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Papers by Moses Rodriguez

The Journal of Immunology

Infection of certain strains of mice with Theiler's murine encephalomyelitis virus results in... more Infection of certain strains of mice with Theiler's murine encephalomyelitis virus results in persistence of virus and an immune-mediated primary demyelination in the central nervous system that resembles multiple sclerosis. Because susceptibility/resistance to demyelination in B10 congeneic mice maps strongly to class I MHC genes (D region) we tested whether expression of a human class I MHC gene (HLA-B27) would alter susceptibility to Theiler's murine encephalomyelitis virus-induced demyelination. Transgenic HLA-B27 mice were found to co-express human and endogenous mouse class I MHC genes by flow microfluorimetry analysis of PBL. In the absence of the human transgene, H-2stf, or v mice but not H-2b mice had chronic demyelination and persistence of virus at 45 days after infection. No difference in degree of demyelination, meningeal inflammation, or virus persistence was seen between transgenic HLA-B27 and nontransgenic littermate mice of H-2f or H-2v haplotype. In contras...

Brain, 2020

Incomplete relapse recovery contributes to disability accrual and earlier onset of secondary prog... more Incomplete relapse recovery contributes to disability accrual and earlier onset of secondary progressive multiple sclerosis. We sought to investigate the effect of age on relapse recovery. We identified patients with multiple sclerosis from two longitudinal prospective studies, with an Expanded Disability Status Scale (EDSS) score within 30 days after onset of an attack, and follow-up EDSS 6 months after attack. Adult patients with multiple sclerosis (n = 632) were identified from the Comprehensive Longitudinal Investigations in Multiple Sclerosis at Brigham study (CLIMB), and paediatric patients (n = 132) from the US Network of Paediatric Multiple Sclerosis Centers (NPMSC) registry. Change in EDSS was defined as the difference in EDSS between attack and follow-up. Change in EDSS at follow-up compared to baseline was significantly lower in children compared to adults (P = 0.001), as were several functional system scores. Stratification by decade at onset for change in EDSS versus ag...

Neurology, 2020

ObjectiveTo characterize disease severity and distribution of disability in pediatric-onset multi... more ObjectiveTo characterize disease severity and distribution of disability in pediatric-onset multiple sclerosis (POMS) and to develop an optimized modeling scale for measuring disability, we performed a multicenter retrospective analysis of disability scores in 873 persons with POMS over time and compared this to previously published data in adults with multiple sclerosis (MS).MethodsThis was a retrospective analysis of prospectively collected data collected from 12 centers of the US Network of Pediatric MS Centers. Patients were stratified by the number of years from first symptoms of MS to Expanded Disability Status Scale (EDSS) assessment and an MS severity score (Pediatric Multiple Sclerosis Severity Score [Ped-MSSS]) was calculated per criteria developed by Roxburgh et al. in 2005.ResultsIn total, 873 patients were evaluated. In our cohort, 52%, 19.4%, and 1.5% of all patients at any time point reached an EDSS of 2.0, 3.0, and 6.0. Comparison of our Ped-MSSS scores and previousl...

Multiple sclerosis (Houndmills, Basingstoke, England), 2017

Strong evidence supports the role of both genetic and environmental factors in pediatric-onset mu... more Strong evidence supports the role of both genetic and environmental factors in pediatric-onset multiple sclerosis (POMS) etiology. We comprehensively investigated the association between established major histocompatibility complex (MHC) and non-MHC adult multiple sclerosis (MS)-associated variants and susceptibility to POMS. Cases with onset <18 years ( n = 569) and controls ( n = 16,251) were included from the United States and Sweden. Adjusted logistic regression and meta-analyses were performed for individual risk variants and a weighted genetic risk score (wGRS) for non-MHC variants. Results were compared to adult MS cases ( n = 7588). HLA-DRB1*15:01 was strongly associated with POMS (odds ratio (OR)meta = 2.95, p < 2.0 × 10(-16)). Furthermore, 28 of 104 non-MHC variants studied (23%) were associated ( p < 0.05); POMS cases carried, on average, a higher burden of these 28 variants compared to adults (ORavg = 1.24 vs 1.13, respectively), though the difference was not si...

Journal of neurology, neurosurgery, and psychiatry, Jan 9, 2017

The role of diet in multiple sclerosis (MS) course remains largely unknown. Children with MS have... more The role of diet in multiple sclerosis (MS) course remains largely unknown. Children with MS have a higher relapse rate compared with MS in adults. Thus, studying the effect of diet on relapse rate in this age group is likely to provide more robust answers. This is a multicentre study done at 11 paediatric MS centres in the USA. Patients with relapsing-remitting MS (RRMS) or clinically isolated syndrome (CIS) with disease onset before 18 years of age and duration of less than 4 years were included in this study. Dietary intake during the week before enrolment was assessed with the validated Block Kids Food Screener. The outcome of the study was time from enrolment to the next relapse. 219 patients with paediatric RRMS or CIS were enrolled. Each 10% increase in energy intake from fat increased the hazard of relapse by 56% (adjusted HR 1.56, 95% CI 1.05 to 2.31, p=0.027), and in particular each 10% increase in saturated fat tripled this hazard (adjusted HR: 3.37, 95% CI 1.34 to 8.43, ...

Multiple Sclerosis and Related Disorders, 2017

Kaylor assisted with the geographic information system analysis and editing of the manuscript. Ms... more Kaylor assisted with the geographic information system analysis and editing of the manuscript. Ms. Roalstad contributed to the acquisition of the data, managed the data and supervised data collection at all sites during the study, and reviewed the final manuscript.

Journal of the neurological sciences, Jan 15, 2017

Multiple sclerosis (MS) and allergies are both considered to be related to imbalanced Th1 and Th2... more Multiple sclerosis (MS) and allergies are both considered to be related to imbalanced Th1 and Th2 immune responses. Previous studies evaluating the relationship between MS and allergies provide conflicting results. To assess allergies and asthma as risk factors for MS and as predictors of MS relapses in a pediatric cohort. The environment and genetic risk factors for pediatric MS study is a national case-control project with 16 participating US sites. An environmental questionnaire is used that includes history of allergies in the first five years of life. Case-control data are entered in the pediatric MS Network database and cases at 12 of the 16 sites enter relapse data prospectively. Annualized relapse rate was calculated for patients with follow-up and adjusted for age at disease onset, gender, race, ethnicity, and use of disease-modifying therapy (DMT). We included 271 cases (mean age at disease onset of 15.7years and 62% female) and 418 controls. Relapse data were available fo...

Neurology, 2011

Background: Because common viruses are encountered during childhood, pediatric multiple sclerosis... more Background: Because common viruses are encountered during childhood, pediatric multiple sclerosis (MS) offers a unique opportunity to investigate the influence of these viruses on disease susceptibility and the interactions between seroprevalence and select HLA genotypes. We studied seroprevalence for Epstein-Barr virus (EBV), cytomegalovirus (CMV), and herpes simplex virus (HSV) type 1 and HLA-DRB1*1501/1503 status as predictors of pediatric MS. Methods: This was a retrospective analysis of prospectively collected demographic, clinical, and biologic data in subjects up to 18 years of age with early MS, control subjects seen at the same regional referral pediatric MS clinics, and additional healthy pediatric control subjects. Results: Patients with early pediatric MS (n ϭ 189) and pediatric control subjects (n ϭ 66) were tested. Epstein-Barr nuclear antigen-1 seropositivity was associated with an increased odds of MS (odds ratio [OR] 3.78, 95% confidence interval [CI] 1.52-9.38, p ϭ 0.004) in analyses adjusted for age, sex, race, ethnicity, and HLA-DRB1*1501/1503 status. In multivariate analyses including EBV status, a remote infection with CMV (OR 0.27, 95% CI 0.11-0.67, p ϭ 0.004) was associated with a lower risk of developing MS. Although a remote infection with HSV-1 was not associated with an increased odds of MS, a strong interaction was found between HSV-1 status and HLA-DRB1 in predicting MS (p Ͻ 0.001). HSV-1 was associated with an increased risk of MS in those without a DRB1*15 allele (OR 4.11, 95% CI 1.17-14.37, p ϭ 0.03), whereas the effect was reversed in those who were DRB1*15-positive (OR 0.07, 95% CI 0.02-0.32, p ϭ 0.001). Conclusions: These findings suggest that some infections with common viruses may in fact lower MS susceptibility. If this is confirmed, the pathways for risk modification remain to be elucidated.

Archives of Neurology, 2011

Background: Currently available disease-modifying therapies (DMTs) are known to be only partially... more Background: Currently available disease-modifying therapies (DMTs) are known to be only partially effective in adults with multiple sclerosis (MS). Little is known about pediatric patients with MS who experience refractory disease while receiving first-line DMTs. Objective: To assess the occurrence and management of refractory disease in a group of pediatric patients with MS treated with first-line DMTs approved for adult patients within a network of pediatric MS centers in the United States. Design, Setting, and Patients: A multicenter, retrospective, longitudinal, open-label study design involving record review of 258 patients with pediatric-onset MS (68.6% female; mean [SD] age at disease onset, 13.2 [3.5] years; range of age at onset, 2.0-17.9 years) who were seen at 6 pediatric MS centers in the United States. Intervention: We evaluated medication changes owing to refractory disease in cases of pediatric-onset MS. Main Outcome Measure: Disease stability as represented by lack of medication change for breakthrough disease. Results: Records of 258 children with a confirmed diagnosis of MS and exposure to DMTs were reviewed. Interferon beta (prescribed to 200 of 258 children [77.5%]) and glatiramer acetate (prescribed to 53 of 258 children [20.5%]) were the 2 most frequently used first-line DMTs. Overall, 144 children (55.8%) continued receiving 1 therapy, while 65 (25.2%), 29 (11.2%), and 20 (7.8%) received 2, 3, or 4 or more sequential therapies, respectively, during a mean (SD) observation period of 3.9 (2.8) years. Second-line DMT use was restricted to interferon beta and glatiramer acetate in 203 children (78.7%), whereas other treatments such as broad-spectrum chemotherapies (cyclophosphamide, mitoxantrone hydrochloride), natalizumab, corticosteroids (monthly), and daclizumab were used at some point during the observation period for disease management in 55 children (21.3%). Hispanic children were more likely to experience breakthrough disease while receiving first-line DMTs than non-Hispanic children. Conclusion: Although switching between first-line DMTs may be effective in pediatric patients with disease that is refractory to initial treatment, a subset of patients may require second-line therapeutic interventions.

Journal of the neurological sciences, Jan 15, 2016

We explored the association between baseline gut microbiota (16S rRNA biomarker sequencing of sto... more We explored the association between baseline gut microbiota (16S rRNA biomarker sequencing of stool samples) in 17 relapsing-remitting pediatric MS cases and risk of relapse over a mean 19.8months follow-up. From the Kaplan-Meier curve, 25% relapsed within an estimated 166days from baseline. A shorter time to relapse was associated with Fusobacteria depletion (p=0.001 log-rank test), expansion of the Firmicutes (p=0.003), and presence of the Archaea Euryarchaeota (p=0.037). After covariate adjustments for age and immunomodulatory drug exposure, only absence (vs. presence) of Fusobacteria was associated with relapse risk (hazard ratio=3.2 (95% CI: 1.2-9.0), p=0.024). Further investigation is warranted. Findings could offer new targets to alter the MS disease course.

Chromosome Research

Chromosomal instability (CIN), an increased rate of chromosomal segregation abnormalities, drives... more Chromosomal instability (CIN), an increased rate of chromosomal segregation abnormalities, drives intratumor heterogeneity and affects most human cancers. In addition to chromosome copy number alterations, CIN results in chromosome(s) (fragments) being mislocalized into the cytoplasm in the form of micronuclei. Micronuclei can be detected by cGAS, a double-strand nucleic acid sensor, which will lead to the production of the second messenger 2′3′-cGAMP, activation of an inflammatory response, and downstream immune cell activation. However, the molecular network underlying the CIN-induced inflammatory response is still poorly understood. Furthermore, there is emerging evidence that cancers that display CIN circumvent this CIN-induced inflammatory response, and thus immune surveillance. The STAT1, STAT3, and NF-κB signaling cascades appear to play an important role in the CIN-induced inflammatory response. In this review, we discuss how these pathways are involved in signaling CIN in c...

The Journal of Immunology

Theiler's murine encephalomyelitis virus induced central nervous system demyelination in susc... more Theiler's murine encephalomyelitis virus induced central nervous system demyelination in susceptible strains of mice with s, q, v, p, and f H-2D alleles. We used immunoelectron microscopy to look for differential production of class II immune response gene products (Ia) within astrocytes, oligodendrocytes, microglia, and endothelial cells. Spinal cord sections from susceptible mice (B10.S and B10.ASR2) showed increased content of Ia in glial and endothelial cells. In contrast, resistant mice [B10.S(9R)] showed minimal Ia production within the CNS. The findings indicate an important role of class II immune response products on glial cells during demyelination after virus infection.

Axon loss is a cardinal neuropathological feature of multiple sclerosis (MS). Axonal injury in MS... more Axon loss is a cardinal neuropathological feature of multiple sclerosis (MS). Axonal injury in MS and experimental disease models is most frequently detected in acutely demyelinating regions. Furthermore, acute axonal injury consistently correlates with the extent of inflammatory demyelination. Following lysolecithin-induced demyelination, we recently reported a compensatory response in neurons, where mitochondria move from the cell body to the acutely demyelinated axon and increase the mitochondrial content. We termed this energetics phenomenon, that is also evident in MS, the axonal response of mitochondria to demyelination (ARMD). In the present study, we assessed axonal mitochondrial content as well as axonal mitochondrial respiratory chain complex IV activity (COX) of axons and related these to axonal injury in nine different experimental disease models. We consistently found ARMD in all experimental disease models. However, the increase in mitochondrial content within demyelin...

Acta Neuropathologica, 2020

Axonal loss is the key pathological substrate of neurological disability in demyelinating disorde... more Axonal loss is the key pathological substrate of neurological disability in demyelinating disorders, including multiple sclerosis (MS). However, the consequences of demyelination on neuronal and axonal biology are poorly understood. The abundance of mitochondria in demyelinated axons in MS raises the possibility that increased mitochondrial content serves as a compensatory response to demyelination. Here, we show that upon demyelination mitochondria move from the neuronal cell body to the demyelinated axon, increasing axonal mitochondrial content, which we term the axonal response of mitochondria to demyelination (ARMD). However, following demyelination axons degenerate before the homeostatic ARMD reaches its peak. Enhancement of ARMD, by targeting mitochondrial biogenesis and mitochondrial transport from the cell body to axon, protects acutely demyelinated axons from degeneration. To determine the relevance of ARMD to disease state, we examined MS autopsy tissue and found a positiv...

ObjectiveRadiotherapy, combined with surgical resection and chemotherapy, remains a first-line tr... more ObjectiveRadiotherapy, combined with surgical resection and chemotherapy, remains a first-line treatment for infiltrative gliomas. However, these tumor are not surgically curable, and often recur, even within the prior radiation field, and may demonstrate a more aggressive phenotype. We recently demonstrated that the radiated brain tumor microenvironment promotes tumor aggressiveness in an orthotopic patient-derived xenograft (PDX) model of glioblastoma (Mayo GBM 143). Importantly, high grade gliomas display diverse molecular phenotypes, and whether this genetic variability leads to divergent behaviour in the radiated tumor microenvironment is unknown. Herein, we characterize the effects of the irradiated brain microenvinroment on nine additional unique GBM cell lines to better understand the nuances of how tumor molecular phenotypes influence cellular dynamics.MethodsFemale athymic nude mice were randomly divided into cranial radiation (15 Gy) and non-radiated groups. Mice then und...

Despite decades of research and numerous basic science advances, there have only marginal gains i... more Despite decades of research and numerous basic science advances, there have only marginal gains in improving glioblastoma multiforme survival. Therefore, new ideas and approaches for treating this aggressive disease are essential to drive progress forward. Conventional therapies, such as radiation and Temozolomide (TMZ), function to cause oxidative stress and DNA damage yielding a senescent-like state of replicative arrest in susceptible cells. However, increasing evidence demonstrates malignant cells can escape senescence leading to tumor recurrence. Ablation of non-replicating senescent tumor cells after radiation and chemotherapy may be an avenue to reduce the rates of tumor recurrence. Senolytic agents have been developed that selectively target senescent cells, but it remains unknown whether senolytics might be utilized against senescent-like glioma cells. We employed radiation or TMZ to induce a functionally senescent state in human glioblastoma cells. Viable cells that surviv...

Journal of Virology, 1996

Mice with targeted disruption of the A beta gene of major histocompatibility complex class II mol... more Mice with targeted disruption of the A beta gene of major histocompatibility complex class II molecules (Abo) were used to investigate the role of class II gene products in resistance or susceptibility to virus-induced chronic demyelination in the central nervous system (CNS). Class-II-deficient mice from the resistant H-2b [H-2b(Abo)] and nonmutant H-2b backgrounds were infected with Theiler's murine encephalomyelitis virus intracerebrally and examined for CNS virus persistence, demyelination, and neurologic clinical signs. Virus titers measured by plaque assays showed that 8 of 10 normally resistant nonmutant H-2b mice had cleared the virus within 21 days, whereas the other 2 mice had low titers. In contrast, all class II-deficient Abo mice had high virus titers for up to 90 days after infection (4.30 log10 PFU per g of CNS tissue). Virus antigens and RNA were localized to the brains (cortex, hippocampus, thalamus, and brain stem) and spinal cords of Abo mice. Colocalization i...

International Journal of Physical Medicine & Rehabilitation, 2016

We provide an overview of rehabilitation in neurological diseases. A large amount of literature a... more We provide an overview of rehabilitation in neurological diseases. A large amount of literature available on neurorehabilitation is based from the rehabilitative work on stroke and spinal cord injuries. After a brief description of rehabilitation, the potential application of neurorehabilitation in neurodegenerative diseases specifically multiple sclerosis (MS) is summarized. Since MS causes a wide variety of symptoms, the rehabilitation in MS patients may benefit from an interdisciplinary approach that encloses physiotherapy, cognitive rehabilitation, psychological therapy, occupational therapy, and other methods to improve fatigue. Neurorehabilitation helps patients to reach and maintain their optimal physical, psychological and intellectual, levels but it does not reverse long-term disabilities that arise from neurological disorders. This calls for the need of better neuroregenerative and neuroprotective treatment strategies in addition to neurorehabilitation. We discuss neuroprotective drugs aimed at preventing axonal, neuronal, myelin and oligodendrocyte damage and cell death that are approved and others that are currently in clinical trials, with an emphasis on human derived natural antibodies with remyleination potential. Our investigative group developed recombinant natural human IgM antibodies against oligodendrocytes and neurons with a potential for CNS repair and remyleination. One such recombinant antibody, rHIgM22 completed a phase 1 clinical trial with no toxicity and with an objective of promoting remyleination in multiple sclerosis. Inclusion of these drugs as a multifaceted approach may further enhance the efficacy of neurorehabilitation in neuroinflammatory and neurodegenerative disorders.

Annals of Clinical and Translational Neurology, 2019

ObjectiveOnset of multiple sclerosis (MS) occurs in childhood for approximately 5% of cases (pedi... more ObjectiveOnset of multiple sclerosis (MS) occurs in childhood for approximately 5% of cases (pediatric MS, or ped‐MS). Epigenetic influences are strongly implicated in MS pathogenesis in adults, including the contribution from microRNAs (miRNAs), small noncoding RNAs that affect gene expression by binding target gene mRNAs. Few studies have specifically examined miRNAs in ped‐MS, but individuals developing MS at an early age may carry a relatively high burden of genetic risk factors, and miRNA dysregulation may therefore play a larger role in the development of ped‐MS than in adult‐onset MS. This study aimed to look for evidence of miRNA involvement in ped‐MS pathogenesis.MethodsGWAS results from 486 ped‐MS cases and 1362 controls from the U.S. Pediatric MS Network and Kaiser Permanente Northern California membership were investigated for miRNA‐specific signals. First, enrichment of miRNA‐target gene network signals was evaluated using MIGWAS software. Second, SNPs in miRNA genes an...

PLOS Genetics, 2019

Multiple sclerosis (MS) is an autoimmune disease with high prevalence among populations of northe... more Multiple sclerosis (MS) is an autoimmune disease with high prevalence among populations of northern European ancestry. Past studies have shown that exposure to ultraviolet radiation could explain the difference in MS prevalence across the globe. In this study, we investigate whether the difference in MS prevalence could be explained by European genetic risk factors. We characterized the ancestry of MS-associated alleles using RFMix, a conditional random field parameterized by random forests, to estimate their local ancestry in the largest assembled admixed population to date, with 3,692 African Americans, 4,915 Asian

The Journal of Immunology

Infection of certain strains of mice with Theiler's murine encephalomyelitis virus results in... more Infection of certain strains of mice with Theiler's murine encephalomyelitis virus results in persistence of virus and an immune-mediated primary demyelination in the central nervous system that resembles multiple sclerosis. Because susceptibility/resistance to demyelination in B10 congeneic mice maps strongly to class I MHC genes (D region) we tested whether expression of a human class I MHC gene (HLA-B27) would alter susceptibility to Theiler's murine encephalomyelitis virus-induced demyelination. Transgenic HLA-B27 mice were found to co-express human and endogenous mouse class I MHC genes by flow microfluorimetry analysis of PBL. In the absence of the human transgene, H-2stf, or v mice but not H-2b mice had chronic demyelination and persistence of virus at 45 days after infection. No difference in degree of demyelination, meningeal inflammation, or virus persistence was seen between transgenic HLA-B27 and nontransgenic littermate mice of H-2f or H-2v haplotype. In contras...

Brain, 2020

Incomplete relapse recovery contributes to disability accrual and earlier onset of secondary prog... more Incomplete relapse recovery contributes to disability accrual and earlier onset of secondary progressive multiple sclerosis. We sought to investigate the effect of age on relapse recovery. We identified patients with multiple sclerosis from two longitudinal prospective studies, with an Expanded Disability Status Scale (EDSS) score within 30 days after onset of an attack, and follow-up EDSS 6 months after attack. Adult patients with multiple sclerosis (n = 632) were identified from the Comprehensive Longitudinal Investigations in Multiple Sclerosis at Brigham study (CLIMB), and paediatric patients (n = 132) from the US Network of Paediatric Multiple Sclerosis Centers (NPMSC) registry. Change in EDSS was defined as the difference in EDSS between attack and follow-up. Change in EDSS at follow-up compared to baseline was significantly lower in children compared to adults (P = 0.001), as were several functional system scores. Stratification by decade at onset for change in EDSS versus ag...

Neurology, 2020

ObjectiveTo characterize disease severity and distribution of disability in pediatric-onset multi... more ObjectiveTo characterize disease severity and distribution of disability in pediatric-onset multiple sclerosis (POMS) and to develop an optimized modeling scale for measuring disability, we performed a multicenter retrospective analysis of disability scores in 873 persons with POMS over time and compared this to previously published data in adults with multiple sclerosis (MS).MethodsThis was a retrospective analysis of prospectively collected data collected from 12 centers of the US Network of Pediatric MS Centers. Patients were stratified by the number of years from first symptoms of MS to Expanded Disability Status Scale (EDSS) assessment and an MS severity score (Pediatric Multiple Sclerosis Severity Score [Ped-MSSS]) was calculated per criteria developed by Roxburgh et al. in 2005.ResultsIn total, 873 patients were evaluated. In our cohort, 52%, 19.4%, and 1.5% of all patients at any time point reached an EDSS of 2.0, 3.0, and 6.0. Comparison of our Ped-MSSS scores and previousl...

Multiple sclerosis (Houndmills, Basingstoke, England), 2017

Strong evidence supports the role of both genetic and environmental factors in pediatric-onset mu... more Strong evidence supports the role of both genetic and environmental factors in pediatric-onset multiple sclerosis (POMS) etiology. We comprehensively investigated the association between established major histocompatibility complex (MHC) and non-MHC adult multiple sclerosis (MS)-associated variants and susceptibility to POMS. Cases with onset <18 years ( n = 569) and controls ( n = 16,251) were included from the United States and Sweden. Adjusted logistic regression and meta-analyses were performed for individual risk variants and a weighted genetic risk score (wGRS) for non-MHC variants. Results were compared to adult MS cases ( n = 7588). HLA-DRB1*15:01 was strongly associated with POMS (odds ratio (OR)meta = 2.95, p < 2.0 × 10(-16)). Furthermore, 28 of 104 non-MHC variants studied (23%) were associated ( p < 0.05); POMS cases carried, on average, a higher burden of these 28 variants compared to adults (ORavg = 1.24 vs 1.13, respectively), though the difference was not si...

Journal of neurology, neurosurgery, and psychiatry, Jan 9, 2017

The role of diet in multiple sclerosis (MS) course remains largely unknown. Children with MS have... more The role of diet in multiple sclerosis (MS) course remains largely unknown. Children with MS have a higher relapse rate compared with MS in adults. Thus, studying the effect of diet on relapse rate in this age group is likely to provide more robust answers. This is a multicentre study done at 11 paediatric MS centres in the USA. Patients with relapsing-remitting MS (RRMS) or clinically isolated syndrome (CIS) with disease onset before 18 years of age and duration of less than 4 years were included in this study. Dietary intake during the week before enrolment was assessed with the validated Block Kids Food Screener. The outcome of the study was time from enrolment to the next relapse. 219 patients with paediatric RRMS or CIS were enrolled. Each 10% increase in energy intake from fat increased the hazard of relapse by 56% (adjusted HR 1.56, 95% CI 1.05 to 2.31, p=0.027), and in particular each 10% increase in saturated fat tripled this hazard (adjusted HR: 3.37, 95% CI 1.34 to 8.43, ...

Multiple Sclerosis and Related Disorders, 2017

Kaylor assisted with the geographic information system analysis and editing of the manuscript. Ms... more Kaylor assisted with the geographic information system analysis and editing of the manuscript. Ms. Roalstad contributed to the acquisition of the data, managed the data and supervised data collection at all sites during the study, and reviewed the final manuscript.

Journal of the neurological sciences, Jan 15, 2017

Multiple sclerosis (MS) and allergies are both considered to be related to imbalanced Th1 and Th2... more Multiple sclerosis (MS) and allergies are both considered to be related to imbalanced Th1 and Th2 immune responses. Previous studies evaluating the relationship between MS and allergies provide conflicting results. To assess allergies and asthma as risk factors for MS and as predictors of MS relapses in a pediatric cohort. The environment and genetic risk factors for pediatric MS study is a national case-control project with 16 participating US sites. An environmental questionnaire is used that includes history of allergies in the first five years of life. Case-control data are entered in the pediatric MS Network database and cases at 12 of the 16 sites enter relapse data prospectively. Annualized relapse rate was calculated for patients with follow-up and adjusted for age at disease onset, gender, race, ethnicity, and use of disease-modifying therapy (DMT). We included 271 cases (mean age at disease onset of 15.7years and 62% female) and 418 controls. Relapse data were available fo...

Neurology, 2011

Background: Because common viruses are encountered during childhood, pediatric multiple sclerosis... more Background: Because common viruses are encountered during childhood, pediatric multiple sclerosis (MS) offers a unique opportunity to investigate the influence of these viruses on disease susceptibility and the interactions between seroprevalence and select HLA genotypes. We studied seroprevalence for Epstein-Barr virus (EBV), cytomegalovirus (CMV), and herpes simplex virus (HSV) type 1 and HLA-DRB1*1501/1503 status as predictors of pediatric MS. Methods: This was a retrospective analysis of prospectively collected demographic, clinical, and biologic data in subjects up to 18 years of age with early MS, control subjects seen at the same regional referral pediatric MS clinics, and additional healthy pediatric control subjects. Results: Patients with early pediatric MS (n ϭ 189) and pediatric control subjects (n ϭ 66) were tested. Epstein-Barr nuclear antigen-1 seropositivity was associated with an increased odds of MS (odds ratio [OR] 3.78, 95% confidence interval [CI] 1.52-9.38, p ϭ 0.004) in analyses adjusted for age, sex, race, ethnicity, and HLA-DRB1*1501/1503 status. In multivariate analyses including EBV status, a remote infection with CMV (OR 0.27, 95% CI 0.11-0.67, p ϭ 0.004) was associated with a lower risk of developing MS. Although a remote infection with HSV-1 was not associated with an increased odds of MS, a strong interaction was found between HSV-1 status and HLA-DRB1 in predicting MS (p Ͻ 0.001). HSV-1 was associated with an increased risk of MS in those without a DRB1*15 allele (OR 4.11, 95% CI 1.17-14.37, p ϭ 0.03), whereas the effect was reversed in those who were DRB1*15-positive (OR 0.07, 95% CI 0.02-0.32, p ϭ 0.001). Conclusions: These findings suggest that some infections with common viruses may in fact lower MS susceptibility. If this is confirmed, the pathways for risk modification remain to be elucidated.

Archives of Neurology, 2011

Background: Currently available disease-modifying therapies (DMTs) are known to be only partially... more Background: Currently available disease-modifying therapies (DMTs) are known to be only partially effective in adults with multiple sclerosis (MS). Little is known about pediatric patients with MS who experience refractory disease while receiving first-line DMTs. Objective: To assess the occurrence and management of refractory disease in a group of pediatric patients with MS treated with first-line DMTs approved for adult patients within a network of pediatric MS centers in the United States. Design, Setting, and Patients: A multicenter, retrospective, longitudinal, open-label study design involving record review of 258 patients with pediatric-onset MS (68.6% female; mean [SD] age at disease onset, 13.2 [3.5] years; range of age at onset, 2.0-17.9 years) who were seen at 6 pediatric MS centers in the United States. Intervention: We evaluated medication changes owing to refractory disease in cases of pediatric-onset MS. Main Outcome Measure: Disease stability as represented by lack of medication change for breakthrough disease. Results: Records of 258 children with a confirmed diagnosis of MS and exposure to DMTs were reviewed. Interferon beta (prescribed to 200 of 258 children [77.5%]) and glatiramer acetate (prescribed to 53 of 258 children [20.5%]) were the 2 most frequently used first-line DMTs. Overall, 144 children (55.8%) continued receiving 1 therapy, while 65 (25.2%), 29 (11.2%), and 20 (7.8%) received 2, 3, or 4 or more sequential therapies, respectively, during a mean (SD) observation period of 3.9 (2.8) years. Second-line DMT use was restricted to interferon beta and glatiramer acetate in 203 children (78.7%), whereas other treatments such as broad-spectrum chemotherapies (cyclophosphamide, mitoxantrone hydrochloride), natalizumab, corticosteroids (monthly), and daclizumab were used at some point during the observation period for disease management in 55 children (21.3%). Hispanic children were more likely to experience breakthrough disease while receiving first-line DMTs than non-Hispanic children. Conclusion: Although switching between first-line DMTs may be effective in pediatric patients with disease that is refractory to initial treatment, a subset of patients may require second-line therapeutic interventions.

Journal of the neurological sciences, Jan 15, 2016

We explored the association between baseline gut microbiota (16S rRNA biomarker sequencing of sto... more We explored the association between baseline gut microbiota (16S rRNA biomarker sequencing of stool samples) in 17 relapsing-remitting pediatric MS cases and risk of relapse over a mean 19.8months follow-up. From the Kaplan-Meier curve, 25% relapsed within an estimated 166days from baseline. A shorter time to relapse was associated with Fusobacteria depletion (p=0.001 log-rank test), expansion of the Firmicutes (p=0.003), and presence of the Archaea Euryarchaeota (p=0.037). After covariate adjustments for age and immunomodulatory drug exposure, only absence (vs. presence) of Fusobacteria was associated with relapse risk (hazard ratio=3.2 (95% CI: 1.2-9.0), p=0.024). Further investigation is warranted. Findings could offer new targets to alter the MS disease course.

Chromosome Research

Chromosomal instability (CIN), an increased rate of chromosomal segregation abnormalities, drives... more Chromosomal instability (CIN), an increased rate of chromosomal segregation abnormalities, drives intratumor heterogeneity and affects most human cancers. In addition to chromosome copy number alterations, CIN results in chromosome(s) (fragments) being mislocalized into the cytoplasm in the form of micronuclei. Micronuclei can be detected by cGAS, a double-strand nucleic acid sensor, which will lead to the production of the second messenger 2′3′-cGAMP, activation of an inflammatory response, and downstream immune cell activation. However, the molecular network underlying the CIN-induced inflammatory response is still poorly understood. Furthermore, there is emerging evidence that cancers that display CIN circumvent this CIN-induced inflammatory response, and thus immune surveillance. The STAT1, STAT3, and NF-κB signaling cascades appear to play an important role in the CIN-induced inflammatory response. In this review, we discuss how these pathways are involved in signaling CIN in c...

The Journal of Immunology

Theiler's murine encephalomyelitis virus induced central nervous system demyelination in susc... more Theiler's murine encephalomyelitis virus induced central nervous system demyelination in susceptible strains of mice with s, q, v, p, and f H-2D alleles. We used immunoelectron microscopy to look for differential production of class II immune response gene products (Ia) within astrocytes, oligodendrocytes, microglia, and endothelial cells. Spinal cord sections from susceptible mice (B10.S and B10.ASR2) showed increased content of Ia in glial and endothelial cells. In contrast, resistant mice [B10.S(9R)] showed minimal Ia production within the CNS. The findings indicate an important role of class II immune response products on glial cells during demyelination after virus infection.

Axon loss is a cardinal neuropathological feature of multiple sclerosis (MS). Axonal injury in MS... more Axon loss is a cardinal neuropathological feature of multiple sclerosis (MS). Axonal injury in MS and experimental disease models is most frequently detected in acutely demyelinating regions. Furthermore, acute axonal injury consistently correlates with the extent of inflammatory demyelination. Following lysolecithin-induced demyelination, we recently reported a compensatory response in neurons, where mitochondria move from the cell body to the acutely demyelinated axon and increase the mitochondrial content. We termed this energetics phenomenon, that is also evident in MS, the axonal response of mitochondria to demyelination (ARMD). In the present study, we assessed axonal mitochondrial content as well as axonal mitochondrial respiratory chain complex IV activity (COX) of axons and related these to axonal injury in nine different experimental disease models. We consistently found ARMD in all experimental disease models. However, the increase in mitochondrial content within demyelin...

Acta Neuropathologica, 2020

Axonal loss is the key pathological substrate of neurological disability in demyelinating disorde... more Axonal loss is the key pathological substrate of neurological disability in demyelinating disorders, including multiple sclerosis (MS). However, the consequences of demyelination on neuronal and axonal biology are poorly understood. The abundance of mitochondria in demyelinated axons in MS raises the possibility that increased mitochondrial content serves as a compensatory response to demyelination. Here, we show that upon demyelination mitochondria move from the neuronal cell body to the demyelinated axon, increasing axonal mitochondrial content, which we term the axonal response of mitochondria to demyelination (ARMD). However, following demyelination axons degenerate before the homeostatic ARMD reaches its peak. Enhancement of ARMD, by targeting mitochondrial biogenesis and mitochondrial transport from the cell body to axon, protects acutely demyelinated axons from degeneration. To determine the relevance of ARMD to disease state, we examined MS autopsy tissue and found a positiv...

ObjectiveRadiotherapy, combined with surgical resection and chemotherapy, remains a first-line tr... more ObjectiveRadiotherapy, combined with surgical resection and chemotherapy, remains a first-line treatment for infiltrative gliomas. However, these tumor are not surgically curable, and often recur, even within the prior radiation field, and may demonstrate a more aggressive phenotype. We recently demonstrated that the radiated brain tumor microenvironment promotes tumor aggressiveness in an orthotopic patient-derived xenograft (PDX) model of glioblastoma (Mayo GBM 143). Importantly, high grade gliomas display diverse molecular phenotypes, and whether this genetic variability leads to divergent behaviour in the radiated tumor microenvironment is unknown. Herein, we characterize the effects of the irradiated brain microenvinroment on nine additional unique GBM cell lines to better understand the nuances of how tumor molecular phenotypes influence cellular dynamics.MethodsFemale athymic nude mice were randomly divided into cranial radiation (15 Gy) and non-radiated groups. Mice then und...

Despite decades of research and numerous basic science advances, there have only marginal gains i... more Despite decades of research and numerous basic science advances, there have only marginal gains in improving glioblastoma multiforme survival. Therefore, new ideas and approaches for treating this aggressive disease are essential to drive progress forward. Conventional therapies, such as radiation and Temozolomide (TMZ), function to cause oxidative stress and DNA damage yielding a senescent-like state of replicative arrest in susceptible cells. However, increasing evidence demonstrates malignant cells can escape senescence leading to tumor recurrence. Ablation of non-replicating senescent tumor cells after radiation and chemotherapy may be an avenue to reduce the rates of tumor recurrence. Senolytic agents have been developed that selectively target senescent cells, but it remains unknown whether senolytics might be utilized against senescent-like glioma cells. We employed radiation or TMZ to induce a functionally senescent state in human glioblastoma cells. Viable cells that surviv...

Journal of Virology, 1996

Mice with targeted disruption of the A beta gene of major histocompatibility complex class II mol... more Mice with targeted disruption of the A beta gene of major histocompatibility complex class II molecules (Abo) were used to investigate the role of class II gene products in resistance or susceptibility to virus-induced chronic demyelination in the central nervous system (CNS). Class-II-deficient mice from the resistant H-2b [H-2b(Abo)] and nonmutant H-2b backgrounds were infected with Theiler's murine encephalomyelitis virus intracerebrally and examined for CNS virus persistence, demyelination, and neurologic clinical signs. Virus titers measured by plaque assays showed that 8 of 10 normally resistant nonmutant H-2b mice had cleared the virus within 21 days, whereas the other 2 mice had low titers. In contrast, all class II-deficient Abo mice had high virus titers for up to 90 days after infection (4.30 log10 PFU per g of CNS tissue). Virus antigens and RNA were localized to the brains (cortex, hippocampus, thalamus, and brain stem) and spinal cords of Abo mice. Colocalization i...

International Journal of Physical Medicine & Rehabilitation, 2016

We provide an overview of rehabilitation in neurological diseases. A large amount of literature a... more We provide an overview of rehabilitation in neurological diseases. A large amount of literature available on neurorehabilitation is based from the rehabilitative work on stroke and spinal cord injuries. After a brief description of rehabilitation, the potential application of neurorehabilitation in neurodegenerative diseases specifically multiple sclerosis (MS) is summarized. Since MS causes a wide variety of symptoms, the rehabilitation in MS patients may benefit from an interdisciplinary approach that encloses physiotherapy, cognitive rehabilitation, psychological therapy, occupational therapy, and other methods to improve fatigue. Neurorehabilitation helps patients to reach and maintain their optimal physical, psychological and intellectual, levels but it does not reverse long-term disabilities that arise from neurological disorders. This calls for the need of better neuroregenerative and neuroprotective treatment strategies in addition to neurorehabilitation. We discuss neuroprotective drugs aimed at preventing axonal, neuronal, myelin and oligodendrocyte damage and cell death that are approved and others that are currently in clinical trials, with an emphasis on human derived natural antibodies with remyleination potential. Our investigative group developed recombinant natural human IgM antibodies against oligodendrocytes and neurons with a potential for CNS repair and remyleination. One such recombinant antibody, rHIgM22 completed a phase 1 clinical trial with no toxicity and with an objective of promoting remyleination in multiple sclerosis. Inclusion of these drugs as a multifaceted approach may further enhance the efficacy of neurorehabilitation in neuroinflammatory and neurodegenerative disorders.

Annals of Clinical and Translational Neurology, 2019

ObjectiveOnset of multiple sclerosis (MS) occurs in childhood for approximately 5% of cases (pedi... more ObjectiveOnset of multiple sclerosis (MS) occurs in childhood for approximately 5% of cases (pediatric MS, or ped‐MS). Epigenetic influences are strongly implicated in MS pathogenesis in adults, including the contribution from microRNAs (miRNAs), small noncoding RNAs that affect gene expression by binding target gene mRNAs. Few studies have specifically examined miRNAs in ped‐MS, but individuals developing MS at an early age may carry a relatively high burden of genetic risk factors, and miRNA dysregulation may therefore play a larger role in the development of ped‐MS than in adult‐onset MS. This study aimed to look for evidence of miRNA involvement in ped‐MS pathogenesis.MethodsGWAS results from 486 ped‐MS cases and 1362 controls from the U.S. Pediatric MS Network and Kaiser Permanente Northern California membership were investigated for miRNA‐specific signals. First, enrichment of miRNA‐target gene network signals was evaluated using MIGWAS software. Second, SNPs in miRNA genes an...

PLOS Genetics, 2019

Multiple sclerosis (MS) is an autoimmune disease with high prevalence among populations of northe... more Multiple sclerosis (MS) is an autoimmune disease with high prevalence among populations of northern European ancestry. Past studies have shown that exposure to ultraviolet radiation could explain the difference in MS prevalence across the globe. In this study, we investigate whether the difference in MS prevalence could be explained by European genetic risk factors. We characterized the ancestry of MS-associated alleles using RFMix, a conditional random field parameterized by random forests, to estimate their local ancestry in the largest assembled admixed population to date, with 3,692 African Americans, 4,915 Asian