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Arginine-Modified Polymers Facilitate Poly (Lactide-Co-Glycolide)-Based Nanoparticle Gene Delivery to Primary Human Astrocytes.

Recent Research Articles from UNTHSC - Thu, 06/18/2020 - 05:21
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Arginine-Modified Polymers Facilitate Poly (Lactide-Co-Glycolide)-Based Nanoparticle Gene Delivery to Primary Human Astrocytes.

Int J Nanomedicine. 2020;15:3639-3647

Authors: Proulx J, Joshi C, Vijayaraghavalu S, Saraswathy M, Labhasetwar V, Ghorpade A, Borgmann K

Abstract
Purpose: Astrocyte dysfunction is a hallmark of central nervous system injury or infection. As a primary contributor to neurodegeneration, astrocytes are an ideal therapeutic target to combat neurodegenerative conditions. Gene therapy has arisen as an innovative technique that provides excellent prospect for disease intervention. Poly (lactide-co-glycolide) (PLGA) and polyethylenimine (PEI) are polymeric nanoparticles commonly used in gene delivery, each manifesting their own set of advantages and disadvantages. As a clinically approved polymer by the Federal Drug Administration, well characterized for its biodegradability and biocompatibility, PLGA-based nanoparticles (PLGA-NPs) are appealing for translational gene delivery systems. However, our investigations revealed PLGA-NPs were ineffective at facilitating exogenous gene expression in primary human astrocytes, despite their success in other cell lines. Furthermore, PEI polymers illustrate high delivery efficiency but induce cytotoxicity. The purpose of this study is to develop viable and biocompatible NPsystem for astrocyte-targeted gene therapy.
Materials and Methods: Successful gene expression by PLGA-NPs alone or in combination with arginine-modified PEI polymers (AnPn) was assessed by a luciferase reporter gene encapsulated in PLGA-NPs. Cytoplasmic release and nuclear localization of DNA were investigated using fluorescent confocal imaging with YOYO-labeled plasmid DNA (pDNA). NP-mediated cytotoxicity was assessed via lactate dehydrogenase in primary human astrocytes and neurons.
Results: Confocal imaging of YOYO-labeled pDNA confirmed PLGA-NPs delivered pDNA to the cytoplasm in a dose and time-dependent manner. However, co-staining revealed pDNA delivered by PLGA-NPs did not localize to the nucleus. The addition of AnPn significantly improved nuclear localization of pDNA and successfully achieved gene expression in primary human astrocytes. Moreover, these formulations were biocompatible with both astrocytes and neurons.
Conclusion: By co-transfecting two polymeric NPs, we developed an improved system for gene delivery and expression in primary human astrocytes. These findings provide a basis for a biocompatible and clinically translatable method to regulate astrocyte function during neurodegenerative diseases and disorders.

PMID: 32547019 [PubMed - in process]

Chronic unilateral cervical vagotomy reduces renal inflammation, blood pressure, and renal injury in a mouse model of lupus.

Recent Research Articles from UNTHSC - Wed, 06/17/2020 - 05:01
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Chronic unilateral cervical vagotomy reduces renal inflammation, blood pressure, and renal injury in a mouse model of lupus.

Am J Physiol Renal Physiol. 2020 Jun 15;:

Authors: Pham GS, Gusson Shimoura C, Chaudhari S, Kulp DV, Mathis KW

Abstract
BACKGROUND: Systemic lupus erythematosus (SLE) is characterized by hypertension that results from chronic renal inflammation and dysautonomia in the form of dampened vagal tone. In health, the vagus nerve regulates inflammatory processes through mechanisms like the cholinergic anti-inflammatory pathway; so in the case of SLE, reduced efferent vagus nerve activity may indirectly affect renal inflammation, and therefore hypertension. In this study, we sought to investigate the impact of disrupting vagal neurotransmission on renal inflammation and hypertension in the setting of chronic inflammatory disease.
METHODS: Female SLE (NZBWF1) and control (NZW) mice were subjected to a right unilateral cervical vagotomy or sham surgery and 3 weeks later were implanted with indwelling catheters to measure blood pressure. Indices of splenic and renal inflammation, as well as renal injury, were assessed.
RESULTS: Unilateral vagotomy blunted SLE-induced increases in mean arterial pressure, albumin excretion rate, and glomerulosclerosis. This protection was associated with reduced splenic T cells and attenuated SLE-induced increases in renal pro-inflammatory mediators.
CONCLUSION: In summary, these data indicate that unilateral vagotomy reduces renal inflammation and reduces blood pressure in SLE mice. The vagus nerves have myriad functions and perhaps other neuroimmune interactions compensate for the ligation of one nerve.

PMID: 32538149 [PubMed - as supplied by publisher]

Human plasma biomarker responses to inhalational general anaesthesia without surgery.

Recent Research Articles from UNTHSC - Wed, 06/17/2020 - 05:01
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Human plasma biomarker responses to inhalational general anaesthesia without surgery.

Br J Anaesth. 2020 Jun 11;:

Authors: Deiner S, Baxter MG, Mincer JS, Sano M, Hall J, Mohammed I, O'Bryant S, Zetterberg H, Blennow K, Eckenhoff R

Abstract
BACKGROUND: Postoperative neurocognitive disorders may arise in part from adverse effects of general anaesthetics on the CNS, especially in older patients or individuals otherwise vulnerable to neurotoxicity because of systemic disease or the presence of pre-existing neuropathology. Previous studies have documented cytokine and injury biomarker responses to surgical procedures that included general anaesthesia, but it is not clear to what degree anaesthetics contribute to these responses.
METHODS: We performed a prospective cohort study of 59 healthy volunteers aged 40-80 yr who did not undergo surgery. Plasma markers of neurological injury and inflammation were measured immediately before and 5 h after induction of general anaesthesia with 1 minimum alveolar concentration of sevoflurane. Biomarkers included interleukin-6 (IL-6), tumour necrosis factor alpha (TNF-α), C-reactive protein (CRP), and neural injury (tau, neurofilament light [NF-L], and glial fibrillary acidic protein [GFAP]).
RESULTS: Baseline biomarkers were in the normal range, although NF-L and GFAP were elevated as a function of age. At 5 h after induction of anaesthesia, plasma tau, NF-L, and GFAP were significantly decreased relative to baseline. Plasma IL-6 was significantly increased after anaesthesia, but by a biologically insignificant degree (<1 pg ml-1); plasma TNF-α and CRP were unchanged.
CONCLUSIONS: Sevoflurane general anaesthesia without surgery, even in older adults, did not provoke an inflammatory state or neuronal injury at a concentration that is detectable by an acute elevation of measured plasma biomarkers in the early hours after exposure.
CLINICAL TRIAL REGISTRATION: NCT02275026.

PMID: 32536445 [PubMed - as supplied by publisher]

Methylenedioxymethamphetamine-like discriminative stimulus effects of pyrrolidinyl cathinones in rats.

Recent Research Articles from UNTHSC - Wed, 06/17/2020 - 05:01
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Methylenedioxymethamphetamine-like discriminative stimulus effects of pyrrolidinyl cathinones in rats.

J Psychopharmacol. 2020 Jun 13;:269881120914213

Authors: Gatch MB, Forster MJ

Abstract
BACKGROUND: Synthetic cathinone derivatives are used as alternatives both for stimulant drugs such as cocaine and methamphetamine and for club drugs such as 3,4-methylenedioxymethamphetamine (MDMA), but little is known about their MDMA-like subjective effects.
METHODS: In order to determine their similarity to MDMA, the discriminative stimulus effects of 10 pyrrolidinyl cathinones (α-pyrrolidinopropiophenone, 4'-methyl-α-pyrrolidinopropiophenone (4'-MePPP), α-pyrrolidinobutiophenone, 3',4'-methylenedioxy-α-pyrrolidinobutyrophenone (MD-PBP), α-pyrrolidinovalerophenone, 3,4-methylenedioxy-pyrovalerone (MDPV), α-pyrrolidinopentiothiophenone, napthylpyrovalerone (naphyrone), α-pyrrolidinohexiophenone, and 4'-methyl-α-pyrrolidinohexiophenone (4'-MePHP)) were assessed in Sprague-Dawley rats trained to discriminate 1.5 mg/kg racemic ±-MDMA from vehicle.
RESULTS: Compounds with no substitutions on the phenyl ring and the thiophene produced 44-67% MDMA-appropriate responding. In contrast, the substituted pyrrolidinyl cathinones produced a range of MDMA-appropriate responding dependent upon the length of the alpha side chain. 4'-MePPP, with a single carbon on the alpha position, produced 99.8% MDMA-appropriate responding, MD-PBP (two carbons) produced 83%, naphyrone (three carbons) produced 71%, MDPV (three carbons) produced, 66%, and 4'-MePHP (four carbons) produced 47%.
CONCLUSIONS: Many cathinone compounds have discriminative stimulus effects similar to those of MDMA. However, the pyrrolidine substitution appears to reduce serotonergic effects, with a commensurate decrease in MDMA-like effects. Substitutions on the phenyl ring appear to be able to restore MDMA-like responding, but only in compounds with short alpha side chains. These findings agree with earlier findings of increasing dopaminergic effects and stronger reinforcing effects with increasing side chain. Assessment of more compounds is necessary to establish the replicability/robustness of this phenomenon. These findings may be of use in predicting which compounds will have MDMA/club drug-like effects versus psychostimulant-like effects.

PMID: 32536334 [PubMed - as supplied by publisher]

Leveraging a Low-Affinity Diazaspiro Orthosteric Fragment to Reduce Dopamine D3 Receptor (D3R) Ligand Promiscuity across Highly Conserved Aminergic G-Protein-Coupled Receptors (GPCRs).

Recent Research Articles from UNTHSC - Wed, 06/17/2020 - 05:01
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Leveraging a Low-Affinity Diazaspiro Orthosteric Fragment to Reduce Dopamine D3 Receptor (D3R) Ligand Promiscuity across Highly Conserved Aminergic G-Protein-Coupled Receptors (GPCRs).

J Med Chem. 2019 05 23;62(10):5132-5147

Authors: Reilly SW, Riad AA, Hsieh CJ, Sahlholm K, Jacome DA, Griffin S, Taylor M, Weng CC, Xu K, Kirschner N, Luedtke RR, Parry C, Malhotra S, Karanicolas J, Mach RH

Abstract
Previously, we reported a 3-(2-methoxyphenyl)-9-(3-((4-methyl-5-phenyl-4 H-1,2,4-triazol-3-yl)thio)propyl)-3,9-diazaspiro[5.5]undecane (1) compound with excellent dopamine D3 receptor (D3R) affinity (D3R Ki = 12.0 nM) and selectivity (D2R/D3R ratio = 905). Herein, we present derivatives of 1 with comparable D3R affinity (32, D3R Ki = 3.2 nM, D2R/D3R ratio = 60) and selectivity (30, D3R Ki = 21.0 nM, D2R/D3R ratio = 934). Fragmentation of 1 revealed orthosteric fragment 5a to express an unusually low D3R affinity ( Ki = 2.7 μM). Compared to piperazine congener 31, which retains a high-affinity orthosteric fragment (5d, D3R Ki = 23.9 nM), 1 was found to be more selective for the D3R among D1- and D2-like receptors and exhibited negligible off-target interactions at serotoninergic and adrenergic G-protein-coupled receptors (GPCRs), common off-target sites for piperazine-containing D3R scaffolds. This study provides a unique rationale for implementing weakly potent orthosteric fragments into D3R ligand systems to minimize drug promiscuity at other aminergic GPCR sites.

PMID: 31021617 [PubMed - indexed for MEDLINE]

Experimental ischemic stroke induces long-term T cell activation in the brain.

Recent Research Articles from UNTHSC - Wed, 06/17/2020 - 05:01
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Experimental ischemic stroke induces long-term T cell activation in the brain.

J Cereb Blood Flow Metab. 2019 11;39(11):2268-2276

Authors: Xie L, Li W, Hersh J, Liu R, Yang SH

Abstract
Mounting evidence has demonstrated that both innate and adaptive immune cells infiltrate into the brain after ischemic stroke. T cell invasion has been found in the ischemic region up to one month post experimental ischemic stroke and has been shown to persist for years in stroke patients. However, the function and phenotypic characteristics of the brain invading T cells after ischemic stroke have not been investigated. In the current study, we determined the function of brain invading T cells in the acute and chronic phase following experimental ischemic stroke induced by transient middle cerebral artery occlusion. We observed a significant increase of CD4+ and CD8+ T cells presented in the peri-infarct area at up to one month after experimental ischemic stroke. The brain invading T cells after ischemic stroke demonstrated close interaction with active astrocytes and a progressive proinflammatory phenotype as evidenced by the increased expression of T cell activation markers CD44 and CD25, proinflammatory cytokines INF-γ, IL-17, IL-10, TNF-α, and perforin, with corresponding transcriptional factors T-bet and RORc. Our results indicated a prolonged activation of brain invading CD4+ and CD8+ T cells after ischemic stroke which may play a role in the neural repair process after stroke.

PMID: 30092705 [PubMed - indexed for MEDLINE]

Brain-Selective Estrogen Therapy Prevents Androgen Deprivation-Associated Hot Flushes in a Rat Model.

Recent Research Articles from UNTHSC - Sun, 06/14/2020 - 06:19
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Brain-Selective Estrogen Therapy Prevents Androgen Deprivation-Associated Hot Flushes in a Rat Model.

Pharmaceuticals (Basel). 2020 Jun 10;13(6):

Authors: Merchenthaler I, Lane M, Stennett C, Zhan M, Nguyen V, Prokai-Tatrai K, Prokai L

Abstract
Hot flushes are best-known for affecting menopausal women, but men who undergo life-saving castration due to androgen-sensitive prostate cancer also suffer from these vasomotor symptoms. Estrogen deficiency in these patients is a direct consequence of androgen deprivation, because estrogens (notably 17β-estradiol, E2) are produced from testosterone. Although estrogens alleviate hot flushes in these patients, they also cause adverse systemic side effects. Because only estrogens can provide mitigation of hot flushes on the basis of current clinical practices, there is an unmet need for an effective and safe pharmacotherapeutic intervention that would also greatly enhance patient adherence. To this end, we evaluated treatment of orchidectomized (ORDX) rats with 10β, 17β-dihydroxyestra-1,4-dien-3-one (DHED), a brain-selective bioprecursor prodrug of E2. A pilot pharmacokinetic study using oral administration of DHED to these animals revealed the formation of E2 in the brain without the appearance of the hormone in the circulation. Therefore, DHED treatment alleviated androgen deprivation-associated hot flushes without peripheral impact in the ORDX rat model. Concomitantly, we showed that DHED-derived E2 induced progesterone receptor gene expression in the hypothalamus without stimulating galanin expression in the anterior pituitary, further indicating the lack of systemic estrogen exposure upon oral treatment with DHED.

PMID: 32531919 [PubMed - as supplied by publisher]

Urine Sample-Derived Cerebral Organoids Suitable for Studying Neurodevelopment and Pharmacological Responses.

Recent Research Articles from UNTHSC - Sat, 06/13/2020 - 05:47
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Urine Sample-Derived Cerebral Organoids Suitable for Studying Neurodevelopment and Pharmacological Responses.

Front Cell Dev Biol. 2020;8:304

Authors: Lin VJT, Hu J, Zolekar A, Yan LJ, Wang YC

Abstract
Cerebral organoids (COs) developed from human induced pluripotent stem cells (hiPSCs) have been noticed for their potential in research and clinical applications. While skin fibroblast-derived hiPSCs are proficient at forming COs, the cellular and molecular features of COs developed using hiPSCs generated from other somatic cells have not been systematically examined. Urinary epithelial cells (UECs) isolated from human urine samples are somatic cells that can be non-invasively collected from most individuals. In this work, we streamlined the production of COs using hiPSCs reprogrammed from urine sample-derived UECs. UEC-derived hiPSC-developed COs presented a robust capacity for neurogenesis and astrogliogenesis. Although UEC-derived hiPSCs required specific protocol optimization to properly form COs, the cellular and transcriptomic features of COs developed from UEC-derived hiPSCs were comparable to those of COs developed from embryonic stem cells. UEC-derived hiPSC-developed COs that were initially committed to forebrain development showed cellular plasticity to transition between prosencephalic and rhombencephalic fates in vitro and in vivo, indicating their potential to develop into the cell components of various brain regions. The opposite regulation of AKT activity and neural differentiation was found in these COs treated with AKT and PTEN inhibitors. Overall, our data reveal the suitability, advantage, and possible limitations of human urine sample-derived COs for studying neurodevelopment and pharmacological responses.

PMID: 32528947 [PubMed]

A tutorial on individual participant data meta-analysis using Bayesian multilevel modeling to estimate alcohol intervention effects across heterogeneous studies.

Recent Research Articles from UNTHSC - Sat, 06/13/2020 - 05:47
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A tutorial on individual participant data meta-analysis using Bayesian multilevel modeling to estimate alcohol intervention effects across heterogeneous studies.

Addict Behav. 2019 07;94:162-170

Authors: Huh D, Mun EY, Walters ST, Zhou Z, Atkins DC

Abstract
This paper provides a tutorial companion for the methodological approach implemented in Huh et al. (2015) that overcame two major challenges for individual participant data (IPD) meta-analysis. Specifically, we show how to validly combine data from heterogeneous studies with varying numbers of treatment arms, and how to analyze highly-skewed count outcomes with many zeroes (e.g., alcohol and substance use outcomes) to estimate overall effect sizes. These issues have important implications for the feasibility, applicability, and interpretation of IPD meta-analysis but have received little attention thus far in the applied research literature. We present a Bayesian multilevel modeling approach for combining multi-arm trials (i.e., those with two or more treatment groups) in a distribution-appropriate IPD analysis. Illustrative data come from Project INTEGRATE, an IPD meta-analysis study of brief motivational interventions to reduce excessive alcohol use and related harm among college students. Our approach preserves the original random allocation within studies, combines within-study estimates across all studies, overcomes between-study heterogeneity in trial design (i.e., number of treatment arms) and/or study-level missing data, and derives two related treatment outcomes in a multivariate IPD meta-analysis. This methodological approach is a favorable alternative to collapsing or excluding intervention groups within multi-arm trials, making it possible to directly compare multiple treatment arms in a one-step IPD meta-analysis. To facilitate application of the method, we provide annotated computer code in R along with the example data used in this tutorial.

PMID: 30791977 [PubMed - indexed for MEDLINE]

Cardiac Structure and Function in Well-Healed Burn Survivors.

Recent Research Articles from UNTHSC - Sat, 06/13/2020 - 05:47
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Cardiac Structure and Function in Well-Healed Burn Survivors.

J Burn Care Res. 2019 02 20;40(2):235-241

Authors: Samuel TJ, Nelson MD, Nasirian A, Jaffery M, Moralez G, Romero SA, Cramer MN, Huang M, Kouda K, Hieda M, Sarma S, Crandall CG

Abstract
Long-term burn survivors have reduced aerobic capacity, placing them at increased risk for cardiovascular disease, morbidity, and mortality. However, the exact mechanism contributing to a reduced aerobic capacity remains incompletely understood, but may be related to adverse cardiovascular remodeling. Therefore, it was hypothesized that well-healed burn survivors would exhibit adverse left ventricular (LV) remodeling and impaired LV function. To test this hypothesis, 22 well-healed moderately burned individuals (age: 41 ± 14 years; BMI: 27.7 ± 5.4 kg/m2; male/female: 12/10; extent of burn: 37 ± 12 %BSA), 11 well-healed severely burned individuals (age: 43 ± 12 years; BMI: 29.5 ± 5.8 kg/m2; male/female: 8/3; extent of burn: 73 ± 11 %BSA), and 12 healthy, age-matched controls (age: 34 ± 9 years; BMI: 28.6 ± 5.2 kg/m2; male/female: 5/7) were enrolled in the study. All subjects were sedentary, performing less than 30 minutes of aerobic exercise per day, 3 days per week. LV morphology and function were assessed via cardiac magnetic resonance imaging. In contrast to the hypothesis, neither the presence nor severity of burn injury adversely affected LV morphology or function, when compared with equally sedentary nonburned controls. However, of note, LV mass of all three groups was in the lowest 5th percentile compared with normative values. Finally, group differences in LV morphology were largely explained by differences in aerobic capacity. Taken together, these data suggest a prior burn injury itself does not result in pathological remodeling of the LV and support a role for aerobic exercise training to improve cardiac function.

PMID: 30649454 [PubMed - indexed for MEDLINE]

Determination of metformin bio-distribution by LC-MS/MS in mice treated with a clinically relevant paradigm.

Recent Research Articles from UNTHSC - Fri, 06/12/2020 - 05:30

Determination of metformin bio-distribution by LC-MS/MS in mice treated with a clinically relevant paradigm.

PLoS One. 2020;15(6):e0234571

Authors: Chaudhari K, Wang J, Xu Y, Winters A, Wang L, Dong X, Cheng EY, Liu R, Yang SH

Abstract
Metformin, an anti-diabetes drug, has been recently emerging as a potential "anti-aging" intervention based on its reported beneficial actions against aging in preclinical studies. Nonetheless, very few metformin studies using mice have determined metformin concentrations and many effects of metformin have been observed in preclinical studies using doses/concentrations that were not relevant to therapeutic levels in human. We developed a liquid chromatography-tandem mass spectrometry protocol for metformin measurement in plasma, liver, brain, kidney, and muscle of mice. Young adult male and female C57BL/6 mice were voluntarily treated with metformin of 4 mg/ml in drinking water which translated to the maximum dose of 2.5 g/day in humans. A clinically relevant steady-state plasma metformin concentrations were achieved at 7 and 30 days after treatment in male and female mice. Metformin concentrations were slightly higher in muscle than in plasma, while, ~3 and 6-fold higher in the liver and kidney than in plasma, respectively. Low metformin concentration was found in the brain at ~20% of the plasma level. Furthermore, gender difference in steady-state metformin bio-distribution was observed. Our study established steady-state metformin levels in plasma, liver, muscle, kidney, and brain of normoglycemic mice treated with a clinically relevant dose, providing insight into future metformin preclinical studies for potential clinical translation.

PMID: 32525922 [PubMed - as supplied by publisher]

Characterization of Tear Immunoglobulins in a Small-Cohort of Keratoconus Patients.

Recent Research Articles from UNTHSC - Fri, 06/12/2020 - 05:30
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Characterization of Tear Immunoglobulins in a Small-Cohort of Keratoconus Patients.

Sci Rep. 2020 Jun 10;10(1):9426

Authors: McKay TB, Serjersen H, Hjortdal J, Zieske JD, Karamichos D

Abstract
Keratoconus (KC) is classically considered a non-inflammatory condition caused by central corneal thinning that leads to astigmatism and reduced visual acuity. Previous studies have identified increased systemic levels of pro-inflammatory factors, including interleukin-6, tumor necrosis factor-α, and matrix metalloproteinase-9, suggesting that KC may have an inflammatory component in at least a subset of patients. In this study, we evaluated the levels of different immunoglobulins (light and heavy chains) based on Ig α, Ig λ, Ig κ, Ig µ, and Ig heavy chain subunits in non-KC tears (n = 7 control individuals) and KC tears (n = 7 KC patients) using tandem-liquid chromatography mass spectrometry. The most abundant Ig heavy chains detected in both control individuals and KC patients were Ig α-1 and Ig α-2 likely correlating to the higher IgA levels reported in human tears. We identified significant differences in immunoglobulin κ-chain V-II levels in KC patients compared to control individuals with no significant difference in Ig κ/Ig λ ratios or heavy chain levels. Our study supports previous findings suggesting that KC possesses a systemic component that may contribute to the KC pathology. Further studies are required to define causality and establish a role for systemic immune system-dependent factors and pro-inflammatory processes in KC development or progression.

PMID: 32523038 [PubMed - in process]

Isolation and characterization of human optic nerve head astrocytes and lamina cribrosa cells.

Recent Research Articles from UNTHSC - Fri, 06/12/2020 - 05:30
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Isolation and characterization of human optic nerve head astrocytes and lamina cribrosa cells.

Exp Eye Res. 2020 Jun 06;:108103

Authors: Lopez NN, Clark AF, Tovar-Vidales T

Abstract
The lamina cribrosa is the initial site of glaucomatous injury. Pathological changes to the lamina cribrosa include posterior displacement of the lamina cribrosa, loss of trophic support, and remodeling of the extracellular matrix. Optic nerve head (ONH) astrocytes and lamina cribrosa cells synthesize extracellular matrix proteins to support and maintain the lamina cribrosa under physiological conditions. During glaucoma, these cells respond to mechanical strain and other stimuli, which leads to pathological remodeling of the ONH. Although ONH astrocytes and lamina cribrosa cells have been previously cultured, there is no well-accepted, straightforward technique to isolate both cell types from a single dissected human ONH. To better understand the pathophysiology of glaucoma, we obtained and cultured lamina cribrosa explants from human donor eyes. Initially, cells that grew out from the explant were ONH astrocytes and lamina cribrosa cells. Using a specialized medium, we isolated pure populations of lamina cribrosa cells and ONH astrocytes. ONH astrocytes expressed glial fibrillary acidic protein (GFAP). Lamina cribrosa cells expressed alpha-smooth muscle actin (α-SMA), but were negative for GFAP. This method of ONH cell isolation and cell-culture will provide a technique to better understand the molecular and cell-specific changes in glaucomatous damage to the ONH.

PMID: 32522476 [PubMed - as supplied by publisher]

A pathway-driven predictive model of tramadol pharmacogenetics.

Recent Research Articles from UNTHSC - Fri, 06/12/2020 - 05:30
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A pathway-driven predictive model of tramadol pharmacogenetics.

Eur J Hum Genet. 2019 07;27(7):1143-1156

Authors: Wendt FR, Novroski NMM, Rahikainen AL, Sajantila A, Budowle B

Abstract
Predicting metabolizer phenotype (MP) is typically performed using data from a single gene. Cytochrome p450 family 2 subfamily D polypeptide 6 (CYP2D6) is considered the primary gene for predicting MP in reference to approximately 30% of marketed drugs and endogenous toxins. CYP2D6 predictions have proven clinically effective but also have well-documented inaccuracies due to relatively high genotype-phenotype discordance in certain populations. Herein, a pathway-driven predictive model employs genetic data from uridine diphosphate glucuronosyltransferase, family 1, polypeptide B7 (UGT2B7), adenosine triphosphate (ATP)-binding cassette, subfamily B, number 1 (ABCB1), opioid receptor mu 1 (OPRM1), and catechol-O-methyltransferase (COMT) to predict the tramadol to primary metabolite ratio (T:M1) and the resulting toxicologically inferred MP (t-MP). These data were then combined with CYP2D6 data to evaluate performance of a fully combinatorial model relative to CYP2D6 alone. These data identify UGT2B7 as a potentially significant explanatory marker for T:M1 variability in a population of tramadol-exposed individuals of Finnish ancestry. Supervised machine learning and feature selection were used to demonstrate that a set of 16 loci from 5 genes can predict t-MP with over 90% accuracy, depending on t-MP category and algorithm, which was significantly greater than predictions made by CYP2D6 alone.

PMID: 30824817 [PubMed - indexed for MEDLINE]

Glucagon-like peptide-1 receptor pathway inhibits extracellular matrix production by mesangial cells through store-operated Ca2+ channel.

Recent Research Articles from UNTHSC - Thu, 06/11/2020 - 05:19
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Glucagon-like peptide-1 receptor pathway inhibits extracellular matrix production by mesangial cells through store-operated Ca2+ channel.

Exp Biol Med (Maywood). 2019 10;244(14):1193-1201

Authors: Huang L, Ma R, Lin T, Chaudhari S, Shotorbani PY, Yang L, Wu P

PMID: 31510798 [PubMed - indexed for MEDLINE]

Diversity in the Era of Precision Medicine - From Bench to Bedside Implementation.

Recent Research Articles from UNTHSC - Thu, 06/11/2020 - 05:19
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Diversity in the Era of Precision Medicine - From Bench to Bedside Implementation.

Ethn Dis. 2019;29(3):517-524

Authors: Mamun A, Nsiah NY, Srinivasan M, Chaturvedula A, Basha R, Cross D, Jones HP, Nandy K, Vishwanatha JK

Abstract
Recent evidence shows how patients' unique genetic makeup can affect disease outcomes and the increasing availability of targeted treatments promises a future in health care, whereby treatments will be tailored to individual needs. This article reports on the topics discussed at the 13th Annual Texas Conference on Health Disparities, organized by the Texas Center for Health Disparities at the University of North Texas Health Science Center; the meeting focused on the theme, "Diversity in the Era of Precision Medicine" and was held during June 2018 in Fort Worth, Texas. The primary focus of this conference, which brought together clinical and basic scientists, was on the inclusion of diversity in precision medicine to bridge the gap in health disparities. Here, we present the highlights of the conference that include the potential application of precision medicine at the population level, the effects of precision medicine and direct-to-consumer testing on health disparities, genetic basis of health disparities, pharmacogenomics, and strategies to enhance participation of under-represented populations in precision medicine. Furthermore, we conclude with recommendations for future implementation, including how to mitigate disparities in genomics services and enhance participation of diverse groups in clinical trials.

PMID: 31367173 [PubMed - indexed for MEDLINE]

Identifying diverse concepts of discharge failure patients at emergency department in the USA: a large-scale retrospective observational study.

Recent Research Articles from UNTHSC - Tue, 06/09/2020 - 07:31
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Identifying diverse concepts of discharge failure patients at emergency department in the USA: a large-scale retrospective observational study.

BMJ Open. 2019 06 27;9(6):e028051

Authors: Schrader CD, Robinson RD, Blair S, Shaikh S, d'Etienne JP, Kirby JJ, Cheeti R, Zenarosa NR, Wang H

Abstract
OBJECTIVES: Identifying patients who are at high risk for discharge failure allows for implementation of interventions to improve their care. However, discharge failure is currently defined in literature with great variability, making targeted interventions more difficult. We aim to derive a screening tool based on the existing diverse discharge failure models.
DESIGN, SETTING AND PARTICIPANTS: This is a single-centre retrospective cohort study in the USA. Data from all patients discharged from the emergency department were collected from 1 January 2015 through 31 December 2017 and followed up within 30 days.
METHODS: Scoring systems were derived using modified Framingham methods. Sensitivity, specificity and area under the receiver operational characteristic (AUC) were calculated and compared using both the broad and restricted discharge failure models.
RESULTS: A total of 227 627 patients were included. The Screening for Healthcare fOllow-Up Tool (SHOUT) scoring system was derived based on the broad and restricted discharge failure models and applied back to the entire study cohort. A sensitivity of 80% and a specificity of 71% were found in SHOUT scores to identify patients with broad discharge failure with AUC of 0.83 (95% CI 0.83 to 0.84). When applied to a 3-day restricted discharge failure model, a sensitivity of 86% and a specificity of 60% were found to identify patients with AUC of 0.79 (95% CI 0.78 to 0.80).
CONCLUSION: The SHOUT scoring system was derived and used to screen and identify patients that would ultimately become discharge failures, especially when using broad definitions of discharge failure. The SHOUT tool was internally validated and can be used to identify patients across a wide spectrum of discharge failure definitions.

PMID: 31248927 [PubMed - indexed for MEDLINE]

Mechanisms of sympathetic restraint in human skeletal muscle during exercise: role of α-adrenergic and non-adrenergic mechanisms.

Recent Research Articles from UNTHSC - Sat, 06/06/2020 - 06:32

Mechanisms of sympathetic restraint in human skeletal muscle during exercise: role of α-adrenergic and non-adrenergic mechanisms.

Am J Physiol Heart Circ Physiol. 2020 Jun 05;:

Authors: Hansen AB, Moralez G, Romero SA, Gasho C, Tymko MM, Ainslie PN, Hofstätter F, Rainer SL, Lawley JS, Hearon CM

Abstract
Sympathetic vasoconstriction is mediated by α-adrenergic receptors under resting conditions. During exercise increased sympathetic nerve activity (SNA) is directed to inactive and active skeletal muscle; however, it is unclear what mechanism(s) are responsible for vasoconstriction during large muscle mass exercise in humans. The aim of this study was to determine the contribution of α-adrenergic receptors to sympathetic restraint of 1) inactive skeletal muscle, and 2) active skeletal muscle, during cycle exercise in healthy humans. In ten male participants (18-35yrs.) mean arterial pressure (intra-arterial catheter) and forearm vascular resistance (FVR) and conductance (FVC) were assessed during 1) cycle exercise (60% total peak workload) alone, and 2) during combined cycle exercise + handgrip exercise (HGE), before and after intra-arterial blockade of α- and β-adrenoreceptors via phentolamine and propranolol, respectively. Cycle exercise caused vasoconstriction in the inactive forearm that was attenuated ~80% with adrenoreceptor blockade (%ΔFVR: +81.7±84.6 vs. +9.7±30.7%; P=0.05). When HGE was performed during cycle exercise, the vasodilatory response to HGE was restrained by ~40% (ΔFVC HGE: +139.3±67.0 vs. cycle exercise: +81.9±66.3 ml min-1 100mmHg-1; P=0.03); however, the restraint of active skeletal muscle blood flow was not due to α-adrenergic signaling. These findings highlight that α-adrenergic receptors are the primary, but not the exclusive mechanism by which sympathetic vasoconstriction occurs in inactive and active skeletal muscle during exercise. Metabolic activity or higher sympathetic firing frequencies may alter the contribution of α-adrenergic receptors to sympathetic vasoconstriction. Finally, non-adrenergic vasoconstrictor mechanisms may be important for understanding the regulation of blood flow during exercise.

PMID: 32502375 [PubMed - as supplied by publisher]

Reduced cerebrovascular and cardioventilatory responses to intermittent hypoxia in elderly.

Recent Research Articles from UNTHSC - Sat, 06/06/2020 - 06:32
Related Articles

Reduced cerebrovascular and cardioventilatory responses to intermittent hypoxia in elderly.

Respir Physiol Neurobiol. 2020 01;271:103306

Authors: Liu X, Chen X, Kline G, Ross SE, Hall JR, Ding Y, Mallet RT, Shi X

Abstract
BACKGROUND: The impact of aging on cerebrovascular function and tissue oxygenation during graded hypoxemia is incompletely known. This study compared the age effect on these variables during cyclic hypoxemia-reoxygenation.
METHODS: Hypoxia-induced changes in arterial (SaO2) and cerebral tissue (ScO2) O2 saturation, middle cerebral arterial flow velocity (VMCA), estimated cerebral vascular conductance (CVC), heart rate (HR) and ventilation were compared between 12 elderly (71 ± 2 yr, 7 women) and 13 young (24 ± 3 yr, 5 women) adults during the first and fifth 5-min exposures to 10% O2.
RESULTS: Although pre-hypoxia SaO2 did not differ between the groups, ScO2 was lower (P < 0.05) in the elderly (68.4 ± 1.2%) than young (73.8 ± 0.9%) adults, commensurate with a lower resting VMCA (P < 0.05). SaO2 fell less sharply (P < 0.05) in the elderly subjects during the first and fifth hypoxia exposures. Moreover, the responses of ScO2, VMCA, CVC, HR and breathing frequency to hypoxia were attenuated in the elderly subjects. Systolic and diastolic arterial pressures fell by 2-6 mmHg during hypoxia in both young and elderly. Thus, hypoxemia developed more gradually in elderly than young adults during normobaric hypoxia, concordant with a reduced metabolic demand in the elderly.
CONCLUSIONS: The elderly adults safely tolerated cyclic, moderate hypoxemia which lowered SaO2 by 20-25%, despite dampening of cerebrovascular and cardiac responses to hypoxemia.

PMID: 31557538 [PubMed - indexed for MEDLINE]

COVID-19 in India: Are Biological and Environmental Factors Helping to Stem the Incidence and Severity?

Recent Research Articles from UNTHSC - Thu, 06/04/2020 - 06:06
Related Articles

COVID-19 in India: Are Biological and Environmental Factors Helping to Stem the Incidence and Severity?

Aging Dis. 2020 May;11(3):480-488

Authors: Chakrabarti SS, Kaur U, Banerjee A, Ganguly U, Banerjee T, Saha S, Parashar G, Prasad S, Chakrabarti S, Mittal A, Agrawal BK, Rawal RK, Zhao RC, Gambhir IS, Khanna R, Shetty AK, Jin K, Chakrabarti S

Abstract
The ongoing Corona virus (COVID-19) pandemic has witnessed global political responses of unimaginable proportions. Many nations have implemented lockdowns that involve mandating citizens not to leave their residences for non-essential work. The Indian government has taken appropriate and commendable steps to curtail the community spread of COVID-19. While this may be extremely beneficial, this perspective discusses the other reasons why COVID-19 may have a lesser impact on India. We analyze the current pattern of SARS-CoV-2 transmission, testing, and mortality in India with an emphasis on the importance of mortality as a marker of the clinical relevance of COVID-19 disease. We also analyze the environmental and biological factors which may lessen the impact of COVID-19 in India. The importance of cross-immunity, innate immune responses, ACE polymorphism, and viral genetic mutations are discussed.

PMID: 32489695 [PubMed]

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