Now showing items 1-20 of 15296

    • 7,8-Dihydroxyflavone improves neuropathological changes in the brain of Tg26 mice, a model for HIV-associated neurocognitive disorder

      Bryant, Joseph; Andhavarapu, Sanketh; Bever, Christopher; Guda, Poornachander; Katuri, Akhil; Gupta, Udit; Arvas, Muhammed; Asemu, Girma; Heredia, Alonso; Gerzanich, Volodymyr; et al. (Springer Nature, 2021-09-16)
      The combined antiretroviral therapy era has significantly increased the lifespan of people with HIV (PWH), turning a fatal disease to a chronic one. However, this lower but persistent level of HIV infection increases the susceptibility of HIV-associated neurocognitive disorder (HAND). Therefore, research is currently seeking improved treatment for this complication of HIV. In PWH, low levels of brain derived neurotrophic factor (BDNF) has been associated with worse neurocognitive impairment. Hence, BDNF administration has been gaining relevance as a possible adjunct therapy for HAND. However, systemic administration of BDNF is impractical because of poor pharmacological profile. Therefore, we investigated the neuroprotective effects of BDNF-mimicking 7,8 dihydroxyflavone (DHF), a bioactive high-affinity TrkB agonist, in the memory-involved hippocampus and brain cortex of Tg26 mice, a murine model for HAND. In these brain regions, we observed astrogliosis, increased expression of chemokine HIV-1 coreceptors CXCR4 and CCR5, neuroinflammation, and mitochondrial damage. Hippocampi and cortices of DHF treated mice exhibited a reversal of these pathological changes, suggesting the therapeutic potential of DHF in HAND. Moreover, our data indicates that DHF increases the phosphorylation of TrkB, providing new insights about the role of the TrkB-Akt-NFkB signaling pathway in mediating these pathological hallmarks. These findings guide future research as DHF shows promise as a TrkB agonist treatment for HAND patients in adjunction to the current antiviral therapies.
    • Can language use in social media help in the treatment of severe mental illness?

      Kelly, Deanna L; Spaderna, Max; Hodzic, Vedrana; Coppersmith, Glen; Chen, Shuo; Resnik, Philip (ProBiologists LLC., 2021-01)
    • Short-term facilitation of breathing upon cessation of hypoxic challenge is impaired in male but not female endothelial NOS knock-out mice.

      Getsy, Paulina M; Sundararajan, Sripriya; May, Walter J; von Schill, Graham C; McLaughlin, Dylan K; Palmer, Lisa A; Lewis, Stephen J (Springer Nature, 2021-09-15)
      Decreases in arterial blood oxygen stimulate increases in minute ventilation via activation of peripheral and central respiratory structures. This study evaluates the role of endothelial nitric oxide synthase (eNOS) in the expression of the ventilatory responses during and following a hypoxic gas challenge (HXC, 10% O2, 90% N2) in freely moving male and female wild-type (WT) C57BL6 and eNOS knock-out (eNOS-/-) mice. Exposure to HXC caused an array of responses (of similar magnitude and duration) in both male and female WT mice such as, rapid increases in frequency of breathing, tidal volume, minute ventilation and peak inspiratory and expiratory flows, that were subject to pronounced roll-off. The responses to HXC in male eNOS-/- mice were similar to male WT mice. In contrast, several of the ventilatory responses in female eNOS-/- mice (e.g., frequency of breathing, and expiratory drive) were greater compared to female WT mice. Upon return to room-air, male and female WT mice showed similar excitatory ventilatory responses (i.e., short-term potentiation phase). These responses were markedly reduced in male eNOS-/- mice, whereas female eNOS-/- mice displayed robust post-HXC responses that were similar to those in female WT mice. Our data demonstrates that eNOS plays important roles in (1) ventilatory responses to HXC in female compared to male C57BL6 mice; and (2) expression of post-HXC responses in male, but not female C57BL6 mice. These data support existing evidence that sex, and the functional roles of specific proteins (e.g., eNOS) have profound influences on ventilatory processes, including the responses to HXC.
    • Risk factors for radiation induced lymphopenia in patients with breast cancer receiving adjuvant radiotherapy

      Chen, Fang; Yu, Hao; Zhang, Hong; Nong, Yaqing; Wang, Qian; Jing, Haiman; Han, Ying; Wu, Junjie; Zhou, Zheng; Yang, Li; et al. (AME Publishing Company, 2021)
      Background: This study aimed to investigate radiation-induced lymphopenia and its potential risk factors in patients with breast cancer receiving adjuvant radiotherapy. Methods: Breast cancer patients received adjuvant radiotherapy (RT) at our hospital with peripheral lymphocyte counts (PLC) at pre-and immediately after RT (post-RT) were eligible. The primary endpoints were any grade of lymphopenia post-RT and nadir-PLC/pre-PLC <0.8. Patient characteristics, tumor factors, and treatment factors were collected for risk assessment. Data are presented as mean and 95% confidence interval (CI) unless otherwise specified. Matched analysis was used to compare the statistical significance between different RT techniques. Results: A total of 735 consecutive patients met the study criteria. The mean PLC was 1.58×109/L before and 0.99×109/L post-RT (P<0.001). At the end of RT, 60.5% of patients had lymphopenia. Univariate and multivariable logistic analyses showed that RT technique involving RapidArc, mean lung dose, and chemotherapy were significant risk factors (P<0.05) for lymphopenia. RT technique was the only significant risk factor (P<0.05) for nadir-PLC/pre-PLC <0.8. Patients treated with RapidArc had a significantly greater reduction of PLC along with greater V5 of the lungs, even after matching mean lung dose and radiated volume. Conclusions: Lymphopenia is common in patients with breast cancer after adjuvant RT. RT technique is the only significant factor for lymphopenia and nadir-PLC/pre-PLC <0.8, suggesting the significance of RT technique choice to minimize lymphopenia and improve treatment outcomes.
    • Announcing UMBPD Chief of Police

      Jarrell, Bruce E.; Rhodes, Dawn M. (2021-09-21)
    • Leveraging Technology to Improve Diabetes Care in Pregnancy

      Crimmins, Sarah D; Ginn-Meadow, Angela; Jessel, Rebecca H; Rosen, Julie A (American Diabetes Association Inc., 2020-12-14)
      Pregnant women with diabetes are at higher risk of adverse outcomes. Prevention of such outcomes depends on strict glycemic control, which is difficult to achieve and maintain. A variety of technologies exist to aid in diabetes management for nonpregnant patients. However, adapting such tools to meet the demands of pregnancy presents multiple challenges. This article reviews the key attributes digital technologies must offer to best support diabetes management during pregnancy, as well as some digital tools developed specifically to meet this need. Despite the opportunities digital health tools present to improve the care of people with diabetes, in the absence of robust data and large research studies, the ability to apply such technologies to diabetes in pregnancy will remain imperfect.
    • Effect of Sofosbuvir/Ledipasvir and Glecaprevir/Pibrentasvir on Serum Creatinine

      Amjad, Waseem; Zhang, Talan; Maheshwari, Anurag; Thuluvath, Paul J. (Elsevier B.V., 2021-08-20)
      Background & objectives: There are reports of worsening renal functions with sofosbuvir, but there are no comparative data of different direct-acting antivirals (DAAs) on serum creatinine. In this retrospective cohort analysis, we examined the treatment effect of two commonly used regimens, sofosbuvir/ledipasvir (SOF/LDV) and glecaprevir/pibrentasvir (GLE/PIB), on serum creatinine. Methods: We included all patients treated with SOF/LDV (n = 825) and GLE/PIB (n = 116) between December 1, 2014, and December 31, 2018. An increase of serum creatinine ≥0.3 mg/dL was considered clinically significant. The change of creatinine values from pretreatment to posttreatment between two treatment groups was tested in unadjusted and adjusted generalized linear model, and risk factors associated with creatinine change were assessed. In addition, GLE/PIB-treated patients were matched 1:2 to SOF/LDV-treated patients using propensity scores, and then serum creatinine changes were compared. Results: The mean baseline creatinine was higher in the GLE/PIB group vs. SOF/LDV group (1.39 ± 1.86 vs. 0.91 ± 0.24, P = 0.007). When compared to baseline, serum creatinine at posttreatment week 4 was significantly higher in SOF/LDV group (0.97 ± 0.4 vs.0.91 ± 0.24, P < 0.001), but there was no significant change in the GLE/PIB group (1.41 ± 1.73 vs. 1.39 ± 1.86, P = 0.52). Overall, there was no significant change in serum creatinine between posttreatment week 4 and week 24 (P = 0.6). Clinically significant increase in serum creatinine was seen in 6% (46/825) of SOF/LDV and 7% (8/116) of GLE/PIB (P = 0.6). The unadjusted and adjusted models indicated that the changes in creatinine from baseline to posttreatment week 4 and week 24 were not associated with the type of DAA combination. Conclusion: Treatment of chronic hepatitis C infection with both SOF/LDV and GLE/PIB regimens may result in an increase of creatinine, and 6–7% will have an increase in serum creatinine of ≥0.3 mg/dL. The increase in creatinine, however, is unrelated to the type of DAA combination. © 2021 Indian National Association for Study of the Liver
    • Building a pipeline of community-engaged researchers: How interdisciplinary translational research training programs can collaborate with their Community Research Advisory Councils

      LaFave, Sarah E; Wallace, Duane J; Grover, Raneitra; Clark, Roger; Marks, Stacey; Lacanienta, Cyd; Evans, Crystal; Kalil, Graziela Z; Ouyang, Pamela; Himmelfarb, Cheryl R; et al. (Cambridge University Press, 2021-07-14)
      Community research advisory councils (C-RAC) bring together community members with interest in research to support design, evaluation, and dissemination of research in the communities they represent. There are few ways for early career researchers, such as TL1 trainees, to develop skills in community-engaged research, and there are limited opportunities for C-RAC members to influence early career researchers. In our novel training collaboration, TL1 trainees presented their research projects to C-RAC members who provided feedback. We present on initial evidence of student learning and summarize lessons learned that TL1 programs and C-RACs can incorporate into future collaborations.
    • Evidence of shared and distinct functional and structural brain signatures in schizophrenia and autism spectrum disorder

      Du, Yuhui; Fu, Zening; Xing, Ying; Lin, Dongdong; Pearlson, Godfrey; Kochunov, Peter; Hong, L Elliot; Qi, Shile; Salman, Mustafa; Abrol, Anees; et al. (Springer Nature, 2021-09-14)
      Schizophrenia (SZ) and autism spectrum disorder (ASD) share considerable clinical features and intertwined historical roots. It is greatly needed to explore their similarities and differences in pathophysiologic mechanisms. We assembled a large sample size of neuroimaging data (about 600 SZ patients, 1000 ASD patients, and 1700 healthy controls) to study the shared and unique brain abnormality of the two illnesses. We analyzed multi-scale brain functional connectivity among functional networks and brain regions, intra-network connectivity, and cerebral gray matter density and volume. Both SZ and ASD showed lower functional integration within default mode and sensorimotor domains, but increased interaction between cognitive control and default mode domains. The shared abnormalties in intra-network connectivity involved default mode, sensorimotor, and cognitive control networks. Reduced gray matter volume and density in the occipital gyrus and cerebellum were observed in both illnesses. Interestingly, ASD had overall weaker changes than SZ in the shared abnormalities. Interaction between visual and cognitive regions showed disorder-unique deficits. In summary, we provide strong neuroimaging evidence of the convergent and divergent changes in SZ and ASD that correlated with clinical features.
    • Safety and Efficacy of a Typhoid Conjugate Vaccine in Malawian Children

      Patel, Priyanka D; Patel, Pratiksha; Liang, Yuanyuan; Meiring, James E; Misiri, Theresa; Mwakiseghile, Felistas; Tracy, J Kathleen; Masesa, Clemens; Msuku, Harrison; Banda, David; et al. (Massachusetts Medical Society, 2021-09-16)
      Background: Typhoid fever caused by multidrug-resistant H58 Salmonella Typhi is an increasing public health threat in sub-Saharan Africa. Methods: We conducted a phase 3, double-blind trial in Blantyre, Malawi, to assess the efficacy of Vi polysaccharide typhoid conjugate vaccine (Vi-TCV). We randomly assigned children who were between 9 months and 12 years of age, in a 1:1 ratio, to receive a single dose of Vi-TCV or meningococcal capsular group A conjugate (MenA) vaccine. The primary outcome was typhoid fever confirmed by blood culture. We report vaccine efficacy and safety outcomes after 18 to 24 months of follow-up. Results: The intention-to-treat analysis included 28,130 children, of whom 14,069 were assigned to receive Vi-TCV and 14,061 were assigned to receive the MenA vaccine. Blood culture-confirmed typhoid fever occurred in 12 children in the Vi-TCV group (46.9 cases per 100,000 person-years) and in 62 children in the MenA group (243.2 cases per 100,000 person-years). Overall, the efficacy of Vi-TCV was 80.7% (95% confidence interval [CI], 64.2 to 89.6) in the intention-to-treat analysis and 83.7% (95% CI, 68.1 to 91.6) in the per-protocol analysis. In total, 130 serious adverse events occurred in the first 6 months after vaccination (52 in the Vi-TCV group and 78 in the MenA group), including 6 deaths (all in the MenA group). No serious adverse events were considered by the investigators to be related to vaccination. Conclusions: Among Malawian children 9 months to 12 years of age, administration of Vi-TCV resulted in a lower incidence of blood culture-confirmed typhoid fever than the MenA vaccine. (Funded by the Bill and Melinda Gates Foundation; number, NCT03299426.).
    • Characterizing enhancer-driven transcriptional networks in schizophrenia

      Casella, Alex; Ament, Seth A. (2021)
      Genetic studies of schizophrenia have demonstrated that more than 90% of genetic risk is confined to non-coding portions of the genome. Advances in chromatin state prediction and chromatin accessibility assays have enabled us to better characterize the genomic features making up these regions and annotate genetic risk to these elements. The focus of this dissertation is to understand the role that tissue- and cell type- specific regulatory elements and the transcription factors that bind them play in risk for schizophrenia. I hypothesized that enhancer-based transcription factor-target networks that direct neuronal development are disrupted in schizophrenia. To test this hypothesis, I used high-quality chromatin state predictions in both the developing and the adult brain to develop a framework for testing enhancer properties for association with genetic risk. Any enhancer-level annotation can be used in this type of test, including transcription factor binding counts and chromosomal contact information. I first described and validated an atlas of transcription factor binding sites across multiple human tissue, including the brain. I then used this atlas to show that neurodevelopmental transcription factors and target genes are most associated with risk for developing schizophrenia.
    • Reliability and Validity of the UMove Mobility Screen

      Wells, C. L.; Pittas, J.; Roman, C.; Lighty, K.; Resnick, B. (2021)
    • C5a activates a pro-inflammatory gene expression profile in human gaucher ipsc-derived macrophages

      Serfecz, Jacquelyn C.; Saadin, Afsoon; Santiago, Clayton P.; Zhang, Yuji; Bentzen, Søren M.; Vogel, Stefanie N.; Feldman, Ricardo A. (MDPI AG, 2021-09-14)
      Gaucher disease (GD) is an autosomal recessive disorder caused by bi-allelic GBA1 mutations that reduce the activity of the lysosomal enzyme β-glucocerebrosidase (GCase). GCase catalyzes the conversion of glucosylceramide (GluCer), a ubiquitous glycosphingolipid, to glucose and ceramide. GCase deficiency causes the accumulation of GluCer and its metabolite glucosylsphingosine (GluSph) in a number of tissues and organs. In the immune system, GCase deficiency deregulates signal transduction events, resulting in an inflammatory environment. It is known that the complement system promotes inflammation, and complement inhibitors are currently being considered as a novel therapy for GD; however, the mechanism by which complement drives systemic macrophagemediated inflammation remains incompletely understood. To help understand the mechanisms involved, we used human GD-induced pluripotent stem cell (iPSC)-derived macrophages. We found that GD macrophages exhibit exacerbated production of inflammatory cytokines via an innate immune response mediated by receptor 1 for complement component C5a (C5aR1). Quantitative RT-PCR and ELISA assays showed that in the presence of recombinant C5a (rC5a), GD macrophages secreted 8–10-fold higher levels of TNF-α compared to rC5a-stimulated control macrophages. PMX53, a C5aR1 blocker, reversed the enhanced GD macrophage TNF-α production, indicating that the observed effect was predominantly C5aR1-mediated. To further analyze the extent of changes induced by rC5a stimulation, we performed gene array analysis of the rC5a-treated macrophage transcriptomes. We found that rC5a-stimulated GD macrophages exhibit increased expression of genes involved in TNF-α inflammatory responses compared to rC5a-stimulated controls. Our results suggest that rC5a-induced inflammation in GD macrophages activates a unique immune response, supporting the potential use of inhibitors of the C5a-C5aR1 receptor axis to mitigate the chronic inflammatory abnormalities associated with GD. © 2021 by the authors.
    • Roadmap Consensus on Carotid Artery Plaque Imaging and Impact on Therapy Strategies and Guidelines: An International, Multispecialty, Expert Review and Position Statement

      Saba, L; Brinjikji, W; Spence, J D; Wintermark, M; Castillo, M; Borst, G J D; Yang, Q; Yuan, C; Buckler, A; Edjlali, M; et al. (American Society of Neuroradiology, 2021-09-07)
      Current guidelines for primary and secondary prevention of stroke in patients with carotid atherosclerosis are based on the quantification of the degree of stenosis and symptom status. Recent publications have demonstrated that plaque morphology and composition, independent of the degree of stenosis, are important in the risk stratification of carotid atherosclerotic disease. This finding raises the question as to whether current guidelines are adequate or if they should be updated with new evidence, including imaging for plaque phenotyping, risk stratification, and clinical decision-making in addition to the degree of stenosis. To further this discussion, this roadmap consensus article defines the limits of luminal imaging and highlights the current evidence supporting the role of plaque imaging. Furthermore, we identify gaps in current knowledge and suggest steps to generate high-quality evidence, to add relevant information to guidelines currently based on the quantification of stenosis. © 2021 American Society of Neuroradiology. All rights reserved.
    • Salvage of the injured upper extremity

      Feliciano, David V. (BMJ Publishing Group, 2021-09-07)
    • Association of CDH11 with Autism Spectrum Disorder Revealed by Matched-gene Co-expression Analysis and Mouse Behavioral Studies

      Wu, Nan; Wang, Yue; Jia, Jing-Yan; Pan, Yi-Hsuan; Yuan, Xiao-Bing (Springer Nature, 2021-09-14)
      A large number of putative risk genes for autism spectrum disorder (ASD) have been reported. The functions of most of these susceptibility genes in developing brains remain unknown, and causal relationships between their variation and autism traits have not been established. The aim of this study was to predict putative risk genes at the whole-genome level based on the analysis of gene co-expression with a group of high-confidence ASD risk genes (hcASDs). The results showed that three gene features – gene size, mRNA abundance, and guanine-cytosine content – affect the genome-wide co-expression profiles of hcASDs. To circumvent the interference of these features in gene co-expression analysis, we developed a method to determine whether a gene is significantly co-expressed with hcASDs by statistically comparing the co-expression profile of this gene with hcASDs to that of this gene with permuted gene sets of feature-matched genes. This method is referred to as "matched-gene co-expression analysis" (MGCA). With MGCA, we demonstrated the convergence in developmental expression profiles of hcASDs and improved the efficacy of risk gene prediction. The results of analysis of two recently-reported ASD candidate genes, CDH11 and CDH9, suggested the involvement of CDH11, but not CDH9, in ASD. Consistent with this prediction, behavioral studies showed that Cdh11-null mice, but not Cdh9-null mice, have multiple autism-like behavioral alterations. This study highlights the power of MGCA in revealing ASD-associated genes and the potential role of CDH11 in ASD. © 2021, The Author(s).
    • Why KN95s?

      Jarrell, Bruce E. (2021-09-17)
    • Behavioral, Anatomical and Heritable Convergence of Affect and Cognition in Superior Frontal Cortex

      Kraljević, Nevena; Schaare, H Lina; Eickhoff, Simon B; Kochunov, Peter; Yeo, B T Thomas; Kharabian Masouleh, Shahrzad; Valk, Sofie L (Elsevier Inc., 2021-09-07)
      Cognitive abilities and affective experience are key human traits that are interrelated in behavior and brain. Individual variation of cognitive and affective traits, as well as brain structure, has been shown to partly underlie genetic effects. However, to what extent affect and cognition have a shared genetic relationship with local brain structure is incompletely understood. Here we studied phenotypic and genetic correlations of cognitive and affective traits in behavior and brain structure (cortical thickness, surface area and subcortical volumes) in the pedigree-based Human Connectome Project sample (N = 1091). Both cognitive and affective trait scores were highly heritable and showed significant phenotypic correlation on the behavioral level. Cortical thickness in the left superior frontal cortex showed a phenotypic association with both affect and cognition. Decomposing the phenotypic correlations into genetic and environmental components showed that the associations were accounted for by shared genetic effects between the traits. Quantitative functional decoding of the left superior frontal cortex further indicated that this region is associated with cognitive and emotional functioning. This study provides a multi-level approach to study the association between affect and cognition and suggests a convergence of both in superior frontal cortical thickness. © 2021