Recent Research Articles from UNTHSC

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

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Updated: 1 hour 14 min ago

Markov Mixed Effects Modeling Using Electronic Adherence Monitoring Records Identifies Influential Covariates to HIV Preexposure Prophylaxis.

Wed, 12/07/2016 - 07:41
Related Articles

Markov Mixed Effects Modeling Using Electronic Adherence Monitoring Records Identifies Influential Covariates to HIV Preexposure Prophylaxis.

J Clin Pharmacol. 2016 Dec 06;:

Authors: Madrasi K, Chaturvedula A, Haberer JE, Sale M, Fossler MJ, Bangsberg D, Baeten JM, Celum C, Hendrix CW

Abstract
Adherence is a major factor in the effectiveness of preexposure prophylaxis (PrEP) for HIV prevention. Modeling patterns of adherence helps to identify influential covariates of different types of adherence as well as to enable clinical trial simulation so that appropriate interventions can be developed. We developed a Markov mixed-effects model to understand the covariates influencing adherence patterns to daily oral PrEP. Electronic adherence records (date and time of medication bottle cap opening) from the Partners PrEP ancillary adherence study with a total of 1147 subjects were used. This study included once-daily dosing regimens of placebo, oral tenofovir disoproxil fumarate (TDF), and TDF in combination with emtricitabine (FTC), administered to HIV-uninfected members of serodiscordant couples. One-coin and first- to third-order Markov models were fit to the data using NONMEM(®) 7.2. Model selection criteria included objective function value (OFV), Akaike information criterion (AIC), visual predictive checks, and posterior predictive checks. Covariates were included based on forward addition (α = 0.05) and backward elimination (α = 0.001). Markov models better described the data than 1-coin models. A third-order Markov model gave the lowest OFV and AIC, but the simpler first-order model was used for covariate model building because no additional benefit on prediction of target measures was observed for higher-order models. Female sex and older age had a positive impact on adherence, whereas Sundays, sexual abstinence, and sex with a partner other than the study partner had a negative impact on adherence. Our findings suggest adherence interventions should consider the role of these factors.

PMID: 27922719 [PubMed - as supplied by publisher]

Plantar Shear Stress in Individuals With a History of Diabetic Foot Ulcer: An Emerging Predictive Marker for Foot Ulceration.

Fri, 12/02/2016 - 13:38
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Plantar Shear Stress in Individuals With a History of Diabetic Foot Ulcer: An Emerging Predictive Marker for Foot Ulceration.

Diabetes Care. 2016 Nov 29;:

Authors: Yavuz M, Ersen A, Hartos J, Schwarz B, Garrett AG, Lavery LA, Wukich DK, Adams LS

PMID: 27899495 [PubMed - as supplied by publisher]

Common Lung Microbiome Identified among Mechanically Ventilated Surgical Patients.

Wed, 11/30/2016 - 07:37

Common Lung Microbiome Identified among Mechanically Ventilated Surgical Patients.

PLoS One. 2016;11(11):e0166313

Authors: Smith AD, Zhang Y, Barber RC, Minshall CT, Huebinger RM, Allen MS

Abstract
The examination of the pulmonary microbiome in patients with non-chronic disease states has not been extensively examined. Traditional culture based screening methods are often unable to identify bacteria from bronchoalveolar lavage samples. The advancement of next-generation sequencing technologies allows for a culture-independent molecular based analysis to determine the microbial composition in the lung of this patient population. For this study, the Ion Torrent PGM system was used to assess the microbial complexity of culture negative bronchoalveolar lavage samples. A group of samples were identified that all displayed high diversity and similar relative abundance of bacteria. This group consisted of Hydrogenophaga, unclassified Bacteroidetes, Pedobacter, Thauera, and Acinetobacter. These bacteria may be representative of a common non-pathogenic pulmonary microbiome associated within this population of patients.

PMID: 27898681 [PubMed - in process]

Biomechanical behavior of novel composite PMMA-CaP bone cements in an anatomically accurate cadaveric vertebroplasty model.

Tue, 11/29/2016 - 07:33

Biomechanical behavior of novel composite PMMA-CaP bone cements in an anatomically accurate cadaveric vertebroplasty model.

J Orthop Res. 2016 Nov 27;:

Authors: Aghyarian S, Hu X, Haddas R, Lieberman IH, Kosmopoulos V, Kim HK, Rodrigues DC

Abstract
Vertebral compression fractures are caused by many factors including trauma and osteoporosis. Osteoporosis induced fractures are a result of loss in bone mass and quality that weaken the vertebral body. Vertebroplasty and kyphoplasty, involving cement augmentation of fractured vertebrae, show promise in restoring vertebral mechanical properties. Some complications however, are reported due to the performance characteristics of commercially available bone cements. In this study, the biomechanical performance characteristics of two novel composite (PMMA-CaP) bone cements were studied using an anatomically accurate human cadaveric vertebroplasty model. The study involves mechanical testing on 2 functional cadaveric spinal unit (2FSU) segments which include monotonic compression and cyclical fatigue tests, treatment by direct cement injection, and microscopic visualization of sectioned vertebrae. The 2FSU segments were fractured, treated, and mechanically tested to investigate the stability provided by two novel bone cements; using readily available commercial acrylic cement as a control. Segment height and stiffness were tracked during the study to establish biomechanical performance. The 2FSU segments were successfully stabilized with all 3 cement groups. Stiffness values were restored to initial levels following fatigue loading. Cement interdigitation was observed with all cement groups. This study demonstrates efficient reinforcement of the fractured vertebrae through stiffness restoration. The pre-mixed composite cements were comparable to the commercial cement in their performance and interdigitative ability, thus holding promise for future clinical use. This article is protected by copyright. All rights reserved.

PMID: 27891670 [PubMed - as supplied by publisher]

The genetic structure of native Americans in North America based on the Globalfiler® STRs.

Tue, 11/29/2016 - 07:33

The genetic structure of native Americans in North America based on the Globalfiler® STRs.

Leg Med (Tokyo). 2016 Nov;23:49-54

Authors: McCulloh KL, Ng J, Oldt RF, Weise JA, Viray J, Budowle B, Glenn Smith D, Kanthaswamy S

Abstract
Current forensic STR databases, such as CODIS, lack population genetic data on Native American populations. Information from a geographically diverse array of tribes is necessary to provide improved statistical estimates of the strength of associations with DNA evidence. The Globalfiler® STR markers were used to characterize the genetic structure of ten tribal populations from seven geographic regions in North America, including those not presently represented in forensic databases. Samples from the Arctic region, Baja California, California/Great Basin, the Southeast, Mexico, the Midwest, and the Southwest were analyzed for allele frequencies, observed and expected heterozygosities, and F-statistics. The tribal samples exhibited an FST or θ value above the conservative 0.03 estimate recommended by the National Research Council (NRC) for calculating random match probabilities among Native Americans. The greater differentiation among tribal populations computed here (θ=0.04) warrants the inclusion of additional regional Native American samples into STR databases.

PMID: 27890103 [PubMed - in process]

Redox imbalance and mitochondrial abnormalities in the diabetic lung.

Sun, 11/27/2016 - 07:32

Redox imbalance and mitochondrial abnormalities in the diabetic lung.

Redox Biol. 2016 Nov 17;11:51-59

Authors: Wu J, Jin Z, Yan LJ

Abstract
Although the lung is one of the least studied organs in diabetes, increasing evidence indicates that it is an inevitable target of diabetic complications. Nevertheless, the underlying biochemical mechanisms of lung injury in diabetes remain largely unexplored. Given that redox imbalance, oxidative stress, and mitochondrial dysfunction have been implicated in diabetic tissue injury, we set out to investigate mechanisms of lung injury in diabetes. The objective of this study was to evaluate NADH/NAD(+) redox status, oxidative stress, and mitochondrial abnormalities in the diabetic lung. Using STZ induced diabetes in rat as a model, we measured redox-imbalance related parameters including aldose reductase activity, level of poly ADP ribose polymerase (PAPR-1), NAD(+) content, NADPH content, reduced form of glutathione (GSH), and glucose 6-phophate dehydrogenase (G6PD) activity. For assessment of mitochondrial abnormalities in the diabetic lung, we measured the activities of mitochondrial electron transport chain complexes I to IV and complex V as well as dihydrolipoamide dehydrogenase (DLDH) content and activity. We also measured the protein content of NAD(+) dependent enzymes such as sirtuin3 (sirt3) and NAD(P)H: quinone oxidoreductase 1 (NQO1). Our results demonstrate that NADH/NAD(+) redox imbalance occurs in the diabetic lung. This redox imbalance upregulates the activities of complexes I to IV, but not complex V; and this upregulation is likely the source of increased mitochondrial ROS production, oxidative stress, and cell death in the diabetic lung. These results, together with the findings that the protein contents of DLDH, sirt3, and NQO1 all are decreased in the diabetic lung, demonstrate that redox imbalance, mitochondrial abnormality, and oxidative stress contribute to lung injury in diabetes.

PMID: 27888691 [PubMed - as supplied by publisher]

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]

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