“Electroconvulsive therapy in treatment resistant depression” (2022) Journal of the Neurological Sciences
Electroconvulsive therapy in treatment resistant depression(2022) Journal of the Neurological Sciences, 434, art. no. 120095, .
Subramanian, S.a b , Lopez, R.a b , Zorumski, C.F.a b , Cristancho, P.a b
a Department of Psychiatry, Washington University in St Louis School of Medicine, St Louis, MO, United Statesb Department of Psychiatry, University of Texas Rio Grande Valley School of Medicine, Harlingen, TX, United States
AbstractElectroconvulsive therapy (ECT) is a treatment modality for patients with treatment resistant depression (TRD), defined as failure of two adequate antidepressant medication trials. We provide a qualitative review of ECT’s effectiveness for TRD, methods to optimize ECT parameters to improve remission rates and side effect profiles, and ECT’s proposed neurobiological mechanisms. Right unilateral (RUL) electrode placement has been shown to be as effective for major depression as bilateral ECT, and RUL is associated with fewer cognitive side effects. There is mixed evidence on how to utilize ECT to sustain remission (i.e., continuation ECT, psychotropic medications alone, or a combination of ECT and psychotropic medications). Related to neurobiological mechanisms, an increase in gray matter volume in the hippocampus-amygdala complex is reported post-ECT. High connectivity between the subgenual anterior cingulate and the middle temporal gyrus before ECT is associated with better treatment response. Rodent models have implicated changes in neurotransmitters including glutamate, GABA, serotonin, and dopamine in ECT’s efficacy; however, findings in humans are limited. Altogether, while ECT remains a highly effective therapy, the neurobiological underpinnings associated with improvement of depression remain uncertain. © 2021 Elsevier B.V.
Author KeywordsElectroconvulsive therapy; Interventional psychiatry; Major depressive disorder; Neuromodulation; Treatment resistant depression
Funding detailsNational Institute of Mental HealthNIMHR25 MH112473Foundation for Barnes-Jewish Hospital
Document Type: ArticlePublication Stage: FinalSource: Scopus
“Enhancing task fMRI preprocessing via individualized model‐based filtering of intrinsic activity dynamics” (2022) NeuroImage
Enhancing task fMRI preprocessing via individualized model‐based filtering of intrinsic activity dynamics(2022) NeuroImage, 247, art. no. 118836, .
Singh, M.F.a b c , Wang, A.a b , Cole, M.c , Ching, S.a d , Braver, T.S.b e
a Department of Electrical and Systems Engineering, Washington University in St. Louis, St. Louis, MO, United Statesb Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United Statesc Center for Molecular and Behavioral Neuroscience, Rutgers University, Newark, NJ 07102, United Statesd Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United Statese Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States
AbstractBrain responses recorded during fMRI are thought to reflect both rapid, stimulus-evoked activity and the propagation of spontaneous activity through brain networks. In the current work, we describe a method to improve the estimation of task-evoked brain activity by first “filtering-out the intrinsic propagation of pre-event activity from the BOLD signal. We do so using Mesoscale Individualized NeuroDynamic (MINDy; Singh et al. 2020b) models built from individualized resting-state data to subtract the propagation of spontaneous activity from the task-fMRI signal (MINDy-based Filtering). After filtering, time-series are analyzed using conventional techniques. Results demonstrate that this simple operation significantly improves the statistical power and temporal precision of estimated group-level effects. Moreover, use of MINDy-based filtering increased the similarity of neural activation profiles and prediction accuracy of individual differences in behavior across tasks measuring the same construct (cognitive control). Thus, by subtracting the propagation of previous activity, we obtain better estimates of task-related neural effects. © 2021
Author KeywordsBrain dynamics; Causal modeling; Cognitive control; Individual differences; Resting state fMRI; Task fMRI
Funding detailsNational Science FoundationNSFT32 DA007261-29National Institute of Mental HealthNIMHNational Institute on Drug AbuseNIDAR37 MH066078Air Force Office of Scientific ResearchAFOSR1509342, 15RT0189, 1835209, NSF CMMI 1537015Burroughs Wellcome FundBWF
Document Type: ArticlePublication Stage: FinalSource: Scopus
“APC7 mediates ubiquitin signaling in constitutive heterochromatin in the developing mammalian brain” (2022) Molecular Cell
APC7 mediates ubiquitin signaling in constitutive heterochromatin in the developing mammalian brain(2022) Molecular Cell, 82 (1), pp. 90-105.e13.
Ferguson, C.J.a b , Urso, O.a , Bodrug, T.c , Gassaway, B.M.d , Watson, E.R.e , Prabu, J.R.e , Lara-Gonzalez, P.f g , Martinez-Chacin, R.C.h , Wu, D.Y.a , Brigatti, K.W.i , Puffenberger, E.G.i , Taylor, C.M.j , Haas-Givler, B.j , Jinks, R.N.k , Strauss, K.A.i , Desai, A.f g , Gabel, H.W.a , Gygi, S.P.d , Schulman, B.A.e , Brown, N.G.h , Bonni, A.a
a Department of Neuroscience, Washington University, St. Louis, MO 63110, United Statesb Department of Pathology & Immunology, Neuropathology Division, Physician-Scientist Training Program, Washington University, St. Louis, MO 63110, United Statesc Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United Statesd Department of Cell Biology, Harvard University, Boston, MA 02138, United Statese Max Planck Institute for Biochemistry, Munich, Germanyf Department of Cellular and Molecular Medicine, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, United Statesg Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, United Statesh Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, United Statesi Clinic for Special Children, Strasburg, PA 17579, United Statesj Geisinger Autism & Developmental Medicine Institute, Lewisburg, PA 17837, United Statesk Department of Biology, Franklin and Marshall College, Lancaster, PA 17603, United States
AbstractNeurodevelopmental cognitive disorders provide insights into mechanisms of human brain development. Here, we report an intellectual disability syndrome caused by the loss of APC7, a core component of the E3 ubiquitin ligase anaphase promoting complex (APC). In mechanistic studies, we uncover a critical role for APC7 during the recruitment and ubiquitination of APC substrates. In proteomics analyses of the brain from mice harboring the patient-specific APC7 mutation, we identify the chromatin-associated protein Ki-67 as an APC7-dependent substrate of the APC in neurons. Conditional knockout of the APC coactivator protein Cdh1, but not Cdc20, leads to the accumulation of Ki-67 protein in neurons in vivo, suggesting that APC7 is required for the function of Cdh1-APC in the brain. Deregulated neuronal Ki-67 upon APC7 loss localizes predominantly to constitutive heterochromatin. Our findings define an essential function for APC7 and Cdh1-APC in neuronal heterochromatin regulation, with implications for understanding human brain development and disease. © 2021 Elsevier Inc.
Author Keywordsanaphase-promoting complex; APC7; brain; Cdh1; chromatin; heterochromatin; Ki-67; neurodevelopment; ubiquitin; ubiquitin ligase
Funding detailsP30CA021765, R37GM065930National Science FoundationNSFDGE-1650116, OD021629, R01GM074215National Institutes of HealthNIHK08HD099314, NS051255, R35GM128855Max-Planck-GesellschaftMPGGM67945, T32GM008570
Document Type: ArticlePublication Stage: FinalSource: Scopus
“Psychotic-like Experiences and Polygenic Liability in the Adolescent Brain Cognitive Development Study” (2022) Biological Psychiatry: Cognitive Neuroscience and Neuroimaging
Psychotic-like Experiences and Polygenic Liability in the Adolescent Brain Cognitive Development Study(2022) Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, 7 (1), pp. 45-55.
Karcher, N.R.a , Paul, S.E.b , Johnson, E.C.a , Hatoum, A.S.a , Baranger, D.A.A.c , Agrawal, A.a , Thompson, W.K.d , Barch, D.M.a b , Bogdan, R.b
a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United Statesb Department of Psychological and Brain Sciences, Washington University, St. Louis, MO, United Statesc Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United Statesd Population Neuroscience and Genetics Laboratory, University of California San Diego, San Diego, CA, United States
AbstractBackground: Childhood psychotic-like experiences (PLEs) often precede the development of later severe psychopathology. This study examined whether childhood PLEs are associated with several psychopathology-related polygenic scores (PGSs) and additionally examined possible neural and behavioral mechanisms. Methods: Adolescent Brain Cognitive Development Study baseline data from children with European ancestry (n = 4650, ages 9–10 years, 46.8% female) were used to estimate associations between PLEs (i.e., both total and presence of significantly distressing) and PGSs for psychopathology (i.e., schizophrenia, psychiatric cross-disorder risk, PLEs) and related phenotypes (i.e., educational attainment [EDU], birth weight, inflammation). We also assessed whether variability in brain structure indices (i.e., volume, cortical thickness, surface area) and behaviors proximal to PGSs (e.g., cognition for EDU) indirectly linked PGSs to PLEs using mediational models. Results: Total and significantly distressing PLEs were associated with EDU and cross-disorder PGSs (all %ΔR2s = 0.202%–0.660%; false discovery rate–corrected ps <.006). Significantly distressing PLEs were also associated with higher schizophrenia and PLE PGSs (both %ΔR2 = 0.120%–0.216%; false discovery rate–corrected ps <.03). There was evidence that global brain volume metrics and cognitive performance indirectly linked EDU PGS to PLEs (estimated proportion mediated = 3.33%–32.22%). Conclusions: Total and significantly distressing PLEs were associated with genomic risk indices of broad-spectrum psychopathology risk (i.e., EDU and cross-disorder PGSs). Significantly distressing PLEs were also associated with genomic risk for psychosis (i.e., schizophrenia, PLEs). Global brain volume metrics and PGS-proximal behaviors represent promising putative intermediary phenotypes that may indirectly link genomic risk to psychopathology. Broadly, polygenic scores derived from genome-wide association studies of adult samples generalize to indices of psychopathology risk among children. © 2021 Society of Biological Psychiatry
Author KeywordsEducational attainment; MRI; Polygenic; Psychopathology; Psychotic-like experiences; Schizophrenia
Funding detailsNational Institutes of HealthNIHDA032573, F32 AA027435, K23MH121792, L30MH120574, MH109532, R01-AG045231, R01-AG052564, R01-DA046224, R01-HD083614, R21-AA027827, T32-DA007261, U01 DA041120, U01DA041022, U01DA041025, U01DA041028, U01DA041048, U01DA041089, U01DA041093, U01DA041106, U01DA041117, U01DA041134, U01DA041148, U01DA041156, U01DA041174, U24DA041123, U24DA041147
Document Type: ArticlePublication Stage: FinalSource: Scopus
“Assessing potentiation of the (α4)3(β2)2 nicotinic acetylcholine receptor by the allosteric agonist CMPI” (2022) Journal of Biological Chemistry
Assessing potentiation of the (α4)3(β2)2 nicotinic acetylcholine receptor by the allosteric agonist CMPI(2022) Journal of Biological Chemistry, 298 (1), art. no. 101455, .
Deba, F.a , Munoz, K.b , Peredia, E.a , Akk, G.c d , Hamouda, A.K.a
a Department of Pharmaceutical Sciences, University of Texas at Tyler, Tyler, TX, United Statesb Department of Pharmaceutical Sciences, Texas A&M HSC, Kingsville, TX, United Statesc Department of Anesthesiology, Washington University in St. Louis, St. Louis, MO, United Statesd The Taylor Family Institute for Innovative Psychiatric Research, Washington University in St. Louis, St. Louis, MO, United States
AbstractThe extracellular domain of the nicotinic acetylcholine receptor isoforms formed by three α4 and two β2 subunits ((α4) 3(β2)2 nAChR) harbors two high-affinity “canonical” acetylcholine (ACh)-binding sites located in the two α4:β2 intersubunit interfaces and a low-affinity “noncanonical” ACh-binding site located in the α4:α4 intersubunit interface. In this study, we used ACh, cytisine, and nicotine (which bind at both the α4:α4 and α4:β2 interfaces), TC-2559 (which binds at the α4:β2 but not at the α4:α4 interface), and 3-(2-chlorophenyl)-5-(5-methyl-1-(piperidin-4-yl)-1H-pyrrazol-4-yl)isoxazole (CMPI, which binds at the α4:α4 but not at the α4:β2 interface), to investigate the binding and gating properties of CMPI at the α4:α4 interface. We recorded whole-cell currents from Xenopus laevis oocytes expressing (α4)3(β2)2 nAChR in response to applications of these ligands, alone or in combination. The electrophysiological data were analyzed in the framework of a modified Monod-Wyman-Changeux allosteric activation model. We show that CMPI is a high-affinity, high-efficacy agonist at the α4:α4 binding site and that its weak direct activating effect is accounted for by its inability to productively interact with the α4:β2 sites. The data presented here enhance our understanding of the functional contributions of ligand binding at the α4:α4 subunit interface to (α4)3(β2)2 nAChR-channel gating. These findings support the potential use of α4:α4 specific ligands to increase the efficacy of the neurotransmitter ACh in conditions associated with decline in nAChRs activity in the brain. © 2021 THE AUTHORS. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Document Type: ArticlePublication Stage: FinalSource: Scopus
“The National Institute on Aging Late-Onset Alzheimer’s Disease Family Based Study: A resource for genetic discovery” (2022) Alzheimer’s and Dementia
The National Institute on Aging Late-Onset Alzheimer’s Disease Family Based Study: A resource for genetic discovery(2022) Alzheimer’s and Dementia, .
Reyes-Dumeyer, D.a , Faber, K.b , Vardarajan, B.a , Goate, A.c , Renton, A.c , Chao, M.c , Boeve, B.d , Cruchaga, C.e , Pericak-Vance, M.f , Haines, J.L.g , Rosenberg, R.h , Tsuang, D.i , Sweet, R.A.j , Bennett, D.A.k , Wilson, R.S.k , Foroud, T.b , Mayeux, R.a
a Department of Neurology, Taub Institute for Research on Alzheimer’s Disease and the Aging Brain and the Gertrude H. Sergievsky Center, Columbia University in the City of New York, New York, NY, United Statesb Department of Medical and Molecular Genetics, National Centralized Repository for Alzheimer’s Disease and Related Dementias (NCRAD), Indiana University School of Medicine, Indianapolis, IN, United Statesc Department of Genetics & Genomic Sciences, Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, NY, United Statesd Department of Neurology, Mayo Clinic, Rochester, MN, United Statese Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United Statesf John P. Hussman Institute for Human Genomics, Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, United Statesg Department of Population & Quantitative Health Sciences and Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, United Statesh Department of Neurology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, United Statesi GRECC VA Puget Sound, Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, United Statesj Departments of Psychiatry and Neurology, University of Pittsburgh, Pittsburgh, PA, United Statesk Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, United States
AbstractIntroduction: The National Institute on Aging Late-Onset Alzheimer’s Disease Family Based Study (NIA-LOAD FBS) was established to study the genetic etiology of Alzheimer’s disease (AD). Methods: Recruitment focused on families with two living affected siblings and a third first-degree relative similar in age with or without dementia. Uniform assessments were completed, DNA was obtained, as was neuropathology, when possible. Apolipoprotein E (APOE) genotypes, genome-wide single nucleotide polymorphism (SNP) arrays, and sequencing was completed in most families. Results: APOE genotype modified the age-at-onset in many large families. Novel variants and known variants associated with early- and late-onset AD and frontotemporal dementia were identified supporting an international effort to solve AD genetics. Discussion: The NIA-LOAD FBS is the largest collection of familial AD worldwide, and data or samples have been included in 123 publications addressing the genetic etiology of AD. Genetic heterogeneity and variability in the age-at-onset provides opportunities to investigate the complexity of familial AD. © 2021 The Authors. Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.
Funding detailsNational Institutes of HealthNIHU.S. Department of DefenseDODNational Institute of Mental HealthNIMHNational Institute on AgingNIAMichael J. Fox Foundation for Parkinson’s ResearchMJFFAlzheimer’s AssociationAAAmerican Academy of NeurologyAANJPB FoundationSächsische AufbaubankSAB
Document Type: ArticlePublication Stage: Article in PressSource: Scopus
“Hypothesizing in the Face of the Opioid Crisis Coupling Genetic Addiction Risk Severity (GARS) Testing with Electrotherapeutic Nonopioid Modalities Such As H-Wave Could Attenuate Both Pain and Hedonic Addictive Behaviors” (2022) International Journal of Environmental Research and Public Health
Hypothesizing in the Face of the Opioid Crisis Coupling Genetic Addiction Risk Severity (GARS) Testing with Electrotherapeutic Nonopioid Modalities Such As H-Wave Could Attenuate Both Pain and Hedonic Addictive Behaviors(2022) International Journal of Environmental Research and Public Health, 19 (1), art. no. 552, .
Gupta, A.a , Bowirrat, A.b , Gomez, L.L.c , Baron, D.d , Elman, I.e f , Giordano, J.g , Jalali, R.c h , Badgaiyan, R.D.i , Modestino, E.J.j , Gold, M.S.k , Braverman, E.R.c , Bajaj, A.l , Blum, K.c d h m n o p
a Future Biologics, Lawrenceville, GA 30043, United Statesb Department of Molecular Biology, Adelson School of Medicine, Ariel University, Ariel, 40700, Israelc The Kenneth Blum Behavioral & Neurogenetic Institute, Austin, TX 78701, United Statesd Graduate College, Western University Health Sciences, Pomona, CA 91766, United Statese Center for Pain and the Brain (P.A.I.N Group), Department of Anesthesiology, Critical Care & Pain Medicine, Boston Children’s Hospital, Boston, MA 02115, United Statesf Cambridge Health Alliance, Harvard Medical School, Cambridge, MA 02139, United Statesg South Beach Detox & Treatment Center, North Miami Beach, FL 33169, United Statesh Department of Precision Behavioral Management, Geneus Health, San Antonio, TX 78249, United Statesi Department of Psychiatry, South Texas Veteran Health Care System, Audie L. Murphy Memorial VA Hospital, Long School of Medicine, University of Texas Medical Center, San Antonio, TX 78229, United Statesj Department of Psychology, Curry College, Milton, MA 02186, United Statesk Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United Statesl Bajaj Chiropractic, New York, NY 10010, United Statesm Institute of Psychology, ELTE Eötvös Loránd University, Egyetem tér 1-3, Budapest, 1053, Hungaryn Department of Psychiatry, School of Medicine, University of Vermont, Burlington, VT 05405, United Stateso Centre for Genomics and Applied Gene Technology, Institute of Integrative Omics and Applied Biotechnology, Nonakuri, Purba Medinipur, West Bengal721172, Indiap Department of Psychiatry, Wright State University Boonshoft School of Medicine and Dayton VA Medical Centre, Dayton, OH 45324, United States
AbstractIn the United States, amid the opioid overdose epidemic, nonaddicting/nonpharmacological proven strategies are available to treat pain and manage chronic pain effectively without opioids. Evidence supporting the long-term use of opioids for pain is lacking, as is the will to alter the drug-embracing culture in American chronic pain management. Some pain clinicians seem to prefer classical analgesic agents that promote unwanted tolerance to analgesics and subsequent biological induction of the “addictive brain”. Reward genes play a vital part in modulation of nociception and adaptations in the dopaminergic circuitry. They may affect various sensory and affective components of the chronic pain syndromes. The Genetic Addiction Risk Severity (GARS) test coupled with the H-Wave at entry in pain clinics could attenuate pain and help prevent addiction. The GARS test results identify high-risk for both drug and alcohol, and H-Wave can be initiated to treat pain instead of opioids. The utilization of H-Wave to aid in pain reduction and mitigation of hedonic addictive behaviors is recommended, notwithstanding required randomized control studies. This frontline approach would reduce the possibility of long-term neurobiological deficits and fatalities associated with potent opioid analgesics. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.
Author KeywordsGenetic Addiction Risk Severity (GARS); H-Wave; Hypodopaminism; RDS; Reward Deficiency Syndrome; Substance use disorder
Funding detailsNational Institutes of HealthNIHR01NS073884
Document Type: ArticlePublication Stage: FinalSource: Scopus
“IL-1 reprogramming of adult neural stem cells limits neurocognitive recovery after viral encephalitis by maintaining a proinflammatory state” (2022) Brain, Behavior, and Immunity
IL-1 reprogramming of adult neural stem cells limits neurocognitive recovery after viral encephalitis by maintaining a proinflammatory state(2022) Brain, Behavior, and Immunity, 99, pp. 383-396.
Soung, A.L.a b , Davé, V.A.a b , Garber, C.a b , Tycksen, E.D.c , Vollmer, L.L.a b , Klein, R.S.a b d e
a Center for Neuroimmunology & Neuroinfectious Diseases, Washington University School of Medicine, St. Louis, MO 63110, United Statesb Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, United Statesc McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO 63110, United Statesd Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, United Statese Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States
AbstractInnate immune responses to emerging RNA viruses are increasingly recognized as having significant contributions to neurologic sequelae, especially memory disorders. Using a recovery model of West Nile virus (WNV) encephalitis, we show that, while macrophages deliver the antiviral and anti-neurogenic cytokine IL-1β during acute infection; viral recovery is associated with continued astrocyte inflammasome-mediated production of inflammatory levels of IL-1β, which is maintained by hippocampal astrogenesis via IL-1R1 signaling in neural stem cells (NSC). Accordingly, aberrant astrogenesis is prevented in the absence of IL-1 signaling in NSC, indicating that only newly generated astrocytes exert neurotoxic effects, preventing synapse repair and promoting spatial learning deficits. Ex vivo evaluation of IL-1β-treated adult hippocampal NSC revealed the upregulation of developmental differentiation pathways that derail adult neurogenesis in favor of astrogenesis, following viral infection. We conclude that NSC-specific IL-1 signaling within the hippocampus during viral encephalitis prevents synapse recovery and promotes spatial learning defects via altered fates of NSC progeny that maintain inflammation. © 2021 The Author(s)
Author KeywordsAdult neural stem cell; Astrogenesis; Flavivirus encephalitis; Interleukin-1; Post-infectious cognitive dysfunction; Spatial learning; Synapse elimination
Funding detailsNational Science FoundationNSFDGE-1745038National Institutes of HealthNIHR012052632, R01NS104471, R01NS116788Center for Cellular Imaging, Washington UniversityWUCCI
Document Type: ArticlePublication Stage: FinalSource: Scopus
“Experimental Pain and Auditory Sensitivity in Overactive Bladder Syndrome: A Symptoms of the Lower Urinary Tract Dysfunction Research Network (LURN) Study” (2022) Journal of Urology
Experimental Pain and Auditory Sensitivity in Overactive Bladder Syndrome: A Symptoms of the Lower Urinary Tract Dysfunction Research Network (LURN) Study(2022) Journal of Urology, 207 (1), pp. 161-171.
Harte, S.E.a , Wiseman, J.b , Wang, Y.c , Smith, A.R.b , Yang, C.C.d , Helmuth, M.b , Kreder, K.e , Kruger, G.H.a , Gillespie, B.W.b , Amundsen, C.f , Kirkali, Z.g , Lai, H.H.h
a Chronic Pain and Fatigue Research Center, Department of Anesthesiology, University of Michigan, Medical School, Ann Arbor, MI, United Statesb Arbor Research Collaborative for Health, Ann Arbor, MI, United Statesc Department of Anesthesia, Stark Neurosciences Research Institute, Indiana University, School of Medicine, Indianapolis, IN, United Statesd Department of Urology, University of Washington, Seattle, WA, United Statese Department of Urology, University of Iowa, Iowa City, IA, United Statesf Department of Obstetrics and Gynecology, Duke University, Durham, NC, United Statesg National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United Statesh Division of Urologic Surgery, Departments of Surgery and Anesthesiology, Washington University, School of Medicine, St. Louis, MO, United States
AbstractPurpose:The objective of this study was to investigate the presence of nonbladder sensory abnormalities in participants with overactive bladder syndrome (OAB).Materials and Methods:Symptoms of Lower Urinary Tract Dysfunction Research Network (LURN) study participants with OAB symptoms and controls were recruited from 6 U.S. tertiary referral centers. Quantitative sensory testing (QST) was performed to determine pressure pain sensitivity at the thumbnail bed and auditory sensitivity. Fixed and mixed effect multivariable linear regressions and Weibull models were used to compare QST responses between groups. Pearson correlations were used to assess the relationship between QST measures. Associations between QST and self-reported symptoms were explored with linear regression.Results:A total of 297 participants were analyzed (191 OAB, 106 controls; 76% white, 51% male). OAB cases were older than controls (57.4 vs 52.2 years, p=0.015). No significant differences in experimental thumbnail (nonbladder) pain or auditory sensitivity were detected between OAB cases and controls. Correlations between pressure and auditory derived metrics were weak to moderate overall for both groups, with some significantly stronger correlations for cases. Exploratory analyses indicated increased pressure pain and auditory sensitivity were modestly associated with greater self-reported bladder pain and pain interference with physical function.Conclusions:As a group, no significant differences between OAB cases and controls were observed in experimental nonbladder pain or auditory sensitivity during QST. Associations between QST outcomes and clinical pain raise the possibility of centrally mediated sensory amplification in some individuals with OAB. © 2022 Lippincott Williams and Wilkins. All rights reserved.
Author Keywordsauditory perception; central nervous system sensitization; pain perception; pain threshold, pain measurement
Funding details5K99AT010012National Institutes of HealthNIHNational Institute of Diabetes and Digestive and Kidney DiseasesNIDDKDK097772, DK097779, DK097780, DK099879, DK099932, DK100011, DK100017Eli Lilly and CompanyNational Center for Advancing Translational SciencesNCATSUL1TR001422Northwestern UniversityNUIndiana University Health
Document Type: ArticlePublication Stage: FinalSource: Scopus
“The Impact of Age on Noise Sensitivity in Cochlear Implant Recipients” (2022) Otology and Neurotology
The Impact of Age on Noise Sensitivity in Cochlear Implant Recipients(2022) Otology and Neurotology, 43 (1), pp. 72-79.
Shew, M.A., Herzog, J.A., Kallogjeri, D., Chen, S., Wick, C., Durakovic, N., McJunkin, J., Buchman, C.A.
Department of Otolaryngology Head and Neck Surgery, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
AbstractObjective:To evaluate the impact of different open set sentence recognition tests in quiet, +10 dB signal to noise ratio (SNR), and +5 dB SNR in adult cochlear implant (CI) recipients above and below 65 years of age.Study Design and Setting:Multi-institution, prospective, non-randomized, single-subject repeated measures design.Patients:Ninety six adults more than or equal to 18 years old with postlingual bilateral sensorineural hearing loss.Interventions:Participants received a CI532 in one ear. Speech perception measures were evaluated before and 6-months after activation.Main Outcome Measure(s):Subjects completed consonant-nucleus-constant (CNC) words in quiet and AzBio sentences in noise using +10 and +5 dB SNR, and Montreal Cognitive Assessment (MOCA).Results:Ninety six adult patients were enrolled (n = 70 older [≥65 yr], n = 26 younger [<65 yr]). There was no difference in CNC scores (CI alone 58.4% versus 67.5%, p = 0.0857; best aided 66.7% versus 76.1%, p = 0.3357). Older adults performed worse on AzBio +10 dB SNR compared with younger patients (CI alone 37.4% versus 56.9%, p = 0.0006; best aided 51.4% versus 68.2%; p = 0.01), and in AzBio +5 dB SNR (CI alone 7.7% versus 11.2%, p = 0.0002; best aided 15.3% versus 22.3%, p = 0.0005). The magnitude of change in AzBio +10 dB SNR was significantly less in older adults in CI alone (15.3% versus 22.3%; p = 0.0493) but not best aided (21.5% versus 31.3%; p = 0.105). The magnitude of change was drastically worse in AzBio +5 dB SNR for older adults (CI alone 6.7% versus 22.1%, p = 0.0014; best aided 9.5% versus 21.5%; p = 0.0142). There was no significant difference in MOCA between the two age groups.Conclusions:While both older and younger patients have similar outcomes with respect to CNC word scores in quiet, the addition of noise disproportionally impacts older patients. Caution should be exercised testing the elderly in noise; testing in noise may disproportionally impact performance expectations and should be more carefully considered when used for candidacy criteria and counseling. Future studies need to further investigate the disproportionate effect of noise on candidacy testing and its impact on how elderly patients are qualified. © 2022 Lippincott Williams and Wilkins. All rights reserved.
Author KeywordsCochlear implant; Cochlear implant candidacy; Elderly; Speech perception
Funding detailsCochlear
Document Type: ArticlePublication Stage: FinalSource: Scopus
“Relationship between Intraoperative Electrocochleography and Hearing Preservation” (2022) Otology and Neurotology
Relationship between Intraoperative Electrocochleography and Hearing Preservation(2022) Otology and Neurotology, 43 (1), pp. E72-E78.
Lenarz, T.a , Buechner, A.a , Gantz, B.b , Hansen, M.b , Tejani, V.D.b , Labadie, R.c , O’Connell, B.d , Buchman, C.A.e , Valenzuela, C.V.e , Adunka, O.F.f , Harris, M.S.g , Riggs, W.J.f , Fitzpatrick, D.h , Koka, K.i
a Hannover Medical School, Department of Otolaryngology, Hannover, Germanyb University of Iowa, Department of Otolaryngology, Iowa City, IA, United Statesc Vanderbilt University and Medical Center, Department of Otolaryngology, Nashville, TN, United Statesd Charlotte Eye Ear Nose and Throat Associates, P.A., Charlotte, NC, United Statese Washington University School of Medicine, Department of Otolaryngology – Head and Neck Surgery, St. Louis, MO, United Statesf The Ohio State University, Department of Otolaryngology, Columbus, OH, United Statesg Medical College of Wisconsin, Milwaukee, WI, United Statesh University of North Carolina at Chapel Hill, Department of Otolaryngology, Chapel Hill, NC, United Statesi Advanced Bionics LLC, Research and Technology, Valencia, CA, United States
AbstractObjectives:To compare intraoperative intracochlear electrocochleography (ECochG) with hearing preservation outcomes in cochlear implant (CI) subjects.Design:Intraoperative electrocochleography was performed in adult CI subjects who were recipients of Advanced Bionics’ Bionics LLC precurved HiFocus MidScala or straight HiFocus SlimJ electrode arrays. ECochG responses were recorded from the most apical electrode contact during insertion. No changes to the insertions were made due to ECochG monitoring. No information about insertion resistance was collected. ECochG drops were estimated as the change in amplitude from peak (defined as maximum amplitude response) to drop (largest drop) point after the peak during insertion was measured following the peak response. Audiometric thresholds from each subject were obtained before and approximately 1 month after CI surgery. The change in pure tone average for frequencies between 125 Hz and 500 Hz was measured after surgery. No postoperative CT scans were collected as part of this study.Results:A total of 68 subjects from five surgical centers participated in the study. The study sample included 30 MidScala and 38 SlimJ electrodes implanted by approximately 20 surgeons who contributed to the study. Although a wide range of results were observed, there was a moderate positive correlation (Pearson Correlation coefficient, r = 0.56, p < 0.01) between the size of the ECochG drop and the magnitude of pure tone average change. This trend was present for both the MidScala and SlimJ arrays. The SlimJ and MidScala arrays produced significantly different hearing loss after surgery.Conclusion:Large ECochG amplitude drops observed during electrode insertion indicated poorer hearing preservation. Although the outcomes were variable, this information may be helpful to guide surgical decision-making when contemplating full electrode insertion and the likelihood of hearing preservation. © 2022 Lippincott Williams and Wilkins. All rights reserved.
Author KeywordsActive insertion monitoring; AIM; Cochlear implants; ECochG; Electrocochleography; Hearing preservation; Intraoperative monitoring; MidScala; SlimJ
Funding detailsNational Institutes of HealthNIHT32DC000022National Institute on Deafness and Other Communication DisordersNIDCD
Document Type: ArticlePublication Stage: FinalSource: Scopus
“Preparation of Giant Escherichia coli spheroplasts for Electrophysiological Recordings” (2021) Bio-protocol
Preparation of Giant Escherichia coli spheroplasts for Electrophysiological Recordings(2021) Bio-protocol, 11 (24), art. no. e4261, .
Jiang, Y.a b c , Idikuda, V.d e , Chanda, B.d e
a Department of Psychiatry, First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, Chinab Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, Chinac The MOE Frontier Research Center of Brain and Brain-machine Integration, Zhejiang University, School of Brain Science and Brain Medicine, Chinad Department of Anesthesiology, Washington University, School of Medicine, St. Louis, MO, United Statese Center for the Investigation of Membrane Excitability Diseases (CIMED)
AbstractProkaryotic ion channels have been instrumental in furthering our understanding of many fundamental aspects of ion channels’ structure and function. However, characterizing the biophysical properties of a prokaryotic ion channel in a native membrane system using patch-clamp electrophysiology is technically challenging. Patch-clamp is regarded as a gold standard technique to study ion channel properties in both native and heterologous expression systems. The presence of a cell wall and the small size of bacterial cells makes it impossible to directly patch clamp using microelectrodes. Here, we describe a method for the preparation of giant E. coli spheroplasts in order to investigate the electrophysiological properties of bacterial cell membranes. Spheroplasts are formed by first inhibiting bacterial cell wall synthesis, followed by enzymatic digestion of the outer cell wall in the presence of a permeabilizing agent. This protocol can be used to characterize the function of any heterologous ion channels or ion transporters expressed in E. coli membranes. © 2021 The Authors.
Author KeywordsBacteria patch clamp; E. coli spheroplast; Electrophysiology; Ion channels; Prokaryotes
Document Type: ArticlePublication Stage: FinalSource: Scopus
“Investigating Late-Onset Pompe Prevalence in Neuromuscular Medicine Academic Practices the IPaNeMA Study” (2021) Neurology: Genetics
Investigating Late-Onset Pompe Prevalence in Neuromuscular Medicine Academic Practices the IPaNeMA Study(2021) Neurology: Genetics, 7 (6), art. no. e623, .
Wencel, M.a , Shaibani, A.b , Goyal, N.A.a , Dimachkie, M.M.c , Trivedi, J.d , Johnson, N.E.e f , Gutmann, L.g h , Wicklund, M.P.j k , Bandyopadhay, S.i , Genge, A.L.l , Freimer, M.L.m , Goyal, N.n , Pestronk, A.o p q , Florence, J.o , Karam, C.p q , Ralph, J.W.r , Rasheed, Z.b , Hays, M.c , Hopkins, S.d , Mozaffar, T.a s
a Department of Neurology, University of California, Irvine, United Statesb Nerve and Muscle Center of Texas, Houston, TX, United Statesc Department of Neurology, University of Kansas Medical Center, Dallas, United Statesd Department of Neurology and Neurotherapeutics, University of Texas Southwestern, Dallas, United Statese Department of Neurology, Virginia Commonwealth University, Richmond, United Statesf University of Utah, Salt Lake City, United Statesg Department of Neurology, Indiana University, School of Medicine, Indianapolis, United Statesh University of Iowa, United Statesi Department of Neurology, Pennsylvania State University, Hershey, United Statesj Department of Neurology, UC DenverCO, United Statesk Department of Neurology, Pennsylvania State University, Hershey, United Statesl Department of Neurology, Montreal Neurological Institute, McGill University, Montreal, QC, Canadam Department of Neurology, Ohio State University, Columbus, United Statesn Department of Neurology, Stanford University, Palo Alto, CA, United Stateso Department of Neurology and Pathology, Washington University, St. Louis, MO, United Statesp Department of Neurology, University of Pennsylvania, Philadelphia, United Statesq Oregon Health and Science University, Portland, United Statesr Department of Neurology, University of California, San Francisco, United Statess Departments of Neurology, Orthopaedic Surgery and Pathology and Laboratory Medicine, University of California, Irvine, United States
AbstractBackground 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. Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
Funding detailsNational Institutes of HealthNIHCenters for Disease Control and PreventionCDCDD19-002U.S. Food and Drug AdministrationFDA7R01FD006071-02National Institute of Neurological Disorders and StrokeNINDS4K23NS091511, R01NS104010Bristol-Myers SquibbBMSSanofiMuscular Dystrophy AssociationMDABiogenAlexion PharmaceuticalsCytokineticsCYTKMyositis AssociationTMA
Document Type: ArticlePublication Stage: FinalSource: Scopus
“AD-linked R47H-TREM2 mutation induces disease-enhancing microglial states via AKT hyperactivation” (2021) Science Translational Medicine
AD-linked R47H-TREM2 mutation induces disease-enhancing microglial states via AKT hyperactivation(2021) Science Translational Medicine, 13 (622), art. no. abe3947, .
Sayed, F.A.a b , Kodama, L.a b c d , Fan, L.c , Carling, G.K.c , Udeochu, J.C.c , Le, D.b , Li, Q.e , Zhou, L.e , Ying Wong, M.c , Horowitz, R.c , Ye, P.c , Mathys, H.f , Wang, M.g , Niu, X.h , Mazutis, L.i , Jiang, X.f , Wang, X.c , Gao, F.j , Brendel, M.k , Telpoukhovskaia, M.b , Tracy, T.E.b , Frost, G.l , Zhou, Y.b , Li, Y.b , Qiu, Y.m , Cheng, Z.n , Yu, G.n , Hardy, J.o , Coppola, G.j , Wang, F.p , DeTure, M.A.q , Zhang, B.g , Xie, L.l , Trajnowski, J.Q.r , Lee, V.M.Y.r , Gong, S.c , Sinha, S.C.c , Dickson, D.W.q , Luo, W.c , Gan, L.b c
a Neuroscience Graduate Program, University of California San Francisco, San Francisco, CA 94158, United Statesb Gladstone Institute of Neurological Disease, San Francisco, CA 94107, United Statesc Helen and Robert Appel Alzheimer’s Disease Research Institute, Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10021, United Statesd Medical Scientist Training Program and Neuroscience Graduate Program, University of California San Francisco, San Francisco, CA 94143, United Statese Department of Neuroscience, Department of Genetics, Washington University, School of Medicine, St Louis, MO 63110, United Statesf The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, United Statesg Department of Genetics and Genomic Sciences, Icahn School of Medicine, Mount Sinai, NY 10029, United Statesh Tri-Institutional Computational Biology and Medicine Program, Weill Cornell Medical CollegeNY 10065, United Statesi Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, United Statesj Departments of Psychiatry and Neurology, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, United Statesk Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10021, United Statesl Chemical Biology Program, Weill Graduate School of Medical Sciences, Cornell University, New York, NY 10065, United Statesm Department of Computer Science, Hunter College, The Graduate Center, The City University of New York, New York, NY 10065, United Statesn Bradley Department of Electrical and Computer Engineering, Virginia Polytechnic Institute and State University, Arlington, VA 24061, United Stateso Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, Queen Square, London, WC1E 6BT, United Kingdomp Department of Population Health Sciences, Weill Cornell Medical College, New York, NY 10065, United Statesq Mayo Clinic, Jacksonville, FL 32224, United Statesr Center for Neurodegenerative Disease Research, University of Pennsylvania, School of Medicine, Philadelphia, PA 19104, United States
AbstractThe hemizygous R47H variant of triggering receptor expressed on myeloid cells 2 (TREM2), a microglia-specific gene in the brain, increases risk for late-onset Alzheimer’s disease (AD). Using transcriptomic analysis of single nuclei from brain tissues of patients with AD carrying the R47H mutation or the common variant (CV)-TREM2, we found that R47H-associated microglial subpopulations had enhanced inflammatory signatures reminiscent of previously identified disease-associated microglia (DAM) and hyperactivation of AKT, one of the signaling pathways downstream of TREM2. We established a tauopathy mouse model with heterozygous knock-in of the human TREM2 with the R47H mutation or CV and found that R47H induced and exacerbated TAU-mediated spatial memory deficits in female mice. Single-cell transcriptomic analysis of microglia from these mice also revealed transcriptomic changes induced by R47H that had substantial overlaps with R47H microglia in human AD brains, including robust increases in proinflammatory cytokines, activation of AKT signaling, and elevation of a subset of DAM signatures. Pharmacological AKT inhibition with MK-2206 largely reversed the enhanced inflammatory signatures in primary R47H microglia treated with TAU fibrils. In R47H heterozygous tauopathy mice, MK-2206 treatment abolished a tauopathy-dependent microglial subcluster and rescued tauopathy-induced synapse loss. By uncovering disease-enhancing mechanisms of the R47H mutation conserved in human and mouse, our study supports inhibitors of AKT signaling as a microglial modulating strategy to treat AD. © 2021 The Authors.
Document Type: ArticlePublication Stage: FinalSource: Scopus
“Long-term Hearing Preservation and Speech Perception Performance Outcomes with the Slim Modiolar Electrode” (2021) Otology and Neurotology
Long-term Hearing Preservation and Speech Perception Performance Outcomes with the Slim Modiolar Electrode(2021) Otology and Neurotology, 42 (10), pp. E1486-E1493.
Shew, M.A., Walia, A., Durakovic, N., Valenzuela, C., Wick, C.C., McJunkin, J.L., Buchman, C.A., Herzog, J.A.
Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
AbstractObjective:Describe audiologic outcomes in hearing preservation (HP) cochlear implant candidates using a slim modiolar electrode (SME).Study Design:Retrospective.Setting:Tertiary referral center.Patients:Two hundred three adult cochlear implant patients with preoperative low-frequency pure-tone average (LFPTA)≤80dB HL that received the SME.Intervention:Implantation with a SME electrode.Main Outcome Measures:Primary outcome was postoperative HP, defined as LFPTA ≤80dB HL. HP status was analyzed at “early” (activation or 3mo) and “long-term” (6 or 12mo) time frames using the patient’s worst audiogram. Speech perception tests were compared between HP and non-HP cohorts.Results:Of the 203 HP candidates, the tip fold-over rate was 7.4%. The mean shifts in LFPTA at the “early” and “long-term” time points were 25.9±16.2dB HL and 29.6±16.9dB HL, respectively. Of 117 patients with preoperative LFPTA ≤60dB HL, the early and long-term mean LFPTA shifts were 19.5±12.3dB HL and 32.6±17.2dB HL, respectively; early and long-term HP rates were 61.1% and 50.8%, respectively. For patients with preoperative LFPTA ≤80dB HL, early and long-term HP rates were 45.5% and 43.7%, respectively. No significant difference was observed in postoperative speech perception performance (CNC, AzBio, HINT) at 3, 6, or 12months between HP versus non-HP groups.Conclusions:HP is feasible using the SME. While electroacoustic stimulation was not studied in this cohort, HP provided no clear advantage in speech perception abilities in this group of patients. The current reporting standard of what constitutes HP candidacy (preoperative LFPTA ≤80dB HL) should be reconsidered. © 2021 Lippincott Williams and Wilkins. All rights reserved.
Author KeywordsCI532; CI632; Cochlear implant; Hearing preservation; Perimodiolar electrode
Document Type: ArticlePublication Stage: FinalSource: Scopus
“Biochemical profile of human infant cerebrospinal fluid in intraventricular hemorrhage and post-hemorrhagic hydrocephalus of prematurity” (2021) Fluids and Barriers of the CNS
Biochemical profile of human infant cerebrospinal fluid in intraventricular hemorrhage and post-hemorrhagic hydrocephalus of prematurity(2021) Fluids and Barriers of the CNS, 18 (1), art. no. 62, .
Otun, A.a , Morales, D.M.a , Garcia-Bonilla, M.a , Goldberg, S.b , Castaneyra-Ruiz, L.e , Yan, Y.c , Isaacs, A.M.d , Strahle, J.M.a , McAllister, J.P., IIa , Limbrick, D.D., Jr.a
a Department of Neurosurgery, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, United Statesb Department of Nephrology, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, United Statesc Department of Surgery, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, United Statesd Division of Neurosurgery, Department of Clinical Neurosciences, University of Calgary, Calgary, AB T2N 2T9, Canadae Children’s Hospital Orange County, Children’s Research Institute, Orange, CA 92868, United States
AbstractBackground: Intraventricular hemorrhage (IVH) and post-hemorrhagic hydrocephalus (PHH) have a complex pathophysiology involving inflammatory response, ventricular zone and cell–cell junction disruption, and choroid-plexus (ChP) hypersecretion. Increased cerebrospinal fluid (CSF) cytokines, extracellular matrix proteins, and blood metabolites have been noted in IVH/PHH, but osmolality and electrolyte disturbances have not been evaluated in human infants with these conditions. We hypothesized that CSF total protein, osmolality, electrolytes, and immune cells increase in PHH. Methods: CSF samples were obtained from lumbar punctures of control infants and infants with IVH prior to the development of PHH and any neurosurgical intervention. Osmolality, total protein, and electrolytes were measured in 52 infants (18 controls, 10 low grade (LG) IVH, 13 high grade (HG) IVH, and 11 PHH). Serum electrolyte concentrations, and CSF and serum cell counts within 1-day of clinical sampling were obtained from clinical charts. Frontal occipital horn ratio (FOR) was measured for estimating the degree of ventriculomegaly. Dunn or Tukey’s post-test ANOVA analysis were used for pair-wise comparisons. Results: CSF osmolality, sodium, potassium, and chloride were elevated in PHH compared to control (p = 0.012 − < 0.0001), LGIVH (p = 0.023 − < 0.0001), and HGIVH (p = 0.015 − 0.0003), while magnesium and calcium levels were higher compared to control (p = 0.031) and LGIVH (p = 0.041). CSF total protein was higher in both HGIVH and PHH compared to control (p = 0.0009 and 0.0006 respectively) and LGIVH (p = 0.034 and 0.028 respectively). These differences were not reflected in serum electrolyte concentrations nor calculated osmolality across the groups. However, quantitatively, CSF sodium and chloride contributed 86% of CSF osmolality change between control and PHH; and CSF osmolality positively correlated with CSF sodium (r, p = 0.55,0.0015), potassium (r, p = 0.51,0.0041), chloride (r, p = 0.60,0.0004), but not total protein across the entire patient cohort. CSF total cells (p = 0.012), total nucleated cells (p = 0.0005), and percent monocyte (p = 0.016) were elevated in PHH compared to control. Serum white blood cell count increased in PHH compared to control (p = 0.042) but there were no differences in serum cell differential across groups. CSF total nucleated cells also positively correlated with CSF osmolality, sodium, potassium, and total protein (p = 0.025 − 0.0008) in the whole cohort. Conclusions: CSF osmolality increased in PHH, largely driven by electrolyte changes rather than protein levels. However, serum electrolytes levels were unchanged across groups. CSF osmolality and electrolyte changes were correlated with CSF total nucleated cells which were also increased in PHH, further suggesting PHH is a neuro-inflammatory condition. © 2021, The Author(s).
Author KeywordsCerebrospinal fluid (CSF); CSF electrolytes; CSF osmolality; Intraventricular hemorrhage (IVH); Post-hemorrhagic hydrocephalus (PHH)
Funding detailsWashington State UniversityWSUCosmetic Surgery FoundationCSF
Document Type: ArticlePublication Stage: FinalSource: Scopus
“Cognitive response to testosterone replacement added to intensive lifestyle intervention in older men with obesity and hypogonadism: prespecified secondary analyses of a randomized clinical trial” (2021) The American Journal of Clinical Nutrition
Cognitive response to testosterone replacement added to intensive lifestyle intervention in older men with obesity and hypogonadism: prespecified secondary analyses of a randomized clinical trial(2021) The American Journal of Clinical Nutrition, 114 (5), pp. 1590-1599.
Gregori, G.a b , Celli, A.a b , Barnouin, Y.a b , Paudyal, A.a b , Armamento-Villareal, R.a b , Napoli, N.c , Qualls, C.d , Villareal, D.T.a b
a Center for Translational Research on Inflammatory Diseases, Michael E DeBakey VA Medical Center, TX, Houston, United Statesb Division of Endocrinology, Diabetes, Metabolism, Baylor College of Medicine, TX, Houston, United Statesc Division of Endocrinology and Metabolism, Washington University School of Medicine, St Louis, MO, USAd Department of Mathematics and Statistics, University of New Mexico School of Medicine, NM, Albuquerque, United States
AbstractBACKGROUND: Both obesity and hypogonadism are common in older men which could additively exacerbate age-related declines in cognitive function. However, little is known about the effects of lifestyle intervention plus testosterone replacement therapy in this population. OBJECTIVES: In this secondary analysis of the LITROS (Lifestyle Intervention and Testosterone Replacement in Obese Seniors) trial, we examined whether testosterone replacement therapy would improve cognitive function when added to intensive lifestyle intervention in older men with obesity and hypogonadism. METHODS: Eighty-three older, obese hypogonadal men with frailty were randomly assigned to lifestyle therapy (weight management and exercise training) plus testosterone (LT + Test) or lifestyle therapy plus placebo (LT + Pbo) for 6 mo. For this report, the primary outcome was change in the global cognition composite z score. Secondary outcomes included changes in z score subcomponents: attention/information processing, memory, executive function, and language. Changes between groups were analyzed using mixed-model repeated-measures ANCOVAs following the intention-to-treat principle. RESULTS: Global cognition z score increased more in the LT + Test than in the LT + Pbo group (mean change: 0.49 compared with 0.21; between-group difference: -0.28; 95% CI: -0.45, -0.11; Cohen’s d = 0.74). Moreover, attention/information z score and memory z score increased more in the LT + Test than in the LT + Pbo group (mean change: 0.55 compared with 0.23; between-group difference: -0.32; 95% CI: -0.55, -0.09; Cohen’s d = 0.49 and mean change: 0.90 compared with 0.37; between-group difference: -0.53; 95% CI: -0.93, -0.13; Cohen’s d = 1.43, respectively). Multiple regression analyses showed that changes in peak oxygen consumption, strength, total testosterone, and luteinizing hormone were independent predictors of the improvement in global cognition (R2 = 0.38; P < 0.001). CONCLUSIONS: These findings suggest that in the high-risk population of older men with obesity and hypogonadism, testosterone replacement may improve cognitive function with lifestyle behaviors controlled via lifestyle intervention therapy.This trial was registered at clinicaltrials.gov as NCT02367105. Published by Oxford University Press on behalf of the American Society for Nutrition 2021.
Author Keywordsadiposity; aging; androgens; cognition; diet; exercise; frailty; obesity
Document Type: ArticlePublication Stage: FinalSource: Scopus
“Environmental Thermal Stress Induces Neuronal Cell Death and Developmental Malformations in Reptiles” (2021) Integrative Organismal Biology
Environmental Thermal Stress Induces Neuronal Cell Death and Developmental Malformations in Reptiles(2021) Integrative Organismal Biology, 3 (1), art. no. obab033, .
Sanger, T.J.a , Harding, L.a , Kyrkos, J.a , Turnquist, A.J.a , Epperlein, L.a , Nunez, S.A.a , Lachance, D.a , Dhindsa, S.a , Stroud, J.T.b , Diaz, R.E.c , Czesny, B.a
a Department of Biology, Loyola University Chicago, 1050 Sheridan Rd., Chicago, IL 60660, United Statesb Department of Biology, Washington University in St. Louis, Campus Box 1137. One Brookings Drive, St. Louis, MO 63130-4899, United Statesc Department of Biological Sciences, California State University, Los Angeles, 5151 State University Dr., Los Angeles, CA 90032, United States
AbstractEvery stage of organismal life history is being challenged by global warming.Many species are already experiencing temperatures approaching their physiological limits; this is particularly true for ectothermic species, such as lizards. Embryos are markedly sensitive to thermal insult. Here, we demonstrate that temperatures currently experienced in natural nesting areas can modify gene expression levels and induce neural and craniofacial malformations in embryos of the lizard Anolis sagrei. Developmental abnormalities ranged from minor changes in facial structure to significant disruption of anterior face and forebrain. The first several days of postoviposition development are particularly sensitive to this thermal insult. These results raise new concern over the viability of ectothermic species under contemporary climate change. Herein, we propose and test a novel developmental hypothesis that describes the cellular and developmental origins of those malformations: Cell death in the developing forebrain and abnormal facial induction due to disrupted Hedgehog signaling. Based on similarities in the embryonic response to thermal stress among distantly related species, we propose that this developmental hypothesis represents a common embryonic response to thermal insult among amniote embryos. Our results emphasize the importance of adopting a broad, multidisciplinary approach that includes both lab and field perspectives when trying to understand the future impacts of anthropogenic change on animal development. © 2021 Pfizer and The Author(s). Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
Document Type: ArticlePublication Stage: FinalSource: Scopus
“Domains of delirium severity in Alzheimer’s disease and related dementias” (2021) Journal of the American Geriatrics Society
Domains of delirium severity in Alzheimer’s disease and related dementias(2021) Journal of the American Geriatrics Society, .
Schulman-Green, D.a , Hshieh, T.b c , Adamis, D.d e , Avidan, M.S.f , Blazer, D.G.g , Fick, D.M.h , Oh, E.i , Morandi, A.j k , Price, C.l , Verghese, J.m , Schmitt, E.M.c , Jones, R.N.n , Inouye, S.K.c o p , For the BASIL Study Groupq
a New York University Rory Meyers College of Nursing, New York, NY, United Statesb Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United Statesc Marcus Institute for Aging Research, Hebrew SeniorLife, Boston, MA, United Statesd Sligo Mental Health Services, Sligo, Irelande Research and Academic Institute of Athens, Athens, Greecef Washington University School of Medicine in St. Louis, St. Louis, MO, United Statesg Duke University School of Medicine, Durham, NC, United Statesh Penn State Ross and Carol Nese College of Nursing, University Park, PA, United Statesi The Johns Hopkins University School of Medicine, Baltimore, MD, United Statesj Fondazione Teresa Camplani, Cremona, Italyk Parc Sanitari Pere Virgili and Vall d’Hebrón Institute of Research, Barcelona, Spainl University of Florida College of Public Health and Health Professions, Gainesville, FL, United Statesm Albert Einstein School of Medicine, Bronx, NY, United Statesn Warren Alpert Medical School, Brown University, Providence, RI, United Stateso Harvard Medical School, Boston, MA, United Statesp Beth Israel Deaconess Medical Center, Boston, MA, United States
AbstractBackground: The ability to rate delirium severity is key to providing optimal care for persons with Alzheimer’s Disease and Related Dementias (ADRD). Such ratings would allow clinicians to assess response to treatment, recovery time and prognosis, nursing burden and staffing needs, and to provide nuanced, appropriate patient-centered care. Given the lack of existing tools, we defined content domains for a new delirium severity instrument for use in individuals with mild to moderate ADRD, the DEL-S-AD. Methods: We built upon our previous study in which we created a content domain framework to inform development of a general delirium severity instrument, the DEL-S. We engaged a new expert panel to discuss issues of measurement in delirium and dementia and to determine which content domains from the prior framework were useful in characterizing delirium severity in ADRD. We also asked panelists to identify new domains. Our panel included eight interdisciplinary members with expertise in delirium and dementia. Panelists participated in two rounds of review followed by two surveys over 2 months. Results: Panelists endorsed the same content domains as for general delirium severity, including Cognitive, Level of Consciousness, Inattention, Psychiatric-Behavioral, Emotional Dysregulation, Psychomotor Features, and Functional; however, they excluded six of the original subdomains which they considered unhelpful in the context of ADRD: cognitive impairment; anxiety; fear/sense of unease; depression; gait/walking; and incontinence. Debated measurement challenges included assessment at one point in time versus over time, accounting for differences in clinical settings, and accurate assessment of symptoms related to delirium versus dementia. Conclusions: By capturing a range of characteristics of delirium severity potentially present in patients with ADRD, a population that may already have attention, functional, and emotional changes at baseline, the DEL-S-AD provides a novel rating tool that will be useful for clinical and research purposes to improve patient care. © 2021 The American Geriatrics Society.
Author KeywordsADRD; delirium; dementia; expert panel; instrument
Funding detailsNational Institutes of HealthNIHNational Institute on AgingNIA01AG044518, 07AG066813, R33AG071744
Document Type: ArticlePublication Stage: Article in PressSource: Scopus