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Cholesterol Sulfate Alters Astrocyte Metabolism and Provides Protection Against Oxidative Stress.

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Cholesterol Sulfate Alters Astrocyte Metabolism and Provides Protection Against Oxidative Stress.

Brain Res. 2019 Aug 16;:146378

Authors: Prah J, Winters A, Chaudhari K, Hersh J, Liu R, Yang SH

Abstract
Cholesterol sulfate (CS) is one of the most important known sterol sulfates in human plasma and it is present as a normal constituent in a variety of human tissues. In both the brain and periphery, CS serves as a substrate for the synthesis of sulfonated adrenal steroids such as pregnenolone sulfate and dehydroepiandrosterone (DHEA) sulfate and as a constituent of many biological membranes including red blood cells where it functions as a stabilizing agent. It also acts as an endogenous regulator of cholesterol synthesis. However, the role of CS in brain metabolism and neurological disorder is unclear. In the current study we investigated the neuroprotective action of CS as well as its role in brain energy metabolism. The neuroprotective effect of CS and its role on cell metabolism were determined in primary astrocyte prepared from the cortex of postnatal day 0-2 C57BL/6 pups and a hippocampal HT-22 cell line using Calcein AM and MTT cell viability assay, flow cytometry, Seahorse extracellular flux analysis, and metabolism assay kits. We found that CS attenuates glutamate and rotenone induced cell death in HT-22 cells, decrease glutamate induced mitochondria membrane potential collapse, and reactive oxygen species production. Additionally, CS activates the Akt/Bcl2 pathway. We observed that CS impacts astrocyte metabolism by increasing mitochondrial phosphorylation, ATP, and glycogen contents. Our study demonstrated that CS modulates brain energy metabolism and its neuroprotective effects might be due to the activation of Akt signaling or its ability to decrease reactive oxygen species production.

PMID: 31425677 [PubMed - as supplied by publisher]

Effects of TAK-639, a novel topical C-type natriuretic peptide analog, on intraocular pressure and aqueous humor dynamics in mice.

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Effects of TAK-639, a novel topical C-type natriuretic peptide analog, on intraocular pressure and aqueous humor dynamics in mice.

Exp Eye Res. 2019 Aug 14;:107763

Authors: Millar JC, Savinainen A, Josiah S, Pang IH

Abstract
Primary open-angle glaucoma (POAG) is a leading cause of irreversible blindness, and individuals with ocular hypertension are at risk to develop POAG. Currently, the only modifiable risk factor for glaucoma progression is lowering of intraocular pressure (IOP). A novel mechanism for lowering IOP involves activation of the type B natriuretic peptide receptor (NPR-B), the naturally occurring agonist of which is C-type natriuretic peptide (CNP). Being a cyclic peptide of 22 amino acids, CNP does not readily penetrate the cornea and its ocular hypotensive effect requires intraocular injection. TAK-639 is a synthetic, cornea-permeable, 9-amino acid CNP analog has been studied for the treatment of ocular hypertension and POAG. We assessed TAK-639 in a receptor binding profile and the effects of TAK-639 on NPR-B-mediated cyclic GMP production in cultured transformed human trabecular meshwork (TM) cells (GTM-3). We also evaluated the effects of topical ocular administration of TAK-639 on mouse IOP and aqueous humor dynamics. Among 89 non-natriuretic peptide receptors, transporters, and channels evaluated, TAK-639 at 10 μM displaced ligand binding by more than 50% to only two receptors: the type 2 angiotensin receptor (IC50 = 8.2 μM) and the cholecystokinin A receptor (IC50 = 25.8 μM). In vitro, TAK-639 selectively activates NPR-B (EC50 = 61 ± 11 nM; GTM-3 cells) relative to NPR-A (EC50 = 2179 ± 670 nM; 293T cells). In vivo, TAK-639 lowered mouse IOP by three mechanisms: increase in aqueous humor outflow facility (C), reduction in the aqueous humor formation rate (Fin), and reduction in episcleral venous pressure (Pe). The maximum mean IOP decreases from baseline were -12.1%, -21.0%, and -36.1% for 0.1%, 0.3%, and 0.6% doses of TAK-639, respectively. Maximum IOP-lowering effect was seen at 2 h, and the duration of action was >6 h. With TAK-639 0.6%, at 2 h post-dose, aqueous outflow facility (C) increased by 155.8%, Fin decreased by 41.0%, the uveoscleral outflow rate (Fu) decreased by 52.6%, and Pe decreased by 31.5% (all p < 0.05). No ocular adverse effects were observed. TAK-639 is an efficacious IOP-lowering agent, with a unique combination of mechanisms of action on both aqueous formation and aqueous outflow facility. Further study of this mechanism of treatment may optimize pharmacologic outcomes and provide disease management in patients with POAG and ocular hypertension.

PMID: 31421135 [PubMed - as supplied by publisher]

Expression and Function of Transient Receptor Potential Ankyrin 1 Ion Channels in the Caudal Nucleus of the Solitary Tract.

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Expression and Function of Transient Receptor Potential Ankyrin 1 Ion Channels in the Caudal Nucleus of the Solitary Tract.

Int J Mol Sci. 2019 Apr 26;20(9):

Authors: Feng L, Uteshev VV, Premkumar LS

Abstract
The nucleus of the solitary tract (NTS) receives visceral information via the solitary tract (ST) that comprises the sensory components of the cranial nerves VII, IX and X. The Transient Receptor Potential Ankyrin 1 (TRPA1) ion channels are non-selective cation channels that are expressed primarily in pain-related sensory neurons and nerve fibers. Thus, TRPA1 expressed in the primary sensory afferents may modulate the function of second order NTS neurons. This hypothesis was tested and confirmed in the present study using acute brainstem slices and caudal NTS neurons by RT-PCR, immunostaining and patch-clamp electrophysiology. The expression of TRPA1 was detected in presynaptic locations, but not the somata of caudal NTS neurons that did not express TRPA1 mRNA or proteins. Moreover, caudal NTS neurons did not show somatodendritic responsiveness to TRPA1 agonists, while TRPA1 immunostaining was detected only in the afferent fibers. Electrophysiological recordings detected activation of presynaptic TRPA1 in glutamatergic terminals synapsing on caudal NTS neurons evidenced by the enhanced glutamatergic synaptic neurotransmission in the presence of TRPA1 agonists. The requirement of TRPA1 for modulation of spontaneous synaptic activity was confirmed using TRPA1 knockout mice where TRPA1 agonists failed to alter synaptic efficacy. Thus, this study provides the first evidence of the TRPA1-dependent modulation of the primary afferent inputs to the caudal NTS. These results suggest that the second order caudal NTS neurons act as a TRPA1-dependent interface for visceral noxious-innocuous integration at the level of the caudal brainstem.

PMID: 31027359 [PubMed - indexed for MEDLINE]

Author Correction: Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing.

Recent Research Articles from UNTHSC - Sat, 08/17/2019 - 06:53
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Author Correction: Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing.

Nat Genet. 2019 Aug 15;:

Authors: Kunkle BW, Grenier-Boley B, Sims R, Bis JC, Damotte V, Naj AC, Boland A, Vronskaya M, van der Lee SJ, Amlie-Wolf A, Bellenguez C, Frizatti A, Chouraki V, Martin ER, Sleegers K, Badarinarayan N, Jakobsdottir J, Hamilton-Nelson KL, Moreno-Grau S, Olaso R, Raybould R, Chen Y, Kuzma AB, Hiltunen M, Morgan T, Ahmad S, Vardarajan BN, Epelbaum J, Hoffmann P, Boada M, Beecham GW, Garnier JG, Harold D, Fitzpatrick AL, Valladares O, Moutet ML, Gerrish A, Smith AV, Qu L, Bacq D, Denning N, Jian X, Zhao Y, Del Zompo M, Fox NC, Choi SH, Mateo I, Hughes JT, Adams HH, Malamon J, Sanchez-Garcia F, Patel Y, Brody JA, Dombroski BA, Naranjo MCD, Daniilidou M, Eiriksdottir G, Mukherjee S, Wallon D, Uphill J, Aspelund T, Cantwell LB, Garzia F, Galimberti D, Hofer E, Butkiewicz M, Fin B, Scarpini E, Sarnowski C, Bush WS, Meslage S, Kornhuber J, White CC, Song Y, Barber RC, Engelborghs S, Sordon S, Voijnovic D, Adams PM, Vandenberghe R, Mayhaus M, Cupples LA, Albert MS, De Deyn PP, Gu W, Himali JJ, Beekly D, Squassina A, Hartmann AM, Orellana A, Blacker D, Rodriguez-Rodriguez E, Lovestone S, Garcia ME, Doody RS, Munoz-Fernadez C, Sussams R, Lin H, Fairchild TJ, Benito YA, Holmes C, Karamujić-Čomić H, Frosch MP, Thonberg H, Maier W, Roshchupkin G, Ghetti B, Giedraitis V, Kawalia A, Li S, Huebinger RM, Kilander L, Moebus S, Hernández I, Kamboh MI, Brundin R, Turton J, Yang Q, Katz MJ, Concari L, Lord J, Beiser AS, Keene CD, Helisalmi S, Kloszewska I, Kukull WA, Koivisto AM, Lynch A, Tarraga L, Larson EB, Haapasalo A, Lawlor B, Mosley TH, Lipton RB, Solfrizzi V, Gill M, Longstreth WT, Montine TJ, Frisardi V, Diez-Fairen M, Rivadeneira F, Petersen RC, Deramecourt V, Alvarez I, Salani F, Ciaramella A, Boerwinkle E, Reiman EM, Fievet N, Rotter JI, Reisch JS, Hanon O, Cupidi C, Uitterlinden AGA, Royall DR, Dufouil C, Maletta RG, de Rojas I, Sano M, Brice A, Cecchetti R, George-Hyslop PS, Ritchie K, Tsolaki M, Tsuang DW, Dubois B, Craig D, Wu CK, Soininen H, Avramidou D, Albin RL, Fratiglioni L, Germanou A, Apostolova LG, Keller L, Koutroumani M, Arnold SE, Panza F, Gkatzima O, Asthana S, Hannequin D, Whitehead P, Atwood CS, Caffarra P, Hampel H, Quintela I, Carracedo Á, Lannfelt L, Rubinsztein DC, Barnes LL, Pasquier F, Frölich L, Barral S, McGuinness B, Beach TG, Johnston JA, Becker JT, Passmore P, Bigio EH, Schott JM, Bird TD, Warren JD, Boeve BF, Lupton MK, Bowen JD, Proitsi P, Boxer A, Powell JF, Burke JR, Kauwe JSK, Burns JM, Mancuso M, Buxbaum JD, Bonuccelli U, Cairns NJ, McQuillin A, Cao C, Livingston G, Carlson CS, Bass NJ, Carlsson CM, Hardy J, Carney RM, Bras J, Carrasquillo MM, Guerreiro R, Allen M, Chui HC, Fisher E, Masullo C, Crocco EA, DeCarli C, Bisceglio G, Dick M, Ma L, Duara R, Graff-Radford NR, Evans DA, Hodges A, Faber KM, Scherer M, Fallon KB, Riemenschneider M, Fardo DW, Heun R, Farlow MR, Kölsch H, Ferris S, Leber M, Foroud TM, Heuser I, Galasko DR, Giegling I, Gearing M, Hüll M, Geschwind DH, Gilbert JR, Morris J, Green RC, Mayo K, Growdon JH, Feulner T, Hamilton RL, Harrell LE, Drichel D, Honig LS, Cushion TD, Huentelman MJ, Hollingworth P, Hulette CM, Hyman BT, Marshall R, Jarvik GP, Meggy A, Abner E, Menzies GE, Jin LW, Leonenko G, Real LM, Jun GR, Baldwin CT, Grozeva D, Karydas A, Russo G, Kaye JA, Kim R, Jessen F, Kowall NW, Vellas B, Kramer JH, Vardy E, LaFerla FM, Jöckel KH, Lah JJ, Dichgans M, Leverenz JB, Mann D, Levey AI, Pickering-Brown S, Lieberman AP, Klopp N, Lunetta KL, Wichmann HE, Lyketsos CG, Morgan K, Marson DC, Brown K, Martiniuk F, Medway C, Mash DC, Nöthen MM, Masliah E, Hooper NM, McCormick WC, Daniele A, McCurry SM, Bayer A, McDavid AN, Gallacher J, McKee AC, van den Bussche H, Mesulam M, Brayne C, Miller BL, Riedel-Heller S, Miller CA, Miller JW, Al-Chalabi A, Morris JC, Shaw CE, Myers AJ, Wiltfang J, O'Bryant S, Olichney JM, Alvarez V, Parisi JE, Singleton AB, Paulson HL, Collinge J, Perry WR, Mead S, Peskind E, Cribbs DH, Rossor M, Pierce A, Ryan NS, Poon WW, Nacmias B, Potter H, Sorbi S, Quinn JF, Sacchinelli E, Raj A, Spalletta G, Raskind M, Caltagirone C, Bossù P, Orfei MD, Reisberg B, Clarke R, Reitz C, Smith AD, Ringman JM, Warden D, Roberson ED, Wilcock G, Rogaeva E, Bruni AC, Rosen HJ, Gallo M, Rosenberg RN, Ben-Shlomo Y, Sager MA, Mecocci P, Saykin AJ, Pastor P, Cuccaro ML, Vance JM, Schneider JA, Schneider LS, Slifer S, Seeley WW, Smith AG, Sonnen JA, Spina S, Stern RA, Swerdlow RH, Tang M, Tanzi RE, Trojanowski JQ, Troncoso JC, Van Deerlin VM, Van Eldik LJ, Vinters HV, Vonsattel JP, Weintraub S, Welsh-Bohmer KA, Wilhelmsen KC, Williamson J, Wingo TS, Woltjer RL, Wright CB, Yu CE, Yu L, Saba Y, Alzheimer Disease Genetics Consortium (ADGC), European Alzheimer’s Disease Initiative (EADI), Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (CHARGE), Genetic and Environmental Risk in AD/Defining Genetic, Polygenic and Environmental Risk for Alzheimer’s Disease Consortium (GERAD/PERADES), Pilotto A, Bullido MJ, Peters O, Crane PK, Bennett D, Bosco P, Coto E, Boccardi V, De Jager PL, Lleo A, Warner N, Lopez OL, Ingelsson M, Deloukas P, Cruchaga C, Graff C, Gwilliam R, Fornage M, Goate AM, Sanchez-Juan P, Kehoe PG, Amin N, Ertekin-Taner N, Berr C, Debette S, Love S, Launer LJ, Younkin SG, Dartigues JF, Corcoran C, Ikram MA, Dickson DW, Nicolas G, Campion D, Tschanz J, Schmidt H, Hakonarson H, Clarimon J, Munger R, Schmidt R, Farrer LA, Van Broeckhoven C, O'Donovan MC, DeStefano AL, Jones L, Haines JL, Deleuze JF, Owen MJ, Gudnason V, Mayeux R, Escott-Price V, Psaty BM, Ramirez A, Wang LS, Ruiz A, van Duijn CM, Holmans PA, Seshadri S, Williams J, Amouyel P, Schellenberg GD, Lambert JC, Pericak-Vance MA

Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.

PMID: 31417202 [PubMed - as supplied by publisher]

Primary care clinics can be a source of exposure to virulent Clostridium (now Clostridioides) difficile: An environmental screening study of hospitals and clinics in Dallas-Fort Worth region.

Recent Research Articles from UNTHSC - Fri, 08/16/2019 - 06:45
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Primary care clinics can be a source of exposure to virulent Clostridium (now Clostridioides) difficile: An environmental screening study of hospitals and clinics in Dallas-Fort Worth region.

PLoS One. 2019;14(8):e0220646

Authors: Simecka JW, Fulda KG, Pulse M, Lee JH, Vitucci J, Nguyen P, Taylor P, Filipetto F, Espinoza AM, Sharma S

Abstract
C. difficile is an endospore-forming pathogen, which is becoming a common cause of microbial health-care associated gastrointestinal disease in the United States. Both healthy and symptomatic patients can shed C. difficile spores into the environment, which can survive for long periods, being resistant to desiccation, heat, and disinfectants. In healthcare facilities, environmental contamination with C. difficile is a major concern as a potential source of exposure to this pathogen and risk of disease in susceptible patients. Although hospital-acquired infection is recognized, community-acquired infection is an increasingly recognized health problem. Primary care clinics may be a significant source of exposure to this pathogen; however, there are limited data about presence of environmental C. difficile within clinics. To address the potential for primary care clinics as a source of environmental exposure to virulent C. difficile, we measured the frequency of environmental contamination with spores in clinic examination rooms and hospital rooms in Dallas-Fort Worth (DFW) area of Texas. The ribotypes and presence of toxin genes from some environmental isolates were compared. Our results indicate primary care clinics have higher frequencies of contamination than hospitals. After notification of the presence of C. difficile spores in the clinics and an educational discussion to emphasize the importance of this infection and methods of infection prevention, environmental contamination in clinics was reduced on subsequent sampling to that found in hospitals. Thus, primary care clinics can be a source of exposure to virulent C. difficile, and recognition of this possibility can result in improved infection prevention, potentially reducing community-acquired C. difficile infections and subsequent disease.

PMID: 31415582 [PubMed - in process]

Buffering chronic kidney disease with sodium bicarbonate.

Recent Research Articles from UNTHSC - Wed, 08/14/2019 - 06:24
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Buffering chronic kidney disease with sodium bicarbonate.

Clin Sci (Lond). 2018 09 14;132(17):1999-2001

Authors: Williams EN, Mathis KW

Abstract
The roles of the kidney are well defined, if there is a progressive loss in renal function, the kidney is no longer able to perform the listed tasks and chronic kidney disease (CKD) persists. In both clinical and experimental studies, NaHCO3 supplementation has been shown to improve glomerular filtration rate (GFR) as well as halt the progression toward end-stage renal disease (ESRD). In an article recently published in Clinical Science (vol 132 (11) 1179-1197), Ray et al. presented an intriguing and timely study, which investigates the mechanisms involved in the protection that follows oral NaHCO3 ingestion. Here we comment on their research findings.

PMID: 30220653 [PubMed - indexed for MEDLINE]

Circulating factors in young blood as potential therapeutic agents for age-related neurodegenerative and neurovascular diseases.

Recent Research Articles from UNTHSC - Sun, 08/11/2019 - 05:58

Circulating factors in young blood as potential therapeutic agents for age-related neurodegenerative and neurovascular diseases.

Brain Res Bull. 2019 Aug 07;:

Authors: Ma J, Gao B, Zhang K, Zhang Q, Jia G, Li J, Li C, Yan LJ, Cai Z

Abstract
Recent animal studies on heterochronic parabiosis (a technique combining the blood circulation of two animals) have revealed that young blood has a powerful rejuvenating effect on brain aging. Circulating factors, especially growth differentiation factor 11 (GDF11) and C-C motif chemokine 11 (CCL11), may play a key role in this effect, which inspires hope for novel approaches to treating age-related cerebral diseases in humans, such as neurodegenerative and neurovascular diseases. Recently, attempts have begun to translate these astonishing and exciting findings from mice to humans and from bench to bedside. However, increasing reports have shown contradictory data, questioning the capacity of these circulating factors to reverse age-related brain dysfunction. In this review, we summarize the current research on the role of young blood, as well as the circulating factors GDF11 and CCL11, in the aging brain and age-related cerebral diseases. We highlight recent controversies, discuss related challenges and provide a future outlook.

PMID: 31400495 [PubMed - as supplied by publisher]

The ADEP biosynthetic gene cluster in Streptomyces hawaiiensis NRRL 15010 reveals an accessory clpP gene as a novel antibiotic resistance factor.

Recent Research Articles from UNTHSC - Sun, 08/11/2019 - 05:58
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The ADEP biosynthetic gene cluster in Streptomyces hawaiiensis NRRL 15010 reveals an accessory clpP gene as a novel antibiotic resistance factor.

Appl Environ Microbiol. 2019 Aug 09;:

Authors: Thomy D, Culp E, Adamek M, Cheng EY, Ziemert N, Wright GD, Sass P, Brötz-Oesterhelt H

Abstract
The increasing threat posed by multi-resistant bacterial pathogens necessitates the discovery of novel antibacterials with unprecedented modes of action. ADEP1, a natural compound produced by Streptomyces hawaiiensis NRRL 15010, is the prototype for a new class of acyldepsipeptide (ADEP) antibiotics. ADEP antibiotics deregulate the proteolytic core ClpP of the bacterial caseinolytic protease, thereby exhibiting potent antibacterial activity against Gram-positive bacteria, including multi-resistant pathogens. ADEP1 and derivatives, here collectively called ADEP, have been previously investigated for their antibiotic potency against different species, structure-activity relationship, and mechanism of action, however, knowledge on the biosynthesis of the natural compound and producer self-resistance has remained elusive. In this study, we identified and analyzed the ADEP biosynthetic gene cluster in S. hawaiiensis NRRL 15010, which comprises two NRPSs, genes necessary for the biosynthesis of (4S,2R)-4-methylproline, and a type II PKS for the assembly of highly reduced polyenes. Whilst no resistance factor could be identified within the gene cluster itself, we discovered an additional clpP homologous gene (named clpPADEP ) located further downstream of the biosynthetic genes, separated from the biosynthetic gene cluster by several transposable elements. Heterologous expression of ClpPADEP in three ADEP-sensitive Streptomyces species proved its role in conferring ADEP resistance, thus revealing a novel type of antibiotic resistance determinant.IMPORTANCEAntibiotic acyldepsipeptides (ADEPs) represent a promising new class of potent antibiotics and, at the same time, are valuable tools to study the molecular functioning of their target ClpP, the proteolytic core of the bacterial caseinolytic protease. We here present a straightforward purification procedure for ADEP1 that yields substantial amounts of the pure compound in a time- and cost-efficient manner, which is a prerequisite to conveniently study the antimicrobial effects of ADEP and the operating mode of bacterial ClpP machineries in diverse bacteria. Identification and characterization of the ADEP biosynthetic gene cluster in Streptomyces hawaiiensis NRRL 15010 enables future bioinformatics screenings for similar gene clusters and/or sub-clusters, to find novel natural compounds with specific sub-structures. Most strikingly, we identified a cluster-associated clpP homolog (named clpPADEP ) as ADEP resistance gene. ClpPADEP constitutes a novel bacterial resistance factor, alone necessary and sufficient to confer high-level ADEP resistance to Streptomyces across species.

PMID: 31399403 [PubMed - as supplied by publisher]

Mechanisms of Sex Disparities in Cardiovascular Function and Remodeling.

Recent Research Articles from UNTHSC - Fri, 08/09/2019 - 07:41
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Mechanisms of Sex Disparities in Cardiovascular Function and Remodeling.

Compr Physiol. 2018 12 13;9(1):375-411

Authors: Chaudhari S, Cushen SC, Osikoya O, Jaini PA, Posey R, Mathis KW, Goulopoulou S

Abstract
Epidemiological studies demonstrate disparities between men and women in cardiovascular disease prevalence, clinical symptoms, treatments, and outcomes. Enrollment of women in clinical trials is lower than men, and experimental studies investigating molecular mechanisms and efficacy of certain therapeutics in cardiovascular disease have been primarily conducted in male animals. These practices bias data interpretation and limit the implication of research findings in female clinical populations. This review will focus on the biological origins of sex differences in cardiovascular physiology, health, and disease, with an emphasis on the sex hormones, estrogen and testosterone. First, we will briefly discuss epidemiological evidence of sex disparities in cardiovascular disease prevalence and clinical manifestation. Second, we will describe studies suggesting sexual dimorphism in normal cardiovascular function from fetal life to older age. Third, we will summarize and critically discuss the current literature regarding the molecular mechanisms underlying the effects of estrogens and androgens on cardiac and vascular physiology and the contribution of these hormones to sex differences in cardiovascular disease. Fourth, we will present cardiovascular disease risk factors that are positively associated with the female sex, and thus, contributing to increased cardiovascular risk in women. We conclude that inclusion of both men and women in the investigation of the role of estrogens and androgens in cardiovascular physiology will advance our understanding of the mechanisms underlying sex differences in cardiovascular disease. In addition, investigating the role of sex-specific factors in the development of cardiovascular disease will reduce sex and gender disparities in the treatment and diagnosis of cardiovascular disease. © 2019 American Physiological Society. Compr Physiol 9:375-411, 2019.

PMID: 30549017 [PubMed - indexed for MEDLINE]

Blood Based Biomarkers for Down Syndrome and Alzheimer's Disease: A Systematic Review.

Recent Research Articles from UNTHSC - Thu, 08/08/2019 - 07:31
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Blood Based Biomarkers for Down Syndrome and Alzheimer's Disease: A Systematic Review.

Dev Neurobiol. 2019 Aug 07;:

Authors: Petersen ME, O'Bryant S

Abstract
Down syndrome (DS) occurs due to triplication of chromosome 21. Individuals with DS face an elevated risk for development of Alzheimer's disease (AD) due to increased amyloid beta (Aβ) resulting from the over-expression of the amyloid precursor protein found on chromosome 21. Diagnosis of AD among individuals with DS poses particular challenges resulting in an increased focus on alternative diagnostic methods such as blood-based biomarkers. The aim of this review was to evaluate the current state of the literature of blood-based biomarkers found in individuals with DS and particularly among those also diagnosed with AD or in prodromal stages (mild cognitive impairment [MCI]). A systematic review was conducted utilizing a comprehensive search strategy. Twenty-four references were identified, of those, 22 fulfilled inclusion criteria and were selected for further analysis with restriction to only plasma-based biomarkers. Studies found Aβ to be consistently higher among individuals with DS; however, the link between Aβ peptides (Aβ 1-42 and Aβ 1-40) and AD among DS was inconsistent. Inflammatory based proteins were more reliably found to be elevated leading to preliminary work focused on an algorithmic approach with predominantly inflammatory based proteins to detect AD and MCI as well as predict risk of incidence among DS. Separate work has also shown remarkable diagnostic accuracy with the use of a single protein (NfL) as compared to combined proteomic profiles. This review serves to outline the current state of the literature and highlight potential plasma-based biomarkers for use in detecting AD and MCI among this at-risk population. This article is protected by copyright. All rights reserved.

PMID: 31389185 [PubMed - as supplied by publisher]

Design, synthesis, and evaluation of N-(4-(4-phenyl piperazin-1-yl)butyl)-4-(thiophen-3-yl)benzamides as selective dopamine D3 receptor ligands.

Recent Research Articles from UNTHSC - Thu, 08/08/2019 - 07:31
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Design, synthesis, and evaluation of N-(4-(4-phenyl piperazin-1-yl)butyl)-4-(thiophen-3-yl)benzamides as selective dopamine D3 receptor ligands.

Bioorg Med Chem Lett. 2019 Jul 11;:

Authors: Chen PJ, Taylor M, Griffin SA, Amani A, Hayatshahi H, Korzekwa K, Ye M, Mach RH, Liu J, Luedtke RR, Gordon JC, Blass BE

Abstract
As part of our on-going effort to explore the role of dopamine receptors in drug addiction and identify potential novel therapies for this condition, we have a identified a series of N-(4-(4-phenyl piperazin-1-yl)butyl)-4-(thiophen-3-yl)benzamide D3 ligands. Members of this class are highly selective for D3 versus D2, and we have identified two compounds (13g and 13r) whose rat in vivo IV pharmacokinetic properties that indicate that they are suitable for assessment in in vivo efficacy models of substance use disorders.

PMID: 31387791 [PubMed - as supplied by publisher]

Novel Investigation of the Deep Band of the Lateral Plantar Aponeurosis and Its Relationship With the Lateral Plantar Nerve.

Recent Research Articles from UNTHSC - Thu, 08/08/2019 - 07:31
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Novel Investigation of the Deep Band of the Lateral Plantar Aponeurosis and Its Relationship With the Lateral Plantar Nerve.

Foot Ankle Int. 2019 Aug 06;:1071100719864352

Authors: Beck CM, Dickerson AR, Kadado KJ, Cohen ZA, Blair SE, Motley TA, Holcomb JC, Fisher CL

Abstract
BACKGROUND: We describe a thick fascial band arising from the medial aspect of the lateral plantar aponeurosis diving deep into the forefoot crossing over a branch of the lateral plantar nerve. Because a review of current literature resulted in limited and outdated sources, we sought to first determine the frequency of this fascial band and the location where it crosses the lateral plantar nerve and, second, discuss the clinical applications these anatomical findings could have.
METHODS: 50 pairs of cadaveric feet (n = 100) were dissected to investigate for presence of the fascial band and its interaction with the lateral plantar nerve. Images were taken of each foot with the fascial band. ImageJ was used to take 2 measurements assessing the relationship of the tuberosity of the base of the fifth metatarsal to where the nerve crossed deep to the fascial band.
RESULTS: Overall, 38% of the feet possessed the fascial band. It was found unilaterally in 10 pairs and bilaterally in 14 pairs. On average, the point at which the lateral plantar nerve passed deep to the fascial band was 2.0 cm medial and 1.7 cm anterior to the tuberosity of the base of the fifth metatarsal.
CONCLUSION: When present, the deep band of the lateral plantar aponeurosis (PA) was consistently found to be crossing the lateral plantar nerve. The discovery of the location where this most commonly occurs has not been previously reported and adds an interesting dimension that elevates an anatomical study to one that has clinical potential.
CLINICAL RELEVANCE: The established target zone gives a precise location for where the relationship between the deep band of the lateral PA and the lateral plantar nerve exists when evaluating the foot. The target zone provides a potential springboard for future investigations concerning said relationship clinically.

PMID: 31387386 [PubMed - as supplied by publisher]

Soft robotic devices for hand rehabilitation and assistance: a narrative review.

Recent Research Articles from UNTHSC - Thu, 08/08/2019 - 07:31
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Soft robotic devices for hand rehabilitation and assistance: a narrative review.

J Neuroeng Rehabil. 2018 02 17;15(1):9

Authors: Chu CY, Patterson RM

Abstract
INTRODUCTION: The debilitating effects on hand function from a number of a neurologic disorders has given rise to the development of rehabilitative robotic devices aimed at restoring hand function in these patients. To combat the shortcomings of previous traditional robotics, soft robotics are rapidly emerging as an alternative due to their inherent safety, less complex designs, and increased potential for portability and efficacy. While several groups have begun designing devices, there are few devices that have progressed enough to provide clinical evidence of their design's therapeutic abilities. Therefore, a global review of devices that have been previously attempted could facilitate the development of new and improved devices in the next step towards obtaining clinical proof of the rehabilitative effects of soft robotics in hand dysfunction.
METHODS: A literature search was performed in SportDiscus, Pubmed, Scopus, and Web of Science for articles related to the design of soft robotic devices for hand rehabilitation. A framework of the key design elements of the devices was developed to ease the comparison of the various approaches to building them. This framework includes an analysis of the trends in portability, safety features, user intent detection methods, actuation systems, total DOF, number of independent actuators, device weight, evaluation metrics, and modes of rehabilitation.
RESULTS: In this study, a total of 62 articles representing 44 unique devices were identified and summarized according to the framework we developed to compare different design aspects. By far, the most common type of device was that which used a pneumatic actuator to guide finger flexion/extension. However, the remainder of our framework elements yielded more heterogeneous results. Consequently, those results are summarized and the advantages and disadvantages of many design choices as well as their rationales were highlighted.
CONCLUSION: The past 3 years has seen a rapid increase in the development of soft robotic devices for hand rehabilitative applications. These mostly preclinical research prototypes display a wide range of technical solutions which have been highlighted in the framework developed in this analysis. More work needs to be done in actuator design, safety, and implementation in order for these devices to progress to clinical trials. It is our goal that this review will guide future developers through the various design considerations in order to develop better devices for patients with hand impairments.

PMID: 29454392 [PubMed - indexed for MEDLINE]

Impact of an electronic medium delivery of warfarin education in a low income, minority outpatient population: a pilot intervention study.

Recent Research Articles from UNTHSC - Wed, 08/07/2019 - 07:22
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Impact of an electronic medium delivery of warfarin education in a low income, minority outpatient population: a pilot intervention study.

BMC Public Health. 2019 Aug 05;19(1):1050

Authors: Heinrich K, Sanchez K, Hui C, Talabi K, Perry M, Qin H, Nguyen H, Tatachar A

Abstract
BACKGROUND: Warfarin is classified as a high-alert medication for ambulatory healthcare and safe guards for high-alert medications are necessary, including the practice of mandatory patient education. The high cost of hospitalizations related to adverse events combined with the average bleeding event rate of 7-8% in spite of routine patient education, suggests the importance of new approaches to standardized health education on warfarin. We sought to evaluate the impact of a warfarin educational video using an electronic tablet on patient knowledge and to determine patients' satisfaction with the use of an electronic tablet for educational purposes in outpatient clinics serving a low income, minority population.
METHODS: A warfarin educational video delivered on an electronic tablet (iPad) was delivered at two pharmacist-managed anticoagulation clinics to uninsured patients whose annual income is equal or less than two hundred percent below the poverty level were offered. Patients (n = 18) completed a pre-video and post-video knowledge test on warfarin before and after viewing the warfarin educational video on an electronic tablet and a follow-up test to measure the retention of knowledge and a patient satisfaction survey at 60 days. The primary outcome was change in knowledge test scores. Other outcome measures included adherence rates, adverse events, time in therapeutic INR range, and patient-reported satisfaction scores.
RESULTS: The majority of patients were uninsured men taking warfarin for atrial fibrillation (n = 5). The median scores at post-video knowledge test and follow-up knowledge test were significantly higher than that for the pre-knowledge test (12 (11-12) vs. 10(8-11), p < 0.001). The study group had a 'time in therapeutic INR' range of 56.3%, a rate of adverse events of 24.5%, and a self-reported adherence rate to warfarin of 94.1%. The majority of patients also had positive responses to the patient satisfaction survey.
CONCLUSIONS: Patient education delivered via iPad to facilitate knowledge of medication can serve as a useful tool for educating patients about warfarin and warfarin therapy. Use of an electronic medium may be a unique way to provide standard medication education to patients.
TRIAL REGISTRATION: The study was retrospectively registered with: NCT03650777 ; 9/18/18.

PMID: 31382942 [PubMed - in process]

Tyrosine Hydroxylase Inhibition in Substantia Nigra Decreases Movement Frequency.

Recent Research Articles from UNTHSC - Wed, 08/07/2019 - 07:22
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Tyrosine Hydroxylase Inhibition in Substantia Nigra Decreases Movement Frequency.

Mol Neurobiol. 2019 Apr;56(4):2728-2740

Authors: Salvatore MF, McInnis TR, Cantu MA, Apple DM, Pruett BS

Abstract
Reduced movement frequency or physical activity (bradykinesia) occurs with high prevalence in the elderly. However, loss of striatal tyrosine hydroxylase (TH) in aging humans, non-human primates, or rodents does not reach the ~ 80% loss threshold associated with bradykinesia onset in Parkinson's disease. Moderate striatal dopamine (DA) loss, either following TH inhibition or decreased TH expression, may not affect movement frequency. In contrast, moderate DA or TH loss in the substantia nigra (SN), as occurs in aging, is of similar magnitude (~ 40%) to nigral TH loss at bradykinesia onset in Parkinson's disease. In aged rats, increased TH expression and DA in SN alone increases movement frequency, suggesting aging-related TH and DA loss in the SN contributes to aging-related bradykinesia or decreased physical activity. To test this hypothesis, the SN was targeted with bilateral guide cannula in young (6 months old) rats, in a within-subjects design, to evaluate the impact of nigral TH inhibition on movement frequency and speed. The TH inhibitor, α-methyl-p-tyrosine (AMPT) reduced nigral DA (~ 40%) 45-150 min following infusion, without affecting DA in striatum, nucleus accumbens, or adjacent ventral tegmental area. Locomotor activity in the open-field was recorded up to 3 h following nigral saline or AMPT infusion in each test subject. During the period of nigra-specific DA reduction, movement frequency, but not movement speed, was significantly decreased. These results indicate that DA or TH loss in the SN, as observed in aging, contributes as a central mechanism of reduced movement frequency.

PMID: 30056575 [PubMed - in process]

Evaluation of mitogenome sequence concordance, heteroplasmy detection, and haplogrouping in a worldwide lineage study using the Precision ID mtDNA Whole Genome Panel.

Recent Research Articles from UNTHSC - Tue, 08/06/2019 - 07:14

Evaluation of mitogenome sequence concordance, heteroplasmy detection, and haplogrouping in a worldwide lineage study using the Precision ID mtDNA Whole Genome Panel.

Forensic Sci Int Genet. 2019 Jul 23;42:244-251

Authors: Strobl C, Churchill Cihlar J, Lagacé R, Wootton S, Roth C, Huber N, Schnaller L, Zimmermann B, Huber G, Lay Hong S, Moura-Neto R, Silva R, Alshamali F, Souto L, Anslinger K, Egyed B, Jankova-Ajanovska R, Casas-Vargas A, Usaquén W, Silva D, Barletta-Carrillo C, Tineo DH, Vullo C, Würzner R, Xavier C, Gusmão L, Niederstätter H, Bodner M, Budowle B, Parson W

Abstract
The emergence of Massively Parallel Sequencing technologies enabled the analysis of full mitochondrial (mt)DNA sequences from forensically relevant samples that have, so far, only been typed in the control region or its hypervariable segments. In this study, we evaluated the performance of a commercially available multiplex-PCR-based assay, the Precision ID mtDNA Whole Genome Panel (Thermo Fisher Scientific), for the amplification and sequencing of the entire mitochondrial genome (mitogenome) from even degraded forensic specimens. For this purpose, more than 500 samples from 24 different populations were selected to cover the vast majority of established superhaplogroups. These are known to harbor different signature sequence motifs corresponding to their phylogenetic background that could have an effect on primer binding and, thus, could limit a broad application of this molecular genetic tool. The selected samples derived from various forensically relevant tissue sources and were DNA extracted using different methods. We evaluated sequence concordance and heteroplasmy detection and compared the findings to conventional Sanger sequencing as well as an orthogonal MPS platform. We discuss advantages and limitations of this approach with respect to forensic genetic workflow and analytical requirements.

PMID: 31382159 [PubMed - as supplied by publisher]

Characterization of the Neurochemical and Behavioral Effects of Solriamfetol (JZP-110), a Selective Dopamine and Norepinephrine Reuptake Inhibitor.

Recent Research Articles from UNTHSC - Tue, 08/06/2019 - 07:14
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Characterization of the Neurochemical and Behavioral Effects of Solriamfetol (JZP-110), a Selective Dopamine and Norepinephrine Reuptake Inhibitor.

J Pharmacol Exp Ther. 2018 08;366(2):367-376

Authors: Baladi MG, Forster MJ, Gatch MB, Mailman RB, Hyman DL, Carter LP, Janowsky A

Abstract
Excessive sleepiness (ES) is associated with several sleep disorders, including narcolepsy and obstructive sleep apnea (OSA). A role for monoaminergic systems in treating these conditions is highlighted by the clinical use of US Food and Drug Administration-approved drugs that act on these systems, such as dextroamphetamine, methylphenidate, modafinil, and armodafinil. Solriamfetol (JZP-110) is a wake-promoting agent that is currently being evaluated to treat ES in patients with narcolepsy or OSA. Clinical and preclinical data suggest that the wake-promoting effects of solriamfetol differ from medications such as modafinil and amphetamine. The goal of the current studies was to characterize the mechanism of action of solriamfetol at monoamine transporters using in vitro and in vivo assays. Results indicate that solriamfetol has dual reuptake inhibition activity at dopamine (DA; IC50 = 2.9 μM) and norepinephrine (NE; IC50 = 4.4 μM) transporters, and this activity is associated in vivo with increased extracellular concentration of DA and NE as measured by microdialysis. Solriamfetol has negligible functional activity at the serotonin transporter (IC50 > 100 μM). Moreover, the wake-promoting effects of solriamfetol are probably owing to activity at DA and NE transporters rather than other neurotransmitter systems, such as histamine or orexin. The dual activity of solriamfetol at DA and NE transporters and the lack of significant monoamine-releasing properties of solriamfetol might explain the differences in the in vivo effects of solriamfetol compared with modafinil or amphetamine. Taken together, these data suggest that solriamfetol may offer an important advancement in the treatment of ES in patients with narcolepsy or OSA.

PMID: 29891587 [PubMed - indexed for MEDLINE]

Safety and Effectiveness of CyPass Supraciliary Micro-Stent in Primary Open-Angle Glaucoma: Five-Year Results from the COMPASS XT Study.

Recent Research Articles from UNTHSC - Mon, 08/05/2019 - 07:04
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Safety and Effectiveness of CyPass Supraciliary Micro-Stent in Primary Open-Angle Glaucoma: Five-Year Results from the COMPASS XT Study.

Am J Ophthalmol. 2019 Aug 01;:

Authors: Reiss G, Clifford B, Vold S, He J, Hamilton C, Dickerson J, Lane S

Abstract
PURPOSE: To characterize the long-term (up to five years) safety and effectiveness of the supraciliary micro-stent implanted at the time of phacoemulsification in eyes with coexisting open-angle glaucoma (OAG) and visually significant cataract DESIGN: Three-year safety extension of a two-year randomized clinical trial.
METHODS: Patients from the multicenter COMPASS trial who underwent micro-stent implantation plus phacoemulsification (n=215) or phacoemulsification alone (n=67) were evaluated 36, 48, and 60 months postoperatively. The primary outcome measure was the occurrence of sight-threatening ocular serious adverse events. Evaluations at each time point included best-corrected visual acuity (BCVA), anterior and posterior segment examinations, tonometry, gonioscopy, pachymetry, perimetry, specular microscopy, and assessment of adverse events.
RESULTS: Three sight-threatening ocular adverse events occurred, two in the micro-stent and one in the control group, but none of these events was related to the micro-stent device. Ocular adverse events were of similar frequencies in both groups, the most common of which were BCVA loss >2 lines compared with best BCVA in COMPASS and worsening of visual field mean defect (VFMD) >2.5 dB compared with Month 24. Changes from baseline in mean BCVA, clinical examinations, pachymetry and VFMD were similar in the two groups. At 60 months, a higher proportion of subjects in the micro-stent (46%; 95% CI 38.9% -53.2%) than in the control (32.1%; 95% CI 19.9%-46.3%) group achieved ≥ 20% IOP reduction without using hypotensive medication.
CONCLUSIONS: Few sight-threatening serious ocular adverse events occurred following micro-stent implantation, and clinical evidence of corneal decompensation was minimal.

PMID: 31377287 [PubMed - as supplied by publisher]

Corneal Endothelial Cell Loss and Morphometric Changes 5 Years after Phacoemulsification With or Without CyPass Micro-Stent.

Recent Research Articles from UNTHSC - Mon, 08/05/2019 - 07:04
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Corneal Endothelial Cell Loss and Morphometric Changes 5 Years after Phacoemulsification With or Without CyPass Micro-Stent.

Am J Ophthalmol. 2019 Aug 01;:

Authors: Lass JH, Benetz BA, He J, Hamilton C, Von Tress M, Dickerson J, Lane S

Abstract
PURPOSE: To characterize long-term corneal endothelial cell changes following phacoemulsification with or without supraciliary micro-stent (CyPass, Alcon, Ft. Worth, TX) implantation in eyes with open-angle glaucoma (OAG) and visually-significant cataract.
DESIGN: Three-year safety extension of a two-year randomized clinical trial.
METHODS: Patients from the multicenter COMPASS trial who underwent micro-stent implantation plus phacoemulsification (n=282) or phacoemulsification alone (n=67) were analyzed post-hoc. Specular microscopy was used to assess endothelial cell loss (ECL), including changes from baseline in endothelial cell density (ECD), coefficient of variation, and percentage of hexagonal cells,.
RESULTS: Preoperative ECD was similar in the microstent (2432.6 cells/mm2 [95% CI: 2382.8, 2482.4]) and control (2434.5 cells/mm2 [95% CI: 2356.5, 2512.4]) groups. ECL at Months 48 and 60 was greater in the micro-stent than in the control group. At Month 60, mean percent changes in ECD were -20.4% (95% CI: -23.5%, -17.5%) in the micro-stent and -10.1% (95% CI: -13.9%, -6.3%) in the control group. No statistically significant between-group changes from baseline in cellular morphology were observed. Nine adverse events were possibly related to ECL, including three eyes with transient focal corneal edema and four eyes that required micro-stent trimming due to protrusion.
CONCLUSIONS: In eyes with OAG, ECL following phacoemulsification is acute and stabilizes after 3 months, whereas ECL following phacoemulsification plus micro-stent implantation proceeds for at least 5 years. Clinical findings associated with ECL in these eyes were uncommon (3.3% of implanted eyes), suggesting that ECL is generally a subclinical phenomenon.

PMID: 31377278 [PubMed - as supplied by publisher]

Correction: Systemically administered peptain-1 inhibits retinal ganglion cell death in animal models: implications for neuroprotection in glaucoma.

Recent Research Articles from UNTHSC - Sat, 08/03/2019 - 06:46
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Correction: Systemically administered peptain-1 inhibits retinal ganglion cell death in animal models: implications for neuroprotection in glaucoma.

Cell Death Discov. 2019;5:122

Authors: Stankowska DL, Nam MH, Nahomi RB, Chaphalkar RM, Nandi SK, Fudala R, Krishnamoorthy RR, Nagaraj RH

Abstract
[This corrects the article DOI: 10.1038/s41420-019-0194-2.].

PMID: 31372242 [PubMed - in process]

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