AMPA-Kainate Receptor Inhibition Promotes Neurologic Recovery in Premature Rabbits with Intraventricular Hemorrhage

Intraventricular hemorrhage (IVH) in preterm infants leads to cerebral inflammation, reduced myelination of the white matter, and neurological deficits. No therapeutic strategy exists against the IVH-induced white matter injury. AMPA-kainate receptor induced excitotoxicity contributes to oligodendrocyte precursor cell (OPC) damage and hypomyelination in both neonatal and adult models of brain injury. Here, we hypothesized that IVH damages white matter via AMPA receptor activation, and that AMPA-kainate receptor inhibition suppresses inflammation and restores OPC maturation, myelination, and neurologic recovery in preterm newborns with IVH. We tested these hypotheses in a rabbit model of glycerol-induced IVH and evaluated the expression of AMPA receptors in autopsy samples from human preterm infants. GluR1-GluR4 expressions were comparable between preterm humans and rabbits with and without IVH. However, GluR1 and GluR2 levels were significantly lower in the embryonic white matter and germinal matrix relative to the neocortex in both infants with and without IVH. Pharmacological blockade of AMPA-kainate receptors with systemic NBQX, or selective AMPA receptor inhibition by intramuscular perampanel restored myelination and neurologic recovery in rabbits with IVH. NBQX administration also reduced the population of apoptotic OPCs, levels of several cytokines (TNFα, IL-β, IL-6, LIF), and the density of Iba1(+) microglia in pups with IVH. Additionally, NBQX treatment inhibited STAT-3 phosphorylation, but not astrogliosis or transcription factors regulating gliosis. Our data suggest that AMPA-kainate receptor inhibition alleviates OPC loss and IVH-induced inflammation and restores myelination and neurologic recovery in preterm rabbits with IVH. Therapeutic use of FDA-approved perampanel treatment might enhance neurologic outcome in premature infants with IVH. SIGNIFICANCE STATEMENT: Intraventricular hemorrhage (IVH) is a major complication of prematurity and a large number of survivors with IVH develop cerebral palsy and cognitive deficits. The development of IVH leads to inflammation of the periventricular white matter, apoptosis and arrested maturation of oligodendrocyte precursor cells, and hypomyelination. Here, we show that AMPA-kainate receptor inhibition by NBQX suppresses inflammation, attenuates apoptosis of oligodendrocyte precursor cells, and promotes myelination as well as clinical recovery in preterm rabbits with IVH. Importantly, AMPA-specific inhibition by the FDA-approved perampanel, which unlike NBQX has a low side-effect profile, also enhances myelination and neurological recovery in rabbits with IVH. Hence, the present study highlights the role of AMPA-kainate receptor in IVH-induced white matter injury and identifies a novel strategy of neuroprotection, which might improve the neurological outcome for premature infants with IVH

EVALUATION OF NEUROLOGICAL MANIFESTATIONS IN HUMAN IMMUNODEFICIENCY VIRUS-AIDS PATIENTS ADMITTED TO SOUTH INDIAN TERTIARY CARE HOSPITAL – A CROSS-SECTIONAL STUDY

Objective: The objective of the study was to describe, evaluate, and analyze neurological manifestation in human immunodeficiency virus HIV positive patients admitted to a tertiary care center. Methods: The study was a prospective cross-sectional study, in which 103 HIV patients were analyzed. All patients were interviewed face to face and evaluated by the investigator with particular reference to neurological manifestations. They were classified into various stages of HIV using the World Health Organization staging system. Results: The mean age in males was 37 (standard deviation [SD] 8.0) years and in females 35 (SD 7.0) years. A greater proportion of females were diagnosed in the asymptomatic state during screening, either during pregnancy or when the spouse was found to be positive. Headache was the most common neurologic symptom and fundus abnormalities were the most common neurological sign documented in patients. The mean CD4 counts in males are 156.5/mm3 and in females are 229.57/mm3 whereas the mean absolute leukocyte count in males is 1088.30/mm3 and in females is 1473.52/mm3. The CD4 counts showed a better correlation with the occurrence of neurological manifestations than absolute leukocyte count. Conclusion: Headache was a significant predictor of the occurrence of neurological complications (p=0.01). CD4 counts were significantly lower in patients with neurological complications and most of the neurological manifestations; on the contrary, all the opportunistic infections were documented in patients with CD4 counts below 200/mm3. Neurological complications did not show any correlation with the patient being on anti-retroviral therapy

Introducing the TISMIR Education Track: What, Why, How?

This editorial introduces the new education track for the Transactions of the International Society for Music Information Retrieval (TISMIR) and aims to provide guidance to both prospective authors and users of this track’s material regarding its context, goals, and scope. To begin, we offer TISMIR-specific context, including the journal’s history, its unchanged scope and remit, and the motivations behind introducing the new track. This context is supplemented by broader insights into developments in the field of Music Information Retrieval (MIR), the personal pedagogical experiences of the authors, and the rapid, extensive development of Open Educational Resources across various domains. We highlight the key characteristics of educational articles in general and explore why the music domain may provide an intuitive and motivating setting for education across various levels and disciplines. The education track aligns with existing tracks in terms of TISMIR’s dedication to scientific research in MIR, broadly defined as the processing, analyzing, organizing, and creating of music and music-related information using computational methods. Educational articles within this track maintain the high standards expected in terms of scientific rigor, clarity of language, and compelling presentation. However, they differ in their focus on a tutorial-style delivery and their emphasis on existing MIR research methods, techniques, principles, and practical matters relevant to the diverse interests of the MIR community. Through this editorial, our objective is to offer guidance, clarify review criteria, and stimulate discussion on crafting effective educational articles, thereby laying the foundation for a broader discourse on education within MIR and beyond

Hyaluronidase and Hyaluronan Oligosaccharides Promote Neurological Recovery After Intraventricular Hemorrhage

Intraventricular hemorrhage (IVH) in premature infants results in inflammation, arrested oligodendrocyte progenitor cell (OPC) maturation, and reduced myelination of the white matter. Hyaluronan (HA) inhibits OPC maturation and complexes with the heavy chain (HC) of glycoprotein inter-α-inhibitor to form pathological HA (HC-HA complex), which exacerbates inflammation. Therefore, we hypothesized that IVH would result in accumulation of HA, and that either degradation of HA by hyaluronidase treatment or elimination of HCs from pathological HA by HA oligosaccharide administration would restore OPC maturation, myelination, and neurological function in survivors with IVH. To test these hypotheses, we used the preterm rabbit model of glycerol-induced IVH and analyzed autopsy samples from premature infants. We found that total HA levels were comparable in both preterm rabbit pups and human infants with and without IVH, but HA receptors--CD44, TLR2, TLR4--were elevated in the forebrain of both humans and rabbits with IVH. Hyaluronidase treatment of rabbits with IVH reduced CD44 and TLR4 expression, proinflammatory cytokine levels, and microglia infiltration. It also promoted OPC maturation, myelination, and neurological recovery. HC-HA and tumor necrosis factor-stimulated gene-6 were elevated in newborns with IVH; and depletion of HC-HA levels by HA oligosaccharide treatment reduced inflammation and enhanced myelination and neurological recovery in rabbits with IVH. Hence, hyaluronidase or HA oligosaccharide treatment represses inflammation, promotes OPC maturation, and restores myelination and neurological function in rabbits with IVH. These therapeutic strategies might improve the neurological outcome of premature infants with IVH. Significance statement: Approximately 12,000 premature infants develop IVH every year in the United States, and a large number of survivors with IVH develop cerebral palsy and cognitive deficits. The onset of IVH induces inflammation of the periventricular white matter, which results in arrested maturation of OPCs and myelination failure. HA is a major component of the extracellular matrix of the brain, which regulates inflammation through CD44 and TLR2/4 receptors. Here, we show two mechanism-based strategies that effectively enhanced myelination and neurological recovery in preterm rabbit model of IVH. First, degrading HA by hyaluronidase treatment reduced CD44 and TLR4 expression, proinflammatory cytokines, and microglial infiltration, as well as promoted oligodendrocyte maturation and myelination. Second, intraventricular injection of HA oligosaccharide reduced inflammation and enhanced myelination, conceivably by depleting HC-HA levels

Geometric discord and Measurement-induced nonlocality for well known bound entangled states

We employ geometric discord and measurement induced nonlocality to quantify non classical correlations of some well-known bipartite bound entangled states, namely the two families of Horodecki's ($2\otimes 4$, $3\otimes 3$ and $4\otimes 4$ dimensional) bound entangled states and that of Bennett etal's in $3\otimes 3$ dimension. In most of the cases our results are analytic and both the measures attain relatively small value. The amount of quantumness in the $4\otimes 4$ bound entangled state of Benatti etal and the $2\otimes 8$ state having the same matrix representation (in computational basis) is same. Coincidently, the $2m\otimes 2m$ Werner and isotropic states also exhibit the same property, when seen as $2\otimes 2m^2$ dimensional states.Comment: V2: Title changed, one more state added; 11 pages (single column), 2 figures, accepted in Quantum Information Processin

1-[6-Chloro-4-(2-chloro­phen­yl)-2-methyl-3-quinol­yl]ethanone

The title compound, C18H13Cl2NO, features an essentially planar quinoline ring system (r.m.s. deviation = 0.023 Å) with the acetyl [C—C—C—O torsion angle = −78.27 (17)°] and benzene [C—C—C—C torsion angle = 110.11 (14)°] substituents being twisted out of the plane; the dihedral angle formed between the mean planes of these two substituents is 58.01 (8)°. The acetyl O and benzene-bound Cl atoms lie to opposite sides of the mol­ecule. Centrosymmetric aggregates mediated by pairs of C—H⋯O contacts are found in the crystal structure, and these are connected into a two-dimensional array in the (01) plane via Cl⋯O [3.0508 (11) Å] inter­actions

Poor Functional Status as a Risk Factor for Severe Clostridium difficile Infection in Hospitalized Older Adults

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/112304/1/jgs12442.pd

Heme metabolism genes Downregulated in COPD Cachexia.

IntroductionCachexia contributes to increased mortality and reduced quality of life in Chronic Obstructive Pulmonary Disease (COPD) and may be associated with underlying gene expression changes. Our goal was to identify differential gene expression signatures associated with COPD cachexia in current and former smokers.MethodsWe analyzed whole-blood gene expression data from participants with COPD in a discovery cohort (COPDGene, N = 400) and assessed replication (ECLIPSE, N = 114). To approximate the consensus definition using available criteria, cachexia was defined as weight-loss > 5% in the past 12 months or low body mass index (BMI) (< 20 kg/m2) and 1/3 criteria: decreased muscle strength (six-minute walk distance < 350 m), anemia (hemoglobin < 12 g/dl), and low fat-free mass index (FFMI) (< 15 kg/m2 among women and < 17 kg/m2 among men) in COPDGene. In ECLIPSE, cachexia was defined as weight-loss > 5% in the past 12 months or low BMI and 3/5 criteria: decreased muscle strength, anorexia, abnormal biochemistry (anemia or high c-reactive protein (> 5 mg/l)), fatigue, and low FFMI. Differential gene expression was assessed between cachectic and non-cachectic subjects, adjusting for age, sex, white blood cell counts, and technical covariates. Gene set enrichment analysis was performed using MSigDB.ResultsThe prevalence of COPD cachexia was 13.7% in COPDGene and 7.9% in ECLIPSE. Fourteen genes were differentially downregulated in cachectic versus non-cachectic COPD patients in COPDGene (FDR < 0.05) and ECLIPSE (FDR < 0.05).DiscussionSeveral replicated genes regulating heme metabolism were downregulated among participants with COPD cachexia. Impaired heme biosynthesis may contribute to cachexia development through free-iron buildup and oxidative tissue damage

Depression by Gender and Associated Factors Among Older Adults in India: Implications for Age-Friendly Policies

Inspite of implementing policies to control mental health problems, depression remains a severe health concern among older adults in India. We examined self-reported differences in the depression among older men and women in India and examined associated factors for gender differences in depression at the population level. We utilized nationally representative data from the Longitudinal Aging Study in India (LASI) wave I, for years 2017-2019. Our analytical sample comprised of 30,637 older adults ages 60 years and above (14,682 men and 15,655 women). We conducted descriptive statistics and Chi-Square tests followed by binary logistic regression and multivariate decomposition analyses to examine our study objectives. Depression was reported in - 7.4% (95% CI 7.0, 7.8) of older men and 9.5% (CI 9.1, 10.0) of older women. Poor self-rated health, multimorbidity status, physical activity, difficulty in activities of daily living (ADL) and instrumental ADL (IADL) were the significant health-related factors associated with depression among older men and women. Not being satisfied with one\u27s life, not being satisfied with their present living arrangement, receiving any type of ill-treatment, and being widowed were the significant factors associated with depression among older men and women. We found gender disparity in self-reported depression. Marital status contributed-to 36.7% of the gender gap in depression among older adults. Additionally, ADL and IADL difficulties among men and women contributed to 17.6% and 34.0%, gender gap, self-rated health contributed to 18.8% gap, whereas not having equal social participation (4.4%) and not satisfied in present living arrangements (8.1%) were other factors that contributed to gender gap for depression in India. Depression is a critical and persistent public health problem among-older females in India. Our findings provide a broader framework for policymakers and health practitioners to focus on gender-specific strategies to mitigate this highly emergent problem