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Sigma-1 Receptor Regulates Mitochondrial Function in Glucose- and Oxygen-Deprived Retinal Ganglion Cells.

Recent Research Articles from UNTHSC - Sat, 05/27/2017 - 07:37

Sigma-1 Receptor Regulates Mitochondrial Function in Glucose- and Oxygen-Deprived Retinal Ganglion Cells.

Invest Ophthalmol Vis Sci. 2017 May 01;58(5):2755-2764

Authors: Ellis DZ, Li L, Park Y, He S, Mueller B, Yorio T

Abstract
Purpose: Understanding the role of mitochondria in retinal ganglion cells (RGCs) is relevant to human disease as studies have shown mitochondrial abnormalities in primary open-angle glaucoma patients. This study seeks to determine the effects of the sigma-1 receptor (σ-1r) and its agonists on mitochondrial function in oxygen- and glucose- deprived (OGD) purified neonatal RGCs.
Methods: Retinal ganglion cells were isolated from rat pups and subjected to OGD in varying conditions in the presence or absence of σ-1r agonist and antagonist and following addition of an AAV2-σ-1r vector that was used to increase σ-1r expression. Western blots and immunofluorescence microscopy validated findings. Mitochondrial function was determined by measuring mitochondrial membrane potential (Δψm) using the dye, fluorescence tetraethylbenzimidazolylcarbocyanineiodide (JC-1), and determination of cytochrome c oxidase activity using a cytochrome c oxidase assay kit. Caspase 3 and 7 activities were also measured using a luminescent assay kit.
Results: Oxygen and glucose deprivation in RGCs resulted in decreased mitochondrial membrane potential and cytochrome c oxidase activity when compared with normoxic RGCs. σ-1r agonists or overexpression of the σ-1r restored the mitochondrial membrane potential comparable to normoxic conditions, while σ-1r antagonists abolished these effects. Oxygen and glucose depreavtation induced decreases in cytochrome c activity were partially restored by overexpression or activation of σ-1r. Caspase activity was increased in response to OGD and was decreased by the addition of σ-1r agonist, pentazocine, and following σ-1r overexpression.
Conclusions: These data suggest that activation and/or overexpression of σ-1r restores RGCs mitochondrial function following OGD and that mitochondrial function is vital to the function of RGCs.

PMID: 28549090 [PubMed - in process]

Soluble antigens from the neurotropic pathogen Angiostrongylus cantonensis directly induce thymus atrophy in a mouse model.

Recent Research Articles from UNTHSC - Sat, 05/27/2017 - 07:37

Soluble antigens from the neurotropic pathogen Angiostrongylus cantonensis directly induce thymus atrophy in a mouse model.

Oncotarget. 2017 May 12;:

Authors: Liu Z, Su DM, Yu ZL, Wu F, Liu RF, Luo SQ, Lv ZY, Zeng X, Sun X, Wu ZD

Abstract
The nematode Angiostrongylus cantonensis (A.C.) is a neurotropic pathogen; stage-III larva invade the human (non-permissive host) central nervous system (CNS) to cause eosinophilic meningitis or meningoencephalitis accompanied by immunosuppression. In an A.C.-infectedmouse (another non-permissive host) model, CNS damage-associated T cell immune deficiency and severe inflammation were proposed to result from activation of the hypothalamic-pituitary-adrenal (HPA) axis. However, glucocorticoids are anti-inflammatory agents. Additionally, while defects in thymic stromal/epithelial cells (TECs) are the major reason for thymic atrophy, TECs do not express the glucocorticoid receptor. Therefore, activation of the HPA axis cannot fully explain the thymic atrophy and inflammation. Using an A.C.-infected mouse model, we found that A.C.-infected mice developed severe thymic atrophy with dramatic impairments in thymocytes and TECs, particularly cortical TECs, which harbor CD4+CD8+ double-positive thymocytes. The impairments resulted from soluble antigens (sAgs) from A.C. in the thymuses of infected mice, as intrathymic injection of these sAgs into live mice and the addition of these sAgs to thymic cell culture resulted in thymic atrophy and cellular apoptosis, respectively. Therefore, in addition to an indirect effect on thymocytes through the HPA axis, our study reveals a novel mechanism by which A.C. infection in non-permissive hosts directly induces defects in both thymocytes and TECs via soluble antigens.

PMID: 28548945 [PubMed - as supplied by publisher]

Expression of Mutant Myocilin Induces Abnormal Intracellular Accumulation of Selected Extracellular Matrix Proteins in the Trabecular Meshwork.

Recent Research Articles from UNTHSC - Sat, 05/27/2017 - 07:37
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Expression of Mutant Myocilin Induces Abnormal Intracellular Accumulation of Selected Extracellular Matrix Proteins in the Trabecular Meshwork.

Invest Ophthalmol Vis Sci. 2016 Nov 01;57(14):6058-6069

Authors: Kasetti RB, Phan TN, Millar JC, Zode GS

Abstract
Purpose: Abnormal accumulation of extracellular matrix (ECM) in the trabecular meshwork (TM) is associated with decreased aqueous humor outflow facility and IOP elevation in POAG. Previously, we have developed a transgenic mouse model of POAG (Tg-MYOCY437H) by expressing human mutant myocilin (MYOC), a known genetic cause of POAG. The purpose of this study is to examine whether expression of mutant myocilin leads to reduced outflow facility and abnormal ECM accumulation in Tg-MYOCY437H mice and in cultured human TM cells.
Methods: Conscious IOP was measured at various ages of Tg-MYOCY437H mice using a rebound tonometer. Outflow facility was measured in 10-month-old Tg-MYOCY437H mice. Selected ECM proteins were examined in human TM-3 cells stably expressing mutant myocilin and primary human TM cells (n = 4) as well as in the TM of Tg-MYOCY437H mice by real-time PCR, Western blotting, and immunostaining. Furthermore, TM cells expressing WT or mutant myocilin were treated with 5 mM sodium 4-phenylbutyrate (PBA), and ECM proteins were examined by Western blot and immunostaining.
Results: Starting from 3 months of age, Tg-MYOCY437H mice exhibited significant IOP elevation compared with wild-type (WT) littermates. Outflow facility was significantly reduced in Tg-MYOCY437H mice (0.0195 μl/min/mm Hg in Tg-MYOCY437H vs. 0.0332 μl/min/mm Hg in WT littermates). Increased accumulation of fibronectin, elastin, and collagen type IV and I was observed in the TM of Tg-MYOCY437H mice compared with WT littermates. Furthermore, increased ECM proteins were also associated with induction of endoplasmic reticulum (ER) stress markers, GRP78 and CHOP in the TM of Tg-MYOCY437H mice. Human TM-3 cells stably expressing DsRed-tagged Y437H mutant MYOC exhibited inhibition of myocilin secretion and its intracellular accumulation compared with TM cells expressing WT MYOC. Expression of mutant MYOC in TM-3 cells or human primary TM cells induced ER stress and also increased intracellular protein levels of fibronectin, elastin, laminin, and collagen IV and I. In addition, TM-3 cells expressing mutant myocilin exhibited reduced active forms of matrix metalloproteinase (MMP)-2 and MMP-9 in conditioned medium compared with TM-3 cells expressing WT myocilin. Interestingly, both intracellularly accumulated fibronectin and collagen I colocalized with mutant myocilin and also with ER marker KDEL further suggesting intracellular accumulation of these proteins in the ER of TM cells. Furthermore, reduction of ER stress via PBA decreased selected ECM proteins in primary TM cells.
Conclusions: These studies demonstrate that mutant myocilin induces abnormal ECM accumulation in the ER of TM cells, which may be responsible for reduced outflow facility and IOP elevation in myocilin-associated glaucoma.

PMID: 27820874 [PubMed - indexed for MEDLINE]

The Role of Presenilin-1 in the Excitotoxicity of Ethanol Withdrawal.

Recent Research Articles from UNTHSC - Sat, 05/27/2017 - 07:37
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The Role of Presenilin-1 in the Excitotoxicity of Ethanol Withdrawal.

J Pharmacol Exp Ther. 2016 Sep;358(3):516-26

Authors: Jung ME, Metzger DB, Das HK

Abstract
Presenilin-1 (PS1) is a core component of γ-secretase that is involved in neurodegeneration. We have previously shown that PS1 interacts with a mitogen-activated protein kinase [(MAPK) jun-NH2-terminal-kinase], and another MAPK (p38) is activated by ethanol withdrawal (EW), abrupt termination from chronic ethanol exposure. EW is excitotoxic in nature, induces glutamate upregulation, and provokes neuronal damage. Here, we explored a potential mechanistic pathway involving glutamate, p38 (p38α isozyme), and PS1 that may mediate EW-induced excitotoxic stress. We used the prefrontal cortex of male rats withdrawn from a chronic ethanol diet. Additionally, we used ethanol-withdrawn HT22 cells (mouse hippocampal) treated with the inhibitor of glutamate receptors [dizocilpine (MK-801)], p38α (SB203580; 4-[4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-1H-imidazol-5-yl]pyridine), or γ-secretase [N-[N- (3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT)] during EW. Separately, ethanol-free HT22 cells were exposed to glutamate with or without SB203580 or DAPT. Protein levels, mRNA levels, and cell viability were assessed using immunoblotting, qualitative polymerase chain reaction, and calcein assay, respectively. The prefrontal cortex of ethanol-withdrawn rats or HT22 cells showed an increase in PS1 and p38α, which was attenuated by MK-801 and SB203580, but mimicked by glutamate treatment to ethanol-free HT22 cells. DAPT attenuated the toxic effect of EW or glutamate on HT22 cells. These results suggest that PS1 expression is triggered by glutamate through p38α, contributing to the excitotoxic stimulus of EW.

PMID: 27278235 [PubMed - indexed for MEDLINE]

Research data management in academic institutions: A scoping review.

Recent Research Articles from UNTHSC - Fri, 05/26/2017 - 07:35
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Research data management in academic institutions: A scoping review.

PLoS One. 2017;12(5):e0178261

Authors: Perrier L, Blondal E, Ayala AP, Dearborn D, Kenny T, Lightfoot D, Reka R, Thuna M, Trimble L, MacDonald H

Abstract
OBJECTIVE: The purpose of this study is to describe the volume, topics, and methodological nature of the existing research literature on research data management in academic institutions.
MATERIALS AND METHODS: We conducted a scoping review by searching forty literature databases encompassing a broad range of disciplines from inception to April 2016. We included all study types and data extracted on study design, discipline, data collection tools, and phase of the research data lifecycle.
RESULTS: We included 301 articles plus 10 companion reports after screening 13,002 titles and abstracts and 654 full-text articles. Most articles (85%) were published from 2010 onwards and conducted within the sciences (86%). More than three-quarters of the articles (78%) reported methods that included interviews, cross-sectional, or case studies. Most articles (68%) included the Giving Access to Data phase of the UK Data Archive Research Data Lifecycle that examines activities such as sharing data. When studies were grouped into five dominant groupings (Stakeholder, Data, Library, Tool/Device, and Publication), data quality emerged as an integral element.
CONCLUSION: Most studies relied on self-reports (interviews, surveys) or accounts from an observer (case studies) and we found few studies that collected empirical evidence on activities amongst data producers, particularly those examining the impact of research data management interventions. As well, fewer studies examined research data management at the early phases of research projects. The quality of all research outputs needs attention, from the application of best practices in research data management studies, to data producers depositing data in repositories for long-term use.

PMID: 28542450 [PubMed - in process]

A technique for setting analytical thresholds in massively parallel sequencing-based forensic DNA analysis.

Recent Research Articles from UNTHSC - Fri, 05/26/2017 - 07:35
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A technique for setting analytical thresholds in massively parallel sequencing-based forensic DNA analysis.

PLoS One. 2017;12(5):e0178005

Authors: Young B, King JL, Budowle B, Armogida L

Abstract
Amplicon (targeted) sequencing by massively parallel sequencing (PCR-MPS) is a potential method for use in forensic DNA analyses. In this application, PCR-MPS may supplement or replace other instrumental analysis methods such as capillary electrophoresis and Sanger sequencing for STR and mitochondrial DNA typing, respectively. PCR-MPS also may enable the expansion of forensic DNA analysis methods to include new marker systems such as single nucleotide polymorphisms (SNPs) and insertion/deletions (indels) that currently are assayable using various instrumental analysis methods including microarray and quantitative PCR. Acceptance of PCR-MPS as a forensic method will depend in part upon developing protocols and criteria that define the limitations of a method, including a defensible analytical threshold or method detection limit. This paper describes an approach to establish objective analytical thresholds suitable for multiplexed PCR-MPS methods. A definition is proposed for PCR-MPS method background noise, and an analytical threshold based on background noise is described.

PMID: 28542338 [PubMed - in process]

Cerebral Oxygenation and Regional Cerebral Perfusion Responses with Resistance Breathing during Central Hypovolemia.

Recent Research Articles from UNTHSC - Fri, 05/26/2017 - 07:35
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Cerebral Oxygenation and Regional Cerebral Perfusion Responses with Resistance Breathing during Central Hypovolemia.

Am J Physiol Regul Integr Comp Physiol. 2017 May 24;:ajpregu.00385.2016

Authors: Kay VL, Sprick JD, Rickards CA

Abstract
Resistance breathing improves tolerance to central hypovolemia induced by lower body negative pressure (LBNP), but this is not related to protection of anterior cerebral blood flow (indexed by mean middle cerebral artery velocity, MCAv). We hypothesized that inspiratory resistance breathing improves tolerance to central hypovolemia by maintaining cerebral oxygenation (ScO2), and protecting cerebral blood flow in the posterior cerebral circulation (indexed by posterior cerebral artery velocity, PCAv). Eight subjects (4M/4F) completed two experimental sessions of a presyncopal-limited LBNP protocol (3 mmHg/min onset rate) with and without (Control) resistance breathing via an impedance threshold device (ITD). ScO2 (via near-infrared spectroscopy), MCAv and PCAv (both via transcranial Doppler ultrasound), and arterial pressure (via finger photoplethysmography) were measured continuously. Hemodynamic responses were analyzed between the Control and ITD condition at baseline (T1) and the time representing 10-s prior to presyncope in the Control condition (T2). While breathing on the ITD increased LBNP tolerance from 1506±75 s to 1704±88 s (P=0.003), both mean MCAv and mean PCAv were similar between conditions at T2 (P≥0.46), and decreased by the same magnitude with and without ITD breathing (P≥0.53). ScO2 also decreased by approximately 9% with or without ITD breathing at T2 (P=0.972), and there were also no differences in deoxygenated (dHb) or oxygenated hemoglobin (HbO2) between conditions at T2 (P≥0.43). There was no evidence that protection of regional cerebral blood velocity (i.e., anterior or posterior cerebral circulation), nor cerebral oxygen extraction played a key role in the determination of tolerance to central hypovolemia with resistance breathing.

PMID: 28539354 [PubMed - as supplied by publisher]

Locomotor and discriminative stimulus effects of four novel hallucinogens in rodents.

Recent Research Articles from UNTHSC - Fri, 05/26/2017 - 07:35
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Locomotor and discriminative stimulus effects of four novel hallucinogens in rodents.

Behav Pharmacol. 2017 May 19;:

Authors: Gatch MB, Dolan SB, Forster MJ

Abstract
There has been increasing use of novel synthetic hallucinogenic compounds, 2-(4-bromo-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine hydrochloride (25B-NBOMe), 2-(4-chloro-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine hydrochloride (25C-NBOMe), 2-(4-iodo-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine hydrochloride (25I-NBOMe), and N,N-diallyl-5-methoxy tryptamine (5-MeO-DALT), which have been associated with severe toxicities. These four compounds were tested for discriminative stimulus effects similar to a prototypical hallucinogen (-)-2,5-dimethoxy-4-methylamphetamine (DOM) and the entactogen (±)-3,4-methylenedioxymethamphetamine (MDMA). Locomotor activity in mice was tested to obtain dose range and time-course information. 25B-NBOMe, 25C-NBOMe, and 25I-NBOMe decreased locomotor activity. 5-MeO-DALT dose dependently increased locomotor activity, with a peak at 10 mg/kg. A higher dose (25 mg/kg) suppressed activity. 25B-NBOMe fully substituted (≥80%) in both DOM-trained and MDMA-trained rats at 0.5 mg/kg. However, higher doses produced much lower levels of drug-appropriate responding in both DOM-trained and MDMA-trained rats. 25C-NBOMe fully substituted in DOM-trained rats, but produced only 67% drug-appropriate responding in MDMA-trained rats at doses that suppressed responding. 25I-NBOMe produced 74-78% drug-appropriate responding in DOM-trained and MDMA-trained rats at doses that suppressed responding. 5-MeO-DALT fully substituted for DOM, but produced few or no MDMA-like effects. All of the compounds, except 25I-NBOMe, fully substituted for DOM, whereas only 25B-NBOMe fully substituted for MDMA. However, the failure of 25I-NBOMe to fully substitute for either MDMA or DOM was more likely because of its substantial rate-depressant effects than weak discriminative stimulus effects. All of the compounds are likely to attract recreational users for their hallucinogenic properties, but probably of much less interest as substitutes for MDMA. Although no acute adverse effects were observed at the doses tested, the substantial toxicities reported in humans, coupled with the high likelihood for illicit use, suggests that these compounds have the same potential for abuse as other, currently scheduled compounds.

PMID: 28537942 [PubMed - as supplied by publisher]

Statin-associated muscle symptoms and SLCO1B1 rs4149056 genotype in patients with familial hypercholesterolemia.

Recent Research Articles from UNTHSC - Fri, 05/26/2017 - 07:35
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Statin-associated muscle symptoms and SLCO1B1 rs4149056 genotype in patients with familial hypercholesterolemia.

Am Heart J. 2016 Sep;179:1-9

Authors: Khine H, Yuet WC, Adams-Huet B, Ahmad Z

Abstract
UNLABELLED: Patients with familial hypercholesterolemia (FH) may be at increased risk for statin-associated muscle symptoms because they require long-term treatment with high-intensity statin therapy. We sought to determine (1) whether other predisposing factors, including the well-known genetic variant associated with statin-associated muscle symptoms-solute carrier organic anion transporter family, member 1B1 (SLCO1B1) rs4149056-also increase the risk of statin-associated muscle symptoms in FH patients, and (2) the natural history and management for FH patients with statin-associated muscle symptoms.
METHODS: We queried electronic records (2004-2014) of 278 genetically screened FH patients (113 men, 165 women; mean [SD] pretreatment low-density lipoprotein cholesterol [LDL-C] 259 [72] mg/dL) recruited from lipid clinics in the Dallas, TX, area from 2004 to 2014. Statin-associated muscle symptoms were defined as muscle symptoms arising while taking a statin and interrupting therapy.
RESULTS: The risk of muscle symptoms was associated with age (odds ratio 1.6 [95% CI 1.2-2.2]), body mass index in non-African Americans (0.90 [0.83-0.97]), and hypertension (0.4 [0.2-0.9]). Simvastatin was the most commonly used statin, and it was the statin most associated with muscle symptoms. Among FH patients with muscle symptoms, 41% (n = 40) reestablished statin therapy ("eventually tolerant") and 29% (n = 28) never reestablished statin therapy ("never tolerant"). Rosuvastatin (43%) and pravastatin (30%) were the most common eventually tolerated statins, and eventually tolerant patients achieved lower treated LDL-C levels (eventually tolerant 127 vs never tolerant 192 mg/dL, P < .001). Never tolerant patients also developed muscle symptoms on nonstatins (16% vs 50%, P = .003). SLCO1B1 rs4149056 genotyping revealed 224 wild-type patients (TT) and 49 heterozygotes (TC). SLCO1B1 genotype was not associated with the risk of statin-associated muscle symptoms (odds ratio 1.40 [95% CI 0.74-2.64]).
CONCLUSION: Age, not SLCO1B1 rs4149056 genotype, was the strongest risk factor for statin-associated muscle symptoms in FH patients. After developing muscle symptoms, many patients reestablished statin therapy and achieved significant LDL-C reductions. Overall, 10% of all FH patients had statin-associated muscle symptoms and never reestablished statin therapy. Such patients developed muscle symptoms even on nonstatin lipid-lowering drugs and continued to have elevations in LDL-C. Further insight is needed into the relationship between FH and statin-associated muscle symptoms so all FH patients can be adequately treated.

PMID: 27595674 [PubMed - indexed for MEDLINE]

Identification and localization of lamina cribrosa cells in the human optic nerve head.

Recent Research Articles from UNTHSC - Fri, 05/26/2017 - 07:35
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Identification and localization of lamina cribrosa cells in the human optic nerve head.

Exp Eye Res. 2016 Jun;147:94-7

Authors: Tovar-Vidales T, Wordinger RJ, Clark AF

Abstract
One of the central features of glaucoma is progressive cupping and excavation of the optic nerve head (ONH). Unmyelinated retinal ganglion cell (RGC) axons exit the eye through the ONH, which is supported by the lamina cribrosa (LC) consisting of plates of connective tissue with channels for bundles of RGC axons. The LC progressively remodels during glaucoma, but the cellular and molecular mechanisms responsible for this remodeling are poorly understood. Two major cell types have been isolated and cultured from the human ONH, which differ in their characteristics. Glial fibrillary acidic protein (GFAP) positive ONH astrocytes are the major cell type and are reactive in glaucoma. GFAP negative LC cells are the second major cell type isolated from the human ONH, and in contrast to ONH astrocytes, are α-smooth muscle actin (α-SMA) positive. Although a number of in vitro studies have been conducted with LC cells, to date there has been no direct evidence for these cells in situ in the human ONH. We used GFAP and α-SMA immunofluorescent staining of human eyes to clearly demonstrate the presence of not only ONH astrocytes within the human ONH, but also LC cells within the cribriform (e.g. laminar) plates/beams of the LC region. Both of these cell types likely play important roles in the homeostatic maintenance of the ONH and pathogenic changes that occur in primary open angle glaucoma (POAG).

PMID: 27167365 [PubMed - indexed for MEDLINE]

Human trabecular meshwork cells express BMP antagonist mRNAs and proteins.

Recent Research Articles from UNTHSC - Fri, 05/26/2017 - 07:35
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Human trabecular meshwork cells express BMP antagonist mRNAs and proteins.

Exp Eye Res. 2016 Jun;147:156-60

Authors: Tovar-Vidales T, Fitzgerald AM, Clark AF

Abstract
Glaucoma patients have elevated aqueous humor and trabecular meshwork (TM) levels of transforming growth factor-beta2 (TGF-β2). TGF-β2 has been associated with increased extracellular matrix (ECM) deposition (i.e. fibronectin), which is attributed to the increased resistance of aqueous humor outflow through the TM. We have previously demonstrated that bone morphogenetic protein (BMP) 4 selectively counteracts the profibrotic effect of TGF-β2 with respect to ECM synthesis in the TM, and this action is reversed by the BMP antagonist gremlin. Thus, the BMP and TGF-β signaling pathways antagonize each other's antifibrotic and profibrotic roles. The purpose of this study was to determine whether cultured human TM cells: (a) express other BMP antagonists including noggin, chordin, BMPER, BAMBI, Smurf1 and 2, and (b) whether expression of these proteins is regulated by exogenous TGF-β2 treatment. Primary human trabecular meshwork (TM) cells were grown to confluency and treated with TGF-β2 (5 ng/ml) for 24 or 48 h in serum-free medium. Untreated cell served as controls. qPCR and Western immunoblots (WB) determined that human TM cells expressed mRNAs and proteins for the BMP antagonist proteins: noggin, chordin, BMPER, BAMBI, and Smurf1/2. Exogenous TGF-β2 decreased chordin, BMPER, BAMBI, and Smurf1 mRNA and protein expression. In contrast, TGF-β2 increased secreted noggin and Smurf2 mRNA and protein levels. BMP antagonist members are expressed in the human TM. These molecules may be involved in the normal function of the TM as well as TM pathogenesis. Altered expression of BMP antagonist members may lead to functional changes in the human TM.

PMID: 27167364 [PubMed - indexed for MEDLINE]

Changes in inflammatory biomarkers following spinal manipulation.

Recent Research Articles from UNTHSC - Wed, 05/24/2017 - 07:35
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Changes in inflammatory biomarkers following spinal manipulation.

Musculoskelet Sci Pract. 2017 May 17;:

Authors: Licciardone JC

PMID: 28533071 [PubMed - as supplied by publisher]

HIV-1 Tat Induces Unfolded Protein Response and Endoplasmic Reticulum Stress in Astrocytes and Causes Neurotoxicity through Glial Fibrillary Acidic Protein (GFAP) Activation and Aggregation.

Recent Research Articles from UNTHSC - Tue, 05/23/2017 - 07:34
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HIV-1 Tat Induces Unfolded Protein Response and Endoplasmic Reticulum Stress in Astrocytes and Causes Neurotoxicity through Glial Fibrillary Acidic Protein (GFAP) Activation and Aggregation.

J Biol Chem. 2016 Oct 21;291(43):22819-22829

Authors: Fan Y, He JJ

Abstract
HIV-1 Tat is a major culprit for HIV/neuroAIDS. One of the consistent hallmarks of HIV/neuroAIDS is reactive astrocytes or astrocytosis, characterized by increased cytoplasmic accumulation of the intermediate filament glial fibrillary acidic protein (GFAP). We have shown that that Tat induces GFAP expression in astrocytes and that GFAP activation is indispensable for astrocyte-mediated Tat neurotoxicity. However, the underlying molecular mechanisms are not known. In this study, we showed that Tat expression or GFAP expression led to formation of GFAP aggregates and induction of unfolded protein response (UPR) and endoplasmic reticulum (ER) stress in astrocytes. In addition, we demonstrated that GFAP up-regulation and aggregation in astrocytes were necessary but also sufficient for UPR/ER stress induction in Tat-expressing astrocytes and for astrocyte-mediated Tat neurotoxicity. Importantly, we demonstrated that inhibition of Tat- or GFAP-induced UPR/ER stress by the chemical chaperone 4-phenylbutyrate significantly alleviated astrocyte-mediated Tat neurotoxicity in vitro and in the brain of Tat-expressing mice. Taken together, these results show that HIV-1 Tat expression leads to UPR/ER stress in astrocytes, which in turn contributes to astrocyte-mediated Tat neurotoxicity, and raise the possibility of developing HIV/neuroAIDS therapeutics targeted at UPR/ER stress.

PMID: 27609520 [PubMed - indexed for MEDLINE]

HIV-1 Tat Promotes Lysosomal Exocytosis in Astrocytes and Contributes to Astrocyte-mediated Tat Neurotoxicity.

Recent Research Articles from UNTHSC - Tue, 05/23/2017 - 07:34
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HIV-1 Tat Promotes Lysosomal Exocytosis in Astrocytes and Contributes to Astrocyte-mediated Tat Neurotoxicity.

J Biol Chem. 2016 Oct 21;291(43):22830-22840

Authors: Fan Y, He JJ

Abstract
Tat interaction with astrocytes has been shown to be important for Tat neurotoxicity and HIV/neuroAIDS. We have recently shown that Tat expression leads to increased glial fibrillary acidic protein (GFAP) expression and aggregation and activation of unfolded protein response/endoplasmic reticulum (ER) stress in astrocytes and causes neurotoxicity. However, the exact molecular mechanism of astrocyte-mediated Tat neurotoxicity is not defined. In this study, we showed that neurotoxic factors other than Tat protein itself were present in the supernatant of Tat-expressing astrocytes. Two-dimensional gel electrophoresis and mass spectrometry revealed significantly elevated lysosomal hydrolytic enzymes and plasma membrane-associated proteins in the supernatant of Tat-expressing astrocytes. We confirmed that Tat expression and infection of pseudotyped HIV.GFP led to increased lysosomal exocytosis from mouse astrocytes and human astrocytes. We found that Tat-induced lysosomal exocytosis was tightly coupled to astrocyte-mediated Tat neurotoxicity. In addition, we demonstrated that Tat-induced lysosomal exocytosis was astrocyte-specific and required GFAP expression and was mediated by ER stress. Taken together, these results show for the first time that Tat promotes lysosomal exocytosis in astrocytes and causes neurotoxicity through GFAP activation and ER stress induction in astrocytes and suggest a common cascade through which aberrant astrocytosis/GFAP up-regulation potentiates neurotoxicity and contributes to neurodegenerative diseases.

PMID: 27609518 [PubMed - indexed for MEDLINE]

Current Alcohol Use is Associated with Sleep Patterns in First-Year College Students.

Recent Research Articles from UNTHSC - Tue, 05/23/2017 - 07:34
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Current Alcohol Use is Associated with Sleep Patterns in First-Year College Students.

Sleep. 2016 06 01;39(6):1321-6

Authors: Van Reen E, Roane BM, Barker DH, McGeary JE, Borsari B, Carskadon MA

Abstract
STUDY OBJECTIVES: To examine whether differences exist in self-reported sleep patterns and self-reported alcohol use for first-semester college students who do or do not report drinking during the last 6 months (mo) of high school.
METHODS: Participants were 878 first-year college students. Students completed a survey in late May/early June about alcohol use and consequences, during the last 6 mo of high school; they later completed a daily record of sleep behavior and alcohol use across the first 9 weeks of the first semester of college. High school drinking status (past 6 mo) was classified as positive (HS-6 mo+) or negative (HS-6mo-) based on any indication of drinking on the May/June survey. Collegiate drinking was determined from first-semester daily diary alcohol reports as non-drinkers (0 reported drinks), drinkers (one or fewer heavy episodic drinking episodes (HED)), and drinkers reporting more than one HED episode. Sleep patterns were compared for non-drinkers, drinkers, and HED with no high school drinking history (HS-6mo-/HED). In addition, a separate analysis compared sleep patterns for college HED with (HS-6mo+/HED) and without (HS-6mo-/HED) high school self-reported alcohol use.
RESULTS: Increased alcohol consumption in the first semester of college was associated with later bedtimes and rise times. We found no association of high school alcohol use and sleep in those with collegiate HED.
CONCLUSIONS: Later sleep timing in those with greater alcohol use, supports a connection between sleep patterns and alcohol use. Such an early appearance of this connection may herald the development of alcohol use disorder in some individuals.

PMID: 27070138 [PubMed - indexed for MEDLINE]

Breaking Up Sedentary Behavior: Perceptions From Cancer Survivors.

Recent Research Articles from UNTHSC - Tue, 05/23/2017 - 07:34
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Breaking Up Sedentary Behavior: Perceptions From Cancer Survivors.

Cancer Nurs. 2016 Jul-Aug;39(4):272-8

Authors: Paxton RJ, Anderson A, Sarkar S, Taylor WC

Abstract
BACKGROUND: Limited data exist on the benefits of, barriers to, and potential strategies to break up time spent sitting in cancer survivors. Such data will be meaningful given the consequences of prolonged sitting.
OBJECTIVES: The aim of this study was to conduct a mixed-method research study consisting of semistructured telephone interviews to identify recurrent themes associated with prolonged sitting in cancer survivors.
METHODS: African American breast cancer survivors (N = 31) were recruited from a local tumor registry. Telephone interviews were conducted and group consensus processes were used to identify recurrent themes. The a priori categories were benefits, barriers, and potential strategies to breaking up prolonged periods of sitting.
RESULTS: Recurrent themes contributing most to prolonged sitting were leisure time interest (45%: eg, watching television and reading) and health challenges (27%: eg, pain and fatigue). Most (66%) women perceived improved health as benefits to breaking up time spent sitting. Nonetheless, many (41%) survivors reported health (eg, pain and fatigue) as the biggest challenge to interrupt time spent sitting. Engaging in light intensity activities (eg, staying active, keep moving) was the most commonly reported strategy for breaking up prolonged sitting.
CONCLUSIONS: African American breast cancer survivors identified the benefits and barriers to breaking up time spent sitting as well as potential strategies to interrupt time-spent sitting.
IMPLICATIONS FOR PRACTICE: Clinicians are integral in promoting breaks from prolonged sitting throughout the initial phases of the cancer continuum. Successful studies will begin with early intervention in the clinical setting, with increasing intensity as survivors transition to the recovery phase.

PMID: 26713501 [PubMed - indexed for MEDLINE]

Genetically engineered probiotic for the treatment of phenylketonuria (PKU); assessment of a novel treatment in vitro and in the PAHenu2 mouse model of PKU.

Recent Research Articles from UNTHSC - Fri, 05/19/2017 - 07:39

Genetically engineered probiotic for the treatment of phenylketonuria (PKU); assessment of a novel treatment in vitro and in the PAHenu2 mouse model of PKU.

PLoS One. 2017;12(5):e0176286

Authors: Durrer KE, Allen MS, Hunt von Herbing I

Abstract
Phenylketonuria (PKU) is a genetic disease characterized by the inability to convert dietary phenylalanine to tyrosine by phenylalanine hydroxylase. Given the importance of gut microbes in digestion, a genetically engineered microbe could potentially degrade some ingested phenylalanine from the diet prior to absorption. To test this, a phenylalanine lyase gene from Anabaena variabilis (AvPAL) was codon-optimized and cloned into a shuttle vector for expression in Lactobacillus reuteri 100-23C (pHENOMMenal). Functional expression of AvPAL was determined in vitro, and subsequently tested in vivo in homozygous PAHenu2 (PKU model) mice. Initial trials of two PAHenu2 homozygous (PKU) mice defined conditions for freeze-drying and delivery of bacteria. Animals showed reduced blood phe within three to four days of treatment with pHENOMMenal probiotic, and blood phe concentrations remained significantly reduced (P < 0.0005) compared to untreated controls during the course of experiments. Although pHENOMMenal probiotic could be cultured from fecal samples at four months post treatment, it could no longer be cultivated from feces at eight months post treatment, indicating eventual loss of the microbe from the gut. Preliminary screens during experimentation found no immune response to AvPAL. Collectively these studies provide data for the use of a genetically engineered probiotic as a potential treatment for PKU.

PMID: 28520731 [PubMed - in process]

Extracellular Superoxide Dismutase Enhances Recruitment of Immature Neutrophils to the Liver.

Recent Research Articles from UNTHSC - Fri, 05/19/2017 - 07:39
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Extracellular Superoxide Dismutase Enhances Recruitment of Immature Neutrophils to the Liver.

Infect Immun. 2016 Dec;84(12):3302-3312

Authors: Break TJ, Witter AR, Indramohan M, Mummert ME, Dory L, Berg RE

Abstract
Listeria monocytogenes is a Gram-positive intracellular pathogen that causes spontaneous abortion in pregnant women, as well as septicemia, meningitis, and gastroenteritis, primarily in immunocompromised individuals. Although L. monocytogenes can usually be effectively treated with antibiotics, there is still around a 25% mortality rate with individuals who develop clinical listeriosis. Neutrophils are innate immune cells required for the clearance of pathogenic organisms, including L. monocytogenes The diverse roles of neutrophils during both infectious and noninfectious inflammation have recently gained much attention. However, the impact of reactive oxygen species, and the enzymes that control their production, on neutrophil recruitment and function is not well understood. Using congenic mice with varying levels of extracellular superoxide dismutase (ecSOD) activity, we have recently shown that the presence of ecSOD decreases clearance of L. monocytogenes while increasing the recruitment of neutrophils that are not protective in the liver. The data presented here show that ecSOD activity does not lead to a cell-intrinsic increase in neutrophil-homing potential or a decrease in protection against L. monocytogenes Instead, ecSOD activity enhances the production of neutrophil-attracting factors and protects hyaluronic acid (HA) from damage. Furthermore, neutrophils from the livers of ecSOD-expressing mice have decreased intracellular and surface-bound myeloperoxidase, are less capable of killing phagocytosed L. monocytogenes, and have decreased oxidative burst. Collectively, our data reveal that ecSOD activity modulates neutrophil recruitment and function in a cell-extrinsic fashion, highlighting the importance of the enzyme in protecting tissues from oxidative damage.

PMID: 27600509 [PubMed - indexed for MEDLINE]

Therapeutic drug monitoring of posaconazole oral suspension in paediatric patients younger than 13 years of age: a retrospective analysis and literature review.

Recent Research Articles from UNTHSC - Thu, 05/18/2017 - 07:40
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Therapeutic drug monitoring of posaconazole oral suspension in paediatric patients younger than 13 years of age: a retrospective analysis and literature review.

J Clin Pharm Ther. 2017 Feb;42(1):75-79

Authors: Jancel T, Shaw PA, Hallahan CW, Kim T, Freeman AF, Holland SM, Penzak SR

Abstract
WHAT IS KNOWN AND OBJECTIVE: Posaconazole is an extended-spectrum triazole antifungal with activity against a variety of clinically significant yeasts and moulds. Posaconazole is not currently approved by the U.S. Food and Drug Administration for use in children younger than 13 years of age. Our primary objective was to describe the dosing and observed trough concentrations with posaconazole oral suspension in paediatric patients at the National Institutes of Health Clinical Center (Bethesda, MD).
METHODS: This retrospective single-centre study reviewed paediatric patients younger than 13 years of age initiated on posaconazole oral suspension. Patients were included if they were initiated on posaconazole for prophylaxis or treatment for fungal infections from September 2006 through March 2013 with at least one trough concentration collected after at least 7 days of therapy.
RESULTS AND DISCUSSION: A total of 20 male patients were included, of whom 15 (75%) had chronic granulomatous disease. The median age of patients was 6·5 years (range: 2·8-10·7). A total of 79 posaconazole trough concentrations were measured in patients receiving posaconazole as prophylaxis (n = 8) or treatment (n = 12). Posaconazole dose referenced to total body weight ranged from 10·0 to 49·2 mg/kg/day. Posaconazole trough concentrations ranged from undetectable (<50 ng/mL) up to 3620 ng/mL and were ≥500, ≥700 and ≥1250 ng/mL in 95%, 60% and 25% of patients, respectively.
WHAT IS NEW AND CONCLUSIONS: Patients younger than 13 years of age had highly variable trough concentrations, and recommendations for the appropriate dosing of posaconazole oral suspension remain challenging. Until studies are conducted to determine the appropriate dosing of posaconazole in this patient population, therapeutic drug monitoring should be considered to ensure adequate posaconazole exposure.

PMID: 27982447 [PubMed - indexed for MEDLINE]

Reiteration of the Statistical Basis of DNA Source Attribution Determinations in View of the Attorney General's Directive on "Reasonable Scientific Certainty" Statements.

Recent Research Articles from UNTHSC - Wed, 05/17/2017 - 10:01
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Reiteration of the Statistical Basis of DNA Source Attribution Determinations in View of the Attorney General's Directive on "Reasonable Scientific Certainty" Statements.

J Forensic Sci. 2017 May 16;:

Authors: Moretti TR, Budowle B

PMID: 28508395 [PubMed - as supplied by publisher]

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