Medicine and Health Sciences Commons^™

Long-Term Survival Of Older Patients Hospitalized For Covid-19. Do Clinical Characteristics Upon Admission Matter?, Michał Chojnicki, Agnieszka Neumann-Podczaska, Mikołaj Seostianin, Zofia Tomczak, Hamza Tariq, Jerzy Chudek, Sławomir Tobis, Iwona Mozer-Lisewska, Aleksandra Suwalska, Andrzej Tykarski, Piotr Merks, Sylwia Kropińska, Małgorzata Sobieszczańska, Frank Romanelli, Katarzyna Wieczorowska-Tobis

Pharmacy Practice and Science Faculty Publications

Older adults are particularly susceptible to COVID-19 in terms of both disease severity and risk of death. To compare clinical differences between older COVID-19 hospitalized survivors and non-survivors, we investigated variables influencing mortality in all older adults with COVID-19 hospitalized in Poznań, Poland, through the end of June 2020 (n = 322). In-hospital, post-discharge, and overall 180-day mortality were analyzed. Functional capacity prior to COVID-19 diagnosis was also documented. The mean age of subjects was 77.5 ± 10.0 years; among them, 191 were females. Ninety-five (29.5%) died during their hospitalization and an additional 30 (9.3%) during the post-discharge period …

Reduced Mitochondrial Dna And Oxphos Protein Content In Skeletal Muscle Of Children With Cerebral Palsy, Ferdinand Von Walden, Ivan J. Vechetti Jr., Davis A. Englund, Vandré C. Figueiredo, Rodrigo Fernandez-Gonzalo, Kevin A. Murach, Jessica Pingel, John J. Mccarthy, Per Stål, Eva Pontén

Physiology Faculty Publications

AIM: To provide a detailed gene and protein expression analysis related to mitochondrial biogenesis and assess mitochondrial content in skeletal muscle of children with cerebral palsy (CP).

METHOD: Biceps brachii muscle samples were collected from 19 children with CP (mean [SD] age 15y 4mo [2y 6mo], range 9-18y, 16 males, three females) and 10 typically developing comparison children (mean [SD] age 15y [4y], range 7-21y, eight males, two females). Gene expression (quantitative reverse transcription polymerase chain reaction [PCR]), mitochondrial DNA (mtDNA) to genomic DNA ratio (quantitative PCR), and protein abundance (western blotting) were analyzed. Microarray data sets (CP/aging/bed rest) were …

Interleukin 1 Alpha Administration Is Neuroprotective And Neuro-Restorative Following Experimental Ischemic Stroke, Kathleen E. Salmeron, Michael E. Maniskas, Danielle N. Edwards, Raymond Wong, Ivana Rajkovic, Amanda L. Trout, Abir A. Rahman, Samantha Hamilton, Justin F. Fraser, Emmanuel Pinteaux, Gregory J. Bix

Sanders-Brown Center on Aging Faculty Publications

BACKGROUND: Stroke remains a leading cause of death and disability worldwide despite recent treatment breakthroughs. A primary event in stroke pathogenesis is the development of a potent and deleterious local and peripheral inflammatory response regulated by the pro-inflammatory cytokine interleukin-1 (IL-1). While the role of IL-1β (main released isoform) has been well studied in stroke, the role of the IL-1α isoform remains largely unknown. With increasing utilization of intravenous tissue plasminogen activator (t-PA) or thrombectomy to pharmacologically or mechanically remove ischemic stroke causing blood clots, respectively, there is interest in pairing successful cerebrovascular recanalization with neurotherapeutic pharmacological interventions (Fraser et …

Proteomic Alterations Of Hdl In Youth With Type 1 Diabetes And Their Associations With Glycemic Control: A Case-Control Study, Evgenia Gourgari, Junfeng Ma, Martin P. Playford, Nehal N. Mehta, Radoslav Goldman, Alan T. Remaley, Scott M. Gordon

Saha Cardiovascular Research Center Faculty Publications

Background: Patients with type 1 diabetes (T1DM) typically have normal or even elevated plasma high density lipoprotein (HDL) cholesterol concentrations; however, HDL protein composition can be altered without a change in cholesterol content. Alteration of the HDL proteome can result in dysfunctional HDL particles with reduced ability to protect against cardiovascular disease (CVD). The objective of this study was to compare the HDL proteomes of youth with T1DM and healthy controls (HC) and to evaluate the influence of glycemic control on HDL protein composition.

Methods: This was a cross-sectional case–control study. Blood samples were obtained from patients with T1DM and …

Efficacy Of Leukemia Inhibitory Factor As A Therapeutic For Permanent Large Vessel Stroke Differs Among Aged Male And Female Rats, Stephanie M. Davis, Lisa A. Collier, Sarah J. Goodwin, Douglas E. Lukins, David K. Powell, Keith R. Pennypacker

Neurology Faculty Publications

Preclinical studies using rodent models of stroke have had difficulty in translating their results to human patients. One possible factor behind this inability is the lack of studies utilizing aged rodents of both sexes. Previously, this lab showed that leukemia inhibitory factor (LIF) promoted recovery after stroke through antioxidant enzyme upregulation. This study examined whether LIF promotes neuroprotection in aged rats of both sexes. LIF did not reduce tissue damage in aged animals, but LIF-treated female rats showed partial motor skill recovery. The LIF receptor (LIFR) showed membrane localization in young male and aged rats of both sexes after stroke. …

Saturated Fatty Acid Activates T Cell Inflammation Through A Nicotinamide Nucleotide Transhydrogenase (Nnt)-Dependent Mechanism, Grace Mccambridge, Madhur Agrawal, Alanna Keady, Philip A. Kern, Hatice Hasturk, Barbara S. Nikolajczyk, Leena P. Bharath

Pharmacology and Nutritional Sciences Faculty Publications

Circulating fatty acids (FAs) increase with obesity and can drive mitochondrial damage and inflammation. Nicotinamide nucleotide transhydrogenase (NNT) is a mitochondrial protein that positively regulates nicotinamide adenine dinucleotide phosphate (NADPH), a key mediator of energy transduction and redox homeostasis. The role that NNT-regulated bioenergetics play in the inflammatory response of immune cells in obesity is untested. Our objective was to determine how free fatty acids (FFAs) regulate inflammation through impacts on mitochondria and redox homeostasis of peripheral blood mononuclear cells (PBMCs). PBMCs from lean subjects were activated with a T cell-specific stimulus in the presence or absence of generally pro-inflammatory …

Distinct White Matter Changes Associated With Cerebrospinal Fluid Amyloid-Β1-42 And Hypertension, Omar M. Al-Janabi, Christopher A. Brown, Ahmed A. Bahrani, Erin L. Abner, Justin M. Barber, Brian T. Gold, Larry B. Goldstein, Richard R. Murphy, Peter T. Nelson, Nathan F. Johnson, Leslie M. Shaw, Charles D. Smith, John Q. Trojanowski, Donna M. Wilcock, Gregory A. Jicha

Sanders-Brown Center on Aging Faculty Publications

BACKGROUND: Alzheimer's disease (AD) pathology and hypertension (HTN) are risk factors for development of white matter (WM) alterations and might be independently associated with these alterations in older adults.

OBJECTIVE: To evaluate the independent and synergistic effects of HTN and AD pathology on WM alterations.

METHODS: Clinical measures of cerebrovascular disease risk were collected from 62 participants in University of Kentucky Alzheimer's Disease Center studies who also had cerebrospinal fluid (CSF) sampling and MRI brain scans. CSF Aβ_1-42 levels were measured as a marker of AD, and fluid-attenuated inversion recovery imaging and diffusion tensor imaging were obtained to assess …

Neural Mechanisms Of The Rejection-Aggression Link, David S. Chester, Donald R. Lynam, Richard Milich, C. Nathan Dewall

Psychology Faculty Publications

Social rejection is a painful event that often increases aggression. However, the neural mechanisms of this rejection–aggression link remain unclear. A potential clue may be that rejected people often recruit the ventrolateral prefrontal cortex’s (VLPFC) self-regulatory processes to manage the pain of rejection. Using functional MRI, we replicated previous links between rejection and activity in the brain’s mentalizing network, social pain network and VLPFC. VLPFC recruitment during rejection was associated with greater activity in the brain’s reward network (i.e. the ventral striatum) when individuals were given an opportunity to retaliate. This retaliation-related striatal response was associated with greater levels of …

Amperometric Self-Referencing Ceramic Based Microelectrode Arrays For D-Serine Detection, Diana Campos-Beltrán, Åsa Konradsson-Geuken, Jorge E. Quintero, Lisa Marshall

Neuroscience Faculty Publications

D-serine is the major D-amino acid in the mammalian central nervous system. As the dominant co-agonist of the endogenous synaptic NMDA receptor, D-serine plays a role in synaptic plasticity, learning, and memory. Alterations in D-serine are linked to neuropsychiatric disorders including schizophrenia. Thus, it is of increasing interest to monitor the concentration of D-serine in vivo as a relevant player in dynamic neuron-glia network activity. Here we present a procedure for amperometric detection of D-serine with self-referencing ceramic-based microelectrode arrays (MEAs) coated with D-amino acid oxidase from the yeast Rhodotorula gracilis (RgDAAO). We demonstrate in vitro D-serine recordings with a …

Protection Effect Of Exogenous Fibroblast Growth Factor 21 On The Kidney Injury In Vascular Calcification Rats, Yu-Chen Shi, Wei-Wei Lu, Yue-Long Hou, Kun Fu, Feng Gan, Shu-Juan Cheng, Shao-Ping Wang, Yong-Fen Qi, Jing-Hua Liu

Pharmacology and Nutritional Sciences Faculty Publications

Background: Chronic kidney disease (CKD) is closely related to the cardiovascular events in vascular calcification (VC). However, little has known about the characteristics of kidney injury caused by VC. Fibroblast growth factor 21 (FGF21) is an endocrine factor, which takes part in various metabolic actions with the potential to alleviate metabolic disorder diseases. Even FGF21 has been regarded as a biomarker in CKD, the role of FGF21 in CKD remains unclear. Therefore, in this study, we evaluate the FGF21 on the kidney injury in VC rats.

Methods: The male Sprague-Dawley rats were divided into three groups: (1) control group, (2) …

In-Hospital Mortality And Post-Surgical Complications Among Cancer Patients With Metabolic Syndrome, Tomi Akinyemiju, Swati Sakhuja, Neomi Vin-Raviv

Epidemiology and Environmental Health Faculty Publications

Background

Metabolic syndrome (MetS) is an important etiologic and prognostic factor for cancer, but few studies have assessed hospitalization outcomes among patients with both conditions.

Methods

Data was obtained from the Healthcare Cost and Utilization project Nationwide Inpatient Sample (HCUP-NIS). Study variables were assessed using ICD-9 codes on adults aged 40 years and over admitted to a US hospital between 2007 and 2011 with primary diagnosis of either breast, colorectal, or prostate cancer. We examined in-hospital mortality, post-surgical complications, and discharge disposition among cancer patients with MetS and compared with non-MetS patients.

Results

Hospitalized breast (OR: 0.31, 95% CI: 0.20–0.46), …

Microrna Expression Patterns In Human Anterior Cingulate And Motor Cortex: A Study Of Dementia With Lewy Bodies Cases And Controls, Peter T. Nelson, Wang-Xia Wang, Sarah A. Janse, Katherine L. Thompson

Sanders-Brown Center on Aging Faculty Publications

Overview

MicroRNAs (miRNAs) have been implicated in neurodegenerative diseases including Parkinson’s disease and Alzheimer’s disease (AD). Here, we evaluated the expression of miRNAs in anterior cingulate (AC; Brodmann area [BA] 24) and primary motor (MO; BA 4) cortical tissue from aged human brains in the University of Kentucky AD Center autopsy cohort, with a focus on dementia with Lewy bodies (DLB).

Methods

RNA was isolated from gray matter of brain samples with pathology-defined DLB, AD, AD+DLB, and low-pathology controls, with n=52 cases initially included (n=23 with DLB), all with low (<4hrs) postmortem intervals. RNA was profiled using Exiqon miRNA microarrays. Quantitative PCR for post-hoc replication was performed on separate cases (n=6 controls) and included RNA isolated from gray matter of MO, AC, primary somatosensory (BA 3), and dorsolateral prefrontal (BA 9) cortical regions.

Results

The miRNA expression patterns differed substantially according to …

Intra-Arterial Nitroglycerin As Directed Acute Treatment In Experimental Ischemic Stroke, Michael E. Maniskas, Jill M. Roberts, Rebecca Trueman, Annastazia E. Learoyd, Amanda A. Gorman, Justin F. Fraser, Gregory J. Bix

Neuroscience Faculty Publications

BACKGROUND: Nitroglycerin (also known as glyceryl trinitrate (GTN)), a vasodilator best known for treatment of ischemic heart disease, has also been investigated for its potential therapeutic benefit in ischemic stroke. The completed Efficacy of Nitric Oxide in Stroke trial suggested that GTN has therapeutic benefit with acute (within 6 hours) transdermal systemic sustained release therapy.

OBJECTIVE: To examine an alternative use of GTN as an acute therapy for ischemic stroke following successful recanalization.

METHODS: We administered GTN IA following transient middle cerebral artery occlusion in mice. Because no standard dose of GTN is available following emergent large vessel occlusion, we …

Cerebral Amyloid Angiopathy In Down Syndrome And Sporadic And Autosomal-Dominant Alzheimer's Disease, María Carmona-Iragui, Mircea Balasa, Bessy Benejam, Daniel Alcolea, Susana Fernández, Laura Videla, Isabel Sala, María Belén Sánchez-Saudinós, Estrella Morenas-Rodriguez, Roser Ribosa-Nogué, Ignacio Illán-Gala, Sofía Gonzalez-Ortiz, Jordi Clarimón, Frederick A. Schmitt, David K. Powell, Beatriz Bosch, Albert Lladó, Michael S. Rafii, Elizabeth Head, José Luis Molinuevo, Rafael Blesa, Sebastián Videla, Alberto Lleó, Raquel Sánchez-Valle, Juan Fortea

Sanders-Brown Center on Aging Faculty Publications

Introduction—We aimed to investigate if cerebral amyloid angiopathy (CAA) is more frequent in genetically determined than in sporadic early-onset forms of Alzheimer's disease (AD) (early-onset AD [EOAD]).

Methods—Neuroimaging features of CAA, APOE, and cerebrospinal fluid-Aβ40 levels were studied in subjects with Down syndrome (DS, n = 117), autosomal-dominant AD (ADAD, n = 29), sporadic EOAD (n = 42), and healthy controls (n = 68).

Results—CAA was present in 31%, 38%, and 12% of cognitively impaired DS, symptomatic ADAD, and sporadic EOAD subjects and in 13% and 4% of cognitively unimpaired DS individuals and healthy controls, respectively. …

Targeting Hepatic Heparin-Binding Egf-Like Growth Factor (Hb-Egf) Induces Anti-Hyperlipidemia Leading To Reduction Of Angiotensin Ii-Induced Aneurysm Development, Seonwook Kim, Lihua Yang, Seongu Kim, Richard G. Lee, Mark J. Graham, Judith A. Berliner, Aldons J. Lusis, Lei Cai, Ryan E. Temel, Debra L. Rateri, Sangderk Lee

Saha Cardiovascular Research Center Faculty Publications

Objective

The upregulated expression of heparin binding EGF-like growth factor (HB-EGF) in the vessel and circulation is associated with risk of cardiovascular disease. In this study, we tested the effects of HB-EGF targeting using HB-EGF-specific antisense oligonucleotide (ASO) on the development of aortic aneurysm in a mouse aneurysm model.

Approach and results

Low-density lipoprotein receptor (LDLR) deficient mice (male, 16 weeks of age) were injected with control and HB-EGF ASOs for 10 weeks. To induce aneurysm, the mice were fed a high fat diet (22% fat, 0.2% cholesterol; w/w) at 5 week point of ASO administration and infused with angiotensin …

Peripheral Inflammation, Apolipoprotein E4, And Amyloid-Β Interact To Induce Cognitive And Cerebrovascular Dysfunction, Felecia M. Marottoli, Yuriko Katsumata, Kevin P. Koster, Riya Thomas, David W. Fardo, Leon M. Tai

Biostatistics Faculty Publications

Cerebrovascular dysfunction is rapidly reemerging as a major process of Alzheimer’s disease (AD). It is, therefore, crucial to delineate the roles of AD risk factors in cerebrovascular dysfunction. While apolipoprotein E4 (APOE4), Amyloid-β (Aβ), and peripheral inflammation independently induce cerebrovascular damage, their collective effects remain to be elucidated. The goal of this study was to determine the interactive effect of APOE4, Aβ, and chronic repeated peripheral inflammation on cerebrovascular and cognitive dysfunction in vivo. EFAD mice are a well-characterized mouse model that express human APOE3 (E3FAD) or APOE4 (E4FAD) and overproduce human Aβ42 via expression of …

Risk Of Incident Clinical Diagnosis Of Alzheimer's Disease-Type Dementia Attributable To Pathology-Confirmed Vascular Disease, Hiroko H. Dodge, Jian Zhu, Randy Woltjer, Peter T. Nelson, David A. Bennett, Nigel J. Cairns, David W. Fardo, Jeffrey A. Kaye, Deniz-Erten Lyons, Nora Mattek, Julie A. Schneider, Lisa C. Silbert, Chengjie Xiong, Lei Yu, Frederick A. Schmitt, Richard J. Kryscio, Erin L. Abner, Smart Data Consortium

Sanders-Brown Center on Aging Faculty Publications

INTRODUCTION: The presence of cerebrovascular pathology may increase the risk of clinical diagnosis of Alzheimer's disease (AD).

METHODS: We examined excess risk of incident clinical diagnosis of AD (probable and possible AD) posed by the presence of lacunes and large infarcts beyond AD pathology using data from the Statistical Modeling of Aging and Risk of Transition study, a consortium of longitudinal cohort studies with more than 2000 autopsies. We created six mutually exclusive pathology patterns combining three levels of AD pathology (low, moderate, or high AD pathology) and two levels of vascular pathology (without lacunes and large infarcts or with …

Outcomes After Diagnosis Of Mild Cognitive Impairment In A Large Autopsy Series, Erin L. Abner, Richard J. Kryscio, Frederick A. Schmitt, David W. Fardo, Daniela C. Moga, Eseosa T. Ighodaro, Gregory A. Jicha, Lei Yu, Hiroko H. Dodge, Chengjie Xiong, Randall L. Woltjer, Julie A. Schneider, Nigel J. Cairns, David A. Bennett, Peter T. Nelson

Epidemiology and Environmental Health Faculty Publications

OBJECTIVE: To determine clinical and neuropathological outcomes following a clinical diagnosis of mild cognitive impairment (MCI).

METHODS: Data were drawn from a large autopsy series (N = 1,337) of individuals followed longitudinally from normal or MCI status to death, derived from 4 Alzheimer Disease (AD) Centers in the United States.

RESULTS: Mean follow‐up was 7.9 years. Of the 874 individuals ever diagnosed with MCI, final clinical diagnoses were varied: 39.2% died with an MCI diagnosis, 46.8% with a dementia diagnosis, and 13.9% with a diagnosis of intact cognition. The latter group had pathological features resembling those with a final clinical …

Csf Protein Changes Associated With Hippocampal Sclerosis Risk Gene Variants Highlight Impact Of Grn/Pgrn, David W. Fardo, Yuriko Katsumata, John S. K. Kauwe, Yuetiva Deming, Oscar Harari, Carlos Cruchaga, Alzheimer’S Disease Neuroimaging Initiative, Peter T. Nelson

Sanders-Brown Center on Aging Faculty Publications

Objective—Hippocampal sclerosis of aging (HS-Aging) is a common cause of dementia in older adults. We tested the variability in cerebrospinal fluid (CSF) proteins associated with previously identified HS-Aging risk single nucleotide polymorphisms (SNPs).

Methods—Alzheimer’s Disease Neuroimaging Initiative cohort (ADNI; n=237) data, combining both multiplexed proteomics CSF and genotype data, were used to assess the association between CSF analytes and risk SNPs in four genes (SNPs): GRN (rs5848), TMEM106B (rs1990622), ABCC9 (rs704180), and KCNMB2 (rs9637454). For controls, non-HS-Aging SNPs in APOE (rs429358/rs7412) and MAPT (rs8070723) were also analyzed against Aβ1-42 and total tau CSF analytes.

Results—The GRN risk …

Cpt1a Methylation Is Associated With Plasma Adiponectin, S. Aslibekyan, A. N. Do, H. Xu, S. Li, M. R. Irvin, D Zhi, H. K. Tiwari, D. M. Absher, A. R. Shuldiner, T. Zhang, W. Chen, K. Tanner, C. Hong, B. D. Mitchell, G. Berenson, Donna K. Arnett

Epidemiology and Environmental Health Faculty Publications

Background and Aims—Adiponectin, an adipose-secreted protein that has been linked to insulin sensitivity, plasma lipids, and inflammatory patterns, is an established biomarker for metabolic health. Despite clinical relevance and high heritability, the determinants of plasma adiponectin levels remain poorly understood.

Methods and Results—We conducted the first epigenome-wide cross-sectional study of adiponectin levels using methylation data on 368,051 cytosine-phosphate-guanine (CpG) sites in CD4+ T-cells from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN, n= 991). We fit linear mixed models, adjusting for age, sex, study site, T-cell purity, and family. We have identified a positive association (regression …

Relb Expression Determines The Differential Effects Of Ascorbic Acid In Normal And Cancer Cells, Xiaowei Wei, Yong Xu, Fang Fang Xu, Luksana Chaiswing, David M. Schnell, Teresa Noel, Chi Wang, Jinfei Chen, Daret K. St. Clair, William H. St. Clair

Toxicology and Cancer Biology Faculty Publications

Cancer cells typically experience higher oxidative stress than normal cells, such that elevating pro-oxidant levels can trigger cancer cell death. Although pre-exposure to mild oxidative agents will sensitize cancer cells to radiation, this pre-exposure may also activate the adaptive stress defense system in normal cells. Ascorbic acid is a prototype redox modulator that when infused intravenously appears to kill cancers without injury to normal tissues; however, the mechanisms involved remain elusive. In this study, we show how ascorbic acid kills cancer cells and sensitizes prostate cancer to radiation therapy while also conferring protection upon normal prostate epithelial cells against radiation-induced …

A Quantitative Lc-Ms/Ms Method For Simultaneous Determination Of Cocaine And Its Metabolites In Whole Blood, Xiabin Chen, Xirong Zheng, Kai Ding, Ziyuan Zhou, Chang-Guo Zhan, Fang Zheng

Molecular Modeling and Biopharmaceutical Center Faculty Publications

As new metabolic pathways of cocaine were recently identified, a high performance liquid chromatography tandem mass spectrometry (LC–MS/MS) method was developed to simultaneously determine cocaine and nine cocaine-related metabolites in whole blood samples. One-step solid phase extraction was used to extract all of the ten compounds and corresponding internal standards from blood samples. All compounds and internal standards extracted were separated on an Atlantis T3 (100 Å, 3 μm, 2.1 mm × 150 mm I.D) column and detected in positive ion and high sensitivity mode with multiple reaction monitoring. This method was validated for its sensitivity, linearity, specificity, accuracy, precision, …

Self-Reported Sleep Apnea And Dementia Risk: Findings From The Prevention Of Alzheimer's Disease With Vitamin E And Selenium Trial, Xiuhua Ding, Richard J. Kryscio, Joshua Turner, Gregory A. Jicha, Gregory E. Cooper, Allison M. Caban-Holt, Frederick A. Schmitt, Erin L. Abner

Sanders-Brown Center on Aging Faculty Publications

OBJECTIVES: To investigate the association between baseline sleep apnea and risk of incident dementia in the Prevention of Alzheimer's Disease with Vitamin E and Selenium (PREADViSE) study and to explore whether the association depends on apolipoprotein E (APOE) ɛ4 allele status.

DESIGN: Secondary analysis based on data collected during PREADViSE.

SETTING: Participants were assessed at 128 local clinical study sites during the clinical trial phase and later were followed by telephone from a centralized location.

PARTICIPANTS: Men enrolled in PREADViSE (without dementia or other active neurological conditions that affect cognition such as major psychiatric disorders, including depression; N = …

Genomics And Csf Analyses Implicate Thyroid Hormone In Hippocampal Sclerosis Of Aging, Peter T. Nelson, Yuriko Katsumata, Kwangsik Nho, Sergey C. Artiushin, Gregory A. Jicha, Wang-Xia Wang, Erin L. Abner, Andrew J. Saykin, Walter A. Kukull, Alzheimer’S Disease Neuroimaging Initiative (Adni), David W. Fardo

Sanders-Brown Center on Aging Faculty Publications

We report evidence of a novel pathogenetic mechanism in which thyroid hormone dysregulation contributes to dementia in elderly persons. Two single nucleotide polymorphisms (SNPs) on chromosome 12p12 were the initial foci of our study: rs704180 and rs73069071. These SNPs were identified by separate research groups as risk alleles for non-Alzheimer’s neurodegeneration. We found that the rs73069071 risk genotype was associated with hippocampal sclerosis (HS) pathology among people with the rs704180 risk genotype (National Alzheimer’s Coordinating Center/Alzheimer’s Disease Genetic Consortium data; n = 2113, including 241 autopsy-confirmed HS cases). Furthermore, both rs704180 and rs73069071 risk genotypes were associated with widespread brain …

Thrombospondin 1 Deficiency Ameliorates The Development Of Adriamycin-Induced Proteinuric Kidney Disease, Hasiyeti Maimaitiyiming, Qi Zhou, Shuxia Wang

Pharmacology and Nutritional Sciences Faculty Publications

Accumulating evidence suggests that thrombospondin 1 (TSP1) is an important player in diabetic nephropathy. However, the role of TSP1 in podocyte injury and the development of non-diabetic proteinuric kidney disease is largely unknown. In the current study, by using a well-established podocyte injury model (adriamycin-induced nephropathy mouse model), we examined the contribution of TSP1 to the development of proteinuric kidney disease. We found that TSP1 was up-regulated in the glomeruli, notably in podocytes, in adriamycin injected mice before the onset of proteinuria. ADR treatment also stimulated TSP1 expression in cultured human podocytes in vitro. Moreover, increased TSP1 mediated ADR-induced …

Diffuse Traumatic Brain Injury Induces Prolonged Immune Sysregulation And Potentiates Hyperalgesia Following A Peripheral Immune Challenge, Rachel K. Rowe, Gavin I. Ellis, Jordan L. Harrison, Adam D. Bachstetter, Gregory F. Corder, Linda J. Van Eldik, Bradley K. Taylor, Francesc Marti, Jonathan Lifshitz

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Background: Nociceptive and neuropathic pain occurs as part of the disease process after traumatic brain injury (TBI) in humans. Central and peripheral inflammation, a major secondary injury process initiated by the traumatic brain injury event, has been implicated in the potentiation of peripheral nociceptive pain. We hypothesized that the inflammatory response to diffuse traumatic brain injury potentiates persistent pain through prolonged immune dysregulation.

Results: To test this, adult, male C57BL/6 mice were subjected to midline fluid percussion brain injury or to sham procedure. One cohort of mice was analyzed for inflammation-related cytokine levels in cortical biopsies and serum along an …

Tgf-Β Neutralization Enhances Angii-Induced Aortic Rupture And Aneurysm In Both Thoracic And Abdominal Regions, Xiaofeng Chen, Debra L. Rateri, Deborah A. Howatt, Anju Balakrishnan, Jessica J. Moorleghen, Lisa A. Cassis, Alan Daugherty

Saha Cardiovascular Research Center Faculty Publications

AngII and TGF-β interact in development of thoracic and abdominal aortic diseases, although there are many facets of this interaction that have not been clearly defined. The aim of the present study was to determine the effects of TGF-β neutralization on AngII induced-aortic pathologies. Male C57BL/6J mice were administered with either a rabbit or mouse TGF-β neutralizing antibody and then infused with AngII. The rabbit TGF-β antibody modestly reduced serum TGF-β concentrations, with no significant enhancements to AngII-induced aneurysm or rupture. Administration of this rabbit TGF-β antibody in mice led to high serum titers against rabbit IgG that may have …

Molecular Analyses Of Circadian Gene Variants Reveal Sex-Dependent Links Between Depression And Clocks, S-Q Shi, M. J. White, H. M. Borsetti, Julie S. Pendergast, A. Hida, C. M. Ciarleglio, P. A. De Verteuil, A. G. Cadar, C. Cala, D. G. Mcmahon, R. C. Shelton, S. M. Williams, C. H. Johnson

Biology Faculty Publications

An extensive literature links circadian irregularities and/or sleep abnormalities to mood disorders. Despite the strong genetic component underlying many mood disorders, however, previous genetic associations between circadian clock gene variants and major depressive disorder (MDD) have been weak. We applied a combined molecular/functional and genetic association approach to circadian gene polymorphisms in sex-stratified populations of control subjects and case subjects suffering from MDD. This approach identified significant sex-dependent associations of common variants of the circadian clock genes hClock, hPer3 and hNpas2 with major depression and demonstrated functional effects of these polymorphisms on the expression or activity of the hCLOCK …

Mw151 Inhibited Il-1Β Levels After Traumatic Brain Injury With No Effect On Microglia Physiological Responses, Adam D. Bachstetter, Zhengqiu Zhou, Rachel K. Rowe, Bin Xing, Danielle S. Goulding, Alyssa N. Conley, Pradoldej Sompol, Shelby Meier, Jose F. Abisambra, Jonathan Lifshitz, D. Martin Watterson, Linda J. Van Eldik

Sanders-Brown Center on Aging Faculty Publications

A prevailing neuroinflammation hypothesis is that increased production of proinflammatory cytokines contributes to progressive neuropathology, secondary to the primary damage caused by a traumatic brain injury (TBI). In support of the hypothesis, post-injury interventions that inhibit the proinflammatory cytokine surge can attenuate the progressive pathology. However, other post-injury neuroinflammatory responses are key to endogenous recovery responses. Therefore, it is critical that pharmacological attenuation of detrimental or dysregulated neuroinflammatory processes avoid pan-suppression of inflammation. MW151 is a CNS-penetrant, small molecule experimental therapeutic that restores injury- or disease-induced overproduction of proinflammatory cytokines towards homeostasis without immunosuppression. Post-injury administration of MW151 in a …

Blockade Of Astrocytic Calcineurin/Nfat Signaling Helps To Normalize Hippocampal Synaptic Function And Plasticity In A Rat Model Of Traumatic Brain Injury, Jennifer L. Furman, Pradoldej Sompol, Susan D. Kraner, Melanie M. Pleiss, Esther J. Putman, Jacob Dunkerson, Hafiz Mohmmad Abdul, Kelly N. Roberts, Stephen William Scheff, Christopher M. Norris

Pharmacology and Nutritional Sciences Faculty Publications

Increasing evidence suggests that the calcineurin (CN)-dependent transcription factor NFAT (Nuclear Factor of Activated T cells) mediates deleterious effects of astrocytes in progressive neurodegenerative conditions. However, the impact of astrocytic CN/NFAT signaling on neural function/recovery after acute injury has not been investigated extensively. Using a controlled cortical impact (CCI) procedure in rats, we show that traumatic brain injury is associated with an increase in the activities of NFATs 1 and 4 in the hippocampus at 7 d after injury. NFAT4, but not NFAT1, exhibited extensive labeling in astrocytes and was found throughout the axon/dendrite layers of CA1 and the dentate …