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Inclusion body myositis is an enigmatic slowly progressive acquired myopathy. There is strong evidence favoring autoimmune origin, including the invasion of non-necrotic myofibers by clonally expanded cytotoxic CD8+ T cells, which have the hallmark of highly and possibly terminally differentiated T cells, expressing the killer cell lectin-like receptor G1 (KLRG1) cell surface ligand, and have features of senescence. Previous research suggests there is greater T cell differentiation with longer disease severity, though there is a paucity of information surrounding how muscle-invading T cells may influence disease behavior. Understanding the frequency of highly differentiated lymphocytes and their relationship to disease severity and behavior may influence novel therapeutic solutions. INSPIRE-IBM is a longitudinal NIH-funded multicenter study including patients ages 40 years or older with clinically defined IBM fulfilled by the ENMC 2011 criteria, and disease onset within the past 10 years of the Baseline visit. Complete dataset for the baseline cross-sectional visit was available from 60 participants. Flow cytometry was used on PBMCs to analyze percentage of immunosenescent lymphocytes staining for CD8+, KRLG1+, TEMRAs, and Tregs. Functional assessments to evaluate disease severity included Manual Muscle Testing (MMT), Timed get up-and-go (TUG), Sydney Swallow Questionnaire (SSQ), and EAT-10. Data will be analyzed in May 2024 and results from Baseline will be presented. [ABSTRACT FROM AUTHOR]

Anti-NT5c1A antibodies, directed against cytosolic 5'-nucleotidase that is abundant in skeletal muscle, were identified as the first serological biomarker for IBM. Prior research suggested that NT5c1A seropositivity prognosticated a more severe motor phenotype with more severe motor weakness and bulbar involvement. Subsequent studies produced conflicting data, either confirming previous observations or not showing any relationship. The debate remains whether serological status may provide insight into functional severity and disease behavior. INSPIRE-IBM is a prospective NIH-funded observational study including patients ages 40 years or older with clinically defined IBM fulfilled by the ENMC 2011 criteria, and disease onset within the past 10 years of the Baseline visit. Serology for NT5c1A was collected at Baseline. Functional assessments to evaluate disease severity included Manual Muscle Testing (MMT), Timed get up-and-go (TUG), Sydney Swallow Questionnaire (SSQ), and EAT-10. Serological status was available for 140 out of 150 participants with IBM who were enrolled. Sixty-nine of the 140 IBM patients (49%) were seropositive for NT5c1A antibodies at Baseline. Patients were divided into two groups (Group A with disease duration between 0-5 years and Group B with disease duration between 6-10 years). Seropositive group A showed significantly greater difficulty swallowing (EAT-10 and SSQ) than seronegative group A. Seropositive group B showed a trend towards more difficulty swallowing (EAT-10 and SSQ) and motor function weakness (MMT) compared to the seronegative group but did not reach statistical significance. Seropositive IBM patients appear to have more swallowing difficulties than seronegative patients, and this difference appears early on in the disease course. [ABSTRACT FROM AUTHOR]

A huge unmet need in sporadic inclusion body myositis (IBM) research is the lack of long-term prospective longitudinal data on disease behavior and progression and the influence of the various blood biomarkers (NT5c1A antibodies and highly differentiated T lymphocytes) on disease behavior and progression. A 13-center observational prospective study is ongoing involving 150 patients with IBM. The study is funded by NIAMS/NIH. Primary eligibility criteria are a diagnosis of IBM, fulfilling the ENMC 2011 criteria for clinicopathologically defined, clinically defined, or probable IBM, within 10 years of onset. Each subject will be seen every 6 months (5 times points) over a 2-year period, and will have serial collection of disease related data, including physical exams, outcome measures (IBMFRS, sIFA, IBM-HI, PROMIS, quantitative muscle strength and grip strength testing, timed get up and go, pulmonary function tests, fall diary, and mobility device assessment). Collection for serum and PBMCs will be done to assess for NT5c1A antibodies, select cytokines, and detailed immunophenotyping for blood-based lymphocytes. RNA and DNA has been collected for future analyses. A subset of 40 patients will undergo fresh open muscle biopsy, along with concurrent blood collection, to assess muscle pathology and correlate blood markers with markers in muscle tissue. The study has completed enrolment of 150 patients as of January 2024. Seventy-two (49.7%) were seropositive for the NT5c1A antibody and 73 (50.3%) were seronegative (5 results pending). Five subjects changed antibody status from the Baseline to the Month 12 visit. Demographics: 30.6% female, 69.4% male; 90% White, 4% Asian, 4% Black, 1.3% more than one race, 8.7% Hispanic or Latino. The study will provide the largest dataset to date on the natural history of IBM including a repository of PBMC, DNA, RNA and muscle tissue from highly characterized and phenotyped IBM patients. [ABSTRACT FROM AUTHOR]

Inclusion body myositis (IBM) is the most common acquired muscle disease found in individuals over the age of 40. Affected individuals experience a progressive and asymmetric weakness that affects mobility and daily activities. Respiratory failure is a common outcome for IBM patients. Previous analysis in small cohorts of IBM patients has shown subjects who are seropositive for NT5c1A antibody demonstrate significantly lower results in pulmonary function testing (specifically maximum inspiratory pressure (MIP) and forced vital capacity (FVC)), thus predicting more severe respiratory involvement. However, further analysis on pulmonary function and seropositivity for NT5c1A antibody in a larger cohort is needed. A 13-center observational prospective study is ongoing involving 150 patients with IBM (INSPIRE-IBM study). We analyzed data collected at the Baseline visit which includes objective pulmonary function tests (sitting and supine FVC, MIP, and MEP) and a self-reported dyspnea questionnaire (NIHPROMIS dyspnea) and compared the association with seropositivity for NT51A antibodies. Results show the mean seated FVC values were 73.6% predicted in seropositive patients versus 88.2% predicted in seronegative patients (p= 0.005). The mean supine FVC values were 71.6% predicted in seropositive patients versus 84.4% predicted in seronegative patients (p= 0.003). Both are statistically significant. The mean MIP and MEP values (58.4, 75.5 cmH2O seropositive and 65.3, 87.1 cmH2O seronegative) trend lower in seropositive patients but were not clinically significant. The PROMIS dyspnea results showed no significant difference between the two groups. These findings amongst a large cohort of IBM patients, support previous studies showing seropositive IBM patients may have more severe respiratory involvement. [ABSTRACT FROM AUTHOR]

Inclusion body myositis (IBM) is a common muscular disorder in individuals over the age of 40 years, characterized by atrophy and progressive muscle weakness. Patient-reported outcomes such as the IBMFRS or the sIFA questionnaire provide valuable insights into disease impact from the patient's perspective on their symptoms, functional limitations, and quality of life. However, it remains a topic of further investigation to determine which of these questionnaires exhibits stronger correlations with disease progression. The INSPIRE-IBM is a natural history study involving 150 IBM patients across 13 different US sites. Evaluations are conducted biannually over two years and patients complete IBMFRS, sIFA, EAT-10, Sydney Swallow Questionnaire, PROMIS, along with manual muscle testing and pulmonary functions tests. This abstract analyzes correlations between IBMFRS and sIFA with the other assessments by regression analysis to identify which is a stronger correlator with disease progression. Preliminary analysis, involving 87 patients who completed three time points, revealed a strong correlation between IBMFRS and sIFA (R2=0.7, p=3.21E-96). Both outcomes show moderate correlation with PFTs (R2 between 0.5-0.7), with no significant difference in strength of correlation. IBMFRS and sIFA exhibit similar correlation with MMTs (R2=0.43, p=0.93). As the study is ongoing, more timepoints will be available per patient closer to the conference date and will be included in the analysis. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the correlation between various outcome measures used to assess disease severity and progression in inclusion body myositis (IBM) clinical trials. A cross-sectional study, involving 51 IBM patients meeting the European Neuromuscular Center (ENMC) 2011 criteria for clinically defined or probable IBM, was completed at the University of California, Irvine. Clinical details, demographic data, and functional data including timed get up (TGU), manual muscle testing, hand grip, pinch dynamometry, as well as IBM functional rating scale (IBMFRS), modified Rankin score, forced vital capacity (FVC), and modified ocular bulbar facial respiratory scale (mOBFRS) were collected on all patients. Descriptive statistics and Pearson's r correlation were performed to analyze the data. Age of the patient did not correlate with any of the outcome measures. Greater severity of IBMFRS scores correlated with longer disease duration as well as greater severity for FVC, strength outcomes, TGU, modified Rankin, and mOBFRS. Additionally, TGU strongly correlated with muscle strength measurements, modified Rankin, and mOBFRS. mOBFRS moderately correlated with IBMFRS, muscle strength, FVC, TGU and modified Rankin score. We demonstrate moderate to strong correlations among the disease severity outcome measures in this study., Competing Interests: Declaration of Competing Interest S.A.G. is an inventor of intellectual property related to myositis diagnostics and therapeutics, owned and managed by Brigham and Women's Hospital (BWH); he is a founder of Abcuro, Inc. Partners HealthCare, the owner of BWH, and S.A.G. have financial interests in Abcuro. The financial interests were reviewed and managed in accordance with the conflict-of-interest policies of Partners HealthCare. A.M.P. was supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant UL1 TR001414. S.A.V. was supported by PHS grants R01NS120060, R21NS114918, and KL2TR001416. T.M. was supported by PHS grants R01AR078340, UL1TR001414 and U24NS107210. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The rest of the authors report no relevant disclosures., (Copyright © 2022. Published by Elsevier B.V.)

Background and Objectives: To evaluate the therapeutic potential of targeting highly differentiated T cells in patients with inclusion body myositis (IBM) by establishing high-resolution mapping of killer cell lectin-like receptor subfamily G member 1 (KLRG1 + ) within the T and natural killer (NK) cell compartments., Methods: Blood was collected from 51 patients with IBM and 19 healthy age-matched donors. Peripheral blood mononuclear cells were interrogated by flow cytometry using a 12-marker antibody panel. The panel allowed the delineation of naive T cells (Tn), central memory T cells (Tcm), 4 stages of effector memory differentiation T cells (Tem 1-4), and effector memory re-expressing CD45RA T cells (TemRA), as well as total and subpopulations of NK cells based on the differential expression of CD16 and C56., Results: We found that a population of KLRG1 + Tem and TemRA were expanded in both the CD4 + and CD8 + T-cell subpopulations in patients with IBM. KLRG1 expression in CD8 + T cells increased with T-cell differentiation with the lowest levels of expression in Tn and highest in highly differentiated TemRA and CD56 + CD8 + T cells. The frequency of KLRG1 + total NK cells and subpopulations did not differ between patients with IBM and healthy donors. IBM disease duration correlated with increased CD8 + T-cell differentiation., Discussion: Our findings reveal that the selective expansion of blood KLRG1 + T cells in patients with IBM is confined to the TemRA and Tem cellular compartments., (© 2022 American Academy of Neurology.)

Introduction/aims: Severe acute respiratory syndrome coronavirus-2 2019 (SARS-CoV2/COVID-19) is frequently more severe in individuals with pre-existing respiratory and cardiovascular conditions. The impact on patients with neuromuscular disorders is of concern, but remains largely unknown. Late-onset Pompe disease (LOPD) is a lysosomal-storage disorder characterized by progressive skeletal and respiratory muscle degeneration. Mortality is typically caused by respiratory failure. We examined the impact of COVID-19 on these patients., Methods: This is a case series of four patients with LOPD who contracted COVID-19., Results: All patients had a mild/moderate illness from COVID-19 and did not require hospitalization. Neurological worsening occurred in one, with no change in physical ability in the other three, and respiratory symptoms remained stable in all four., Discussion: COVID-19 infection can result in a benign course in some patients with LOPD. However, individuals with LOPD remain at high risk and should receive COVID-19 vaccinations and exercise precautions to avoid exposure to COVID-19 infection., (© 2021 Wiley Periodicals LLC.)

Background and Objectives: We investigated the prevalence of late-onset Pompe disease (LOPD) in patients presenting to 13 academic, tertiary neuromuscular practices in the United States and Canada., Methods: All successive patients presenting with proximal muscle weakness or isolated hyperCKemia and/or neck muscle weakness to these 13 centers were invited to participate in the study. Whole blood was tested for acid alpha-glucosidase (GAA) assay through the fluorometric method, and all cases with enzyme levels of ≤10 pmoL/punch/h were reflexed to molecular testing for mutations in the GAA gene. Clinical and demographic information was abstracted from their clinical visit and, along with study data, entered into a purpose-built REDCap database, and analyzed at the University of California, Irvine., Results: GAA enzyme assay results were available on 906 of the 921 participants who consented for the study. LOPD was confirmed in 9 participants (1% prevalence). Another 9 (1%) were determined to have pseudodeficiency of GAA, whereas 19 (1.9%) were found to be heterozygous for a pathogenic GAA mutation (carriers). Of the definite LOPD participants, 8 (89%) were Caucasian and were heterozygous for the common leaky (IVS1) splice site mutation in the GAA gene (c -32-13T>G), with a second mutation that was previously confirmed to be pathogenic., Discussion: The prevalence of LOPD in undiagnosed patients meeting the criteria of proximal muscle weakness, high creatine kinase, and/or neck weakness in academic, tertiary neuromuscular practices in the United States and Canada is estimated to be 1%, with an equal prevalence rate of pseudodeficiency alleles., Trial Registration Information: Clinical trial registration number: NCT02838368., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Introduction: Prader-Willi syndrome (PWS) is a complex genetic condition characterized by hyperphagia, hypotonia, low muscle mass, excess body fat, developmental delays, intellectual disability, behavioral problems, and growth hormone deficiency. This study evaluated the safety and efficacy of orally administered Diazoxide Choline Controlled-Release Tablets (DCCR) in subjects with PWS., Method: This was a single-center, Phase II study and included a 10-week Open-Label Treatment Period during which subjects were dose escalated, followed by a 4-week Double-Blind, Placebo-Controlled Treatment Period., Results: Five female and eight male overweight or obese, adolescent and adult subjects with genetically-confirmed PWS with an average age of 15.5±2.9 years were enrolled in the study. There was a statistically significant reduction in hyperphagia at the end of the Open-Label Treatment Period (-4.32, n = 11, p = 0.006). The onset of effect on hyperphagia was rapid and greater reductions in hyperphagia were seen in subjects with moderate to severe Baseline hyperphagia (-5.50, n = 6, p = 0.03), in subjects treated with the highest dose (-6.25, n = 4, p = 0.08), and in subjects with moderate to severe Baseline hyperphagia treated with the highest dose (-7.83, n = 3, p = 0.09). DCCR treatment resulted in a reduction in the number of subjects displaying aggressive behaviors (-57.1%, n = 10, p = 0.01), clinically-relevant reductions in fat mass (-1.58 kg, n = 11, p = 0.02) and increases in lean body mass (2.26 kg, n = 11, p = 0.003). There was a corresponding decrease in waist circumference, and trends for improvements in lipids and insulin resistance. The most common adverse events were peripheral edema and transient increases in glucose. Many of the adverse events were common medical complications of PWS and diazoxide., Conclusion: DCCR treatment appears to address various unmet needs associated with PWS, including hyperphagia and aggressive behaviors in this proof-of-concept study. If the results were replicated in a larger scale study, DCCR may be a preferred therapeutic option for patients with PWS., Competing Interests: The authors have read the journal’s policy and have the following conflicts: Virginia Kimonis has received support from Essentialis Therapeutics, Inc, Carlsbad, CA and Rhythm Pharmaceuticals for a clinical trial. Neil M. Cowen is affiliated with Essentialis Therapeutics, Inc, Carlsbad, CA, now Soleno Therapeutics, Redwood City, California. This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials.

Background: Pompe disease is a lysosomal storage disorder caused by the deficiency of enzyme acid alpha-glucosidase ( GAA ) which results in accumulation of glycogen, particularly in the skeletal, cardiac, and smooth muscles. The late-onset form with symptoms presenting in childhood through adulthood, is characterized by proximal muscle weakness, respiratory insufficiency, and unlike the infantile-onset form often with no cardiac involvement., Methods: We report our experience with 18 adult patients (14 males/4 females) with Pompe disease, several of whom had unique findings and novel pathogenic variants. Patients ranged in ages from 22-74 years (mean 53.7 years) and were diagnosed at an age range of 11-65 years (mean 43.6 years), often after a history of progressive muscle disease of several years' duration. All 18 patients were treated with alglucosidase alfa (Lumizyme) and their response to treatment was monitored by measurements of their pulmonary function and muscle weakness, six-minute walk test (6MWT), and other functional studies., Results: Genetic sequencing revealed that 16 out of 18 individuals had the common c.-32-13T>G splicing variant, and six patients, including two sibships had four novel pathogenic variants: c.1594G>A, c.2655_2656delCG, c.1951-1952delGGinsT, and c.1134C>G. A male with the c.1594G>A variant developed an intracerebral aneurysm at the age of 43 years treated with surgery. Two siblings with the c.2655_2656delCG developed very high antibody titers, one of whom developed a severe infusion reaction. Other clinical features included BiPAP requirement in twelve, tinnitus in seven, scoliosis in five, cardiomyopathy in three, one individual was diagnosed with a cerebral aneurysm who underwent successful Penumbra coil placement, and another individual was diagnosed with both Graves' disease and testicular cancer., Conclusions: Our study illustrates significant variability in the range of clinical features, and the variable clinical response to enzyme replacement therapy. It also alerts us to the importance of careful monitoring and early management of complications. Possible genotype-phenotype associations with the novel mutations identified may emerge with larger studies., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

The combination of vertebral, anal, cardiac, tracheo-esophageal, renal and limb anomalies termed VACTERL association, also referred to as VATER, has been used as a clinical descriptor and more recently, a diagnosis of exclusion, for a specific group of phenotypic manifestations that have been observed to co-occur non-randomly. Though the causes remain elusive and poorly understood in most patients, VACTERL association is thought to be due to defects in early embryogenesis and is likely genetically heterogeneous. We present data on 36 patients diagnosed with VACTERL association in addition to describing the phenotypic diversity of each component feature. Unique cases in our cohort include a patient with a 498.59 kb microdeletion in the 16p11.2 region and another with a 215 kb duplication in the 3p25.2 region. Our findings expand upon the current understanding of VACTERL association and guide future research aimed at determining its etiology., (© 2018 Wiley Periodicals, Inc.)

Inclusion body myopathy (IBM) associated with Paget disease of the bone and frontotemporal dementia or IBMPFD is an autosomal dominant degenerative disorder caused by mutations in the valosin-containing protein (VCP) gene. We aim to establish a detailed clinical phenotype of VCP disease amongst 35 (28 affected individuals, 7 presymptomatic gene carriers) individuals versus 14 unaffected first-degree relatives in 14 families to establish useful biomarkers for IBMPFD and identify the most meaningful tests for monitoring disease progression in future clinical trials. Comprehensive studies included the Inclusion Body Myositis Functional Rating Scale (IBMFRS) and fatigue severity scale questionairres, strength measurements using the Manual Muscle Test with Medical Research Council (MRC) scales, hand-held dynamometry using the microFET and Biodex dynamometers, 6 minute walk test (6MWT), and pulmonary function studies. Strong correlation was observed between the IBMFRS and measurements of muscle strength with dynamometry and the other functional tests, indicating that it may be utilized in long-term follow-up assessments due to its relative simplicity. This cross-section study represents the most comprehensive evaluation of individuals with VCP disease to date and provides a useful guide for evaluating and possible monitoring of muscle weakness and pulmonary function progression in this unique cohort of individuals., (Copyright © 2018. Published by Elsevier B.V.)

FG-3019 is a fully human monoclonal antibody that interferes with the action of connective tissue growth factor, a central mediator in the pathogenesis of fibrosis.This open-label phase 2 trial evaluated the safety and efficacy of two doses of FG-3019 administered by intravenous infusion every 3 weeks for 45 weeks in patients with idiopathic pulmonary fibrosis (IPF). Subjects had a diagnosis of IPF within the prior 5 years defined by either usual interstitial pneumonia (UIP) pattern on a recent high-resolution computed tomography (HRCT) scan, or a possible UIP pattern on HRCT scan and a recent surgical lung biopsy showing UIP pattern. Pulmonary function tests were performed every 12 weeks, and changes in the extent of pulmonary fibrosis were measured by quantitative HRCT scans performed at baseline and every 24 weeks.FG-3019 was safe and well-tolerated in IPF patients participating in the study. Changes in fibrosis were correlated with changes in pulmonary function.Further investigation of FG-3019 in IPF with a placebo-controlled clinical trial is warranted and is underway., (Copyright ©ERS 2016.)

Inclusion Body Myopathy associated with Paget's disease of bone and Fronto-temporal Dementia, also known as multisystem proteinopathy is an autosomal dominant, late onset neurodegenerative disorder caused by mutations in Valosin containing protein (VCP) gene. This study aimed to assess uptake and decision making for predictive genetic testing and the impact on psychological well-being. Individuals who had participated in the gene discovery study with a 50 % a priori risk of inheriting VCP disease were sent a letter of invitation offering genetic counseling and testing and were also invited to participate in this psychosocial study. A total of 102 individuals received an invitation and 33 individuals participated in genetic counseling and testing (32.3 %) with 29 completing baseline questionnaires. Twenty completed the follow-up post-test Hospital Anxiety and Depression Scale questionnaire including 13 of the 18 who had tested positive. Mean risk perception at baseline was 50.1 %. Reasons for testing included planning for the future, relieving uncertainty, informing children and satisfying curiosity. At baseline, one quarter of the participants had high levels of anxiety. However, scores were normal one year following testing. In this small cohort, one third of individuals at 50 % risk chose pre-symptomatic testing. Although one quarter of those choosing testing had high anxiety at baseline, this was not evident at follow-up.

Inclusion body myopathy, Paget disease of bone and/or frontotemporal dementia is an autosomal dominant disease caused by mutations in the Valosin Containing Protein (VCP) gene. We compared clinical findings including MRI images and neuropsychological assessment data in affected and unaffected twin brothers aged 56 years from a family with the p.R155C VCP gene mutation. The affected twin presented with a 10 year history of progressive proximal muscle weakness, difficulty swallowing, gastroesophageal reflux, fecal incontinence, and peripheral neuropathy. Comprehensive neuropsychological testing revealed rapid cognitive decline in the absence of any behavioral changes in a span of 1 year. This case illustrates that frontotemporal dementia related cognitive impairment may precede behavioral changes in VCP disease as compared with predominance of behavioral impairment reported in previous studies. Our findings suggest that there is a need to establish VCP disease specific tools and normative rates of decline to detect pre-clinical cognitive impairment among affected individuals., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Unlabelled: Abstract Background: Currently, there is limited information on the effects of growth hormone and of the different genetic subtypes on bone mineral density (BMD) in Prader-Willi syndrome (PWS)., Methods: We evaluated BMD in 79 individuals with the common subtypes of PWS (48 with deletion and 27 with UPD) and the effect of growth hormone treatment (n=46) vs. no growth hormone treatment., Results: Forty-four percent of the individuals studied had whole body, hip, or spine BMD <-1 standard deviation (SD) and 10% had a BMD <-2 SD. BMD Z-scores and total BMD (g/cm2) of the spine were significantly higher in the growth hormone group. With each year of growth hormone treatment, these values increased by a factor of 0.207 and 0.011 (p=0.006 and 0.032), respectively. Individuals with uniparental disomy revealed higher spine BMD compared with deletion subclass; however, the differences were not significant., Conclusion: This study emphasizes the importance of evaluating bone mineralization in individuals with PWS and the beneficial effects of prolonged treatment with growth hormone. There was a trend for a higher BMD in individuals with uniparental disomy.

While the pathologic events associated with multiple sclerosis (MS), diffuse axonal injury, cognitive damage, and white matter plaques, have been known for some time, the etiology of MS is still unknown and therapeutic efforts are somewhat disappointing. This may be due to a lack of fundamental knowledge on how to buffer the brain from secondary injury following immune attack. Maintenance of central nervous system (CNS) homeostasis is a complex set of regulatory adjustments by the neurovascular unit that includes induction of adaptive angiogenesis. Although aspects of adaptive angiogenesis are induced in MS and experimental autoimmune encephalomyelitis (EAE), vascular remodeling is ineffective and the balance between metabolic need and oxygen (O(2)) and glucose availability is disrupted.We hypothesized that restoration of metabolic homeostasis in the CNS would ameliorate tissue damage and promote repair in myelin oligodendrocyte glycoprotein(MOG)-induced EAE in mice. Exposure of animals to chronic mild hypoxia (10% O(2)) increased vascular density and significantly delayed onset and severity of clinical EAE. When animals were exposed to hypoxia after the onset of clinical symptoms, the severity of chronic inflammatory disease was reduced or even inhibited. In addition, spinal cord pathology was decreased.While the mechanism of protection is unclear, results suggest that hypoxia has therapeutic potential in EAE.

Elevated atmospheric CO(2) can cause increased carbon fixation and altered foliar chemical composition in a variety of plants, which has the potential to impact forested headwater streams because they are detritus-based ecosystems that rely on leaf litter as their primary source of organic carbon. Fungi and bacteria play key roles in the entry of terrestrial carbon into aquatic food webs, as they decompose leaf litter and serve as a source of nutrition for invertebrate consumers. This study tested the hypothesis that changes in leaf chemistry caused by elevated atmospheric CO(2) would result in changes in the size and composition of microbial communities colonizing leaves in a woodland stream. Three tree species, Populus tremuloides, Salix alba, and Acer saccharum, were grown under ambient (360 ppm) or elevated (720 ppm) CO(2), and their leaves were incubated in a woodland stream. Elevated-CO(2) treatment resulted in significant increases in the phenolic and tannin contents and C/N ratios of leaves. Microbial effects, which occurred only for P. tremuloides leaves, included decreased fungal biomass and decreased bacterial counts. Analysis of fungal and bacterial communities on P. tremuloides leaves via terminal restriction fragment length polymorphism (T-RFLP) and clone library sequencing revealed that fungal community composition was mostly unchanged by the elevated-CO(2) treatment, whereas bacterial communities showed a significant shift in composition and a significant increase in diversity. Specific changes in bacterial communities included increased numbers of alphaproteobacterial and cytophaga-flavobacter-bacteroides (CFB) group sequences and decreased numbers of betaproteobacterial and firmicutes sequences, as well as a pronounced decrease in overall gram-positive bacterial sequences.

A 39-yr-old woman developed progressive exertional dyspnea 13 yr after receiving mediastinal irradiation for Hodgkin's disease. Chest roentgenogram showed a hyperlucent right lung. Pulmonary blood flow was markedly reduced on the right by ventilation-perfusion scanning. Pulmonary angiography showed attenuation and diffuse atrophy of the right pulmonary artery and its branches. This case represents a late and uncommon complication of mediastinal irradiation manifesting as a unilateral hyperlucent lung.