genome damage repair pathway as a potential target for reducing pro-oxidant metal toxicity in neurological diseases. PMID:25036887

  9. Progress in pediatrics in 2013: choices in allergology, endocrinology, gastroenterology, hypertension, infectious diseases, neonatology, neurology, nutrition and respiratory tract illnesses.

    PubMed

    Caffarelli, Carlo; Santamaria, Francesca; Vottero, Alessandra; Dascola, Carlotta Povesi; Mirra, Virginia; Sperli, Francesco; Bernasconi, Sergio

    2014-07-12

    This review will provide new information related to pathophysiology and management of specific diseases that have been addressed by selected articles published in the Italian Journal of Pediatrics in 2013, focusing on allergology, endocrinology, gastroenterology, hypertension, infectious diseases, neonatology, neurology, nutrition and respiratory tract illnesses in children. Recommendations for interpretation of skin prick test to foods in atopic eczema, management of allergic conjunctivitis, hypertension and breastfeeding in women treated with antiepileptic drugs and healthy breakfast have been reported. Epidemiological studies have given emphasis to high incidence of autoimmune disorders in patients with Turner syndrome, increasing prevalence of celiac disease, frequency of hypertension in adolescents, incidence and risk factor for retinopathy of prematurity. Advances in prevention include elucidation of the role of probiotics in reducing occurrence of allergies and feeding intolerance, and events of foetal life that influence later onset of diseases. Mechanistic studies suggested a role for vitamin D deficiency in asthma and type 1 diabetes and for reactivation of Varicella-Zoster virus in aseptic meningitis. Regarding diagnosis, a new mean for the diagnosis of hyperbilirubinaemia in newborns, a score for recognition of impaired nutritional status and growth and criteria for early Dyke-Davidoff-Masson Syndrome have been suggested. New therapeutic approaches consist of use of etanercept for reducing insulin dose in type 1 diabetes, probiotics in atopic eczema, and melatonin in viral infections.

  10. A critical appraisal of the mild axonal peripheral neuropathy of late neurologic Lyme disease.

    PubMed

    Wormser, Gary P; Strle, Franc; Shapiro, Eugene D; Dattwyler, Raymond J; Auwaerter, Paul G

    2017-02-01

    In older studies, a chronic distal symmetric sensory neuropathy was reported as a relatively common manifestation of late Lyme disease in the United States. However, the original papers describing this entity had notable inconsistencies and certain inexplicable findings, such as reports that this condition developed in patients despite prior antibiotic treatment known to be highly effective for other manifestations of Lyme disease. More recent literature suggests that this entity is seen rarely, if at all. A chronic distal symmetric sensory neuropathy as a manifestation of late Lyme disease in North America should be regarded as controversial and in need of rigorous validation studies before acceptance as a documented clinical entity.

  11. Human Neural Precursor Cells Promote Neurologic Recovery in a Viral Model of Multiple Sclerosis

    PubMed Central

    Chen, Lu; Coleman, Ronald; Leang, Ronika; Tran, Ha; Kopf, Alexandra; Walsh, Craig M.; Sears-Kraxberger, Ilse; Steward, Oswald; Macklin, Wendy B.; Loring, Jeanne F.; Lane, Thomas E.

    2014-01-01

    Summary Using a viral model of the demyelinating disease multiple sclerosis (MS), we show that intraspinal transplantation of human embryonic stem cell-derived neural precursor cells (hNPCs) results in sustained clinical recovery, although hNPCs were not detectable beyond day 8 posttransplantation. Improved motor skills were associated with a reduction in neuroinflammation, decreased demyelination, and enhanced remyelination. Evidence indicates that the reduced neuroinflammation is correlated with an increased number of CD4+CD25+FOXP3+ regulatory T cells (Tregs) within the spinal cords. Coculture of hNPCs with activated T cells resulted in reduced T cell proliferation and increased Treg numbers. The hNPCs acted, in part, through secretion of TGF-β1 and TGF-β2. These findings indicate that the transient presence of hNPCs transplanted in an animal model of MS has powerful immunomodulatory effects and mediates recovery. Further investigation of the restorative effects of hNPC transplantation may aid in the development of clinically relevant MS treatments. PMID:24936469

  12. Sarcopenia or muscle modifications in neurologic diseases: a lexical or patophysiological difference?

    PubMed

    Carda, S; Cisari, C; Invernizzi, M

    2013-02-01

    Sarcopenia is a condition characterized by a decrease in muscle mass and function (strength and mobility) that is frequently observed in the elderly. In people with paresis and altered mobility due to central nervous system (CNS) diseases, this definition then may not be applicable. In CNS diseases, mainly stroke and spinal cord injury, different and specific patterns of muscle loss and muscle changes have been described, due to denervation, disuse atrophy, spasticity and myosteatosis. The main observations available about these phenomena in CNS diseases are reviewed, and a broad view on the specific physiopathological mechanisms is also described. Moreover, a description of the potential pharmacological targets and treatment strategies (physical and nutritional) is provided. Since sarcopenia of the elderly and muscle modifications and muscle atrophy in CNS diseases have different mechanisms, it is probable that they do not respond equally to the same treatments.

  13. Multi-resolution entropy analysis of gait symmetry in neurological degenerative diseases and amyotrophic lateral sclerosis.

    PubMed

    Liao, Fuyuan; Wang, Jue; He, Ping

    2008-04-01

    Gait rhythm of patients with Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS) has been studied focusing on the fractal and correlation properties of stride time fluctuations. In this study, we investigated gait asymmetry in these diseases using the multi-resolution entropy analysis of stance time fluctuations. Since stance time is likely to exhibit fluctuations across multiple spatial and temporal scales, the data series were decomposed into appropriate levels by applying stationary wavelet transform. The similarity between two corresponding wavelet coefficient series in terms of their regularities at each level was quantified based on a modified sample entropy method and a weighted sum was then used as gait symmetry index. We found that gait symmetry in subjects with PD and HD, especially with ALS is significantly disturbed. This method may be useful in characterizing certain pathologies of motor control and, possibly, in monitoring disease progression and evaluating the effect of an individual treatment.

  14. Neurological lesions in chickens experimentally infected with virulent Newcastle disease virus isolates

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Neuropil reaction was evaluated in chickens inoculated with four different Newcastle disease virus (NDV) isolates, including Texas GB, Turkey North Dakota, Nevada Cormorant (velogenic neurotropic) and Anhinga (mesogenic). Tissues for this study included archived formalin-fixed, paraffin embedded br...

  15. Development of a patient reported outcome measure for fatigue in motor neurone disease: the Neurological Fatigue Index (NFI-MND)

    PubMed Central

    2011-01-01

    Background The objective of this research was to develop a disease-specific measure for fatigue in patients with motor neurone disease (MND) by generating data that would fit the Rasch measurement model. Fatigue was defined as reversible motor weakness and whole-body tiredness that was predominantly brought on by muscular exertion and was partially relieved by rest. Methods Qualitative interviews were undertaken to confirm the suitability of a previously identified set of 52 neurological fatigue items as relevant to patients with MND. Patients were recruited from five U.K. MND clinics. Questionnaires were administered during clinic or by post. A sub-sample of patients completed the questionnaire again after 2-4 weeks to assess test-retest validity. Exploratory factor analyses and Rasch analysis were conducted on the item set. Results Qualitative interviews with ten MND patients confirmed the suitability of 52 previously identified neurological fatigue items as relevant to patients with MND. 298 patients consented to completing the initial questionnaire including this item set, with an additional 78 patients completing the questionnaire a second time after 4-6 weeks. Exploratory Factor Analysis identified five potential subscales that could be conceptualised as representing: 'Energy', 'Reversible muscular weakness' (shortened to 'Weakness'), 'Concentration', 'Effects of heat' and 'Rest'. Of the original five factors, two factors 'Energy' and 'Weakness' met the expectations of the Rasch model. A higher order fatigue summary scale, consisting of items from the 'Energy' and 'Weakness' subscales, was found to fit the Rasch model and have acceptable unidimensionality. The two scales and the higher order summary scale were shown to fulfil model expectations, including assumptions of unidimensionality, local independency and an absence of differential item functioning. Conclusions The Neurological Fatigue Index for MND (NFI-MND) is a simple, easy-to-administer fatigue

  16. Chromosomal localization of glutamate receptor genes: relationship to familial amyotrophic lateral sclerosis and other neurological disorders of mice and humans.

    PubMed Central

    Gregor, P; Reeves, R H; Jabs, E W; Yang, X; Dackowski, W; Rochelle, J M; Brown, R H; Haines, J L; O'Hara, B F; Uhl, G R

    1993-01-01

    Receptors for the major excitatory neurotransmitter glutamate may play key roles in neurodegeneration. The mouse Glur-5 gene maps to chromosome 16 between App and Sod-1. The homologous human GLUR5 gene maps to the corresponding region of human chromosome 21, which contains the locus for familial amyotrophic lateral sclerosis. This location, and other features, render GLUR5 a possible candidate gene for familial amyotrophic lateral sclerosis. In addition, dosage imbalance of GLUR5 may have a role in the trisomy 21 (Down syndrome). Further characterization of the murine glutamate receptor family includes mapping of Glur-1 to the same region as neurological mutants spasmodic, shaker-2, tipsy, and vibrator on chromosome 11; Glur-2 near spastic on chromosome 3; Glur-6 near waltzer and Jackson circler on chromosome 10; and Glur-7 near clasper on chromosome 4. Images Fig. 3 PMID:8464923

  17. Neurological disease mutations of α3 Na(+),K(+)-ATPase: Structural and functional perspectives and rescue of compromised function.

    PubMed

    Holm, Rikke; Toustrup-Jensen, Mads S; Einholm, Anja P; Schack, Vivien R; Andersen, Jens P; Vilsen, Bente

    2016-11-01

    Na(+),K(+)-ATPase creates transmembrane ion gradients crucial to the function of the central nervous system. The α-subunit of Na(+),K(+)-ATPase exists as four isoforms (α1-α4). Several neurological phenotypes derive from α3 mutations. The effects of some of these mutations on Na(+),K(+)-ATPase function have been studied in vitro. Here we discuss the α3 disease mutations as well as information derived from studies of corresponding mutations of α1 in the light of the high-resolution crystal structures of the Na(+),K(+)-ATPase. A high proportion of the α3 disease mutations occur in the transmembrane sector and nearby regions essential to Na(+) and K(+) binding. In several cases the compromised function can be traced to disturbance of the Na(+) specific binding site III. Recently, a secondary mutation was found to rescue the defective Na(+) binding caused by a disease mutation. A perspective is that it may be possible to develop an efficient pharmaceutical mimicking the rescuing effect.

  18. Towards Therapeutic Applications of Arthropod Venom K+-Channel Blockers in CNS Neurologic Diseases Involving Memory Acquisition and Storage

    PubMed Central

    Gati, Christiano D. C.; Mortari, Márcia R.; Schwartz, Elisabeth F.

    2012-01-01

    Potassium channels are the most heterogeneous and widely distributed group of ion channels and play important functions in all cells, in both normal and pathological mechanisms, including learning and memory processes. Being fundamental for many diverse physiological processes, K+-channels are recognized as potential therapeutic targets in the treatment of several Central Nervous System (CNS) diseases, such as multiple sclerosis, Parkinson's and Alzheimer's diseases, schizophrenia, HIV-1-associated dementia, and epilepsy. Blockers of these channels are therefore potential candidates for the symptomatic treatment of these neuropathies, through their neurological effects. Venomous animals have evolved a wide set of toxins for prey capture and defense. These compounds, mainly peptides, act on various pharmacological targets, making them an innumerable source of ligands for answering experimental paradigms, as well as for therapeutic application. This paper provides an overview of CNS K+-channels involved in memory acquisition and storage and aims at evaluating the use of highly selective K+-channel blockers derived from arthropod venoms as potential therapeutic agents for CNS diseases involving learning and memory mechanisms. PMID:22701481

  19. William Shakespeare's neurology.

    PubMed

    Paciaroni, Maurizio; Bogousslavsky, Julien

    2013-01-01

    Many of Shakespeare's plays contain characters who appear to be afflicted by neurological or psychiatric disorders. Shakespeare, in his descriptive analysis of his protagonists, was contributing to the understanding of these disorders. In fact, Charcot frequently used Shakespearean references in his neurological teaching sessions, stressing how acute objective insight is essential to achieving expert clinical diagnosis. Charcot found in Shakespeare the same rigorous observational techniques for which he himself became famous. This chapter describes many of Shakespearean characters suffering from varied neurological disorders, including Parkinsonism, epilepsy, sleeping disturbances, dementia, headache, prion disease, and paralyses.

  20. Neurological lesions in chickens experimentally infected with virulent Newcastle disease virus isolates

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Distribution, character, and severity of lesions were evaluated in tissues from the central nervous system of chickens inoculated with 10 different Newcastle disease virus (NDV) isolates: CA 1083, Korea 97-147, Australia (all velogenic viscerotropic); Texas GB and Turkey North Dakota (both velogenic...

  1. Borna disease virus infection in animals and humans.

    PubMed Central

    Richt, J. A.; Pfeuffer, I.; Christ, M.; Frese, K.; Bechter, K.; Herzog, S.

    1997-01-01

    The geographic distribution and host range of Borna disease (BD), a fatal neurologic disease of horses and sheep, are larger than previously thought. The etiologic agent, Borna disease virus (BDV), has been identified as an enveloped nonsegmented negative-strand RNA virus with unique properties of replication. Data indicate a high degree of genetic stability of BDV in its natural host, the horse. Studies in the Lewis rat have shown that BDV replication does not directly influence vital functions; rather, the disease is caused by a virus-induced T-cell mediated immune reaction. Because antibodies reactive with BDV have been found in the sera of patients with neuropsychiatric disorders, this review examines the possible link between BDV and such disorders. Seroepidemiologic and cerebrospinal fluid investigations of psychiatric patients suggest a causal role of BDV infection in human psychiatric disorders. In diagnostically unselected psychiatric patients, the distribution of psychiatric disorders was found to be similar in BDV seropositive and seronegative patients. In addition, BDV-seropositive neurologic patients became ill with lymphocytic meningoencephalitis. In contrast to others, we found no evidence is reported for BDV RNA, BDV antigens, or infectious B DV in peripheral blood cells of psychiatric patients. PMID:9284379

  2. Human Microbiota and Ophthalmic Disease

    PubMed Central

    Lu, Louise J.; Liu, Ji

    2016-01-01

    The human ocular surface, consisting of the cornea and conjunctiva, is colonized by an expansive, diverse microbial community. Molecular-based methods, such as 16S rRNA sequencing, has allowed for more comprehensive and precise identification of the species composition of the ocular surface microbiota compared to traditional culture-based methods. Evidence suggests that the normal microbiota plays a protective immunological role in preventing the proliferation of pathogenic species and thus, alterations in the homeostatic microbiome may be linked to ophthalmic pathologies. Further investigation of the ocular surface microbiome, as well as the microbiome of other areas of the body such as the oral mucosa and gut, and their role in the pathophysiology of diseases is a significant, emerging field of research, and may someday enable the development of novel probiotic approaches for the treatment and prevention of ophthalmic diseases. PMID:27698616

  3. The chemokine receptor CXCR2 and coronavirus-induced neurologic disease

    PubMed Central

    Weinger, Jason G.; Marro, Brett S.; Hosking, Martin P.; Lane, Thomas E.

    2012-01-01

    Inoculation of the neurotropic JHM strain of mouse hepatitis virus (MHV) into the central nervous system (CNS) of susceptible strains of mice results in an acute encephalomyelitis in which virus preferentially replicates within glial cells while excluding neurons. Control of viral replication during acute disease is mediated by infiltrating virus-specific T cells via cytokine secretion and cytolytic activity, however sterile immunity is not achieved and virus persists resulting in chronic neuroinflammation associated with demyelination. CXCR2 is a chemokine receptor that upon binding to specific ligands promotes host defense through recruitment of myeloid cells to the CNS as well as protecting oligodendroglia from cytokine-mediated death in response to MHV infection. These findings highlight growing evidence of the diverse and important role of CXCR2 in regulating neuroinflammatory diseases. PMID:23217621

  4. A Parent's Journey: Incorporating Principles of Palliative Care into Practice for Children with Chronic Neurologic Diseases.

    PubMed

    Brown, Allyson; Clark, Jonna D

    2015-09-01

    Rather than in conflict or in competition with the curative model of care, pediatric palliative care is a complementary and transdisciplinary approach used to optimize medical care for children with complex medical conditions. It provides care to the whole child, including physical, mental, and spiritual dimensions, in addition to support for the family. Through the voice of a parent, the following case-based discussion demonstrates how the fundamentals of palliative care medicine, when instituted early in the course of disease, can assist parents and families with shared medical decision making, ultimately improving the quality of life for children with life-limiting illnesses. Pediatric neurologists, as subspecialists who provide medical care for children with chronic and complex conditions, should consider invoking the principles of palliative care early in the course of a disease process, either through applying general facets or, if available, through consultation with a specialty palliative care service.

  5. The Role of TREM2 in Alzheimer’s Disease and Other Neurological Disorders

    PubMed Central

    Yaghmoor, Faris; Noorsaeed, Ahmed; Alsaggaf, Samar; Aljohani, Waleed; Scholtzova, Henrieta; Boutajangout, Allal; Wisniewski, Thomas

    2015-01-01

    Alzheimer’s disease (AD) is the leading cause of dementia worldwide. Late-onset AD (LOAD), is the most common form of Alzheimer’s disease, representing about >95% of cases and early-onset AD represents <5% of cases. Several risk factors have been discovered that are associated with AD, with advancing age being the most prominent. Other environmental risk factors include diabetes mellitus, level of physical activity, educational status, hypertension and head injury. The most well known genetic risk factor for LOAD is inheritance of the apolipoprotein (apo) E4 allele. Recently, rare variants of TREM2 have been reported as a significant risk factor for LOAD, comparable to inheritance of apoE4. In this review we will focus on the role(s) of TREM2 in AD as well as in other neurodegenerative disorders. PMID:25664220

  6. Aluminium and human breast diseases.

    PubMed

    Darbre, P D; Pugazhendhi, D; Mannello, F

    2011-11-01

    The human breast is exposed to aluminium from many sources including diet and personal care products, but dermal application of aluminium-based antiperspirant salts provides a local long-term source of exposure. Recent measurements have shown that aluminium is present in both tissue and fat of the human breast but at levels which vary both between breasts and between tissue samples from the same breast. We have recently found increased levels of aluminium in noninvasively collected nipple aspirate fluids taken from breast cancer patients (mean 268 ± 28 μg/l) compared with control healthy subjects (mean 131 ± 10 μg/l) providing evidence of raised aluminium levels in the breast microenvironment when cancer is present. The measurement of higher levels of aluminium in type I human breast cyst fluids (median 150 μg/l) compared with human serum (median 6 μg/l) or human milk (median 25 μg/l) warrants further investigation into any possible role of aluminium in development of this benign breast disease. Emerging evidence for aluminium in several breast structures now requires biomarkers of aluminium action in order to ascertain whether the presence of aluminium has any biological impact. To this end, we report raised levels of proteins that modulate iron homeostasis (ferritin, transferrin) in parallel with raised aluminium in nipple aspirate fluids in vivo, and we report overexpression of mRNA for several S100 calcium binding proteins following long-term exposure of MCF-7 human breast cancer cells in vitro to aluminium chlorhydrate.

  7. Disseminated necrotizing myeloencephalitis: a herpes-associated neurological disease of horses.

    PubMed

    Little, P B; Thorsen, J

    1976-01-01

    Equine viral rhinopneumonitis type I virus was isolated from spinal cord and brain of a paraparetic horse with disseminated necrotizing myeloencephalitis. Necrotic arteriolitis,nonsuppurative necrotizing myeloencephalitis and Gasserian ganglioneuritis were present. On record were 12 more cases of horses with similar lesions. The horses had been ataxic or paretic for up to several weeks. A field survey indicated that 14 of 24 horses with acute myelitic signs developed them after recent exposure to respiratory disease.

  8. DNA Secondary Structure at Chromosomal Fragile Sites in Human Disease

    PubMed Central

    Thys, Ryan G; Lehman, Christine E; Pierce, Levi C. T; Wang, Yuh-Hwa

    2015-01-01

    DNA has the ability to form a variety of secondary structures that can interfere with normal cellular processes, and many of these structures have been associated with neurological diseases and cancer. Secondary structure-forming sequences are often found at chromosomal fragile sites, which are hotspots for sister chromatid exchange, chromosomal translocations, and deletions. Structures formed at fragile sites can lead to instability by disrupting normal cellular processes such as DNA replication and transcription. The instability caused by disruption of replication and transcription can lead to DNA breakage, resulting in gene rearrangements and deletions that cause disease. In this review, we discuss the role of DNA secondary structure at fragile sites in human disease. PMID:25937814

  9. Genomic imprinting and human disease.

    PubMed

    Hirasawa, Ryutaro; Feil, Robert

    2010-09-20

    In many epigenetic phenomena, covalent modifications on DNA and chromatin mediate somatically heritable patterns of gene expression. Genomic imprinting is a classical example of epigenetic regulation in mammals. To date, more than 100 imprinted genes have been identified in humans and mice. Many of these are involved in foetal growth and deve lopment, others control behaviour. Mono-allelic expression of imprinted genes depends on whether the gene is inherited from the mother or the father. This remarkable pattern of expression is controlled by specialized sequence elements called ICRs (imprinting control regions). ICRs are marked by DNA methylation on one of the two parental alleles. These allelic marks originate from either the maternal or the paternal germ line. Perturbation of the allelic DNA methylation at ICRs is causally involved in several human diseases, including the Beckwith-Wiedemann and Silver-Russell syndromes, associated with aberrant foetal growth. Perturbed imprinted gene expression is also implicated in the neuro-developmental disorders Prader-Willi syndrome and Angelman syndrome. Embryo culture and human-assisted reproduction procedures can increase the occurrence of imprinting-related disorders. Recent research shows that, besides DNA methylation, covalent histone modifications and non-histone proteins also contribute to imprinting regulation. The involvement of imprinting in specific human pathologies (and in cancer) emphasizes the need to further explore the underlying molecular mechanisms.

  10. Altered manifestations of skin disease at sites affected by neurological deficit

    PubMed Central

    Azimi, E.; Lerner, E.A.; Elmariah, S.B.

    2014-01-01

    The contribution of the nervous system to inflammation in general and inflammatory skin disease in particular has been underappreciated. It is now apparent that the conventional clinical manifestations of many inflammatory skin diseases require an intact neural component. We reviewed the literature and identified 23 cases of alterations in the appearance or distribution of skin disorders in patients with acquired central or peripheral neural damage or dysfunction. In 19 cases, near or complete resolution of pre-existing skin lesions occurred in areas directly or indirectly supplied by a subsequently injured nervous system. Exacerbation or new onset of skin lesions occurred in only 4 cases. The neural deficits described included damage within the peripheral or central nervous system resulting in pure sensory, pure motor, or combined sensory and motor deficits. These cases highlight the importance of neural innervation and neurogenic inflammation in the development of inflammatory skin disease and prompt further examination of the use of neural blockade as an adjunctive therapy in the treatment of inflammatory dermatoses. PMID:25132518

  11. The severity of Minamata disease declined in 25 years: temporal profile of the neurological findings analyzed by multiple logistic regression model.

    PubMed

    Uchino, Makoto; Hirano, Teruyuki; Satoh, Hiroshi; Arimura, Kimiyoshi; Nakagawa, Masanori; Wakamiya, Jyunji

    2005-01-01

    Minamata disease (MD) was caused by ingestion of seafood from the methylmercury-contaminated areas. Although 50 years have passed since the discovery of MD, there have been only a few studies on the temporal profile of neurological findings in certified MD patients. Thus, we evaluated changes in neurological symptoms and signs of MD using discriminants by multiple logistic regression analysis. The severity of predictive index declined in 25 years in most of the patients. Only a few patients showed aggravation of neurological findings, which was due to complications such as spino-cerebellar degeneration. Patients with chronic MD aged over 45 years had several concomitant diseases so that their clinical pictures were complicated. It was difficult to differentiate chronic MD using statistically established discriminants based on sensory disturbance alone. In conclusion, the severity of MD declined in 25 years along with the modification by age-related concomitant disorders.

  12. Wikipedia and neurological disorders.

    PubMed

    Brigo, Francesco; Igwe, Stanley C; Nardone, Raffaele; Lochner, Piergiorgio; Tezzon, Frediano; Otte, Willem M

    2015-07-01

    Our aim was to evaluate Wikipedia page visits in relation to the most common neurological disorders by determining which factors are related to peaks in Wikipedia searches for these conditions. Millions of people worldwide use the internet daily as a source of health information. Wikipedia is a popular free online encyclopedia used by patients and physicians to search for health-related information. The following Wikipedia articles were considered: Alzheimer's disease; Amyotrophic lateral sclerosis; Dementia; Epilepsy; Epileptic seizure; Migraine; Multiple sclerosis; Parkinson's disease; Stroke; Traumatic brain injury. We analyzed information regarding the total article views for 90 days and the rank of these articles among all those available in Wikipedia. We determined the highest search volume peaks to identify possible relation with online news headlines. No relation between incidence or prevalence of neurological disorders and the search volume for the related articles was found. Seven out of 10 neurological conditions showed relations in search volume peaks and news headlines. Six out of these seven peaks were related to news about famous people suffering from neurological disorders, especially those from showbusiness. Identification of discrepancies between disease burden and health seeking behavior on Wikipedia is useful in the planning of public health campaigns. Celebrities who publicly announce their neurological diagnosis might effectively promote awareness programs, increase public knowledge and reduce stigma related to diagnoses of neurological disorders.

  13. Genomics in neurological disorders.

    PubMed

    Han, Guangchun; Sun, Jiya; Wang, Jiajia; Bai, Zhouxian; Song, Fuhai; Lei, Hongxing

    2014-08-01

    Neurological disorders comprise a variety of complex diseases in the central nervous system, which can be roughly classified as neurodegenerative diseases and psychiatric disorders. The basic and translational research of neurological disorders has been hindered by the difficulty in accessing the pathological center (i.e., the brain) in live patients. The rapid advancement of sequencing and array technologies has made it possible to investigate the disease mechanism and biomarkers from a systems perspective. In this review, recent progresses in the discovery of novel risk genes, treatment targets and peripheral biomarkers employing genomic technologies will be discussed. Our major focus will be on two of the most heavily investigated neurological disorders, namely Alzheimer's disease and autism spectrum disorder.

  14. Aluminum-Induced Entropy in Biological Systems: Implications for Neurological Disease

    PubMed Central

    Shaw, Christopher A.; Seneff, Stephanie; Kette, Stephen D.; Tomljenovic, Lucija; Oller, John W.; Davidson, Robert M.

    2014-01-01

    Over the last 200 years, mining, smelting, and refining of aluminum (Al) in various forms have increasingly exposed living species to this naturally abundant metal. Because of its prevalence in the earth's crust, prior to its recent uses it was regarded as inert and therefore harmless. However, Al is invariably toxic to living systems and has no known beneficial role in any biological systems. Humans are increasingly exposed to Al from food, water, medicinals, vaccines, and cosmetics, as well as from industrial occupational exposure. Al disrupts biological self-ordering, energy transduction, and signaling systems, thus increasing biosemiotic entropy. Beginning with the biophysics of water, disruption progresses through the macromolecules that are crucial to living processes (DNAs, RNAs, proteoglycans, and proteins). It injures cells, circuits, and subsystems and can cause catastrophic failures ending in death. Al forms toxic complexes with other elements, such as fluorine, and interacts negatively with mercury, lead, and glyphosate. Al negatively impacts the central nervous system in all species that have been studied, including humans. Because of the global impacts of Al on water dynamics and biosemiotic systems, CNS disorders in humans are sensitive indicators of the Al toxicants to which we are being exposed. PMID:25349607

  15. Anti-NMDA receptor encephalitis: a neurological disease in psychiatric disguise.

    PubMed

    Sharma, Bhawna; Handa, Rahul; Prakash, Swayam; Nagpal, Kadam; Gupta, Pankaj

    2014-02-01

    Anti-NMDA receptor encephalitis was first described in 2005 when psychiatric features, memory loss and altered consciousness were found in four women with ovarian teratoma. We report a case of anti-NMDA receptor encephalitis in a 16-year-old female who presented with psychiatric features followed by autonomic dysfunction and orofacial dyskinesias that showed drastic improvement to intravenous immunoglobulin. As many patients of anti-NMDAR encephalitis initially present with psychiatric features, it is important for psychiatrists to have high index of suspicion for this disease and thus avoid the delay in diagnosing this treatable condition which may be otherwise fatal.

  16. Neurological assessment.

    PubMed

    Maher, Ann Butler

    2016-08-01

    Neurological system assessment is an important skill for the orthopaedic nurse because the nervous system has such an overlap with the musculoskeletal system. Nurses whose scope of practice includes such advanced evaluation, e.g. nurse practitioners, may conduct the examination described here but the information will also be useful for nurses caring for patients who have abnormal neurological assessment findings. Within the context of orthopaedic physical assessment, possible neurological findings are evaluated as they complement the patient's history and the examiner's findings. Specific neurological assessment is integral to diagnosis of some orthopaedic conditions such as carpal tunnel syndrome. In other situations such as crushing injury to the extremities, there is high risk of associated neurological or neurovascular injury. These patients need anticipatory examination and monitoring to prevent complications. This article describes a basic neurological assessment; emphasis is on sensory and motor findings that may overlap with an orthopaedic presentation. The orthopaedic nurse may incorporate all the testing covered here or choose those parts that further elucidate specific diagnostic questions suggested by the patient's history, general evaluation and focused musculoskeletal examination. Abnormal findings help to suggest further testing, consultation with colleagues or referral to a specialist.

  17. Impulse Control Disorders in Parkinson’s Disease: Crossroads between Neurology, Psychiatry and Neuroscience

    PubMed Central

    Bugalho, Paulo; Oliveira-Maia, Albino J.

    2013-01-01

    Non-motor symptoms contribute significantly to Parkinson’s disease (PD) related disability. Impulse control disorders (ICDs) have been recently added to the behavioural spectrum of PD-related non-motor symptoms. Such behaviours are characterized by an inappropriate drive to conduct repetitive behaviours that are usually socially inadequate or result in harmful consequences. Parkinson disease impulse control disorders (PD-ICDs) have raised significant interest in the scientific and medical community, not only because of their incapacitating nature, but also because they may represent a valid model of ICDs beyond PD and a means to study the physiology of drive, impulse control and compulsive actions in the normal brain. In this review, we discuss some unresolved issues regarding PD-ICDs, including the association with psychiatric co-morbidities such as obsessive-compulsive disorder and with dopamine related side effects, such as hallucinations and dyskinesias; the relationship with executive cognitive dysfunction; and the neural underpinnings of ICDs in PD. We also discuss the contribution of neuroscience studies based on animal-models towards a mechanistic explanation of the development of PD-ICDs, specifically regarding corticostriatal control of goal directed and habitual actions. PMID:23242359

  18. Distinguishing the cerebrospinal fluid cytokine profile in neuropsychiatric systemic lupus erythematosus from other autoimmune neurological diseases.

    PubMed

    Ichinose, Kunihiro; Arima, Kazuhiko; Ushigusa, Takeshi; Nishino, Ayako; Nakashima, Yoshikazu; Suzuki, Takahisa; Horai, Yoshiro; Nakajima, Hideki; Kawashiri, Shin-Ya; Iwamoto, Naoki; Tamai, Mami; Nakamura, Hideki; Origuchi, Tomoki; Motomura, Masakatsu; Kawakami, Atsushi

    2015-04-01

    Neuropsychiatric systemic lupus erythematosus (NPSLE) is a serious complication in SLE. Although the mechanism of NPSLE remains unclear, cytokines and chemokines are considered to be involved in their pathogenesis. Here we used Bio-Plex Pro assays to examine 27 types of cytokines and chemokines in the cerebrospinal fluid (CSF) of 32 NPSLE patients. We used the CSF of 20 patients with multiple sclerosis (MS) and 22 patients with neuromyelitis optica (NMO) as a disease control group. Fourteen of 27 cytokines/chemokines were significantly higher in the NPSLE patients compared to the MS/NMO patients. We could identify six "minimum predictive markers" by using a weighted-voting algorithm that could distinguish NPSLE from MS and NMO: interleukin (IL)-17, IL-2, interferon (IFN)-γ, IL-5, basic fibroblast growth factor (FGF)-basic and IL-15. The determination of various types of CSF cytokine profiles may contribute to the diagnosis of NPSLE and may help elucidate the mechanisms underlying this disease.

  19. Outline structure of the human L1 cell adhesion molecule and the sites where mutations cause neurological disorders.

    PubMed Central

    Bateman, A; Jouet, M; MacFarlane, J; Du, J S; Kenwrick, S; Chothia, C

    1996-01-01

    The L1 cell adhesion molecule has six domains homologous to members of the immunoglobulin superfamily and five homologous to fibronectin type III domains. We determined the outline structure of the L1 domains by showing that they have, at the key sites that determine conformation, residues similar to those in proteins of known structure. The outline structure describes the relative positions of residues, the major secondary structures and residue solvent accessibility. We use the outline structure to investigate the likely effects of 22 mutations that cause neurological diseases. The mutations are not randomly distributed but cluster in a few regions of the structure. They can be divided into those that act mainly by changing conformation or denaturing their domain and those that alter its surface properties. Images PMID:8947027

  20. The neurological effects of ghrelin in brain diseases: Beyond metabolic functions.

    PubMed

    Jiao, Qian; Du, Xixun; Li, Yong; Gong, Bing; Shi, Limin; Tang, Tingting; Jiang, Hong

    2017-02-01

    Ghrelin, a peptide released by the stomach that plays a major role in regulating energy metabolism, has recently been shown to have effects on neurobiological behaviors. Ghrelin enhances neuronal survival by reducing apoptosis, alleviating inflammation and oxidative stress, and accordingly improving mitochondrial function. Ghrelin also stimulates the proliferation, differentiation and migration of neural stem/progenitor cells (NS/PCs). Additionally, the ghrelin is benefit for the recovery of memory, mood and cognitive dysfunction after stroke or traumatic brain injury. Because of its neuroprotective and neurogenic roles, ghrelin may be used as a therapeutic agent in the brain to combat neurodegenerative disease. In this review, we highlight the pre-clinical evidence and the proposed mechanisms underlying the role of ghrelin in physiological and pathological brain function.

  1. Coping with chronic neurological impairment: a contrastive analysis of Parkinson's disease and stroke.

    PubMed

    Herrmann, M; Freyholdt, U; Fuchs, G; Wallesch, C W

    1997-01-01

    This study aimed at a contrastive analysis of coping strategies and psychosocial alterations in patients with Parkinson's disease (PD) and stroke (CVA) and their relatives. Fifty-four PD and 50 CVA patients were investigated with a standardized semistructured interview to assess the severity of psychosocial changes following illness, the Freiburg Questionnaire on Coping with Illness, the Cornell Depression Scale and instruments to assess motor impairment. Psychosocial alterations were most prominent in the professional and emotional-cognitive domains. Degree of depression correlated with familial and emotional-cognitive alterations in both patient groups. Active problem-oriented coping and distraction predominated as coping styles. Religious relief and quest for sense were significantly more important for the PD patients. Coping styles did not correlate with degrees of depression, motor impairment or psychosocial alterations.

  2. Identification of avian bornavirus in a Himalayan monal (Lophophorus impejanus) with neurological disease.

    PubMed

    Bourque, Laura; Laniesse, Delphine; Beaufrère, Hugues; Pastor, Adriana; Ojkic, Davor; Smith, Dale A

    2015-01-01

    A one-year-old male Himalayan monal (Lophophorus impejanus) was presented for veterinary attention with a history of chronic wasting, weakness and ataxia. The bird died, and post-mortem findings included mild non-suppurative encephalitis and degenerative encephalopathy, lymphoplasmacytic myenteric ganglioneuritis (particularly of the proventriculus), and Wallerian degeneration of the sciatic nerves. Avian bornavirus (ABV) was identified in the brain by immunohistochemistry and reverse-transcriptase polymerase chain reaction. Sequencing of the reverse-transcriptase polymerase chain reaction product indicated the presence of ABV genotype 4, which is generally associated with disease in psittacine birds. Subsequent to the death of the pheasant, ABV genotype 4 was identified at autopsy from a juvenile white-bellied caique (Pionites leucogaster) in the same collection. We hypothesize that the pheasant became infected through contact with psittacine birds with which it shared an aviary. We believe this to be the first reported case of natural ABV infection in a bird in the Order Galliformes.

  3. Modeling cognition and disease using human glial chimeric mice.

    PubMed

    Goldman, Steven A; Nedergaard, Maiken; Windrem, Martha S

    2015-08-01

    As new methods for producing and isolating human glial progenitor cells (hGPCs) have been developed, the disorders of myelin have become especially compelling targets for cell-based therapy. Yet as animal modeling of glial progenitor cell-based therapies has progressed, it has become clear that transplanted hGPCs not only engraft and expand within murine hosts, but dynamically outcompete the resident progenitors so as to ultimately dominate the host brain. The engrafted human progenitor cells proceed to generate parenchymal astrocytes, and when faced with a hypomyelinated environment, oligodendrocytes as well. As a result, the recipient brains may become inexorably humanized with regards to their resident glial populations, yielding human glial chimeric mouse brains. These brains provide us a fundamentally new tool by which to assess the species-specific attributes of glia in modulating human cognition and information processing. In addition, the cellular humanization of these brains permits their use in studying glial infectious and inflammatory disorders unique to humans, and the effects of those disorders on the glial contributions to cognition. Perhaps most intriguingly, by pairing our ability to construct human glial chimeras with the production of patient-specific hGPCs derived from pluripotential stem cells, we may now establish mice in which a substantial proportion of resident glia are both human and disease-derived. These mice in particular may provide us new opportunities for studying the human-specific contributions of glia to psychopathology, as well as to higher cognition. As such, the assessment of human glial chimeric mice may provide us new insight into the species-specific contributions of glia to human cognitive evolution, as well as to the pathogenesis of human neurological and neuropsychiatric disease.

  4. Neurology in Asia.

    PubMed

    Tan, Chong-Tin

    2015-02-10

    Asia is important as it accounts for more than half of the world population. The majority of Asian countries fall into the middle income category. As for cultural traditions, Asia is highly varied, with many languages spoken. The pattern of neurologic diseases in Asia is largely similar to the West, with some disease features being specific to Asia. Whereas Asia constitutes 60% of the world's population, it contains only 20% of the world's neurologists. This disparity is particularly evident in South and South East Asia. As for neurologic care, it is highly variable depending on whether it is an urban or rural setting, the level of economic development, and the system of health care financing. To help remedy the shortage of neurologists, most counties with larger populations have established training programs in neurology. These programs are diverse, with many areas of concern. There are regional organizations serving as a vehicle for networking in neurology and various subspecialties, as well as an official journal (Neurology Asia). The Asian Epilepsy Academy, with its emphasis on workshops in various locations, EEG certification examination, and fellowships, may provide a template of effective regional networking for improving neurology care in the region.

  5. Neurologic complications of immunizations.

    PubMed

    Rutledge, S L; Snead, O C

    1986-12-01

    Although there does appear to be at least a temporal relationship between pertussis immunization and serious acute neurologic illness, data to suggest that children with stable preexisting neurologic disease or positive family history of neurologic disease are at increased risk for complications of pertussis immunizations are inconclusive. Furthermore, there are no firm statistical data concerning the incidence of pertussis vaccine-related encephalopathy. Rather, the literature on pertussis vaccine complications is replete with anecdotal reports and retrospective studies with a number of questionable conclusions drawn from this inadequate data base. Unfortunately, these conclusions have been sensationalized and exploited with litigious fervor to the point that the practice of pertussis immunization is being questioned in the United States. A number of points should be reiterated: pertussis is a dangerous and deadly disease, as seen in the epidemic in Great Britain; pertussis immunization is effective in protecting against the disease; and there is no conclusive proof that the incidence of complications from pertussis vaccination of children with seizure disorders or other preexisting stable neurologic abnormalities is higher, because appropriate studies have not been done to define such a risk. We would do well to keep these facts in mind in order to avoid a disaster similar to the pertussis epidemic in Great Britain. Pertussis vaccination should be given to all children except those with allergic hypersensitivity, a progressive neurologic disorder, or an adverse reaction to a previous pertussis dose.

  6. Neurological Complications in Controlled HIV Infection.

    PubMed

    Crossley, Kate M; Brew, Bruce J

    2013-12-01

    In recent years, there have been great advances in therapies for human immunodeficiency virus (HIV) that have allowed suppression of the virus and its effects on the body. Despite this progress, neurological complications persist in HIV-infected individuals. In this review we consider the possible ways that HIV might cause neurotoxicity and neuroinflammation. We discuss the spectrum of neurological disorders caused by HIV and its treatment, with a particular focus on both HIV-associated neurocognitive disorders and peripheral neuropathies. Since there has been a shift to HIV being a chronic illness, we also review the increasing prevalence of cerebrovascular disease and neurodegenerative disorders.

  7. A Stochastic Multiscale Model That Explains the Segregation of Axonal Microtubules and Neurofilaments in Neurological Diseases

    PubMed Central

    Xue, Chuan; Shtylla, Blerta; Brown, Anthony

    2015-01-01

    The organization of the axonal cytoskeleton is a key determinant of the normal function of an axon, which is a long thin projection of a neuron. Under normal conditions two axonal cytoskeletal polymers, microtubules and neurofilaments, align longitudinally in axons and are interspersed in axonal cross-sections. However, in many neurotoxic and neurodegenerative disorders, microtubules and neurofilaments segregate apart from each other, with microtubules and membranous organelles clustered centrally and neurofilaments displaced to the periphery. This striking segregation precedes the abnormal and excessive neurofilament accumulation in these diseases, which in turn leads to focal axonal swellings. While neurofilament accumulation suggests an impairment of neurofilament transport along axons, the underlying mechanism of their segregation from microtubules remains poorly understood for over 30 years. To address this question, we developed a stochastic multiscale model for the cross-sectional distribution of microtubules and neurofilaments in axons. The model describes microtubules, neurofilaments and organelles as interacting particles in a 2D cross-section, and is built upon molecular processes that occur on a time scale of seconds or shorter. It incorporates the longitudinal transport of neurofilaments and organelles through this domain by allowing stochastic arrival and departure of these cargoes, and integrates the dynamic interactions of these cargoes with microtubules mediated by molecular motors. Simulations of the model demonstrate that organelles can pull nearby microtubules together, and in the absence of neurofilament transport, this mechanism gradually segregates microtubules from neurofilaments on a time scale of hours, similar to that observed in toxic neuropathies. This suggests that the microtubule-neurofilament segregation can be a consequence of the selective impairment of neurofilament transport. The model generates the experimentally testable

  8. Complex I deficiencies in neurological disorders.

    PubMed

    Papa, Sergio; De Rasmo, Domenico

    2013-01-01

    Complex I is the point of entry in the mitochondrial electron transport chain for NADH reducing equivalents, and it behaves as a regulatable pacemaker of respiratory ATP production in human cells. Defects in complex I are associated with several human neurological disorders, including primary mitochondrial diseases, Parkinson disease (PD), and Down syndrome, and understanding the activity and regulation of complex I may reveal aspects of the underlying pathogenic mechanisms. Complex I is regulated by cyclic AMP (cAMP) and the protein kinase A (PKA) signal transduction pathway, and elucidating the role of the cAMP/PKA system in regulating complex I and oxygen free radical production provides new perspectives for devising therapeutic strategies for neurological diseases.

  9. A mouse-adapted enterovirus 71 strain causes neurological disease in mice after oral infection.

    PubMed

    Wang, Ya-Fang; Chou, Chun-Ting; Lei, Huan-Yao; Liu, Ching-Chuan; Wang, Shih-Min; Yan, Jing-Jou; Su, Ih-Jen; Wang, Jen-Reng; Yeh, Trai-Ming; Chen, Shun-Hua; Yu, Chun-Keung

    2004-08-01

    A mouse-adapted enterovirus 71 (EV71) strain with increased virulence in mice, MP4, was generated after four serial passages of the parental EV71 strain 4643 in mice. Strain MP4 exhibited a larger plaque size, grew more rapidly, and was more cytotoxic in vitro than strain 4643. Although strains 4643 and MP4 both induced apoptosis of SK-N-SH human neuroblastoma cells, MP4 was more virulent than 4643 in 1-day-old mice (50% lethal doses, 10(2) and 10(4) PFU/mouse, respectively). Strain MP4 (5 x 10(6) PFU/mouse), but not 4643, could orally infect 7-day-old mice, resulting in rear-limb paralysis followed by death 5 to 9 days after inoculation with the virus. Histopathologically, neuronal loss and apoptosis were evident in the spinal cords as well as the brain stems of the infected mice. The limb muscles displayed massive necrosis. There was early and transient virus replication in the intestines, whereas the spinal cord, brain, and muscle became the sites of viral replication during the late phase of the infection. Virus transmission occurred among infected and noninfected cagemates, as demonstrated by the occurrence of seroconversion and the presence of viable viruses in the stool samples of the latter. Protection against EV71 challenge was demonstrated following administration of hyperimmune serum 1 day after inoculation with the virus. Nucleotide sequence analysis of the genome of EV71 strain MP4 revealed four nucleotide changes on the 5' untranslated region, three on the VP2 region, and eight on the 2C region, resulting in one and four amino acid substitutions in the VP2 and 2C proteins, respectively.

  10. Adult neurology training during child neurology residency.

    PubMed

    Schor, Nina F

    2012-08-21

    As it is currently configured, completion of child neurology residency requires performance of 12 months of training in adult neurology. Exploration of whether or not this duration of training in adult neurology is appropriate for what child neurology is today must take into account the initial reasons for this requirement and the goals of adult neurology training during child neurology residency.

  11. Molecular mechanistic associations of human diseases

    PubMed Central

    2010-01-01

    Background The study of relationships between human diseases provides new possibilities for biomedical research. Recent achievements on human genetic diseases have stimulated interest to derive methods to identify disease associations in order to gain further insight into the network of human diseases and to predict disease genes. Results Using about 10000 manually collected causal disease/gene associations, we developed a statistical approach to infer meaningful associations between human morbidities. The derived method clustered cardiometabolic and endocrine disorders, immune system-related diseases, solid tissue neoplasms and neurodegenerative pathologies into prominent disease groups. Analysis of biological functions confirmed characteristic features of corresponding disease clusters. Inference of disease associations was further employed as a starting point for prediction of disease genes. Efforts were made to underpin the validity of results by relevant literature evidence. Interestingly, many inferred disease relationships correspond to known clinical associations and comorbidities, and several predicted disease genes were subjects of therapeutic target research. Conclusions Causal molecular mechanisms present a unifying principle to derive methods for disease classification, analysis of clinical disorder associations, and prediction of disease genes. According to the definition of causal disease genes applied in this study, these results are not restricted to genetic disease/gene relationships. This may be particularly useful for the study of long-term or chronic illnesses, where pathological derangement due to environmental or as part of sequel conditions is of importance and may not be fully explained by genetic background. PMID:20815942

  12. Neurologic manifestations of von Hippel-Lindau disease. Grand Rounds at the Clinical Center of the National Institutes of Health

    PubMed Central

    Butman, John A.; Linehan, W. Marston; Lonser, Russell R.

    2012-01-01

    von Hippel-Lindau disease (VHL) is an autosomal dominant neoplasia syndrome that is the result of a germline mutation of the VHL tumor suppressor gene on the short arm of chromosome 3. VHL patients are predisposed to develop lesions of the central nervous system (CNS) and viscera. CNS lesions include hemangioblastomas (the most common tumor in VHL) and endolymphatic sac tumors (ELSTs). Visceral manifestations include renal carcinomas and cysts, pancreatic neuroendocrine tumors and cysts, pheochromocytomas and cystadenomas of the reproductive adnexal organs. Despite their benign pathology, hemangioblastomas and ELSTs are a frequent cause of morbidity and mortality in VHL patients. Recent molecular biologic investigations into these VHL-associated CNS lesions provide new insight into their origin and development. Emerging data from serial imaging and clinical surveillance protocols provide insight into the natural history of these lesions. Because of the dissimilar pathobiology and clinical course between hemangioblastomas and ELSTs, the optimal management strategies for these neurologic manifestations of VHL are very different. PMID:18799446

  13. An Eye-Blinking-Based Beamforming Control Protocol for Hearing Aid Users With Neurological Motor Disease or Limb Amputation.

    PubMed

    Yoon, Jungmin; Nam, Kyoung Won; Lee, Jun Chang; Jang, Dong Pyo; Kim, In Young

    2017-02-01

    For hearing-impaired individuals with neurological motor deficits or finger/arm amputation due to accident or disease, hearing aid adjustment using a conventional finger manipulation-based remote controller is unavailable, and a more dedicated, hands-free alternative is required. In this study, we propose an eye-blinking-based beamforming control scheme for hearing aid users. Three electroencephalogram signals measured around the ears were utilized to detect eye-blinking patterns based on a three-layer artificial neural network. The performance of the proposed control scheme was evaluated by both subjective experiments and objective index comparison tests in simulated situations. Experimental results from the subjective test demonstrated that without the pretraining phase, the accuracy and latency time were 68.57 ± 18.50% and 10.06 ± 0.94 s, respectively; in contrast, after the pretraining phase, both the accuracy and latency time were improved to 91.00 ± 4.69% and 8.60 ± 1.05 s, respectively. In index comparison tests, the proposed control scheme exhibited improvements in the signal-to-noise ratio (SNR) as well as the segmental SNR in all tested situations, as compared to a conventional forward-focusing beamforming algorithm. We believe that the proposed control scheme provides a novel, hands-free way in which to control the operation of hearing aids for hearing-impaired patients with additional motor deficits or amputation.

  14. Leading the way: finding genes for neurologic disease in dogs using genome-wide mRNA sequencing.

    PubMed

    Ostrander, Elaine A; Beale, Holly C

    2012-07-10

    Because of dogs' unique population structure, human-like disease biology, and advantageous genomic features, the canine system has risen dramatically in popularity as a tool for discovering disease alleles that have been difficult to find by studying human families or populations. To date, disease studies in dogs have primarily employed either linkage analysis, leveraging the typically large family size, or genome-wide association, which requires only modest-sized case and control groups in dogs. Both have been successful but, like most techniques, each requires a specific combination of time and money, and there are inherent problems associated with each. Here we review the first report of mRNA-Seq in the dog, a study that provides insights into the potential value of applying high-throughput sequencing to the study of genetic diseases in dogs. Forman and colleagues apply high-throughput sequencing to a single case of canine neonatal cerebellar cortical degeneration. This implementation of whole genome mRNA sequencing, the first reported in dog, is additionally unusual due to the analysis: the data was used not to examine transcript levels or annotate genes, but as a form of target capture that revealed the sequence of transcripts of genes associated with ataxia in humans. This approach entails risks. It would fail if, for example, the relevant transcripts were not sufficiently expressed for genotyping or were not associated with ataxia in humans. But here it pays off handsomely, identifying a single frameshift mutation that segregates with the disease. This work sets the stage for similar studies that take advantage of recent advances in genomics while exploiting the historical background of dog breeds to identify disease-causing mutations.

  15. Progress in Pediatrics in 2012: choices in allergy, endocrinology, gastroenterology, hematology, infectious diseases, neurology, nutrition and respiratory tract illnesses.

    PubMed

    Caffarelli, Carlo; Santamaria, Francesca; Vottero, Alessandra; Bernasconi, Sergio

    2013-05-08

    In this review, we summarize the progresses in allergy, endocrinology, gastroenterology, hematology, infectious diseases, neurology, nutrition and respiratory tract illnesses that have been published in The Italian Journal of Pediatrics in 2012. The induction of Treg activity by probiotics might be effective for promoting tolerance towards food allergens. Nasal cytology is useful in patients with rhinitis for diagnosing chronic non-allergic non-infectious diseases. Atopic eczema is associated both with an aberrant skin matrix and impaired systemic immune response. Therefore, isolated topical treatment may have suboptimal effect. Diagnostic work-up of exercise-induced anaphylaxis, including exercise challenge test, is necessary to reach a diagnosis. Studies may support a role for nutrition on prevention of asthma and cardiovascular diseases. Clinicians need to early identify adolescent menstrual abnormalities to minimize sequelae, and to promote health information. In Multiple Endocrine Neoplasia type 2B investigations include acetylcholinesterase study of rectal mucosa followed by the molecular analysis of RET mutation. Low adherence to gluten-free diet and osteopenia are common problems in children with diabetes mellitus type 1 and celiac disease. In infantile colic, laboratory tests are usually unnecessary and the treatment is based on reassurance. Prevalence of obesity and stunting is elucidated by several studies. Evidences are growing that dietetic measures are needed to prevent obesity in children with acute leukemia. Treatment studies for infectious diseases show promise for probiotics along with standard triple therapy in children with Helicobacter pilori infection, while zinc has no effect on pneumonia. Educational programs about the proper management of the febrile child are warranted. A new hour-specific total serum bilirubin nomogram has been shown to be able to predict newborns without hyperbilirubinemia after 48 to 72 hours of life. Newborns with

  16. Progress in Pediatrics in 2012: choices in allergy, endocrinology, gastroenterology, hematology, infectious diseases, neurology, nutrition and respiratory tract illnesses

    PubMed Central

    2013-01-01

    In this review, we summarize the progresses in allergy, endocrinology, gastroenterology, hematology, infectious diseases, neurology, nutrition and respiratory tract illnesses that have been published in The Italian Journal of Pediatrics in 2012. The induction of Treg activity by probiotics might be effective for promoting tolerance towards food allergens. Nasal cytology is useful in patients with rhinitis for diagnosing chronic non-allergic non-infectious diseases. Atopic eczema is associated both with an aberrant skin matrix and impaired systemic immune response. Therefore, isolated topical treatment may have suboptimal effect. Diagnostic work-up of exercise-induced anaphylaxis, including exercise challenge test, is necessary to reach a diagnosis. Studies may support a role for nutrition on prevention of asthma and cardiovascular diseases. Clinicians need to early identify adolescent menstrual abnormalities to minimize sequelae, and to promote health information. In Multiple Endocrine Neoplasia type 2B investigations include acetylcholinesterase study of rectal mucosa followed by the molecular analysis of RET mutation. Low adherence to gluten-free diet and osteopenia are common problems in children with diabetes mellitus type 1 and celiac disease. In infantile colic, laboratory tests are usually unnecessary and the treatment is based on reassurance. Prevalence of obesity and stunting is elucidated by several studies. Evidences are growing that dietetic measures are needed to prevent obesity in children with acute leukemia. Treatment studies for infectious diseases show promise for probiotics along with standard triple therapy in children with Helicobacter pilori infection, while zinc has no effect on pneumonia. Educational programs about the proper management of the febrile child are warranted. A new hour-specific total serum bilirubin nomogram has been shown to be able to predict newborns without hyperbilirubinemia after 48 to 72 hours of life. Newborns with

  17. Experimental primates and non-human primate (NHP) models of human diseases in China: current status and progress.

    PubMed

    Zhang, Xiao-Liang; Pang, Wei; Hu, Xin-Tian; Li, Jia-Li; Yao, Yong-Gang; Zheng, Yong-Tang

    2014-11-18

    Non-human primates (NHPs) are phylogenetically close to humans, with many similarities in terms of physiology, anatomy, immunology, as well as neurology, all of which make them excellent experimental models for biomedical research. Compared with developed countries in America and Europe, China has relatively rich primate resources and has continually aimed to develop NHPs resources. Currently, China is a leading producer and a major supplier of NHPs on the international market. However, there are some deficiencies in feeding and management that have hampered China's growth in NHP research and materials. Nonetheless, China has recently established a number of primate animal models for human diseases and achieved marked scientific progress on infectious diseases, cardiovascular diseases, endocrine diseases, reproductive diseases, neurological diseases, and ophthalmic diseases, etc. Advances in these fields via NHP models will undoubtedly further promote the development of China's life sciences and pharmaceutical industry, and enhance China's position as a leader in NHP research. This review covers the current status of NHPs in China and other areas, highlighting the latest developments in disease models using NHPs, as well as outlining basic problems and proposing effective countermeasures to better utilize NHP resources and further foster NHP research in China.

  18. Experimental primates and non-human primate (NHP) models of human diseases in China: current status and progress

    PubMed Central

    ZHANG, Xiao-Liang; PANG, Wei; HU, Xin-Tian; LI, Jia-Li; YAO, Yong-Gang; ZHENG, Yong-Tang

    2014-01-01

    Non-human primates (NHPs) are phylogenetically close to humans, with many similarities in terms of physiology, anatomy, immunology, as well as neurology, all of which make them excellent experimental models for biomedical research. Compared with developed countries in America and Europe, China has relatively rich primate resources and has continually aimed to develop NHPs resources. Currently, China is a leading producer and a major supplier of NHPs on the international market. However, there are some deficiencies in feeding and management that have hampered China’s growth in NHP research and materials. Nonetheless, China has recently established a number of primate animal models for human diseases and achieved marked scientific progress on infectious diseases, cardiovascular diseases, endocrine diseases, reproductive diseases, neurological diseases, and ophthalmic diseases, etc. Advances in these fields via NHP models will undoubtedly further promote the development of China’s life sciences and pharmaceutical industry, and enhance China’s position as a leader in NHP research. This review covers the current status of NHPs in China and other areas, highlighting the latest developments in disease models using NHPs, as well as outlining basic problems and proposing effective countermeasures to better utilize NHP resources and further foster NHP research in China. PMID:25465081

  19. Substrate profiling of human vaccinia-related kinases identifies coilin, a Cajal body nuclear protein, as a phosphorylation target with neurological implications.

    PubMed

    Sanz-García, Marta; Vázquez-Cedeira, Marta; Kellerman, Efrat; Renbaum, Paul; Levy-Lahad, Ephrat; Lazo, Pedro A

    2011-12-21

    Protein phosphorylation by kinases plays a central role in the regulation and coordination of multiple biological processes. In general, knowledge on kinase specificity is restricted to substrates identified in the context of specific cellular responses, but kinases are likely to have multiple additional substrates and be integrated in signaling networks that might be spatially and temporally different, and in which protein complexes and subcellular localization can play an important role. In this report the substrate specificity of atypical human vaccinia-related kinases (VRK1 and VRK2) using a human peptide-array containing 1080 sequences phosphorylated in known signaling pathways has been studied. The two kinases identify a subset of potential peptide targets, all of them result in a consensus sequence composed of at least four basic residues in peptide targets. Linear peptide arrays are therefore a useful approach in the characterization of kinases and substrate identification, which can contribute to delineate the signaling network in which VRK proteins participate. One of these target proteins is coilin; a basic protein located in nuclear Cajal bodies. Coilin is phosphorylated in Ser184 by both VRK1 and VRK2. Coilin colocalizes and interacts with VRK1 in Cajal bodies, but not with the mutant VRK1 (R358X). VRK1 (R358X) is less active than VRK1. Altered regulation of coilin might be implicated in several neurological diseases such as ataxias and spinal muscular atrophies.

  20. Franklin Delano Roosevelt's (FDR's) (1882-1945) 1921 neurological disease revisited; the most likely diagnosis remains Guillain-Barré syndrome.

    PubMed

    Goldman, Armond S; Schmalstieg, Elisabeth J; Dreyer, Charles F; Schmalstieg, Frank C; Goldman, Daniel A

    2016-11-01

    In 2003, we published evidence that the most likely cause of FDR's 1921 neurological disease was Guillain-Barré syndrome. Afterwards, several historians and neurologists stated in their publications that FDR had paralytic poliomyelitis. However, significant criticism of our article or new support for that diagnosis was not revealed. One critic claimed that FDR's cerebrospinal fluid indicated poliomyelitis, but we did not find evidence that a lumbar puncture was performed. The diagnosis of FDR's neurological disease still depends upon documented clinical abnormalities. His age, prolonged symmetric ascending paralysis, transient numbness, protracted dysaesthesia (pain on slight touch), facial paralysis, bladder and bowel dysfunction, and absence of meningismus are typical of Guillain-Barré syndrome and are inconsistent with paralytic poliomyelitis. FDR's prolonged fever was atypical for both diseases. Finally, permanent paralysis, though commoner in paralytic poliomyelitis, is frequent in Guillain-Barré syndrome. Thus, the clinical findings indicate the most likely diagnosis in FDR's case remains Guillain-Barré syndrome.

  1. A Neurological Enigma: The Inborn Numerical Competence of Humans and Animals

    NASA Astrophysics Data System (ADS)

    Gross, Hans J.

    2012-03-01

    "Subitizing" means our ability to recognize and memorize object numbers precisely under conditions where counting is impossible. This is an inborn archaic process which was named after the Latin "subito" = suddenly, immediately, indicating that the objects in question are presented to test persons only for the fraction of a second in order to prevent counting. Sequential counting, however, is an outstanding cultural achievement of mankind and means to count "1, 2, 3, 4, 5, 6, 7, 8 ..." without a limit. In contrast to inborn "subitizing", counting has to be trained, beginning in our early childhood with the help of our fingers. For humans we know since 140 years that we can "subitize" only up to 4 objects correctly and that mistakes occur from 5 objects on. Similar results have been obtained for a number of non-human vertebrates from salamanders to pigeons and dolphins. To our surprise, we have detected this inborn numerical competence for the first time in case of an invertebrate, the honeybee which recognizes and memorizes 3 to 4 objects under rigorous test conditions. This common ability of humans and honeybees to "subitize" up to 4 objects correctly and the miraculous but rare ability of persons with Savant syndrome to "subitize" more than hundred objects precisely raises a number of intriguing questions concerning the evolution and the significance of this biological enigma.

  2. Toxoplasmosis and Polygenic Disease Susceptibility Genes: Extensive Toxoplasma gondii Host/Pathogen Interactome Enrichment in Nine Psychiatric or Neurological Disorders

    PubMed Central

    Carter, C. J.

    2013-01-01

    Toxoplasma gondii is not only implicated in schizophrenia and related disorders, but also in Alzheimer's or Parkinson's disease, cancer, cardiac myopathies, and autoimmune disorders. During its life cycle, the pathogen interacts with ~3000 host genes or proteins. Susceptibility genes for multiple sclerosis, Alzheimer's disease, schizophrenia, bipolar disorder, depression, childhood obesity, Parkinson's disease, attention deficit hyperactivity disorder (P  from  8.01E − 05  (ADHD)  to  1.22E − 71) (multiple sclerosis), and autism (P = 0.013), but not anorexia or chronic fatigue are highly enriched in the human arm of this interactome and 18 (ADHD) to 33% (MS) of the susceptibility genes relate to it. The signalling pathways involved in the susceptibility gene/interactome overlaps are relatively specific and relevant to each disease suggesting a means whereby susceptibility genes could orient the attentions of a single pathogen towards disruption of the specific pathways that together contribute (positively or negatively) to the endophenotypes of different diseases. Conditional protein knockdown, orchestrated by T. gondii proteins or antibodies binding to those of the host (pathogen derived autoimmunity) and metabolite exchange, may contribute to this disruption. Susceptibility genes may thus be related to the causes and influencers of disease, rather than (and as well as) to the disease itself. PMID:23533776

  3. Neurologic emergencies.

    PubMed

    Piecuch, J F; Lieblich, S E

    1995-07-01

    Neurologic emergencies are rare, and they usually occur in easily identifiable patients, provided that a thorough medical history has been previously obtained. Rare as these may be, however, they occur without warning and are potentially life threatening. Consequently, the dentist should be prepared by virtue of knowledge of the pathophysiology and therapy and by formal training and certification in basic life support.

  4. N-methyl-D-aspartate receptor antibody-mediated neurological disease: results of a UK-based surveillance study in children

    PubMed Central

    Wright, Sukhvir; Hacohen, Yael; Jacobson, Leslie; Agrawal, Shakti; Gupta, Rajat; Philip, Sunny; Smith, Martin; Lim, Ming; Wassmer, Evangeline; Vincent, Angela

    2015-01-01

    Objective N-methyl-D-aspartate receptor antibody (NMDAR-Ab) encephalitis is a well-recognised clinico-immunological syndrome that presents with neuropsychiatric symptoms cognitive decline, movement disorder and seizures. This study reports the clinical features, management and neurological outcomes of paediatric NMDAR-Ab-mediated neurological disease in the UK. Design A prospective surveillance study. Children with NMDAR-Ab-mediated neurological diseases were voluntarily reported to the British Neurological Surveillance Unit (BPNSU) from November 2010 to December 2011. Initial and follow-up questionnaires were sent out to physicians. Results Thirty-one children fulfilled the criteria for the study. Eight presented during the study period giving an incidence of 0.85 per million children per year (95% CI 0.64 to 1.06); 23 cases were historical. Behavioural change and neuropsychiatric features were present in 90% of patients, and seizures and movement disorders both in 67%. Typical NMDAR-Ab encephalitis was reported in 24 children and partial phenotype without encephalopathy in seven, including predominantly psychiatric (four) and movement disorder (three). All patients received steroids, 22 (71%) received intravenous immunoglobulin, 9 (29%) received plasma exchange,and 10 (32%) received second-line immunotherapy. Of the 23 patients who were diagnosed early, 18 (78%) made a full recovery compared with only 1 of 8 (13%) of the late diagnosed patients (p=0.002, Fisher's exact test). Seven patients relapsed, with four needing additional second-line immunotherapy. Conclusions Paediatric NMDAR-Ab-mediated neurological disease appears to be similar to adult NMDAR-Ab encephalitis, but some presented with a partial phenotype. Early treatment was associated with a quick and often full recovery. PMID:25637141

  5. Individuals with neurological diseases are at increased risk of fractures within 180 days of admission to long-term care in Ontario

    PubMed Central

    Jantzi, Micaela; Maher, Amy C.; Ioannidis, George; Hirdes, John P.; Giangregorio, Lora M.; Papaioannou, Alexandra

    2016-01-01

    Background individuals residing in long-term care (LTC) are more likely to have a fragility fracture than community-dwelling seniors. The purpose of this study was to determine whether the presence of neurological diseases was associated with an increased risk of fracture within 180 days of admission to LTC. Methods this retrospective cohort study used data collected in the LTC setting using the Resident Assessment Instrument (RAI) 2.0 during the period from 2006 to 2011 (N = 42,089). Multivariable logistic regression analyses were conducted to determine the associations between the presence of neurological conditions and incident fractures, with and without adjustment for clinical variables. Results the incident fracture rate for all LTC residents was 2.6% (N = 1,094). Neurological condition group size ranged from n = 21,015 for Alzheimer’s disease or related dementias (ADRD) to n = 21 for muscular dystrophy (MD). The incidence of fracture among residents with specific neurological diseases was as follows: ADRD, 3.2% (n = 672), MD, 4.8% (n = 1), Parkinson’s disease, 2.5% (n = 57), stroke, 2.3% (n = 166), epilepsy, 2.5% (n = 38), Huntington’s disease, 1.4% (n = 1), multiple sclerosis, 0.3% (n = 1) and traumatic brain injury, 3.8% (n = 11); among the comparison group with no neurological conditions, the fracture rate was 2.0% (n = 366). The neurological diseases that were associated with a significantly greater odds of having an incident fracture in the first 180 days of LTC admission were as follows: ADRD (1.3; 95% CI: 1.1–1.5), epilepsy (1.5; 95% CI: 1.0–2.1) and traumatic brain injury (2.7; 95% CI: 1.4–5.0). Conclusion LTC residents with ADRD, epilepsy and traumatic brain injury are at a higher risk for sustaining an incident fracture in the first 180 days of admission and should be considered for fracture prevention strategies. PMID:25398885

  6. [Diagnosis of Alzheimer's disease in Brazil: cognitive and functional evaluation. Recommendations of the Scientific Department of Cognitive Neurology and Aging of the Brazilian Academy of Neurology].

    PubMed

    Nitrini, Ricardo; Caramelli, Paulo; Bottino, Cássio Machado de Campos; Damasceno, Benito Pereira; Brucki, Sonia Maria Dozzi; Anghinah, Renato

    2005-09-01

    The educational and cultural heterogeneity of the Brazilian population leads to peculiar characteristics regarding the diagnosis of Alzheimer's disease (AD). This consensus had the objective of recommending evidence-based guidelines for the clinical diagnosis of AD in Brazil. Studies on the diagnosis of AD published in Brazil were systematically evaluated in a thorough research of PUBMED and LILACS databases. For global cognitive evaluation, the Mini-Mental State Examination was recommended; for memory evaluation: delayed recall subtest of CERAD or of objects presented as drawings; attention: trail-making or digit-span; language: Boston naming, naming test from ADAS-Cog or NEUROPSI; executive functions: verbal fluency or clock-drawing; conceptualization and abstraction: similarities from CAMDEX or NEUROPSI; construction: drawings from CERAD. For functional evaluation, IQCODE, or Pfeffer Questionnaire or Bayer Scale for Activities of Daily Living was recommended. The panel concluded that the combined use of cognitive and functional evaluation based on interview with informant is recommended.

  7. Between destiny and disease: genetics and molecular pathways of human central nervous system aging

    PubMed Central

    Glorioso, Christin; Sibille, Etienne

    2010-01-01

    Aging of the human brain is associated with “normal” functional, structural, and molecular changes that underlie alterations in cognition, memory, mood and motor function, amongst other processes. Normal aging also imposes a robust constraint on the onset of many neurological diseases, ranging from late onset neurodegenerative diseases, such as Alzheimer’s (AD) and Parkinson’s diseases (PD), to early onset psychiatric disorders, such as bipolar disorder (BPD) and schizophrenia (SCZ). The molecular mechanisms and genetic underpinnings of age-related changes in the brain are understudied, and, while they share some overlap with peripheral mechanisms of aging, many are unique to the largely non-mitotic brain. Hence, understanding mechanisms of brain aging and identifying associated modulators may have profound consequences for the prevention and treatment of age-related impairments and diseases. Here we review current knowledge on age-related functional and structural changes, their molecular and genetic underpinnings, and discuss how these pathways may contribute to the vulnerability to develop age-related neurological diseases. We highlight recent findings from human postmortem brain microarray studies, which we hypothesize, point to a potential genetically-controlled transcriptional program underlying molecular changes and age-gating of neurological diseases. Finally, we discuss the implications of this model for understanding basic mechanisms of brain aging and for the future investigation of therapeutic approaches. PMID:21130140

  8. New techniques for positron emission tomography in the study of human neurological disorders

    SciTech Connect

    Kuhl, D.E.

    1992-01-01

    The general goals of the physics and kinetic modeling projects are to: (1) improve the quantitative information extractable from PET images, and (2) develop, implement and optimize tracer kinetic models for new PET neurotransmitter/receptor ligands aided by computer simulations. Work towards improving PET quantification has included projects evaluating: (1) iterative reconstruction algorithms using supplemental boundary information, (2) automated registration of dynamic PET emission and transmission data using sinogram edge detection, and (3) automated registration of multiple subjects to a common coordinate system, including the use of non-linear warping methods. Simulation routines have been developed providing more accurate representation of data generated from neurotransmitter/receptor studies. Routines consider data generated from complex compartmental models, high or low specific activity administrations, non-specific binding, pre- or post-injection of cold or competing ligands, temporal resolution of the data, and radiolabeled metabolites. Computer simulations and human PET studies have been performed to optimize kinetic models for four new neurotransmitter/receptor ligands, ({sup 11}C)TRB (muscarinic), ({sup 11}C)flumazenil (benzodiazepine), ({sup 18}F)GBR12909, (dopamine), and ({sup 11}C)NMPB (muscarinic).

  9. New techniques for positron emission tomography in the study of human neurological disorders

    SciTech Connect

    Kuhl, D.E.

    1992-07-01

    The general goals of the physics and kinetic modeling projects are to: (1) improve the quantitative information extractable from PET images, and (2) develop, implement and optimize tracer kinetic models for new PET neurotransmitter/receptor ligands aided by computer simulations. Work towards improving PET quantification has included projects evaluating: (1) iterative reconstruction algorithms using supplemental boundary information, (2) automated registration of dynamic PET emission and transmission data using sinogram edge detection, and (3) automated registration of multiple subjects to a common coordinate system, including the use of non-linear warping methods. Simulation routines have been developed providing more accurate representation of data generated from neurotransmitter/receptor studies. Routines consider data generated from complex compartmental models, high or low specific activity administrations, non-specific binding, pre- or post-injection of cold or competing ligands, temporal resolution of the data, and radiolabeled metabolites. Computer simulations and human PET studies have been performed to optimize kinetic models for four new neurotransmitter/receptor ligands, [{sup 11}C]TRB (muscarinic), [{sup 11}C]flumazenil (benzodiazepine), [{sup 18}F]GBR12909, (dopamine), and [{sup 11}C]NMPB (muscarinic).

  10. Structural Variation of Alu Element and Human Disease

    PubMed Central

    Kim, Songmi; Cho, Chun-Sung; Han, Kyudong

    2016-01-01

    Transposable elements are one of major sources to cause genomic instability through various mechanisms including de novo insertion, insertion-mediated genomic deletion, and recombination-associated genomic deletion. Among them is Alu element which is the most abundant element, composing ~10% of the human genome. The element emerged in the primate genome 65 million years ago and has since propagated successfully in the human and non-human primate genomes. Alu element is a non-autonomous retrotransposon and therefore retrotransposed using L1-enzyme machinery. The 'master gene' model has been generally accepted to explain Alu element amplification in primate genomes. According to the model, different subfamilies of Alu elements are created by mutations on the master gene and most Alu elements are amplified from the hyperactive master genes. Alu element is frequently involved in genomic rearrangements in the human genome due to its abundance and sequence identity between them. The genomic rearrangements caused by Alu elements could lead to genetic disorders such as hereditary disease, blood disorder, and neurological disorder. In fact, Alu elements are associated with approximately 0.1% of human genetic disorders. The first part of this review discusses mechanisms of Alu amplification and diversity among different Alu subfamilies. The second part discusses the particular role of Alu elements in generating genomic rearrangements as well as human genetic disorders. PMID:27729835

  11. Does biodiversity protect humans against infectious disease?

    PubMed

    Wood, Chelsea L; Lafferty, Kevin D; DeLeo, Giulio; Young, Hillary S; Hudson, Peter J; Kuris, Armand M

    2014-04-01

    Control of human infectious disease has been promoted as a valuable ecosystem service arising from the conservation of biodiversity. There are two commonly discussed mechanisms by which biodiversity loss could increase rates of infectious disease in a landscape. First, loss of competitors or predators could facilitate an increase in the abundance of competent reservoir hosts. Second, biodiversity loss could disproportionately affect non-competent, or less competent reservoir hosts, which would otherwise interfere with pathogen transmission to human populations by, for example, wasting the bites of infected vectors. A negative association between biodiversity and disease risk, sometimes called the "dilution effect hypothesis," has been supported for a few disease agents, suggests an exciting win-win outcome for the environment and society, and has become a pervasive topic in the disease ecology literature. Case studies have been assembled to argue that the dilution effect is general across disease agents. Less touted are examples in which elevated biodiversity does not affect or increases infectious disease risk for pathogens of public health concern. In order to assess the likely generality of the dilution effect, we review the association between biodiversity and public health across a broad variety of human disease agents. Overall, we hypothesize that conditions for the dilution effect are unlikely to be met for most important diseases of humans. Biodiversity probably has little net effect on most human infectious diseases but, when it does have an effect, observation and basic logic suggest that biodiversity will be more likely to increase than to decrease infectious disease risk.

  12. Parasitic diseases in humans transmitted by vectors.

    PubMed

    Cholewiński, Marcin; Derda, Monika; Hadaś, Edward

    2015-01-01

    Despite the considerable progress of medicine, parasitic diseases still pose a great threat to human health and life. Among parasitic diseases, those transmitted by vectors, mainly arthropods, play a particular role. These diseases occur most frequently in the poorest countries and affect a vast part of the human population. They include malaria, babesiosis, trypanosomiasis, leishmaniasis and filariasis. This study presents those vector-transmitted diseases that are responsible for the greatest incidence and mortality of people on a global scale. Attention is focused primarily on diseases transmitted by mosquitoes, flies, Hemiptera and ticks.

  13. Genetically modified pigs to model human diseases.

    PubMed

    Flisikowska, Tatiana; Kind, Alexander; Schnieke, Angelika

    2014-02-01

    Genetically modified mice are powerful tools to investigate the molecular basis of many human diseases. Mice are, however, of limited value for preclinical studies, because they differ significantly from humans in size, general physiology, anatomy and lifespan. Considerable efforts are, thus, being made to develop alternative animal models for a range of human diseases. These promise powerful new resources that will aid the development of new diagnostics, medicines and medical procedures. Here, we provide a comprehensive review of genetically modified porcine models described in the scientific literature: various cancers, cystic fibrosis, Duchenne muscular dystrophy, autosomal polycystic kidney disease, Huntington’s disease, spinal muscular atrophy, haemophilia A, X-linked severe combined immunodeficiency, retinitis pigmentosa, Stargardt disease, Alzheimer’s disease, various forms of diabetes mellitus and cardiovascular diseases.

  14. MicroRNAs in Human Diseases: From Cancer to Cardiovascular Disease

    PubMed Central

    2011-01-01

    The great discovery of microRNAs (miRNAs) has revolutionized current cell biology and medical science. miRNAs are small conserved non-coding RNA molecules that post-transcriptionally regulate gene expression by targeting the 3' untranslated region of specific messenger RNAs for degradation or translational repression. New members of the miRNA family are being discovered on a daily basis and emerging evidence has demonstrated that miRNAs play a major role in a wide range of developmental process including cell proliferation, cell cycle, cell differentiation, metabolism, apoptosis, developmental timing, neuronal cell fate, neuronal gene expression, brain morphogenesis, muscle differentiation and stem cell division. Moreover, a large number of studies have reported links between alterations of miRNA homeostasis and pathological conditions such as cancer, psychiatric and neurological diseases, cardiovascular disease, and autoimmune disease. Interestingly, in addition, miRNA deficiencies or excesses have been correlated with a number of clinically important diseases ranging from cancer to myocardial infarction. miRNAs can repress the gene translation of hundreds of their targets and are therefore well-positioned to target a multitude of cellular mechanisms. As a consequence of extensive participation in normal functions, it is quite logical to ask the question if abnormalities in miRNAs should have importance in human diseases. Great discoveries and rapid progress in the past few years on miRNAs provide the hope that miRNAs will in the near future have a great potential in the diagnosis and treatment of many diseases. Currently, an explosive literature has focussed on the role of miRNA in human cancer and cardiovascular disease. In this review, I briefly summarize the explosive current studies about involvement of miRNA in various human cancers and cardiovascular disease. PMID:21860607

  15. HTLV-1 Associated Neurological Disorders.

    PubMed

    Khan, Muhammad Yasir; Khan, Ishaq Nasib; Farman, Muhammad; Al Karim, Saleh; Qadri, Ishtiaq; Kamal, Muhammad Amjad; Al Ghamdi, Khalid; Harakeh, Steve

    2016-12-22

    Human T-cell lymphotropic virus type 1 (HTLV-1) is a retrovirus which is endemic to certain regions of the world and infects around 10-20 million people. HTLV-1 is the etiologic agent of Adult T cell leukemia/lymphoma and HTLV-1 associated neurological disorders including mainly HTLV-1 associated myelopathy/Tropical spastic paraparesis. The involvement of the central nervous diseases occurs among: HTLV-1 infected patients from endemic areas, HIV positive individuals and drug users. The ability of HTLV-1 to cause associated neuropathies starts with the virus crossing the blood brain barrier (BBB), then entering and infecting the cells of the central nervous system. As a consequence, to the viral attack, HTLV-1 infected lymphocytes produce pro-inflammatory cytokines like tumor necrosis factor alpha, Interleukin 1 beta and interleukin 6 which further disrupts the BBB. Different serological tests have been used in the diagnosis of HTLV-1. These include: ELISA and Western Blotting (WB), Immunofluorescence, Particle Agglutination and Polymerase Chain Reaction which is used as a confirmatory test. Danazol, pentoxifylline, azathioprine and vitamin C have been used in the treatment of the HTLV-1 associated neurological disorders. Other antiviral drugs (lamivudine, zidovudine), monoclonal antibodies (Daclizumab) and therapeutic agents (valporic acid, interferons) have also been evaluated. No known drug, so far, has been shown to be efficacious. The aim of this review is to present the complexities of HTLV-1 associated neurological disorders and their current ongoing treatment. In addition to discussing future possible therapeutic strategies, by targeting HTVL-1 viral components and gene/s products, for the treatment of those neurological conditions.

  16. Sarcocystis neurona infections in raccoons (Procyon lotor): evidence for natural infection with sarcocysts, transmission of infection to opossums (Didelphis virginiana), and experimental induction of neurologic disease in raccoons.

    PubMed

    Dubey, J P; Saville, W J; Stanek, J F; Lindsay, D S; Rosenthal, B M; Oglesbee, M J; Rosypal, A C; Njoku, C J; Stich, R W; Kwok, O C; Shen, S K; Hamir, A N; Reed, S M

    2001-10-24

    Equine protozoal myeloencephalitis (EPM) is a serious neurologic disease of horses in the Americas and Sarcocystis neurona is the most common etiologic agent. The distribution of S. neurona infections follows the geographical distributions of its definitive hosts, opossums (Didelphis virginiana, Didelphis albiventris). Recently, cats and skunks were reported as experimental and armadillos as natural intermediate hosts of S. neurona. In the present report, raccoons (Procyon lotor) were identified as a natural intermediate host of S. neurona. Two laboratory-raised opossums were found to shed S. neurona-like sporocysts after ingesting tongues of naturally-infected raccoons. Interferon-gamma gene knockout (KO) mice fed raccoon-opossum-derived sporocysts developed neurologic signs. S. neurona was identified immunohistochemically in tissues of KO mice fed sporocysts and the parasite was isolated in cell cultures inoculated with infected KO mouse tissues. The DNA obtained from the tongue of a naturally-infected raccoon, brains of KO mice that had neurological signs, and from the organisms recovered in cell cultures inoculated with brains of neurologic KO mice, corresponded to that of S. neurona. Two raccoons fed mature S. neurona sarcocysts did not shed sporocysts in their feces, indicating raccoons are not likely to be its definitive host. Two raccoons fed sporocysts from opossum feces developed clinical illness and S. neurona-associated encephalomyelitis was found in raccoons killed 14 and 22 days after feeding sporocysts; schizonts and merozoites were seen in encephalitic lesions.

  17. [Neurological sleep disorders].

    PubMed

    Khatami, Ramin

    2014-11-01

    Neurological sleep disorders are common in the general population and may have a strong impact on quality of life. General practitioners play a key role in recognizing and managing sleep disorders in the general population. They should therefore be familiar with the most important neurological sleep disorders. This review provides a comprehensive overview of the most prevalent and important neurological sleep disorders, including Restless legs syndrome (with and without periodic limb movements in sleep), narcolepsy, NREM- and REM-sleep parasomnias and the complex relationship between sleep and epilepsies. Although narcolepsy is considered as a rare disease, recent discoveries in narcolepsy research provided insight in the function of brain circuitries involved in sleep wake regulation. REM sleep behavioral parasomnia (RBD) is increasingly recognized to represent an early manifestation of neurodegenerative disorders, in particular evolving synucleinopathies. Early diagnosis may thus open new perspectives for developing novel treatment options by targeting neuroprotective substances.

  18. History of neurologic examination books.

    PubMed

    Boes, Christopher J

    2015-04-01

    The objective of this study was to create an annotated list of textbooks dedicated to teaching the neurologic examination. Monographs focused primarily on the complete neurologic examination published prior to 1960 were reviewed. This analysis was limited to books with the word "examination" in the title, with exceptions for the texts of Robert Wartenberg and Gordon Holmes. Ten manuals met the criteria. Works dedicated primarily to the neurologic examination without a major emphasis on disease description or treatment first appeared in the early 1900s. Georg Monrad-Krohn's "Blue Book of Neurology" ("Blue Bible") was the earliest success. These treatises served the important purpose of educating trainees on proper neurologic examination technique. They could make a reputation and be profitable for the author (Monrad-Krohn), highlight how neurology was practiced at individual institutions (McKendree, Denny-Brown, Holmes, DeJong, Mayo Clinic authors), and honor retiring mentors (Mayo Clinic authors).

  19. Child neurology services in Africa.

    PubMed

    Wilmshurst, Jo M; Badoe, Eben; Wammanda, Robinson D; Mallewa, Macpherson; Kakooza-Mwesige, Angelina; Venter, Andre; Newton, Charles R

    2011-12-01

    The first African Child Neurology Association meeting identified key challenges that the continent faces to improve the health of children with neurology disorders. The capacity to diagnose common neurologic conditions and rare disorders is lacking. The burden of neurologic disease on the continent is not known, and this lack of knowledge limits the ability to lobby for better health care provision. Inability to practice in resource-limited settings has led to the migration of skilled professionals away from Africa. Referral systems from primary to tertiary are often unpredictable and chaotic. There is a lack of access to reliable supplies of basic neurology treatments such as antiepileptic drugs. Few countries have nationally accepted guidelines either for the management of epilepsy or status epilepticus. There is a great need to develop better training capacity across Africa in the recognition and management of neurologic conditions in children, from primary health care to the subspecialist level.

  20. Epilepsy, psychiatry, and neurology.

    PubMed

    Reynolds, Edward H; Trimble, Michael R

    2009-03-01

    This article reviews the relationship between the psychiatry and neurology of epilepsy, especially in the last 100 years. Throughout most of its recorded history of 3 to 4 millennia epilepsy has been viewed as a supernatural or mental disorder. Although first suggested by Hippocrates in the 5th century B.C., the concept of epilepsy as a brain disorder only began to take root in the 17th and 18th centuries. The discipline of neurology emerged from "nervous disorders" or neuropsychiatry in the late 19th century, when vascular theories of epilepsy predominated. By the turn of the 19th century psychiatry and neurology were diverging and epilepsy remained to some extent in both disciplines. It was only in the middle of the 20th century with the development of electromagnetic theories of epilepsy that the concept of epilepsy per se as a neurological disorder was finally adopted in international classifications of disease. This was associated with a refined definition of the ictal, pre-, post-, and interictal psychological disorders of epilepsy, which have contributed to a renaissance of neuropsychiatry. At the beginning of the 21st century and the centenary of the ILAE psychiatry and neurology have been converging again, led in some respects by epilepsy, which has provided several useful models of mental illness and a bridge between the two disciplines.

  1. [History of neurology and education on neurology in Japan].

    PubMed

    Kuzuhara, Shigeki

    2009-11-01

    The first medical society of Japanese neurologists and psychiatrists was founded in 1902, but psychiatrists gradually dominated in number. New "Japanese Society of Neurology" (JSN) was founded in 1960. The number of members was only 643 in 1960, while it rose up to 8,555 in 2009, including regular, junior, senior and associate members. JSN contributed much to solve the causes and treatment of the medicosocial and iatrogenic diseases such as Minamata disease and SMON (subacute myelopticoneuropathy) at its early period. In undergraduate education at medical school neurology is one of the core subjects in the curriculum, and almost all the 80 medical schools have at least one faculty neurologist. The Board of neurology of JSN was started in 1975, as the third earliest of the Japanese Medical Associations. It takes at least 6 years' clinical training after graduating from the medical school to take the neurology Board examinations. By 2009, 4,000 members passed the Board examinations. In 2002 JSN published evidence-based "Treatment Guidelines 2002" of 6 diseases: Parkinson's disease, stroke, chronic headache, dementia and ALS. As to the international issues, JSN hosted the 12th World Congress of Neurology in 1981, and international activities markedly increased after that. The first informal meeting with JSN and Korean Neurological Association (KNA) was held at the 48th JSN Annual Meeting in Nagoya in May 2007. In May 2008 the KNA-JSN 1st Joint symposium was held at the 49th Annual Meeting of JSN in Yokohama on "International comparison of neurological disorders: focusing on spinocerebellar atrophies (SCA) and epilepsies". In May 2009, KNA-JNS 2 nd Joint Symposium was held at the 50th JSN Annual Meeting in Sendai, inviting a speaker from Taiwan Neurological Society, on the subject "History and Education of Neurology in Japan, Korea and Taiwan". In this symposium, a strategy to make up the Northeast Asian Neurological Association was discussed.

  2. Humanized mouse models of clinical disease

    PubMed Central

    Walsh, Nicole; Kenney, Laurie; Jangalwe, Sonal; Aryee, Ken-Edwin; Greiner, Dale L.; Brehm, Michael A.; Shultz, Leonard D.

    2017-01-01

    Immunodeficient mice engrafted with functional human cells and tissues, i.e., “humanized mice”, have become increasingly important as small pre-clinical animal models for the study of human diseases. Since the description of immunodeficient mice bearing mutations in the IL2 receptor common gamma chain (IL2rgnull) in the early 2000’s, investigators have been able to engraft murine recipients with human hematopoietic stem cells that develop into functional human immune systems. These mice can also be engrafted with human tissues such as islets, liver, skin, and most solid and hematologic cancers. Humanized mice are permitting significant progress in studies of human infectious disease, cancer, regenerative medicine, graft versus host disease, allergies, and immunity. Ultimately, use of humanized mice may lead to the implementation of truly “personalized” medicine in the clinic. This review discusses recent progress in the development and use of humanized mice, and highlights their utility for the study of human diseases. PMID:27959627

  3. Genetically Engineered Pig Models for Human Diseases

    PubMed Central

    Prather, Randall S.; Lorson, Monique; Ross, Jason W.; Whyte, Jeffrey J.; Walters, Eric

    2015-01-01

    Although pigs are used widely as models of human disease, their utility as models has been enhanced by genetic engineering. Initially, transgenes were added randomly to the genome, but with the application of homologous recombination, zinc finger nucleases, and transcription activator-like effector nuclease (TALEN) technologies, now most any genetic change that can be envisioned can be completed. To date these genetic modifications have resulted in animals that have the potential to provide new insights into human diseases for which a good animal model did not exist previously. These new animal models should provide the preclinical data for treatments that are developed for diseases such as Alzheimer's disease, cystic fibrosis, retinitis pigmentosa, spinal muscular atrophy, diabetes, and organ failure. These new models will help to uncover aspects and treatments of these diseases that were otherwise unattainable. The focus of this review is to describe genetically engineered pigs that have resulted in models of human diseases. PMID:25387017

  4. Tissue Specificity of Human Disease Module

    PubMed Central

    Kitsak, Maksim; Sharma, Amitabh; Menche, Jörg; Guney, Emre; Ghiassian, Susan Dina; Loscalzo, Joseph; Barabási, Albert-László

    2016-01-01

    Genes carrying mutations associated with genetic diseases are present in all human cells; yet, clinical manifestations of genetic diseases are usually highly tissue-specific. Although some disease genes are expressed only in selected tissues, the expression patterns of disease genes alone cannot explain the observed tissue specificity of human diseases. Here we hypothesize that for a disease to manifest itself in a particular tissue, a whole functional subnetwork of genes (disease module) needs to be expressed in that tissue. Driven by this hypothesis, we conducted a systematic study of the expression patterns of disease genes within the human interactome. We find that genes expressed in a specific tissue tend to be localized in the same neighborhood of the interactome. By contrast, genes expressed in different tissues are segregated in distinct network neighborhoods. Most important, we show that it is the integrity and the completeness of the expression of the disease module that determines disease manifestation in selected tissues. This approach allows us to construct a disease-tissue network that confirms known and predicts unexpected disease-tissue associations. PMID:27748412

  5. [Pathophysiology of human mitochondrial diseases].

    PubMed

    Lombès, Anne; Auré, Karine; Jardel, Claude

    2015-01-01

    Mitochondrial diseases, defined as the diseases due to oxidative phosphorylation defects, are the most frequent inborn errors of metabolism. Their clinical presentation is highly diverse. Their diagnosis is difficult. It relies on metabolic parameters, histological anomalies and enzymatic assays showing defective activity, all of which are both inconstant and relatively unspecific. Most mitochondrial diseases have a genetic origin. Candidate genes are very numerous, located either in the mitochondrial genome or the nuclear DNA. Pathophysiological mechanisms of mitochondrial diseases are still the matter of much debate. Those underlying the tissue-specificity of diseases due to the alterations of a ubiquitously expressed gene are discussed including (i) quantitative aspect of the expression of the causal gene or its partners when appropriate, (ii) quantitative aspects of the bioenergetic function in each tissue, and (iii) tissue distribution of heteroplasmic mitochondrial DNA alterations.

  6. Neurologic Music Therapy Training for Mobility and Stability Rehabilitation with Parkinson’s Disease – A Pilot Study

    PubMed Central

    Bukowska, Anna A.; Krężałek, Piotr; Mirek, Elżbieta; Bujas, Przemysław; Marchewka, Anna

    2016-01-01

    Idiopathic Parkinson’s Disease (PD) is a progressive condition with gait disturbance and balance disorder as the main symptoms. Previous research studies focused on the application of Rhythmic Auditory Stimulation (RAS) in PD gait rehabilitation. The key hypothesis of this pilot study, however, assumes the major role of the combination of all three Neurologic Music Therapy (NMT) sensorimotor techniques in improving spatio-temporal gait parameters, and postural stability in the course of PD. The 55 PD-diagnosed subjects invited to the study were divided into two groups: 30 in the experimental and 25 in the control group. Inclusion criteria included Hoehn and Yahr stages 2 or 3, the ability to walk independently without any aid and stable pharmacological treatment for the duration of the experiment. In order to evaluate the efficacy of the chosen therapy procedure the following measures were applied: Optoelectrical 3D Movement Analysis, System BTS Smart for gait, and Computerized Dynamic Posturography CQ Stab for stability and balance. All measures were conducted both before and after the therapy cycle. The subjects from the experimental group attended music therapy sessions four times a week for 4 weeks. Therapeutic Instrumental Music Performance (TIMP), Pattern Sensory Enhancement (PSE) and RAS were used in every 45-min session for practicing daily life activities, balance, pre-gait, and gait pattern. Percussion instruments, the metronome and rhythmic music were the basis for each session. The subjects from the control group were asked to stay active and perform daily life activities between the measures. The research showed that the combination of the three NMT sensorimotor techniques can be used to improve gait and other rhythmical activities in PD rehabilitation. The results demonstrated significant improvement in the majority of the spatiotemporal gait parameters in the experimental group in comparison to the control group. In the stability tests with eyes

  7. Dihydrofolate Reductase Deficiency Due to a Homozygous DHFR Mutation Causes Megaloblastic Anemia and Cerebral Folate Deficiency Leading to Severe Neurologic Disease

    PubMed Central

    Cario, Holger; Smith, Desirée E.C.; Blom, Henk; Blau, Nenad; Bode, Harald; Holzmann, Karlheinz; Pannicke, Ulrich; Hopfner, Karl-Peter; Rump, Eva-Maria; Ayric, Zuleya; Kohne, Elisabeth; Debatin, Klaus-Michael; Smulders, Yvo; Schwarz, Klaus

    2011-01-01

    The importance of intracellular folate metabolism is illustrated by the severity of symptoms and complications caused by inborn disorders of folate metabolism or by folate deficiency. We examined three children of healthy, distantly related parents presenting with megaloblastic anemia and cerebral folate deficiency causing neurologic disease with atypical childhood absence epilepsy. Genome-wide homozygosity mapping revealed a candidate region on chromosome 5 including the dihydrofolate reductase (DHFR) locus. DHFR sequencing revealed a homozygous DHFR mutation, c.458A>T (p.Asp153Val), in all siblings. The patients' folate profile in red blood cells (RBC), plasma, and cerebrospinal fluid (CSF), analyzed by liquid chromatography tandem mass spectrometry, was compatible with DHFR deficiency. DHFR activity and fluorescein-labeled methotrexate (FMTX) binding were severely reduced in EBV-immortalized lymphoblastoid cells of all patients. Heterozygous cells displayed intermediate DHFR activity and FMTX binding. RT-PCR of DHFR mRNA revealed no differences between wild-type and DHFR mutation-carrying cells, whereas protein expression was reduced in cells with the DHFR mutation. Treatment with folinic acid resulted in the resolution of hematological abnormalities, normalization of CSF folate levels, and improvement of neurological symptoms. In conclusion, the homozygous DHFR mutation p.Asp153Val causes DHFR deficiency and leads to a complex hematological and neurological disease that can be successfully treated with folinic acid. DHFR is necessary for maintaining sufficient CSF and RBC folate levels, even in the presence of adequate nutritional folate supply and normal plasma folate. PMID:21310277

  8. Dihydrofolate reductase deficiency due to a homozygous DHFR mutation causes megaloblastic anemia and cerebral folate deficiency leading to severe neurologic disease.

    PubMed

    Cario, Holger; Smith, Desirée E C; Blom, Henk; Blau, Nenad; Bode, Harald; Holzmann, Karlheinz; Pannicke, Ulrich; Hopfner, Karl-Peter; Rump, Eva-Maria; Ayric, Zuleya; Kohne, Elisabeth; Debatin, Klaus-Michael; Smulders, Yvo; Schwarz, Klaus

    2011-02-11

    The importance of intracellular folate metabolism is illustrated by the severity of symptoms and complications caused by inborn disorders of folate metabolism or by folate deficiency. We examined three children of healthy, distantly related parents presenting with megaloblastic anemia and cerebral folate deficiency causing neurologic disease with atypical childhood absence epilepsy. Genome-wide homozygosity mapping revealed a candidate region on chromosome 5 including the dihydrofolate reductase (DHFR) locus. DHFR sequencing revealed a homozygous DHFR mutation, c.458A>T (p.Asp153Val), in all siblings. The patients' folate profile in red blood cells (RBC), plasma, and cerebrospinal fluid (CSF), analyzed by liquid chromatography tandem mass spectrometry, was compatible with DHFR deficiency. DHFR activity and fluorescein-labeled methotrexate (FMTX) binding were severely reduced in EBV-immortalized lymphoblastoid cells of all patients. Heterozygous cells displayed intermediate DHFR activity and FMTX binding. RT-PCR of DHFR mRNA revealed no differences between wild-type and DHFR mutation-carrying cells, whereas protein expression was reduced in cells with the DHFR mutation. Treatment with folinic acid resulted in the resolution of hematological abnormalities, normalization of CSF folate levels, and improvement of neurological symptoms. In conclusion, the homozygous DHFR mutation p.Asp153Val causes DHFR deficiency and leads to a complex hematological and neurological disease that can be successfully treated with folinic acid. DHFR is necessary for maintaining sufficient CSF and RBC folate levels, even in the presence of adequate nutritional folate supply and normal plasma folate.

  9. Pentraxin-3 is upregulated in the central nervous system during MS and EAE, but does not modulate experimental neurological disease.

    PubMed

    Ummenthum, Kimberley; Peferoen, Laura A N; Finardi, Annamaria; Baker, David; Pryce, Gareth; Mantovani, Alberto; Bsibsi, Malika; Bottazzi, Barbara; Peferoen-Baert, Regina; van der Valk, Paul; Garlanda, Cecilia; Kipp, Markus; Furlan, Roberto; van Noort, Johannes M; Amor, Sandra

    2016-03-01

    Pentraxin-3 (PTX3), an acute-phase protein released during inflammation, aids phagocytic clearance of pathogens and apoptotic cells, and plays diverse immunoregulatory roles in tissue injury. In neuroinflammatory diseases, like MS, resident microglia could become activated by endogenous agonists for Toll like receptors (TLRs). Previously we showed a strong TLR2-mediated induction of PTX3 in cultured human microglia and macrophages by HspB5, which accumulates in glia during MS. Given the anti-inflammatory effects of HspB5, we examined the contribution of PTX3 to these effects in MS and its animal model EAE. Our data indicate that TLR engagement effectively induces PTX3 expression in human microglia, and that such expression is readily detectable in MS lesions. Enhanced PTX3 expression is prominently expressed in microglia in preactive MS lesions, and in microglia/macrophages engaged in myelin phagocytosis in actively demyelinating lesions. Yet, we did not detect PTX3 in cerebrospinal fluid of MS patients. PTX3 expression is also elevated in spinal cords during chronic relapsing EAE in Biozzi ABH mice, but the EAE severity and time course in PTX3-deficient mice did not differ from WT mice. Moreover, systemic PTX3 administration did not alter the disease onset or severity. Our findings reveal local functions of PTX3 during neuroinflammation in facilitating myelin phagocytosis, but do not point to a role for PTX3 in controlling the development of autoimmune neuroinflammation.

  10. Large Animal Models of Neurological Disorders for Gene Therapy

    PubMed Central

    Gagliardi, Christine; Bunnell, Bruce A.

    2009-01-01

    The development of therapeutic interventions for genetic disorders and diseases that affect the central nervous system (CNS) has proven challenging. There has been significant progress in the development of gene therapy strategies in murine models of human disease, but gene therapy outcomes in these models do not always translate to the human setting. Therefore, large animal models are crucial to the development of diagnostics, treatments, and eventual cures for debilitating neurological disorders. This review focuses on the description of large animal models of neurological diseases such as lysosomal storage diseases, Parkinson’s disease, Huntington’s disease, and neuroAIDS. The review also describes the contributions of these models to progress in gene therapy research. PMID:19293458

  11. Proteomics of Human Neurodegenerative Diseases

    PubMed Central

    Zhang, Jing; Keene, C. Dirk; Pan, Catherine; Montine, Kathleen S.; Montine, Thomas J.

    2009-01-01

    The technology, experimental approaches, and bioinformatics that support proteomic research are evolving rapidly. The application of these new capabilities to the study of neurodegenerative diseases is providing insight into the biochemical pathogenesis of neurodegeneration as well as fueling major efforts in biomarker discovery. Here, we review the fundamentals of commonly used proteomic approaches and the outcomes of these investigations with autopsy and cerebrospinal fluid samples from patients with neurodegenerative diseases. PMID:18800015

  12. Tyrosine Kinase Inhibitors as a New Therapy for Ischemic Stroke and other Neurologic Diseases: Is there any Hope for a Better Outcome?

    PubMed Central

    Gągało, Iwona; Rusiecka, Izabela; Kocić, Ivan

    2015-01-01

    The relevance of tyrosine kinase inhibitors (TKIs) in the treatment of malignancies has been already defined. Aberrant activation of tyrosine kinase signaling pathways has been causally linked not only to cancers but also to other non-oncological diseases. This review concentrates on the novel plausible usage of this group of drugs in neurological disorders, such as ischemic brain stroke, subarachnoid hemorrhage, Alzheimer’s disease, multiple sclerosis. The drugs considered here are representatives of both receptor and non-receptor TKIs. Among them imatinib and masitinib have the broadest spectrum of therapeutic usage. Both drugs are effective in ischemic brain stroke and multiple sclerosis, but only imatinib produces a therapeutic effect in subarachnoid hemorrhage. Masitinib and dasatinib reduce the symptoms of Alzheimer’s disease. In the case of multiple sclerosis several TKIs are useful, including apart from imatinib and masitinib, also sunitinib, sorafenib, lestaurtinib. Furthermore, the possible molecular targets for the drugs are described in connection with the underlying pathophysiological mechanisms in the diseases in question. The most frequent target for the TKIs is PDGFR which plays a pivotal role particularly in ischemic brain stroke and subarachnoid hemorrhage. The collected data indicates that TKIs are very promising candidates for new therapeutic interventions in neurological diseases. PMID:26630962

  13. Inebilizumab, a B Cell-Depleting Anti-CD19 Antibody for the Treatment of Autoimmune Neurological Diseases: Insights from Preclinical Studies

    PubMed Central

    Chen, Ding; Gallagher, Sandra; Monson, Nancy L.; Herbst, Ronald; Wang, Yue

    2016-01-01

    Exaggerated or inappropriate responses by B cells are an important feature in many types of autoimmune neurological diseases. The recent success of B-cell depletion in the treatment of multiple sclerosis (MS) has stimulated the development of novel B-cell-targeting therapies with the potential for improved efficacy. CD19 has emerged as a promising target for the depletion of B cells as well as CD19-positive plasmablasts and plasma cells. Inebilizumab (MEDI-551), an anti-CD19 antibody with enhanced antibody-dependent cell-mediated cytotoxicity against B cells, is currently being evaluated in MS and neuromyelitis optica. This review discusses the role of B cells in autoimmune neurological disorders, summarizes the development of inebilizumab, and analyzes the recent results for inebilizumab treatment in an autoimmune encephalitis mouse model. The novel insights obtained from these preclinical studies can potentially guide future investigation of inebilizumab in patients. PMID:27886126

  14. Evolutionary Conservation and Expression of Human RNA-Binding Proteins and Their Role in Human Genetic Disease

    PubMed Central

    Gerstberger, Stefanie; Hafner, Markus; Ascano, Manuel

    2014-01-01

    RNA-binding proteins (RBPs) are effectors and regulators of posttranscriptional gene regulation (PTGR). RBPs regulate stability, maturation, and turnover of all RNAs, often binding thousands of targets at many sites. The importance of RBPs is underscored by their dysregulation or mutations causing a variety of developmental and neurological diseases. This chapter globally discusses human RBPs and provides a brief introduction to their identification and RNA targets. We review RBPs based on common structural RNA-binding domains, study their evolutionary conservation and expression, and summarize disease associations of different RBP classes. PMID:25201102

  15. Human genome project and sickle cell disease.

    PubMed

    Norman, Brenda J; Miller, Sheila D

    2011-01-01

    Sickle cell disease is one of the most common genetic blood disorders in the United States that affects 1 in every 375 African Americans. Sickle cell disease is an inherited condition caused by abnormal hemoglobin in the red blood cells. The Human Genome Project has provided valuable insight and extensive research advances in the understanding of the human genome and sickle cell disease. Significant progress in genetic knowledge has led to an increase in the ability for researchers to map and sequence genes for diagnosis, treatment, and prevention of sickle cell disease and other chronic illnesses. This article explores some of the recent knowledge and advances about sickle cell disease and the Human Genome Project.

  16. Evolutionary Response to Human Infectious Diseases

    ERIC Educational Resources Information Center

    Armelagos, George J.; Dewey, John R.

    1970-01-01

    Gives an overview of human history, relating cultural changes with resulting changes in population density and in ecological balance to patterns of infectious diseases in man. Discusses mechanisms of evolution of resistance. Suggests that in populations where infectious diseases can be controlled, attention should shift to degenerative diseases…

  17. Melanized Fungi in Human Disease

    PubMed Central

    Revankar, Sanjay G.; Sutton, Deanna A.

    2010-01-01

    Summary: Melanized or dematiaceous fungi are associated with a wide variety of infectious syndromes. Many are soil organisms and are generally distributed worldwide, though certain species appear to have restricted geographic ranges. Though they are uncommon causes of disease, melanized fungi have been increasingly recognized as important pathogens, with most reports occurring in the past 20 years. The spectrum of diseases with which they are associated has also broadened and includes allergic disease, superficial and deep local infections, pneumonia, brain abscess, and disseminated infection. For some infections in immunocompetent individuals, such as allergic fungal sinusitis and brain abscess, they are among the most common etiologic fungi. Melanin is a likely virulence factor for these fungi. Diagnosis relies on careful microscopic and pathological examination, as well as clinical assessment of the patient, as these fungi are often considered contaminants. Therapy varies depending upon the clinical syndrome. Local infection may be cured with excision alone, while systemic disease is often refractory to therapy. Triazoles such as voriconazole, posaconazole, and itraconazole have the most consistent in vitro activity. Further studies are needed to better understand the pathogenesis and optimal treatment of these uncommon infections. PMID:20930077

  18. Global biogeography of human infectious diseases.

    PubMed

    Murray, Kris A; Preston, Nicholas; Allen, Toph; Zambrana-Torrelio, Carlos; Hosseini, Parviez R; Daszak, Peter

    2015-10-13

    The distributions of most infectious agents causing disease in humans are poorly resolved or unknown. However, poorly known and unknown agents contribute to the global burden of disease and will underlie many future disease risks. Existing patterns of infectious disease co-occurrence could thus play a critical role in resolving or anticipating current and future disease threats. We analyzed the global occurrence patterns of 187 human infectious diseases across 225 countries and seven epidemiological classes (human-specific, zoonotic, vector-borne, non-vector-borne, bacterial, viral, and parasitic) to show that human infectious diseases exhibit distinct spatial grouping patterns at a global scale. We demonstrate, using outbreaks of Ebola virus as a test case, that this spatial structuring provides an untapped source of prior information that could be used to tighten the focus of a range of health-related research and management activities at early stages or in data-poor settings, including disease surveillance, outbreak responses, or optimizing pathogen discovery. In examining the correlates of these spatial patterns, among a range of geographic, epidemiological, environmental, and social factors, mammalian biodiversity was the strongest predictor of infectious disease co-occurrence overall and for six of the seven disease classes examined, giving rise to a striking congruence between global pathogeographic and "Wallacean" zoogeographic patterns. This clear biogeographic signal suggests that infectious disease assemblages remain fundamentally constrained in their distributions by ecological barriers to dispersal or establishment, despite the homogenizing forces of globalization. Pathogeography thus provides an overarching context in which other factors promoting infectious disease emergence and spread are set.

  19. Small molecule adenosine 5'-monophosphate activated protein kinase (AMPK) modulators and human diseases.

    PubMed

    Rana, Sandeep; Blowers, Elizabeth C; Natarajan, Amarnath

    2015-01-08

    Adenosine 5'-monophosphate activated protein kinase (AMPK) is a master sensor of cellular energy status that plays a key role in the regulation of whole-body energy homeostasis. AMPK is a serine/threonine kinase that is activated by upstream kinases LKB1, CaMKKβ, and Tak1, among others. AMPK exists as αβγ trimeric complexes that are allosterically regulated by AMP, ADP, and ATP. Dysregulation of AMPK has been implicated in a number of metabolic diseases including type 2 diabetes mellitus and obesity. Recent studies have associated roles of AMPK with the development of cancer and neurological disorders, making it a potential therapeutic target to treat human diseases. This review focuses on the structure and function of AMPK, its role in human diseases, and its direct substrates and provides a brief synopsis of key AMPK modulators and their relevance in human diseases.

  20. TOXICOGENOMICS AND HUMAN DISEASE RISK ASSESSMENT

    EPA Science Inventory


    Toxicogenomics and Human Disease Risk Assessment.

    Complete sequencing of human and other genomes, availability of large-scale gene
    expression arrays with ever-increasing numbers of genes displayed, and steady
    improvements in protein expression technology can hav...

  1. Test of 259 serums from patients with arthritis or neurological symptoms confirmed existence of Lyme disease in Hainan province, China

    PubMed Central

    Zhang, Lin; Zhu, Xiong; Hou, Xuexia; Geng, Zhen; Chen, Hai; Hao, Qin

    2015-01-01

    Indirect Fluorescent-Antibody Test (IFA), Western Blot (WB) and Nested-PCR were applied to identify the Borrelia burgdorferi in human serum samples in Hainan province. A total of 259 serum samples were collected from Sanya Peoples’ Hospital, Hainan province. These samples were examined for the presence of B. burgdorferi serologically and etiologically by the two tier tests (IFA and WB) and Nested-PCR. 43 in total of 259 serum samples were tested positive by IFA assay, the positive rate was 16.6%. Among 43 IFA-positive samples, 6 were identified positive by WB. Nested-PCR were also used to test B. burgdorferi DNA in 259 serum samples at the same time, 27 samples were tested positive with positive rate of 10.42%. It is the first time to confirm that there are Lyme patients in Hainan province of China. The study suggested that Lyme disease should be commonly considered by clinicians with the patients who had correlated symptoms with lyme disease in Hainan. PMID:26309619

  2. Melatonin and human mitochondrial diseases

    PubMed Central

    Sharafati-Chaleshtori, Reza; Shirzad, Hedayatollah; Rafieian-Kopaei, Mahmoud; Soltani, Amin

    2017-01-01

    Mitochondrial dysfunction is one of the main causative factors in a wide variety of complications such as neurodegenerative disorders, ischemia/reperfusion, aging process, and septic shock. Decrease in respiratory complex activity, increase in free radical production, increase in mitochondrial synthase activity, increase in nitric oxide production, and impair in electron transport system and/or mitochondrial permeability are considered as the main factors responsible for mitochondrial dysfunction. Melatonin, the pineal gland hormone, is selectively taken up by mitochondria and acts as a powerful antioxidant, regulating the mitochondrial bioenergetic function. Melatonin increases the permeability of membranes and is the stimulator of antioxidant enzymes including superoxide dismutase, glutathione peroxidase, glutathione reductase, and catalase. It also acts as an inhibitor of lipoxygenase. Melatonin can cause resistance to oxidation damage by fixing the microsomal membranes. Melatonin has been shown to retard aging and inhibit neurodegenerative disorders, ischemia/reperfusion, septic shock, diabetes, cancer, and other complications related to oxidative stress. The purpose of the current study, other than introducing melatonin, was to present the recent findings on clinical effects in diseases related to mitochondrial dysfunction including diabetes, cancer, gastrointestinal diseases, and diseases related to brain function.

  3. Cis-regulatory mutations in human disease

    PubMed Central

    2009-01-01

    Cis-acting regulatory sequences are required for the proper temporal and spatial control of gene expression. Variation in gene expression is highly heritable and a significant determinant of human disease susceptibility. The diversity of human genetic diseases attributed, in whole or in part, to mutations in non-coding regulatory sequences is on the rise. Improvements in genome-wide methods of associating genetic variation with human disease and predicting DNA with cis-regulatory potential are two of the major reasons for these recent advances. This review will highlight select examples from the literature that have successfully integrated genetic and genomic approaches to uncover the molecular basis by which cis-regulatory mutations alter gene expression and contribute to human disease. The fine mapping of disease-causing variants has led to the discovery of novel cis-acting regulatory elements that, in some instances, are located as far away as 1.5 Mb from the target gene. In other cases, the prior knowledge of the regulatory landscape surrounding the gene of interest aided in the selection of enhancers for mutation screening. The success of these studies should provide a framework for following up on the large number of genome-wide association studies that have identified common variants in non-coding regions of the genome that associate with increased risk of human diseases including, diabetes, autism, Crohn's, colorectal cancer, and asthma, to name a few. PMID:19641089

  4. Cis-regulatory mutations in human disease.

    PubMed

    Epstein, Douglas J

    2009-07-01

    Cis-acting regulatory sequences are required for the proper temporal and spatial control of gene expression. Variation in gene expression is highly heritable and a significant determinant of human disease susceptibility. The diversity of human genetic diseases attributed, in whole or in part, to mutations in non-coding regulatory sequences is on the rise. Improvements in genome-wide methods of associating genetic variation with human disease and predicting DNA with cis-regulatory potential are two of the major reasons for these recent advances. This review will highlight select examples from the literature that have successfully integrated genetic and genomic approaches to uncover the molecular basis by which cis-regulatory mutations alter gene expression and contribute to human disease. The fine mapping of disease-causing variants has led to the discovery of novel cis-acting regulatory elements that, in some instances, are located as far away as 1.5 Mb from the target gene. In other cases, the prior knowledge of the regulatory landscape surrounding the gene of interest aided in the selection of enhancers for mutation screening. The success of these studies should provide a framework for following up on the large number of genome-wide association studies that have identified common variants in non-coding regions of the genome that associate with increased risk of human diseases including, diabetes, autism, Crohn's, colorectal cancer, and asthma, to name a few.

  5. Addressing the burden of mental, neurological, and substance use disorders: key messages from Disease Control Priorities, 3rd edition.

    PubMed

    Patel, Vikram; Chisholm, Dan; Parikh, Rachana; Charlson, Fiona J; Degenhardt, Louisa; Dua, Tarun; Ferrari, Alize J; Hyman, Steve; Laxminarayan, Ramanan; Levin, Carol; Lund, Crick; Medina Mora, María Elena; Petersen, Inge; Scott, James; Shidhaye, Rahul; Vijayakumar, Lakshmi; Thornicroft, Graham; Whiteford, Harvey

    2016-04-16

    The burden of mental, neurological, and substance use (MNS) disorders increased by 41% between 1990 and 2010 and now accounts for one in every 10 lost years of health globally. This sobering statistic does not take into account the substantial excess mortality associated with these disorders or the social and economic consequences of MNS disorders on affected persons, their caregivers, and society. A wide variety of effective interventions, including drugs, psychological treatments, and social interventions, can prevent and treat MNS disorders. At the population-level platform of service delivery, best practices include legislative measures to restrict access to means of self-harm or suicide and to reduce the availability of and demand for alcohol. At the community-level platform, best practices include life-skills training in schools to build social and emotional competencies. At the health-care-level platform, we identify three delivery channels. Two of these delivery channels are especially relevant from a public health perspective: self-management (eg, web-based psychological therapy for depression and anxiety disorders) and primary care and community outreach (eg, non-specialist health worker delivering psychological and pharmacological management of selected disorders). The third delivery channel, hospital care, which includes specialist services for MNS disorders and first-level hospitals providing other types of services (such as general medicine, HIV, or paediatric care), play an important part for a smaller proportion of cases with severe, refractory, or emergency presentations and for the integration of mental health care in other health-care channels, respectively. The costs of providing a significantly scaled up package of specified cost-effective interventions for prioritised MNS disorders in low-income and lower-middle-income countries is estimated at US$3-4 per head of population per year. Since a substantial proportion of MNS disorders run a

  6. Preclinical