Recent Research Articles from UNTHSC

Recent research articles indexed in PubMed from authors affiliated with the UNT Health Science Center.

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NCBI: db=pubmed; Term="University of North Texas Health Science Center"[All Fields] OR "Univ. of North Texas Health Science Center"[All Fields] OR "UNT Health Science Center"[All Fields] OR "Osteopathic Research Center"[All Fields] OR "University of North Texas System College of Pharmacy"[All Fields] OR "UNT System College of Pharmacy"[All Fields] OR "College of Pharmacy, University of North Texas System"[All Fields]
Updated: 2 hours 18 min ago

Hormone-related Migraine Headaches and Mood Disorders: Treatment with Estrogen Stabilization.

Sun, 11/27/2016 - 07:32

Hormone-related Migraine Headaches and Mood Disorders: Treatment with Estrogen Stabilization.

Pharmacotherapy. 2016 Nov 26;:

Authors: Warnock JK, Cohen LJ, Blumenthal H, Hammond JE

Abstract
Since estrogens and the trigeminal system are inherently linked, prescribers who are treating a woman with a hormonally-related mood disorder and migraine headachesshould consider hormonal options to optimize the patient's treatment. This paper will discuss the interrelationships of estrogen, serotonin, and the trigeminal system as they relate to menstrual migraine occurrence and hormone-related mood symptoms. In addition, clinical examples are provided to facilitate the prescribers treating women during reproductive transitions in which declining estrogens are related to their suffering. This article is protected by copyright. All rights reserved.

PMID: 27888528 [PubMed - as supplied by publisher]

Retrograde conditioning of place preference and motor activity with cocaine in mice.

Sun, 11/27/2016 - 07:32

Retrograde conditioning of place preference and motor activity with cocaine in mice.

Psychopharmacology (Berl). 2016 Nov 25;

Authors: Shetty RA, Rutledge MA, Forster MJ

Abstract
RATIONALE: In order to improve understanding of the nature of drug-associated memory, the current studies addressed whether conditioned place preference (CPP) could develop under conditions in which there was a delay between presentation of context and drug exposure (i.e., retrograde or trace conditioning).
OBJECTIVES: The objective was to assess development of CPP when cocaine or methamphetamine was injected simultaneously with exposure to a salient context (S+), or after delays differing in length.
METHODS: Dose response curves for conventional CPP were established using separate groups of Swiss-Webster mice injected with cocaine or methamphetamine just prior to S+ exposure. To assess the development of retrograde CPP, other groups received trace conditioning, where cocaine (15 mg/kg) or methamphetamine (0.5 mg/kg) was injected after a delay of 15, 60, 120, 180, 240, or 480 min following the end of the S+ session.
RESULTS: Mice receiving conventional CPP with cocaine or methamphetamine during S+ showed significant place preference. None of the groups receiving delayed methamphetamine showed significant CPP; however, CPP was evident in mice receiving cocaine after delays of up to 4 h following S+. In a separate study, delayed methamphetamine also did not result in significant place preference when presented in doses of 0.25 or 1 mg/kg.
CONCLUSIONS: These results suggest that psychostimulant drug taking may be broadly generalized to context through retrograde association with events in recent memory, a factor that may contribute to drug-seeking and relapse following abstinence.

PMID: 27888283 [PubMed - as supplied by publisher]

Cas9-catalyzed DNA Cleavage Generates Staggered Ends: Evidence from Molecular Dynamics Simulations.

Wed, 11/23/2016 - 07:31

Cas9-catalyzed DNA Cleavage Generates Staggered Ends: Evidence from Molecular Dynamics Simulations.

Sci Rep. 2016 Nov 22;5:37584

Authors: Zuo Z, Liu J

Abstract
The CRISPR-associated endonuclease Cas9 from Streptococcus pyogenes (spCas9) along with a single guide RNA (sgRNA) has emerged as a versatile toolbox for genome editing. Despite recent advances in the mechanism studies on spCas9-sgRNA-mediated double-stranded DNA (dsDNA) recognition and cleavage, it is still unclear how the catalytic Mg(2+) ions induce the conformation changes toward the catalytic active state. It also remains controversial whether Cas9 generates blunt-ended or staggered-ended breaks with overhangs in the DNA. To investigate these issues, here we performed the first all-atom molecular dynamics simulations of the spCas9-sgRNA-dsDNA system with and without Mg(2+) bound. The simulation results showed that binding of two Mg(2+) ions at the RuvC domain active site could lead to structurally and energetically favorable coordination ready for the non-target DNA strand cleavage. Importantly, we demonstrated with our simulations that Cas9-catalyzed DNA cleavage produces 1-bp staggered ends rather than generally assumed blunt ends.

PMID: 27874072 [PubMed - in process]

Blood-based biomarkers in Alzheimer disease: Current state of the science and a novel collaborative paradigm for advancing from discovery to clinic.

Tue, 11/22/2016 - 07:35
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Blood-based biomarkers in Alzheimer disease: Current state of the science and a novel collaborative paradigm for advancing from discovery to clinic.

Alzheimers Dement. 2016 Nov 18;:

Authors: O'Bryant SE, Mielke MM, Rissman RA, Lista S, Vanderstichele H, Zetterberg H, Lewczuk P, Posner H, Hall J, Johnson L, Fong YL, Luthman J, Jeromin A, Batrla-Utermann R, Villarreal A, Britton G, Snyder PJ, Henriksen K, Grammas P, Gupta V, Martins R, Hampel H, Biofluid Based Biomarker Professional Interest Area

Abstract
The last decade has seen a substantial increase in research focused on the identification of blood-based biomarkers that have utility in Alzheimer's disease (AD). Blood-based biomarkers have significant advantages of being time- and cost-efficient as well as reduced invasiveness and increased patient acceptance. Despite these advantages and increased research efforts, the field has been hampered by lack of reproducibility and an unclear path for moving basic discovery toward clinical utilization. Here we reviewed the recent literature on blood-based biomarkers in AD to provide a current state of the art. In addition, a collaborative model is proposed that leverages academic and industry strengths to facilitate the field in moving past discovery only work and toward clinical use. Key resources are provided. This new public-private partnership model is intended to circumvent the traditional handoff model and provide a clear and useful paradigm for the advancement of biomarker science in AD and other neurodegenerative diseases.

PMID: 27870940 [PubMed - as supplied by publisher]

Brain globins in physiology and pathology.

Tue, 11/22/2016 - 07:35
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Brain globins in physiology and pathology.

Med Gas Res. 2016 Jul-Sep;6(3):154-163

Authors: Xie LK, Yang SH

Abstract
Globins are globular proteins for either transport or storage of oxygen which are critical for cellular metabolism. Four globins have been identified in rodent and human brains. Among them, neuroglobin, cytoglobin and hemoglobin chains are constitutively expressed in normal brain, while myoglobin is only expressed in some neurological disorders. Studies on the molecular structure, expression and functional features of these brain globins indicated that they may play crucial roles in maintenance of neural cell survival and activity, including neurons and astrocytes. Their regulation in neurological disorders may help thoroughly understand initiation and progression of ischemia, Alzheimer's disease and glioma, etc. Elucidation of the brain globin functions might remarkably improve medical strategies that sustain neurological homeostasis and treat neurological diseases. Here the expression pattern and functions of brain globins and their involvement in neurological disorders are reviewed.

PMID: 27867483 [PubMed - in process]

Retention in care and reasons for discontinuation of lifelong antiretroviral therapy in a cohort of Cameroonian pregnant and breastfeeding HIV-positive women initiating "Option B+" in the South West Region.

Sun, 11/20/2016 - 07:33

Retention in care and reasons for discontinuation of lifelong antiretroviral therapy in a cohort of Cameroonian pregnant and breastfeeding HIV-positive women initiating "Option B+" in the South West Region.

Trop Med Int Health. 2016 Nov 16;:

Authors: Atanga PN, Ndetan HT, Achidi EA, Meriki HD, Hoelscher M, Kroidl A

Abstract
OBJECTIVE: To assess linkage and retention in care along the PMTCT cascade in HIV-positive pregnant and breastfeeding women initiating Option B+ in Cameroon.
METHODS: We prospectively determined uptake of HIV testing and counselling (HTC), uptake of ART and retention in care after Option B+ initiation between October 2013 and December 2014 in pregnant and breastfeeding women from five sites within the Kumba Health District. Retention in care was assessed over at least 12 months follow-up and estimated by Kaplan Meier analysis. During follow-up, tracing outcomes and reasons for discontinuing treatment were documented.
RESULTS: The uptake of HTC of 5,813 women with unknown HIV status was 98.5%, 251 (4.4%) were newly diagnosed HIV-positive, and ART uptake in women eligible to start Option B+ was 96.8%. We enrolled 268 women initiating lifelong ART in the follow-up. Overall, 65 (24.3%) discontinued treatment, either defined by loss to follow-up (44.6%) or actively stopped treatment (55.8%). Retention in care was 88.0% and 81.1% at 6 and 12 months, respectively. Discontinuation was significantly associated in multivaiate analysis with small sites and high staff turnover [aOR 2.5 (95% CI 1.6, 3.9), p < 0.001]. Main reasons for stopping treatment were HIV status denial and stigma (52.8%), religious reasons (25.0%), and lack of transport fare (11.1%).
CONCLUSION: We observed good uptake of HTC, ART and retention in care, which declined over time. Discontinuation of Option B+ was highest at small sites with a high staff turnover. Improved staffing, adequate task shifting and community interventions to track defaulters including reducing stigma and religious beliefs may improve Option B+ retention. This article is protected by copyright. All rights reserved.

PMID: 27865052 [PubMed - as supplied by publisher]

Pharmacokinetic Drug Interactions with Panax ginseng.

Sun, 11/20/2016 - 07:33
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Pharmacokinetic Drug Interactions with Panax ginseng.

Eur J Drug Metab Pharmacokinet. 2016 Nov 18;

Authors: Ramanathan MR, Penzak SR

Abstract
Panax ginseng is widely used as an adaptogen throughout the world. The major active constituents of P. ginseng are ginsenosides. Most naturally occurring ginsenosides are deglycosylated by colonic bacteria to intestinal metabolites. Ginsenosides along with these metabolites are widely accepted as being responsible for the pharmacologic activity and drug interaction potential of ginseng. Numerous preclinical studies have assessed the influence of various ginseng components on cytochrome P450 (CYP), glucuronidation, and drug transport activity. Results from these investigations have been largely inconclusive due to the use of different ginseng products and variations in methodology between studies. Drug interaction studies in humans have been conflicting and have largely yielded negative results or results that suggest only a weak interaction. One study using a midazolam probe found weak CYP3A induction and another using a fexofenadine probe found weak P-gp inhibition. Despite several case reports indicating a drug interaction between warfarin and P. ginseng, pharmacokinetic studies involving these agents in combination have failed to find significant pharmacokinetic or pharmacodynamic interactions. To this end, drug interactions involving P. ginseng appear to be rare; however, close clinical monitoring is still suggested for patients taking warfarin or CYP3A or P-gp substrates with narrow therapeutic indices.

PMID: 27864798 [PubMed - as supplied by publisher]

NIH's mentoring makes progress.

Sun, 11/20/2016 - 07:33
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NIH's mentoring makes progress.

Science. 2016 Nov 18;354(6314):840-841

Authors: Vishwanatha J, Pfund C, Ofili E, Okuyemi K

PMID: 27856873 [PubMed - in process]

Impact of Booster Breaks and Computer Prompts on Physical Activity and Sedentary Behavior Among Desk-Based Workers: A Cluster-Randomized Controlled Trial.

Fri, 11/18/2016 - 07:33

Impact of Booster Breaks and Computer Prompts on Physical Activity and Sedentary Behavior Among Desk-Based Workers: A Cluster-Randomized Controlled Trial.

Prev Chronic Dis. 2016 Nov 17;13:E155

Authors: Taylor WC, Paxton RJ, Shegog R, Coan SP, Dubin A, Page TF, Rempel DM

Abstract
INTRODUCTION: The 15-minute work break provides an opportunity to promote health, yet few studies have examined this part of the workday. We studied physical activity and sedentary behavior among office workers and compared the results of the Booster Break program with those of a second intervention and a control group to determine whether the Booster Break program improved physical and behavioral health outcomes.
METHODS: We conducted a 3-arm, cluster-randomized controlled trial at 4 worksites in Texas from 2010 through 2013 to compare a group-based, structured Booster Break program to an individual-based computer-prompt intervention and a usual-break control group; we analyzed physiologic, behavioral, and employee measures such as work social support, quality of life, and perceived stress. We also identified consistent and inconsistent attendees of the Booster Break sessions.
RESULTS: We obtained data from 175 participants (mean age, 43 y; 67% racial/ethnic minority). Compared with the other groups, the consistent Booster Break attendees had greater weekly pedometer counts (P < .001), significant decreases in sedentary behavior and self-reported leisure-time physical activity (P < .001), and a significant increase in triglyceride concentrations (P = .02) (levels remained within the normal range). Usual-break participants significantly increased their body mass index, whereas Booster Break participants maintained body mass index status during the 6 months. Overall, Booster Break participants were 6.8 and 4.3 times more likely to have decreases in BMI and weekend sedentary time, respectively, than usual-break participants.
CONCLUSION: Findings varied among the 3 study groups; however, results indicate the potential for consistent attendees of the Booster Break intervention to achieve significant, positive changes related to physical activity, sedentary behavior, and body mass index.

PMID: 27854422 [PubMed - in process]

Construct Validity of the Late-Life Function and Disability Instrument in African American Breast Cancer Survivors.

Fri, 11/18/2016 - 07:33

Construct Validity of the Late-Life Function and Disability Instrument in African American Breast Cancer Survivors.

Healthcare (Basel). 2016 Nov 16;4(4):

Authors: Pandya E, Mistry J, Dobhal M, Borra S, Paxton RJ

Abstract
Limited data exist on the validity of the Late-Life Function and Disability (LLFD) instrument in cancer survivors. We examined the construct validity of the abbreviated LLFD instrument in a sample of African-American breast cancer survivors. African American breast cancer survivors (n = 181) aged 50 years and older completed the abbreviated LLFD instrument and questions about sociodemographic and lifestyle characteristics. Confirmatory factor analysis (CFA), Cronbach alphas, and structural models were used to evaluate the construct validity of these measures. Minor modifications were made to the three-factor functional component portion of the inventory to improve model fit. Cronbach alpha's (range 0.85-0.92) and inter-factor correlations (r = 0.3-0.5, all p < 0.05) were appropriate. The two-factor disability component fit the data and Cronbach alpha's (0.91 and 0.98) were appropriate with a high inter-factor correlation (r = 0.95, p < 0.01). The average variance extracted (range = 0.55-0.93) and composite reliabilities (range = 0.86-0.98) were in acceptable ranges. Floor effects ranged from 7% for advanced lower function to 74% for personal role disability. Education and number of comorbidities were correlated significantly with functional outcomes. The abbreviated LLFD instrument had adequate construct validity in this sample of African American breast cancer survivors. Further studies are needed that examine the stability of the instrument over time.

PMID: 27854321 [PubMed - in process]

Chest Pain Risk Scores Can Reduce Emergent Cardiac Imaging Test Needs With Low Major Adverse Cardiac Events Occurrence in an Emergency Department Observation Unit.

Wed, 11/16/2016 - 07:32

Chest Pain Risk Scores Can Reduce Emergent Cardiac Imaging Test Needs With Low Major Adverse Cardiac Events Occurrence in an Emergency Department Observation Unit.

Crit Pathw Cardiol. 2016 Dec;15(4):145-151

Authors: Wang H, Watson K, Robinson RD, Domanski KH, Umejiego J, Hamblin L, Overstreet SE, Akin AM, Hoang S, Shrivastav M, Collyer M, Krech RN, Schrader CD, Zenarosa NR

Abstract
OBJECTIVE: To compare and evaluate the performance of the HEART, Global Registry of Acute Coronary Events (GRACE), and Thrombolysis in Myocardial Infarction (TIMI) scores to predict major adverse cardiac event (MACE) rates after index placement in an emergency department observation unit (EDOU) and to determine the need for observation unit initiation of emergent cardiac imaging tests, that is, noninvasive cardiac stress tests and invasive coronary angiography.
METHODS: A prospective observational single center study was conducted from January 2014 through June 2015. EDOU chest pain patients were included. HEART, GRACE, and TIMI scores were categorized as low (HEART ≤ 3, GRACE ≤ 108, and TIMI ≤1) versus elevated based on thresholds suggested in prior studies. Patients were followed for 6 months postdischarge. The results of emergent cardiac imaging tests, EDOU length of stay (LOS), and MACE occurrences were compared. Student t test was used to compare groups with continuous data, and χ testing was used for categorical data analysis.
RESULTS: Of 986 patients, emergent cardiac imaging tests were performed on 62%. A majority of patients were scored as low risk by all tools (85% by HEART, 81% by GRACE, and 80% by TIMI, P < 0.05). The low-risk patients had few abnormal cardiac imaging test results as compared with patients scored as intermediate to high risk (1% vs. 11% in HEART, 1% vs. 9% in TIMI, and 2% vs. 4% in GRACE, P < 0.05). The average LOS was 33 hours for patients with emergent cardiac imaging tests performed and 25 hours for patients without (P < 0.05). MACE occurrence rate demonstrated no significant difference regardless of whether tests were performed emergently (0.31% vs. 0.97% in HEART, 0.27% vs. 0.95% in TIMI, and 0% vs. 0.81% in GRACE, P > 0.05).
CONCLUSIONS: Chest pain risk stratification via clinical decision tool scores can minimize the need for emergent cardiac imaging tests with less than 1% MACE occurrence, especially when the HEART score is used.

PMID: 27846006 [PubMed - in process]

Thiopurine Prodrugs Mediate Immunosuppressive Effects by Interfering with Rac1 Protein Function.

Fri, 11/11/2016 - 07:31
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Thiopurine Prodrugs Mediate Immunosuppressive Effects by Interfering with Rac1 Protein Function.

J Biol Chem. 2016 Jun 24;291(26):13699-714

Authors: Shin JY, Wey M, Umutesi HG, Sun X, Simecka J, Heo J

Abstract
6-Thiopurine (6-TP) prodrugs include 6-thioguanine and azathioprine. Both are widely used to treat autoimmune disorders and certain cancers. This study showed that a 6-thioguanosine triphosphate (6-TGTP), converted in T-cells from 6-TP, targets Rac1 to form a disulfide adduct between 6-TGTP and the redox-sensitive GXXXXGK(S/T)C motif of Rac1. This study also showed that, despite the conservation of the catalytic activity of RhoGAP (Rho-specific GAP) on the 6-TGTP-Rac1 adduct to produce the biologically inactive 6-thioguanosine diphosphate (6-TGDP)-Rac1 adduct, RhoGEF (Rho-specific GEF) cannot exchange the 6-TGDP adducted on Rac1 with free guanine nucleotide. The biologically inactive 6-TGDP-Rac1 adduct accumulates in cells because of the ongoing combined actions of RhoGEF and RhoGAP. Because other Rho GTPases, such as RhoA and Cdc42, also possess the GXXXXGK(S/T)C motif, the proposed mechanism for the inactivation of Rac1 also applies to RhoA and Cdc42. However, previous studies have shown that CD3/CD28-stimulated T-cells contain more activated Rac1 than other Rho GTPases such as RhoA and Cdc42. Accordingly, Rac1 is the main target of 6-TP in activated T-cells. This explains the T-cell-specific Rac1-targeting therapeutic action of 6-TP that suppresses the immune response. This proposed mechanism for the action of 6-TP on Rac1 performs a critical role in demonstrating the capability to design a Rac1-targeting chemotherapeutic agent(s) for autoimmune disorders. Nevertheless, the results also suggest that the targeting action of other Rho GTPases in other organ cells, such as RhoA in vascular cells, may be linked to cytotoxicities because RhoA plays a key role in vasculature functions.

PMID: 27189938 [PubMed - indexed for MEDLINE]

Super Skin.

Thu, 11/10/2016 - 07:33
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Super Skin.

JAMA Dermatol. 2016 Nov 1;152(11):1208

Authors: Roman J, Reynolds SD

PMID: 27829109 [PubMed - in process]

Salvianolic Acid B (Sal B) Protects Retinal Pigment Epithelial Cells from Oxidative Stress-Induced Cell Death by Activating Glutaredoxin 1 (Grx1).

Thu, 11/10/2016 - 07:33
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Salvianolic Acid B (Sal B) Protects Retinal Pigment Epithelial Cells from Oxidative Stress-Induced Cell Death by Activating Glutaredoxin 1 (Grx1).

Int J Mol Sci. 2016 Nov 03;17(11):

Authors: Liu X, Xavier C, Jann J, Wu H

Abstract
Protein glutathionylation, defined as the formation of protein mixed disulfides (PSSG) between cysteine residues and glutathione (GSH), can lead to cell death. Glutaredoxin 1 (Grx1) is a thiol repair enzyme which catalyzes the reduction of PSSG. Therefore, Grx1 exerts strong anti-apoptotic effects by improving the redox state, especially in times of oxidative stress. However, there is currently no compound that is identified as a Grx1 activator. In this study, we identified and characterized Salvianolic acid B (Sal B), a natural compound, as a Grx1 inducer, which potently protected retinal pigment epithelial (RPE) cells from oxidative injury. Our results showed that treatment with Sal B protected primary human RPE cells from H₂O₂-induced cell damage. Interestingly, we found Sal B pretreatment upregulated Grx1 expression in RPE cells in a time- and dose-dependent manner. Furthermore, NF-E2-related factor 2 (Nrf2), the key transcription factor that regulates the expression of Grx1, was activated in Sal B treated RPE cells. Further investigation showed that knockdown of Grx1 by small interfering RNA (siRNA) significantly reduced the protective effects of Sal B. We conclude that Sal B protects RPE cells against H₂O₂-induced cell injury through Grx1 induction by activating Nrf2 pathway, thus preventing lethal accumulation of PSSG and reversing oxidative damage.

PMID: 27827892 [PubMed - in process]

Sex-specific and genotype-specific differences in vocalization development in FMR1 knockout mice.

Wed, 11/09/2016 - 16:45
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Sex-specific and genotype-specific differences in vocalization development in FMR1 knockout mice.

Neuroreport. 2016 Dec 14;27(18):1331-1335

Authors: Reynolds CD, Nolan SO, Jefferson T, Lugo JN

Abstract
Fragile X syndrome is a neurodevelopmental disorder caused by a trinucleotide (CGG) hyperexpansion in the FMR1 gene, functionally silencing transcription of the fragile X mental retardation protein (FMRP). This disorder is characterized by impaired cognition, communication, and social behavior. The aim of this study was to investigate the development of ultrasonic vocalization (USV) behavior in a Fmr1-deficient mouse model. On postnatal days (PD) 9-14, separate cohorts of FVB/NJ pups were removed from their homecage and isolation-induced USVs were recorded. There were significant genotype-dependent and sex-dependent differences in USV behavior across the different testing days. Fmr1 knockout (KO) mice showed a significant reduction in vocalizations across all days. There was also a significant difference in vocalizations between male and female mice. We found a significant decrease in the total number of calls for KO males on PD9 and PD13 as well as an increase in the total number of calls for KO males on PD12. The KO males also showed a significant increase in the total call duration on PD12 and a reduction on PD13. The KO female showed a significant decrease in the total number of calls on PD9 and PD10. They also showed a significant decrease in the total call duration on PD9 and a marginal decrease in the total call duration on PD10. These results provide additional evidence for communication deficits in Fmr1 deficient mice and provide new insight suggesting sexually dimorphic vocalizations during the neonatal period.

PMID: 27824730 [PubMed - in process]

Aerobic Exercise Training Improves Orthostatic Tolerance in Aging Humans.

Wed, 11/09/2016 - 16:45
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Aerobic Exercise Training Improves Orthostatic Tolerance in Aging Humans.

Med Sci Sports Exerc. 2016 Nov 7;

Authors: Xu D, Wang H, Chen S, Ross S, Liu H, Olivencia-Yurvati A, Raven PB, Shi X

Abstract
PURPOSE: This study was designed to test the hypothesis that aerobic exercise training of the elderly will increase aerobic fitness without compromising orthostatic tolerance (OT).
METHODS: Eight healthy sedentary volunteers (67.0±1.7 years old, 4 women) participated in 1-year of endurance exercise training (stationary bicycle and/or treadmill) program at the individuals' 65%-75% of peak heart rate (HRpeak). Peak O2 uptake (VO2peak) and HRpeak were determined by a maximal exercise stress test using a bicycle ergometer. Carotid baroreceptor reflex (CBR) control of HR and mean arterial pressure (MAP) were assessed by a neck pressure-neck suction (NP/NS) protocol. Each subject's maximal gain (Gmax), or sensitivity, of the CBR function curves were derived from fitting their reflex HR and MAP responses to the corresponding NP/NS stimuli using a logistic function curve. The subjects' OT was assessed using lower-body negative pressure (LBNP) graded to -50 mmHg; the sum of the product of LBNP intensity and time (mmHg•min) was calculated as the cumulative stress index (CSI).
RESULTS: Training increased VO2peak (before vs after: 22.8±0.92 vs 27.9±1.33 ml/min/kg, P < 0.01) and HRpeak (154±4 vs 159±3 beats/min, P < 0.02); and decreased resting HR (65±5 vs 59±5 beats/min, P < 0.02) and MAP (99±2 vs 87±2 mmHg, P < 0.05). CBR stimulus-response curves identified a leftward shift with an increase in CBR-HR Gmax (from -0.13±0.02 to -0.27±0.04 bpm/mmHg, P = 0.01). CSI was increased from 767±68 mmHg•min pre-training to 946±44 mmHg•min post-training (P < 0.05).
CONCLUSION: Aerobic exercise training improved the aerobic fitness and OT in elderly subjects. An improved OT is likely associated with an enhanced CBR function that has been reset to better maintain cerebral perfusion and cerebral tissue oxygenation during LBNP.

PMID: 27824693 [PubMed - as supplied by publisher]

In vitro and in vivo neuroprotective effects of cJun N-terminal kinase inhibitors on retinal ganglion cells.

Wed, 11/09/2016 - 16:45
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In vitro and in vivo neuroprotective effects of cJun N-terminal kinase inhibitors on retinal ganglion cells.

Mol Neurodegener. 2016 Apr 21;11:30

Authors: Kim BJ, Silverman SM, Liu Y, Wordinger RJ, Pang IH, Clark AF

Abstract
BACKGROUND: The c-Jun N-terminal kinase (JNK) signaling pathway plays an important role in neuronal pathophysiology. Using JNK inhibitors, we examined involvement of the JNK pathway in cultured rat retinal ganglion cell (RGC) death and in mouse retinal ischemia/reperfusion (I/R) injury of the visual axis. The in vitro effects of JNK inhibitors were evaluated in cultured adult rat retinal cells enriched in RGCs. Retinal I/R was induced in C57BL/6J mice through elevation of intraocular pressure to 120 mmHg for 60 min followed by reperfusion. SP600125 was administered intraperitoneally once daily for 28 days. Phosphorylation of JNK and c-Jun in the retina was examined by immunoblotting and immunohistochemistry. The thickness of retinal layers and cell numbers in the ganglion cell layer (GCL) were examined using H&E stained retinal cross sections and spectral domain optical coherence tomography (SD-OCT). Retinal function was measured by scotopic flash electroretinography (ERG). Volumetric measurement of the superior colliculus (SC) as well as VGLUT2 and PSD95 expression were studied.
RESULTS: JNK inhibitors SP600125 and TAT-JNK-III, dose-dependently and significantly (p < 0.05) protected against glutamate excitotoxicity and trophic factor withdrawal induced RGC death in culture. In the I/R model, phosphorylation of JNK (pJNK) in the retina was significantly (p < 0.05) increased after injury. I/R injury significantly (p < 0.05) decreased the thickness of retinal layers, including the whole retina, inner plexiform layer, and inner nuclear layer and cell numbers in the GCL. Administration of SP600125 for 28 days protected against all these degenerative morphological changes (p < 0.05). In addition, SP600125 significantly (p < 0.05) protected against I/R-induced reduction in scotopic ERG b-wave amplitude at 3, 7, 14, 21 and 28 days after injury. SP600125 also protected against the I/R-induced losses in volume and levels of synaptic markers in the SC. Moreover, the protective effects of SP600125 in the retina and SC were also detected even with only 7 days (Days 1-7 after I/R) of SP600125 treatment.
CONCLUSIONS: Our results demonstrate the important role the JNK pathway plays in retinal degeneration in both in vitro and in vivo models and suggest that JNK inhibitors may be a useful therapeutic strategy for neuroprotection of RGCs in the retina.

PMID: 27098079 [PubMed - indexed for MEDLINE]

C1q propagates microglial activation and neurodegeneration in the visual axis following retinal ischemia/reperfusion injury.

Wed, 11/09/2016 - 16:45
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C1q propagates microglial activation and neurodegeneration in the visual axis following retinal ischemia/reperfusion injury.

Mol Neurodegener. 2016 Mar 24;11:24

Authors: Silverman SM, Kim BJ, Howell GR, Miller J, John SW, Wordinger RJ, Clark AF

Abstract
BACKGROUND: C1q represents the initiating protein of the classical complement cascade, however recent findings indicate pathway independent roles such as developmental pruning of retinal ganglion cell (RGC) axons. Furthermore, chronic neuroinflammation, including increased expression of C1q and activation of microglia and astrocytes, appears to be a common finding among many neurodegenerative disease models. Here we compare the effects of a retinal ischemia/reperfusion (I/R) injury on glial activation and neurodegeneration in wild type (WT) and C1qa-deficient mice in the retina and superior colliculus (SC). Retinal I/R was induced in mice through elevation of intraocular pressure to 120 mmHg for 60 min followed by reperfusion. Glial cell activation and population changes were assessed using immunofluorescence. Neuroprotection was determined using histological measurements of retinal layer thickness, RGC counts, and visual function by flash electroretinography (ERG).
RESULTS: Retinal I/R injury significantly upregulated C1q expression in the retina as early as 72 h and within 7 days in the superficial SC, and was sustained as long as 28 days. Accompanying increased C1q expression was activation of microglia and astrocytes as well as a significantly increased glial population density observed in the retina and SC. Microglial activation and changes in density were completely ablated in C1qa-deficient mice, interestingly however there was no effect on astrocytes. Furthermore, loss of C1qa significantly rescued I/R-induced loss of RGCs and protected against retinal layer thinning in comparison to WT mice. ERG assessment revealed early preservation of b-wave amplitude deficits from retinal I/R injury due to C1qa-deficiency that was lost by day 28.
CONCLUSIONS: Our results for the first time demonstrate the spatiotemporal changes in the neuroinflammatory response following retinal I/R injury at both local and distal sites of injury. In addition, we have shown a role for C1q as a primary mediator of microglial activation and pathological damage. This suggests developmental mechanisms of C1q may be re-engaged during injury response, modulation of which may be beneficial for neuroprotection.

PMID: 27008854 [PubMed - indexed for MEDLINE]

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

Tue, 11/08/2016 - 07:33

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

Invest Ophthalmol Vis Sci. 2016 Nov 1;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 - in process]

Clear cell "sugar" tumor of the lung: benign or malignant?

Tue, 11/08/2016 - 07:33
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Clear cell "sugar" tumor of the lung: benign or malignant?

Int Surg. 2015 May;100(5):924-6

Authors: Olivencia-Yurvati AH, Rodriguez AE

Abstract
Clear cell "sugar" tumors of the lung are rare pulmonary tumors. This case study illustrates a patient who was found to have a persistent nodule in the left-upper lobe of the lung. Positron emission tomographic scanning showed mild-moderate 18-fluorodeoxyglucose uptake. Based on these findings, a video-assisted resection of the tumor was undertaken. The mass was identified histologically, as a clear cell "sugar" tumor of the lung. This case report discusses the benign versus malignant nature of this rare tumor.

PMID: 26011217 [PubMed - indexed for MEDLINE]

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