Polyunsaturated fatty acids in the pathogenesis and treatment of multiple sclerosis

Epidemiological, biochemical, animal model and clinical trial data described in this overview strongly suggest that polyunsaturated fatty acids, particularly n-6 fatty acids, have a role in the pathogenesis and treatment of multiple sclerosis (MS). Data presented provides further evidence for a disturbance in n-6 fatty acid metabolism in MS. Disturbance of n-6 fatty acid metabolism and dysregulation of cytokines are shown to be linked and a "proof of concept clinical trial" further supports such a hypothesis. In a randomised double-blind, placebo controlled trial of a high dose and low dose selected GLA (18:3n-6)-rich oil and placebo control, the high dose had a marked clinical effect in relapsing-remitting MS, significantly decreasing the relapse rate and the progression of disease. Laboratory findings paralleled clinical changes in the placebo group in that production of mononuclear cell pro-inflammatory cytokines (TNF-alpha, IL-1 beta) was increased and anti-inflammatory TGF-beta markedly decreased with loss of membrane n-6 fatty acids linoleic (18:2n-6) and arachidonic acids (20:4n-6). In contrast there were no such changes in the high dose group. The improvement in disability (Expanded Disability Status Scale) in the high dose suggests there maybe a beneficial effect on neuronal lipids and neural function in MS. Thus disturbed n-6 fatty acid metabolism in MS gives rise to loss of membrane long chain n-6 fatty acids and loss of the anti-inflammatory regulatory cytokine TGF-beta, particularly during the relapse phase, as well as loss of these important neural fatty acids for CNS structure and function and consequent long term neurological deficit in MS.

Monitorización de la temperatura del pie como herramienta en la neuropatía diabética

Objteivo: Valorar si existe relación entre el aumento de temperatura en el pie y la neuropatía diabética periférica. Métodos: La muestra fueron 27 pacientes diabéticos a que se le realizó una exploración neurológica y vascular, además, haciendo uso de un termómetro infrarrojo medimos la temperatura en distintos puntos anatómicos de la planta del pie. Resultados: La temperatura es mayor los pacientes con neuropatía con una diferencia de 2,24ºC (p=0,454) en el pie derecho y 0,86ºC (p=0,589) en el pie izquierdo. Conclusión: Los resultados sugieren que la automonitorización de la temperatura del pie por parte del paciente diabético podría ayudar a reducir la alta incidencia de complicaciones en el pie diabético.

Tight junctional abnormality in multiple sclerosis white matter affects all calibres of vessel and is associated with blood-brain barrier leakage and active demyelination

Blood-brain barrier (BBB) hyperpermeability in multiple sclerosis (MS) is associated with lesion pathogenesis and has been linked to pathology in microvascular tight junctions (TJs). This study quantifies the uneven distribution of TJ pathology and its association with BBB leakage. Frozen sections from plaque and normal-appearing white matter (NAWM) in 14 cases were studied together with white matter from six neurological and five normal controls. Using single and double immunofluorescence and confocal microscopy, the TJ-associated protein zonula occludens-1 (ZO-1) was examined across lesion types and tissue categories, and in relation to fibrinogen leakage. Confocal image data sets were analysed for 2198 MS and 1062 control vessels. Significant differences in the incidence of TJ abnormalities were detected between the different lesion types in MS and between MS and control white matter. These were frequent in oil-red O (ORO)+ active plaques, affecting 42% of vessel segments, but less frequent in ORO- inactive plaques (23%), NAWM (13%), and normal (3.7%) and neurological controls (8%). A similar pattern was found irrespective of the vessel size, supporting a causal role for diffusible inflammatory mediators. In both NAWM and inactive lesions, dual labelling showed that vessels with the most TJ abnormality also showed most fibrinogen leakage. This was even more pronounced in active lesions, where 41% of vessels in the highest grade for TJ alteration showed severe leakage. It is concluded that disruption of TJs in MS, affecting both paracellular and transcellular paths, contributes to BBB leakage. TJ abnormality and BBB leakage in inactive lesions suggests either failure of TJ repair or a continuing pathological process. In NAWM, it suggests either pre-lesional change or secondary damage. Clinically inapparent TJ pathology has prognostic implications and should be considered when planning disease-modifying therapy

COGNITIVE ASSESSMENT USING THE KINARM EXOSKELETON ROBOT IN PATIENTS WITH TRANSIENT ISCHEMIC ATTACK

Background: Transient ischemic attack (TIA) is a condition causing focal neurological deficits lasting less than 24hrs. TIA patients present similarly to other conditions with rapid onset of neurological symptoms such as migraine. The accurate diagnosis of TIA is critical because it serves as a warning for subsequent stroke. Furthermore, cognitive deficit associated with TIA may predict the development of dementia. Therefore, characterizing the cognitive symptoms of TIA patients and discriminating these patients from those with similar symptoms is important for proper diagnosis and treatment. Currently the diagnosis of TIA is made on clinical and radiographic evidence. Robotic assessment, with instruments such as the KINARM, may improve the identification of cognitive impairment in TIA patients. Methods: In this prospective cohort study, two KINARM tests, trail making task (TMT) and spatial span task (SST), were used to detect cognitive deficits. Two study groups were made. The TIA group was tested at 5 time points over the span of a year. The migraine active control group had one initial visit and another a year later. Both of these groups were compared to a normative database of approximately 400 healthy volunteers. From this database age and sex matched normative data was used to calculate Z-scores for the TMT. The Montreal Cognitive Assessment (MoCA) was also administered to both groups. Results: 31 participants were recruited, 20 TIA group and 11 active controls (mean ± SD age= 66 ± 11.3 and 62 ± 14.5). There was no significant difference in TIA and active control group MoCA scores. The TMT was able to detect cognitive impairment in TIA and migraine group. Also, both KINARM tasks could detect significant differences in performance between TIA and migraine patients while the MoCA could not. Changes in TIA and migraine performance on the MoCA, TMT, and SST were observed. Conclusions: The robotic KINARM exoskeleton can be used to assess cognitive deficits in TIA patients.

Lifestyle limitations of children and young people with severe cerebral palsy: a population study protocol

Aim.  This paper is a presentation of a study protocol to establish the prevalence of orthopaedic problems (hip dislocation, pelvic obliquity, spinal deformity and contractures) and their impact on pain, function, participation and health in a population of children and young people with severe cerebral palsy.

Background.  Cerebral palsy is the commonest cause of motor impairment in childhood and is associated with life-long disability. An estimated 30% of people with cerebral palsy have severe forms and are non-ambulant. Although the underlying neurological damage is not amenable to correction, many health services are dedicated to providing therapeutic and adaptive support to help people with the condition reach their potential.

Method.  A cross-sectional survey of children and young people, aged 4–25 years with severe, non-ambulant cerebral palsy as defined using the Gross Motor Function Classification System (Levels IV and V). Study participants will be identified from a pre-existing, geographically defined case register and recruited via a healthcare professional known to them. Two assessments will be undertaken: one involving parents/carers at home and using questionnaires; the other involving the child/young person ideally in one of three settings and including X-rays if clinically indicated.

Discussion.  This study will contribute to our knowledge of the history and epidemiology of orthopaedic problems in children and young people with cerebral palsy and how these problems accumulate and impact on participation, health and well-being. The study will also identify unmet need and make recommendations for good practice in relation to the orthopaedic care and management for people with severe cerebral palsy

Abnormal integrity of association fiber tracts in amnestic mild cognitive impairment.

The association fiber tracts integrity of the inter-hemispheric and within-hemispheric communication was poor understood in amnestic type mild cognitive impairment (aMCI) patients by diffusion tensor imaging (DTI). A region of interest-based DTI approach was applied to explore fiber tract differences between 22 aMCI patients and 22 well-matched normal aging. Correlations were also sought between fractional anisotropy (FA) values and the cognitive performance scores in the aMCI patients. Extensive impairment of association fiber tracts integrity was observed in aMCI patients, including bilateral inferior fronto-occipital fascicles, the genu of corpus callosum, bilateral cingulate bundles and bilateral superior longitudinal fascicles II (SLE II) subcomponent. In addition, the FA value of right SLE II was significantly negatively correlated to the performance of Trail Making Test A and B, whilst the values of right posterior cingulate bundle was significantly positive correlation with MMSE score. As aMCI is a putative prodromal syndrome to Alzheimer's disease (AD), this study suggested that investigation of association fiber tracts between remote cortexes may yield important new data to predict whether a patient will eventually develop AD.

Recessive congenital methaemoglobinaemia: cytochrome b(5) reductase deficiency

Some 60 years ago, Quentin Gibson reported the first hereditary disorder involving an enzyme when he deduced that familial methaemoglobinaemia was caused by an enzymatic lesion associated with the glycolysis pathway in red blood cells. This disorder, now known as recessive congenital methaemoglobinaemia (RCM), is caused by NADH-cytochrome b5 reductase (cb(5)r) deficiency. Two distinct clinical forms, types I and II, have been recognized, both characterized by cyanosis from birth. In type II, the cyanosis is accompanied by neurological impairment and reduced life expectancy. Cytochrome b(5) reductase is composed of one FAD and one NADH binding domain linked by a hinge region. It is encoded by the CYB5R3 (previously known as DIA1) gene and more than 40 mutations have been described, some of which are common to both types of RCM. Mutations associated with type II tend to cause incorrect splicing, disruption of the active site or truncation of the protein. At present the description of the sequence variants of cb(5)r in the literature is confusing, due to the use of two conventions which differ by one codon position. Herein we propose a new system for nomenclature of cb(5)r based on recommendations of the Human Genome Variation Society. The development of a heterologous expression system has allowed the impact of naturally occurring variants of cb(5)r to be assessed and has provided insight into the function of cb(5)r.

Pathophysiology of anemia and erythrocytosis.

An increasing understanding of the process of erythropoiesis raises some interesting questions about the pathophysiology, diagnosis and treatment of anemia and erythrocytosis. The mechanisms underlying the development of many of the erythrocytoses, previously characterised as idiopathic, have been elucidated leading to an increased understanding of oxygen homeostasis. Characterisation of anemia and erythrocytosis in relation to serum erythropoietin levels can be a useful addition to clinical diagnostic criteria and provide a rationale for treatment with erythropoiesis stimulating agents (ESAs). Recombinant human erythropoietin as well as other ESAs are now widely used to treat anemias associated with a range of conditions, including chronic kidney disease, chronic inflammatory disorders and cancer. There is also heightened awareness of the potential abuse of ESAs to boost athletic performance in competitive sport. The discovery of erythropoietin receptors outside of the erythropoietic compartment may herald future applications for ESAs in the management of neurological and cardiac diseases. The current controversy concerning optimal hemoglobin levels in chronic kidney disease patients treated with ESAs and the potential negative clinical outcomes of ESA treatment in cancer reinforces the need for cautious evaluation of the pleiotropic effects of ESAs in non-erythroid tissues.

Increased cerebral output of free radicals during hypoxia: implications for acute mountain sickness?

Bailey DM, Taudorf S, Berg RMG, Lundby C, McEneny J, Young IS, Evans KA, James PE, Shore A, Hullin DA, McCord JM, Pedersen BK, Moller K. Increased cerebral output of free radicals during hypoxia: implications for acute mountain sickness? Am J Physiol Regul Integr Comp Physiol 297: R1283-R1292, 2009. First published September 2, 2009; doi: 10.1152/ajpregu.00366.2009.-This study examined whether hypoxia causes free radical-mediated disruption of the blood-brain barrier (BBB) and impaired cerebral oxidative metabolism and whether this has any bearing on neurological symptoms ascribed to acute mountain sickness (AMS). Ten men provided internal jugular vein and radial artery blood samples during normoxia and 9-h passive exposure to hypoxia (12.9% O-2). Cerebral blood flow was determined by the Kety-Schmidt technique with net exchange calculated by the Fick principle. AMS and headache were determined with clinically validated questionnaires. Electron paramagnetic resonance spectroscopy and ozone-based chemiluminescence were employed for direct detection of spin-trapped free radicals and nitric oxide metabolites. Neuron-specific enolase (NSE), S100 beta, and 3-nitrotyrosine (3-NT) were determined by ELISA. Hypoxia increased the arterio-jugular venous concentration difference (a-v(D)) and net cerebral output of lipid-derived alkoxyl-alkyl free radicals and lipid hydroperoxides (P

Detecting motor abnormalities in preterm infants

As a consequence of the fragility of various neural structures, preterm infants born at a low gestation and/or birthweight are at an increased risk of developing motor abnormalities. The lack of a reliable means of assessing motor integrity prevents early therapeutic intervention. In this paper, we propose a new method of assessing neonatal motor performance, namely the recording and subsequent analysis of intraoral sucking pressures generated when feeding nutritively. By measuring the infant's control of sucking in terms of a new development of tau theory, normal patterns of intraoral motor control were established for term infants. Using this same measure, the present study revealed irregularities in sucking control of preterm infants. When these findings were compared to a physiotherapist's assessment six months later, the preterm infants who sucked irregularly were found to be delayed in their motor development. Perhaps a goal-directed behaviour such as sucking control that can be measured objectively at a very young age, could be included as part of the neurological assessment of the preterm infant. More accurate classification of a preterm infant's movement abnormalities would allow for early therapeutic interventions to be realised when the infant is still acquiring the most basic of motor functions. (C) Springer-Verlag 2000.

The use of cues for attention in ancient Greek art: aspects that influence concentration in the work of art and its elements

The goal of this study is to identify cues for the cognitive process of attention in ancient Greek art, aiming to find confirmation of its possible use by ancient Greek audiences and artists. Evidence of cues that trigger attention’s psychological dispositions was searched through content analysis of image reproductions of ancient Greek sculpture and fine vase painting from the archaic to the Hellenistic period - ca. 7th -1st cent. BC. Through this analysis, it was possible to observe the presence of cues that trigger orientation to the work of art (i.e. amplification, contrast, emotional salience, simplification, symmetry), of a cue that triggers a disseminate attention to the parts of the work (i.e. distribution of elements) and of cues that activate selective attention to specific elements in the work of art (i.e. contrast of elements, salient color, central positioning of elements, composition regarding the flow of elements and significant objects). Results support the universality of those dispositions, probably connected with basic competencies that are hard-wired in the nervous system and in the cognitive processes.

Repeat Stereotactic Radiosurgery for Acoustic Neuromas.

Purpose
To evaluate the outcome of repeat stereotactic radiosurgery (SRS) for acoustic neuromas, we assessed tumor control, clinical outcomes, and the risk of adverse radiation effects in patients whose tumors progressed after initial management.

Methods and Materials
During a 21-year experience at our center, 1,352 patients underwent SRS as management for their acoustic neuromas. We retrospectively identified 6 patients who underwent SRS twice for the same tumor. The median patient age was 47 years (range, 35–71 years). All patients had imaging evidence of tumor progression despite initial SRS. One patient also had incomplete surgical resection after initial SRS. All patients were deaf at the time of the second SRS. The median radiosurgery target volume at the time of the initial SRS was 0.5 cc and was 2.1 cc at the time of the second SRS. The median margin dose at the time of the initial SRS was 13 Gy and was 11 Gy at the time of the second SRS. The median interval between initial SRS and repeat SRS was 63 months (range, 25–169 months).

Results
At a median follow-up of 29 months after the second SRS (range, 13–71 months), tumor control or regression was achieved in all 6 patients. No patient developed symptomatic adverse radiation effects or new neurological symptoms after the second SRS.

Conclusions
With this limited experience, we found that repeat SRS for a persistently enlarging acoustic neuroma can be performed safely and effectively.

Oral Resveratrol Reduces Neuronal Damage in a Model of Multiple Sclerosis

Background: Neuronal loss in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), correlates with permanent neurological dysfunction. Current MS therapies have limited the ability to prevent neuronal damage. Methods: We examined whether oral therapy with SRT501, a pharmaceutical grade formulation of resveratrol, reduces neuronal loss during relapsing-remitting EAE. Resveratrol activates SIRT1, an NAD-dependent deacetylase that promotes mitochondrial function. Results: Oral SRT501 prevented neuronal loss during optic neuritis, an inflammatory optic nerve lesion in MS and EAE. SRT501 also suppressed neurological dysfunction during EAE remission, and spinal cords from SRT501-treated mice had significantly higher axonal density than vehicle-treated mice. Similar neuroprotection was mediated by SRT1720, another SIRT1-activating compound; and sirtinol, an SIRT1 inhibitor, attenuated SRT501 neuroprotective effects. SIRT1 activators did not prevent inflammation. Conclusions: These studies demonstrate that SRT501 attenuates neuronal damage and neurological dysfunction in EAE by a mechanism involving SIRT1 activation. SIRT1 activators are a potential oral therapy in MS. © 2010 by North American Neuro-Ophthalmology Society.

miR-7 and miR-214 are specifically expressed during neuroblastoma differentiation, cortical development and embryonic stem cells differentiation, and control neurite outgrowth in vitro

The mammalian nervous system exerts essential control on many physiological processes in the organism and is itself controlled extensively by a variety of genetic regulatory mechanisms. microRNA (miR), an abundant class of small non-coding RNA, are emerging as important post-transcriptional regulators of gene expression in the brain. Increasing evidence indicates that miR regulate both the development and function of the nervous system. Moreover, deficiency in miR function has also been implicated in a number of neurological disorders. Expression profile analysis of miR is necessary to understand their complex role in the regulation of gene expression during the development and differentiation of cells. Here we present a comparative study of miR expression profiles in neuroblastoma, in cortical development, and in neuronal differentiation of embryonic stem (ES) cells. By microarray profiling in combination with real time PCR we show that miR-7 and miR-214 are modulated in neuronal differentiation (as compared to miR-1, -16 and -133a), and control neurite outgrowth in vitro. These findings provide an important step toward further elucidation of miR function and miR-related gene regulatory networks in the mammalian central nervous system. (C) 2010 Elsevier Inc. All rights reserved.