Chronic Cerebrospinal Venous Insufficiency in Multiple Sclerosis: Fact or Fiction{exclamation_point}? Comment on Dr. Jim Reeker's Reply
No abstract prepared.
62 RADIOLOGY AND NUCLEAR MEDICINE↗
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Systematic review of risk of SARS-CoV-2 infection and severity of COVID-19 with therapies approved to treat multiple sclerosis
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Neurosciences & Neurology↗
Increased postural sway in persons with multiple sclerosis during short-term exposure to warm ambient temperatures
Not Available
Poh, Paula Y. S.↗
Novel animal model of multiple sclerosis: The glial connexin gap junction as an environmental tuner for neuroinflammation
Abstract Connexins, which comprise gap junctions (GJs) via homotypic/heterotypic oligomerization, act as channels to connect opposing cells, mainly in solid organs such as the skin, liver, heart, and central/peripheral nervous system. Connexins are synthesized in the endoplasmic reticulum, assembled in the Golgi apparatus as hexamers, and inserted into the cell membrane as hemichannels. These hemichannels are closed under normal conditions until they combine to form clusters and connect to neighboring cells via GJs in a head‐to‐head configuration. Opening of hemichannels, which depends on the intra‐ or extracellular environment, allows various bioactive molecules to enter into or be released from the host cells. Recent pathological studies on human demyelinating diseases have revealed alterations of connexin expression patterns in demyelinating lesions. To elucidate the molecular mechanisms of connexins in the pathomechanisms of inflammatory demyelination, we induced experimental autoimmune encephalomyelitis (EAE) in connexin 30 (Cx30)‐deficient mice, oligodendroglia‐specific Cx47‐ablated mice, and astroglia‐specific Cx43‐ablated mice. We found that both astroglial‐Cx30‐deficient mice and Cx43‐ablated mice showed amelioration of the clinical course of EAE, while oligodendroglial‐Cx47‐ablated mice showed aggravation. These findings indicate the distinct role of connexins expressed in different cell types and the substantial contribution of connexin‐mediated pathology to demyelinating disorders. The imbalance in connexin expression, which is caused by the inflammatory environment, results in an increase in hemichannels in glial cells. The release of proinflammatory molecules induced by the increase in hemichannels on activated glial cells is a crucial mechanism of demyelinating disorders.
Yamasaki, Ryo↗
Correction: Tran et al. Delayed Maturation of Oligodendrocyte Progenitors by Microgravity: Implications for Multiple Sclerosis and Space Flight. Life 2022, 12, 797
Explore the source record for details and available documents.
Victoria Tran↗
Sequence similarity between SARS-CoV-2 nucleocapsid and multiple sclerosis-associated proteins provides insight into viral neuropathogenesis following infection
Abstract The novel coronavirus SARS-CoV-2 continues to cause death and disease throughout the world, underscoring the necessity of understanding the virus and host immune response. From the start of the pandemic, a prominent pattern of central nervous system (CNS) pathologies, including demyelination, has emerged, suggesting an underlying mechanism of viral mimicry to CNS proteins. We hypothesized that immunodominant epitopes of SARS-CoV-2 share homology with proteins associated with multiple sclerosis (MS). Using PEPMatch, a newly developed bioinformatics package which predicts peptide similarity within specific amino acid mismatching parameters consistent with published MHC binding capacity, we discovered that nucleocapsid protein shares significant overlap with 22 MS-associated proteins, including myelin proteolipid protein (PLP). Further computational evaluation demonstrated that this overlap may have critical implications for T cell responses in MS patients and is likely unique to SARS-CoV-2 among the major human coronaviruses. Our findings substantiate the hypothesis of viral molecular mimicry in the pathogenesis of MS and warrant further experimental exploration.
60 APPLIED LIFE SCIENCES↗
Biomedical Use of Aerospace Personal Cooling Garments
Personal thermoregulatory systems are required during extravehicular activity (EVA) to remove the metabolic heat generated by the suited astronaut. The Extravehicular and Protective Systems (STE) Branch of NASA Ames Research Center has developed advanced concepts or liquid cooling garments for both industrial and biomedical applications for the past 25 years. Examples of this work include: (1) liquid cooled helmets for helicopter pilots and race car drivers; (2) vests for fire and mine rescue personnel; (3) bras to increase the definition of tumors during thermography; (4) lower body garments for young women with erythomelaigia; and (5) whole body garments used by patients with multiple sclerosis (MS). The benefits of the biomedical application of artificial thermoregulation received national attention through two recent events: (1) the liquid-cooled garment technology was inducted into the United States Space Foundation's Space Technology Hall of Fame (1993); and (2) NASA has signed a joint Memorandum of Understanding with the Multiple Sclerosis Association (1994) to share this technology for use with MS patient treatment. The STE Branch is currently pursuing a program to refine thermoregulatory design in light of recent technology developments that might be applicable for use by several medical patient populations. Projects have been initiated to apply thermoregulatory technology for the treatment and/or rehabilitation of patients with spinal cord injuries, multiple sclerosis, migraine headaches, and to help prevent the loss of hair during chemotherapy.
Webbon, Bruce W.↗
Threshold selection for classification of MR brain images by clustering method
Given a grey-intensity image, our method detects the optimal threshold for a suitable binarization of MR brain images. In MR brain image processing, the grey levels of pixels belonging to the object are not substantially different from the grey levels belonging to the background. Threshold optimization is an effective tool to separate objects from the background and further, in classification applications. This paper gives a detailed investigation on the selection of thresholds. Our method does not use the well-known method for binarization. Instead, we perform a simple threshold optimization which, in turn, will allow the best classification of the analyzed images into healthy and multiple sclerosis disease. The dissimilarity (or the distance between classes) has been established using the clustering method based on dendrograms. We tested our method using two classes of images: the first consists of 20 T2-weighted and 20 proton density PD-weighted scans from two healthy subjects and from two patients with multiple sclerosis. For each image and for each threshold, the number of the white pixels (or the area of white objects in binary image) has been determined. These pixel numbers represent the objects in clustering operation. The following optimum threshold values are obtained, T = 80 for PD images and T = 30 for T2w images. Each mentioned threshold separate clearly the clusters that belonging of the studied groups, healthy patient and multiple sclerosis disease.
71 CLASSICAL AND QUANTUM MECHANICS, GENERAL PHYSIC↗
Butylphthalide ameliorates experimental autoimmune encephalomyelitis by suppressing PGAM5-induced necroptosis and inflammation in microglia
Highlights: • The Dl-3-n-butylphthalide ameliorates the disease severity of multiple sclerosis. • Necroptosis and inflammation play important roles in the function of NBP on EAE. • PGAM5 functions as a key mediator for the protective role of NBP on the progression of EAE. Multiple sclerosis (MS) is a long-lasting autoimmune disease of the central nervous system. Currently, the etiology of MS is not known. Experimental autoimmune encephalomyelitis (EAE), has been recognized as the most widely used animal models to study the molecular mechanisms underlying MS and the efficacy of potential drugs for treatment of MS. In the present study, we found that Dl-3-n-butylphthalide (NBP), a neuroprotective drug in ischemic brain injury, prevented development of disease in experimental autoimmune encephalomyelitis (EAE) and significantly reduced inflammatory factors and necroptosis-associated genes, including PGAM5 in the spinal cord tissues. Similarly, silence of PGAM5 in spinal cord also ameliorated the disease severity in the mice with EAE. Moreover, re-expression of PGAM5 counteracted the protective effect of NBP on the pathogenesis of EAE. Importantly, we found that both NBP and silence of PGAM5 inhibited cellular necroptosis and inflammation in microglia induced by TNFα plus zVAD-fmk. Meanwhile, overexpression of PGAM5 reactivated cellular necroptosis and inflammation suppressed by NBP in vitro. Taken together, our findings provide evidence that NBP can attenuate the progression of EAE by suppressing PGAM5-induced necroptosis and inflammation in microglia and represents a new therapeutic strategy for treating autoimmune diseases.
60 APPLIED LIFE SCIENCES↗
New Help for MS Patients
The Mark VII MicroClimate Medical Personal Cooling system enables multiple sclerosis' victims, as well as cerebral palsy, spinabifida patients and others to lower their body temperatures. Although this is not a cure, cooling can produce a dramatic improvement in symptoms. The Multiple Sclerosis Association of America has placed cool suits in MS research care centers. This technology originated in the need for cooling systems in spa@esuits. "Cool Suits" are now used by hazardous materials workers, armored vehicle crews, firefighters and crop dusters. A surgical personal cooling system has also been developed for medical personnel working in hot operating room environments.
Source record↗
Association between environmental exposure to pesticides and neurodegenerative diseases
Preliminary studies have shown associations between chronic pesticide exposure in occupational settings and neurological disorders. However, data on the effects of long-term non-occupational exposures are too sparse to allow any conclusions. This study examines the influence of environmental pesticide exposure on a number of neuropsychiatric conditions and discusses their underlying pathologic mechanisms. An ecological study was conducted using averaged prevalence rates of Alzheimer's disease, Parkinson's disease, multiple sclerosis, cerebral degeneration, polyneuropathies, affective psychosis and suicide attempts in selected Andalusian health districts categorized into areas of high and low environmental pesticide exposure based on the number of hectares devoted to intensive agriculture and pesticide sales per capita. A total of 17,429 cases were collected from computerized hospital records (minimum dataset) between 1998 and 2005. Prevalence rates and the risk of having Alzheimer's disease, Parkinson's disease, multiple sclerosis and suicide were significantly higher in districts with greater pesticide use as compared to those with lower pesticide use. The multivariate analyses showed that the population living in areas with high pesticide use had an increased risk for Alzheimer's disease and suicide attempts and that males living in these areas had increased risks for polyneuropathies, affective disorders and suicide attempts. In conclusion, this study supports and extends previous findings and provides an indication that environmental exposure to pesticides may affect the human health by increasing the incidence of certain neurological disorders at the level of the general population. -- Highlights: Black-Right-Pointing-Pointer Environmental exposure to pesticides and neurodegenerative-psychiatric disorders. Black-Right-Pointing-Pointer Increased risk for Alzheimer's disease and suicide attempts in high exposure areas. Black-Right-Pointing-Pointer Males from areas with high pesticide exposure had a higher risk of polyneuropathy. Black-Right-Pointing-Pointer Males from high exposure areas had a higher risk of affective psychosis and suicide. Black-Right-Pointing-Pointer Nerve tissue degeneration due to oxidative damage may underlie the pathomechanism.
60 APPLIED LIFE SCIENCES↗
Drosophila Evi5 is a critical regulator of intracellular iron transport via transferrin and ferritin interactions
Abstract Vesicular transport is essential for delivering cargo to intracellular destinations. Evi5 is a Rab11-GTPase-activating protein involved in endosome recycling. In humans, Evi5 is a high-risk locus for multiple sclerosis, a debilitating disease that also presents with excess iron in the CNS. In insects, the prothoracic gland (PG) requires entry of extracellular iron to synthesize steroidogenic enzyme cofactors. The mechanism of peripheral iron uptake in insect cells remains controversial. We show that Evi5-depletion in the Drosophila PG affected vesicle morphology and density, blocked endosome recycling and impaired trafficking of transferrin-1, thus disrupting heme synthesis due to reduced cellular iron concentrations. We show that ferritin delivers iron to the PG as well, and interacts physically with Evi5. Further, ferritin-injection rescued developmental delays associated with Evi5-depletion. To summarize, our findings show that Evi5 is critical for intracellular iron trafficking via transferrin-1 and ferritin, and implicate altered iron homeostasis in the etiology of multiple sclerosis.
59 BASIC BIOLOGICAL SCIENCES↗
Hemodynamic and thermal responses to head and neck cooling in men and women
Personal cooling systems are used to alleviate symptoms of multiple sclerosis and to prevent increased core temperature during daily activities. The objective of this study was to determine the operating characteristics and the physiologic changes produced by short term use of one commercially available thermal control system. A Life Support Systems, Inc. Mark VII portable cooling system and a liquid cooling helmet were used to cool the head and neck regions of 12 female and 12 male subjects (25-55 yr) in this study. The healthy subjects, seated in an upright position at normal room temperature (approximately 21 degrees C), were tested for 30 min with the liquid cooling garment operated at its maximum cooling capacity. Electrocardiograms and scalp and intracranial blood flows were recorded periodically during each test sequence. Scalp, right and left ear, and oral temperatures and cooling system parameters were logged every 5 min. Scalp, right and left ear canal, and oral temperatures were all significantly (P <0.05) reduced by 30 min of head and neck cooling. Oral temperatures decreased approximately 0.2-0.6 degrees C after 30 min and continued to decrease further (approximately 0.1-0.2 degrees C) for a period of approximately 10 min after removal of the cooling helmet. Intracranial blood flow decreased significantly (P < 0.05) during the first 10 min of the cooling period. Both right and left ear temperatures in the women were significantly lower than those of the men during the cooling period. These data indicate that head and neck cooling may be used to reduce core temperature to that needed for symptomatic relief of both male and female multiple sclerosis patients. This study quantifies the operating characteristics of one liquid cooling garment as an example of the information needed to compare the efficiency of other garments operated under different test conditions.
NASA Center ARC↗
In silico pharmacogenetic approach: The natalizumab case study
Natalizumab is a humanized monoclonal antibody to α{sub 4}β{sub 1} integrin and is approved for the treatment of Multiple Sclerosis. In patients there is a great variation in drug response and there is much evidence that genetic contributors play an important role in defining an individual's susceptibility. Natalizumab binds to α{sub 4}-residues Gln-152, Lys-201, Lys256, and these seem to be essential for its activity. Studies on a range of species in disease model have showed a loss of reactivity when any one of those three residues were different to human. Based on these animal studies, we thought that the single nucleotide polymorphism in the ITGA4 human gene causing a lysine to arginine transversion at amino acid position 256 require further investigations in the context of individual drug susceptibility. So, the aim of our study was to investigate the association between this genetic polymorphism and the resistance to natalizumab. We had applied molecular dynamics simulation to study the possible conformational changes induced by Lys256Arg transversion on the overall structure of integrin and we have analyzed the binding affinities of natalizumab in the non-mutated and mutated structures through HINT score. We found that this SNP does not affect the VLA4-natalizumab interaction. Instead, the binding affinities are slightly higher in the mutated complex than in the wild-type. We reported one of the first work in which MD simulation was applied in the pharmacogenetic context, and this approach is rapid and cost effective, since a population survey is carried out only after the positive prediction of simulation. - Highlights: • Untraditional computational approach to discover drugs mechanisms of action (MOA) in pharmacogenetic • Molecular dynamics to predict protein-monoclonal antibody complexes for multiple sclerosis • Computational prediction of mutation behavior to determine or not a human population survey.
60 APPLIED LIFE SCIENCES↗
Learning epistatic polygenic phenotypes with Boolean interactions
Detecting epistatic drivers of human phenotypes is a considerable challenge. Traditional approaches use regression to sequentially test multiplicative interaction terms involving pairs of genetic variants. For higher-order interactions and genome-wide large-scale data, this strategy is computationally intractable. Moreover, multiplicative terms used in regression modeling may not capture the form of biological interactions. Building on the Predictability, Computability, Stability (PCS) framework, we introduce the epiTree pipeline to extract higher-order interactions from genomic data using tree-based models. The epiTree pipeline first selects a set of variants derived from tissue-specific estimates of gene expression. Next, it uses iterative random forests (iRF) to search training data for candidate Boolean interactions (pairwise and higher-order). We derive significance tests for interactions, based on a stabilized likelihood ratio test, by simulating Boolean tree-structured null (no epistasis) and alternative (epistasis) distributions on hold-out test data. Finally, our pipeline computes PCS epistasis p-values that probabilisticly quantify improvement in prediction accuracy via bootstrap sampling on the test set. We validate the epiTree pipeline in two case studies using data from the UK Biobank: predicting red hair and multiple sclerosis (MS). In the case of predicting red hair, epiTree recovers known epistatic interactions surrounding MC1R and novel interactions, representing non-linearities not captured by logistic regression models. In the case of predicting MS, a more complex phenotype than red hair, epiTree rankings prioritize novel interactions surrounding HLA-DRB1 , a variant previously associated with MS in several populations. Taken together, these results highlight the potential for epiTree rankings to help reduce the design space for follow up experiments.
59 BASIC BIOLOGICAL SCIENCES↗
Pathogenic implications of distinct patterns of iron and zinc in chronic MS lesions
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) in which oligodendrocytes, the CNS cells that stain most robustly for iron and myelin are the targets of injury. Metals are essential for normal CNS functioning, and metal imbalances have been linked to demyelination and neurodegeneration. Using a multidisciplinary approach involving synchrotron techniques, iron histochemistry and immunohistochemistry, we compared the distribution and quantification of iron and zinc in MS lesions to the surrounding normal appearing and periplaque white matter, and assessed the involvement of these metals in MS lesion pathogenesis. We found that the distribution of iron and zinc is heterogeneous in MS plaques, and with few remarkable exceptions they do not accumulate in chronic MS lesions. We show that brain iron tends to decrease with increasing age and disease duration of MS patients; reactive astrocytes organized in large astrogliotic areas in a subset of smoldering and inactive plaques accumulate iron and safely store it in ferritin; a subset of smoldering lesions do not contain a rim of iron-loaded macrophages/microglia; and the iron content of shadow plaques varies with the stage of remyelination. Zinc in MS lesions was generally decreased, paralleling myelin loss. Iron accumulates concentrically in a subset of chronic inactive lesions suggesting that not all iron rims around MS lesions equate with smoldering plaques. Furthermore, upon degeneration of iron-loaded microglia/macrophages, astrocytes may form an additional protective barrier that may prevent iron-induced oxidative damage.
59 BASIC BIOLOGICAL SCIENCES↗
A potent and selective C-11 labeled PET tracer for imaging sphingosine-1-phosphate receptor 2 in the CNS demonstrates sexually dimorphic expression
Sphingosine-1-phosphate receptor 2 (S1PR2) plays an essential role in regulating blood–brain barrier (BBB) function during demyelinating central nervous system (CNS) disease. Increased expression of S1PR2 occurs in disease-susceptible CNS regions of female versus male SJL mice and in female multiple sclerosis (MS) patients. Here we reported a novel sensitive and noninvasive method to quantitatively assess S1PR2 expression using a C-11 labeled positron emission tomography (PET) radioligand [ 11 C]5a for in vivo imaging of S1PR2. Compound 5a exhibited promising binding potency with IC 50 value of 9.52 ± 0.70 nM for S1PR2 and high selectivity over S1PR1 and S1PR3 (both IC 50 > 1000 nM). [ 11 C]5a was synthesized in ~40 min with radiochemistry yield of 20 ± 5% (decayed to the end of bombardment (EOB), n > 10), specific activity of 222–370 GBq μmol –1 (decayed to EOB). The biodistribution study in female SJL mice showed the cerebellar uptake of radioactivity at 30 min of post-injection of [11C]5a was increased by Cyclosporin A (CsA) pretreatment (from 0.84 ± 0.04 ID% per g to 2.21 ± 0.21 ID% per g, n = 4, p < 0.01). MicroPET data revealed that naive female SJL mice exhibited higher cerebellar uptake compared with males following CsA pretreatment (standardized uptake values (SUV) 0.58 ± 0.16 vs. 0.48 ± 0.12 at 30 min of post-injection, n = 4, p < 0.05), which was consistent with the autoradiographic results. This data suggested that [ 11 C]5a had the capability in assessing the sexual dimorphism of S1PR2 expression in the cerebellum of the SJL mice. Furthermore, the development of radioligands for S1PR2 to identify a clinical suitable S1PR2 PET radiotracer, may greatly contribute to investigating sex differences in S1PR2 expression that contribute to MS subtype and disease progression and it will be very useful for detecting MS in early state and differentiating MS with other patients with neuroinflammatory diseases, and monitoring the efficacy of treating diseases using S1PR2 antagonism.
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
Discovery and Lead-Optimization of 4,5-Dihydropyrazoles as Mono-Kinase Selective, Orally Bioavailable and Efficacious Inhibitors of Receptor Interacting Protein 1 (RIP1) Kinase
RIP1 kinase regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including inflammatory and neurological diseases. Currently, RIP1 kinase inhibitors have advanced into early clinical trials for evaluation in inflammatory diseases such as psoriasis, rheumatoid arthritis, and ulcerative colitis and neurological diseases such as amyotrophic lateral sclerosis and Alzheimer’s disease. Here, we report on the design of potent and highly selective dihydropyrazole (DHP) RIP1 kinase inhibitors starting from a high-throughput screen and the lead-optimization of this series from a lead with minimal rat oral exposure to the identification of dihydropyrazole 77 with good pharmacokinetic profiles in multiple species. Additionally, we identified a potent murine RIP1 kinase inhibitor 76 as a valuable in vivo tool molecule suitable for evaluating the role of RIP1 kinase in chronic models of disease. DHP 76 showed efficacy in mouse models of both multiple sclerosis and human retinitis pigmentosa.
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗