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 26 min ago

Hemorrhage simulated by lower body negative pressure provokes an oxidative stress response in healthy young adults.

Fri, 02/08/2019 - 17:46
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Hemorrhage simulated by lower body negative pressure provokes an oxidative stress response in healthy young adults.

Exp Biol Med (Maywood). 2019 Feb 06;:1535370219828706

Authors: Park FS, Kay VL, Sprick JD, Rosenberg AJ, Anderson GK, Mallet RT, Rickards CA

Abstract
IMPACT STATEMENT: We characterize the systemic oxidative stress response in young, healthy human subjects with exposure to simulated hemorrhage via application of lower body negative pressure (LBNP). Prior work has demonstrated that LBNP and actual blood loss evoke similar hemodynamic and immune responses (i.e. white blood cell count), but it is unknown whether LBNP elicits oxidative stress resembling that produced by blood loss. We show that LBNP induces a 29% increase in F2-isoprostanes, a systemic marker of oxidative stress. The findings of this investigation may have important implications for the study of hemorrhage using LBNP, including future assessments of targeted interventions that may reduce oxidative stress, such as novel fluid resuscitation approaches.

PMID: 30727766 [PubMed - as supplied by publisher]

Signature molecules expressed differentially in a liver disease stage-specific manner by HIV-1 and HCV co-infection.

Fri, 02/08/2019 - 17:46
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Signature molecules expressed differentially in a liver disease stage-specific manner by HIV-1 and HCV co-infection.

PLoS One. 2018;13(8):e0202524

Authors: Whitmill A, Kim S, Rojas V, Gulraiz F, Afreen K, Jain M, Singh M, Park IW

Abstract
To elucidate HIV-1 co-infection-induced acceleration of HCV liver disease and identify stage-specific molecular signatures, we applied a new high-resolution molecular screen, the Affymetrix GeneChip Human Transcriptome Array (HTA2.0), to HCV-mono- and HIV/HCV-co-infected liver specimens from subjects with early and advanced disease. Out of 67,528 well-annotated genes, we have analyzed the functional and statistical significance of 75 and 28 genes expressed differentially between early and advanced stages of HCV mono- and HIV/HCV co-infected patient liver samples, respectively. We also evaluated the expression of 25 and 17 genes between early stages of mono- and co-infected liver tissues and between advanced stages of mono- and co-infected patient's samples, respectively. Based on our analysis of fold-change in gene expression as a function of disease stage (i.e., early vs. advanced), coupled with consideration of the known relevant functions of these genes, we focused on four candidate genes, ACSL4, GNMT, IFI27, and miR122, which are expressed stage-specifically in HCV mono- and HIV-1/HCV co-infective liver disease and are known to play a pivotal role in regulating HCV-mediated hepatocellular carcinoma (HCC). Our qRT-PCR analysis of the four genes in patient liver specimens supported the microarray data. Protein products of each gene were detected in the endoplasmic reticulum (ER) where HCV replication takes place, and the genes' expression significantly altered replicability of HCV in the subgenomic replicon harboring regulatory genes of the JFH1 strain of HCV in Huh7.5.1. With respect to three well-known transferrable HIV-1 viral elements-Env, Nef, and Tat-Nef uniquely augmented replicon expression, while Tat, but not the others, substantially modulated expression of the candidate genes in hepatocytic cells. Combinatorial expression of these cellular and viral genes in the replicon cells further altered replicon expression. Taken together, these results showed that HIV-1 viral proteins can exacerbate liver pathology in the co-infected patients by disparate molecular mechanisms-directly or indirectly dysregulating HCV replication, even if lack of association of HCV load and end-stage liver disease in hemophilic patients were reported, and modulating expression of hepatocellular genes critical for disease progression. These findings also provide major insights into development of stage-specific hepatocellular biomarkers for improved diagnosis and prognosis of HCV-mediated liver disease.

PMID: 30138348 [PubMed - indexed for MEDLINE]

Blood-Based Biomarker Screening with Agnostic Biological Definitions for an Accurate Diagnosis Within the Dimensional Spectrum of Neurodegenerative Diseases.

Thu, 02/07/2019 - 05:24
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Blood-Based Biomarker Screening with Agnostic Biological Definitions for an Accurate Diagnosis Within the Dimensional Spectrum of Neurodegenerative Diseases.

Methods Mol Biol. 2018;1750:139-155

Authors: Baldacci F, Lista S, O'Bryant SE, Ceravolo R, Toschi N, Hampel H, Alzheimer Precision Medicine Initiative (APMI)

Abstract
The discovery, development, and validation of novel candidate biomarkers in Alzheimer's disease (AD) and other neurodegenerative diseases (NDs) are increasingly gaining momentum. As a result, evolving diagnostic research criteria of NDs are beginning to integrate biofluid and neuroimaging indicators of pathophysiological mechanisms. More than 10% of people aged over 65 suffer from NDs. There is an urgent need for a refined two-stage diagnostic model to first initiate an early, sensitive, and noninvasive process in primary care settings. Individuals that meet detection criteria will then be channeled to more specific, costly (positron-emission tomography), and invasive (cerebrospinal fluid) assessment methods for confirmatory biological characterization and diagnosis.A reliable and sensitive blood test for AD and other NDs is not yet established; however, it would provide the golden screening gate for an efficient primary care management. A limitation to the development of a large-scale blood-screening biomarker-based test is the traditional application of clinically descriptive criteria for the categorization of single late-stage ND constructs. These are genetically and biologically heterogeneous, reflected in multiple pathophysiological mechanisms and subsequent pathologies throughout a dimensional continuum. Evidence suggests that a shared, "open-source" integrated multilevel categorization of NDs that clusters individuals based on descriptive clinical phenotypes and pathophysiological biomarker signatures will provide the next incremental step toward an improved diagnostic process of NDs. This intermediate objective toward unbiased biomarker-guided early detection of individuals at risk for NDs is currently carried out by the international pilot Alzheimer Precision Medicine Initiative Cohort Program (APMI-CP).

PMID: 29512070 [PubMed - indexed for MEDLINE]

Remote Antimicrobial Stewardship: A Solution for Meeting The Joint Commission Stewardship Standard?

Wed, 02/06/2019 - 05:16
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Remote Antimicrobial Stewardship: A Solution for Meeting The Joint Commission Stewardship Standard?

Hosp Pharm. 2019 Feb;54(1):51-56

Authors: Howell CK, Jacob J, Mok S

Abstract
Purpose: The purpose of this study was to determine the time required for antimicrobial stewardship (AS) activities at a small community hospital (SCH) as well as barriers to remote AS to satisfy The Joint Commission (TJC)'s AS standard. Methods: This was a prospective chart review and time study conducted in patients identified by a clinical decision support application as potential opportunities for antimicrobial therapy modification at a SCH between December 12, 2016, and March 31, 2017. Potential interventions were communicated electronically to the clinical pharmacy specialist, who would then communicate the recommendations to the patient's provider. The primary endpoint was a time study for stewardship activities. Secondary endpoints included describing barriers encountered to remote AS as well as a cost-benefit analysis of remote AS. Results: The time study revealed an average of 11 alerts per day, 9 chart reviews per day, 8 interventions per day, and 5 minutes per chart. Seven hundred twenty-four alerts were evaluated with the most common alerts constituting opportunities for de-escalation (29%), targeted drugs (22%), positive blood cultures (18%), Intravenous (IV) to oral (PO) (17%), and antimicrobial renal monitoring (8%).Interventions were accepted (11%), accepted modified (6%), rejected (35%), or undetermined (48%). Barriers to implementation included workflow and indirect communication. For patients with accepted interventions, there was an average savings of $279.82 per patient in pharmacy charges. Conclusion: Through remote AS, a SCH can have an antimicrobial stewardship program that is in compliance with the basic elements of the TJC standard MM.09.01.01, performs daily chart review by an infectious diseases trained pharmacist to increase the quality of patient care, and achieves a mean savings of $279.82 in pharmacy charges and $1,126.26 in hospital charges per patient with accepted interventions.

PMID: 30718935 [PubMed]

HEART Score Risk Stratification of Low-Risk Chest Pain Patients in the Emergency Department: A Systematic Review and Meta-Analysis.

Wed, 02/06/2019 - 05:16
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HEART Score Risk Stratification of Low-Risk Chest Pain Patients in the Emergency Department: A Systematic Review and Meta-Analysis.

Ann Emerg Med. 2019 Feb 01;:

Authors: Laureano-Phillips J, Robinson RD, Aryal S, Blair S, Wilson D, Boyd K, Schrader CD, Zenarosa NR, Wang H

Abstract
STUDY OBJECTIVE: The objectives of this systematic review and meta-analysis are to appraise the evidence in regard to the diagnostic accuracy of a low-risk History, ECG, Age, Risk Factors, and Troponin (HEART) score for prediction of major adverse cardiac events in emergency department (ED) patients. These included 4 subgroup analyses: by geographic region, the use of a modified low-risk HEART score (traditional HEART score [0 to 3] in addition to negative troponin results), using conventional versus high-sensitivity troponin assays in the HEART score, and a comparison of different post-ED-discharge patient follow-up intervals.
METHODS: We searched MEDLINE, EBSCO, Web of Science, and Cochrane Database for studies on the diagnostic performance of low-risk HEART scores to predict major adverse cardiac events among ED chest pain patients. Two reviewers independently screened articles for inclusion, assessed the quality of studies with both an adapted Quality Assessment of Diagnostic Accuracy Studies version 2 tool and an internally developed tool that combined components of the Quality in Prognostic Studies; Checklist for Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies; and Grading of Recommendations Assessment, Development and Evaluation. Pooled sensitivity, specificity, positive predictive value, negative predictive value, and positive and negative likelihood ratios were calculated.
RESULTS: There were 25 studies published from 2010 to 2017, with a total of 25,266 patients included in the final meta-analysis, of whom 9,919 (39.3%) were deemed to have low-risk HEART scores (0 to 3). Among patients with low-risk HEART scores, short-term major adverse cardiac events (30 days to 6 weeks) occurred in 2.1% of the population (182/8,832) compared with 21.9% of patients (3,290/15,038) with non-low-risk HEART scores (4 to 10). For patients with HEART scores of 0 to 3, the pooled sensitivity of short-term major adverse cardiac event predictions was 0.96 (95% confidence interval [CI] 0.93 to 0.98), specificity was 0.42 (95% CI 0.36 to 0.49), positive predictive value was 0.19 (95% CI 0.14 to 0.24), negative predictive value was 0.99 (95% CI 0.98 to 0.99), positive likelihood ratio was 1.66 (95% CI 1.50 to 1.85), and negative likelihood ratio was 0.09 (95% CI 0.06 to 0.15). Subgroup analysis showed that lower short-term major adverse cardiac events occurred among North American patients (0.7%), occurred when modified low-risk HEART score was used (0.8%), or occurred when high-sensitivity troponin was used for low-risk HEART score calculations (0.8%).
CONCLUSION: In this meta-analysis, despite its use in different patient populations, the troponin type used, and timeline of follow-up, a low-risk HEART score had high sensitivity, negative predictive value, and negative likelihood ratio for predicting short-term major adverse cardiac events, although risk of bias and statistical heterogeneity were high.

PMID: 30718010 [PubMed - as supplied by publisher]

Chronic Inhibition of Mitochondrial Dihydrolipoamide Dehydrogenase (DLDH) as an Approach to Managing Diabetic Oxidative Stress.

Wed, 02/06/2019 - 05:16
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Chronic Inhibition of Mitochondrial Dihydrolipoamide Dehydrogenase (DLDH) as an Approach to Managing Diabetic Oxidative Stress.

Antioxidants (Basel). 2019 Feb 02;8(2):

Authors: Yang X, Song J, Yan LJ

Abstract
Mitochondrial dihydrolipoamide dehydrogenase (DLDH) is a redox enzyme involved in decarboxylation of pyruvate to form acetyl-CoA during the cascade of glucose metabolism and mitochondrial adenine triphosphate (ATP) production. Depending on physiological or pathophysiological conditions, DLDH can either enhance or attenuate the production of reactive oxygen species (ROS) and reactive nitrogen species. Recent research in our laboratory has demonstrated that inhibition of DLDH induced antioxidative responses and could serve as a protective approach against oxidative stress in stroke injury. In this perspective article, we postulated that chronic inhibition of DLDH could also attenuate oxidative stress in type 2 diabetes. We discussed DLDH-involving mitochondrial metabolic pathways and metabolic intermediates that could accumulate upon DLDH inhibition and their corresponding roles in abrogating oxidative stress in diabetes. We also discussed a couple of DLDH inhibitors that could be tested in animal models of type 2 diabetes. It is our belief that DLDH inhibition could be a novel approach to fighting type 2 diabetes.

PMID: 30717346 [PubMed]

An exploratory investigation of brain-selective estrogen treatment in males using a mouse model of Alzheimer's disease.

Tue, 02/05/2019 - 05:08
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An exploratory investigation of brain-selective estrogen treatment in males using a mouse model of Alzheimer's disease.

Horm Behav. 2018 02;98:16-21

Authors: Tschiffely AE, Schuh RA, Prokai-Tatrai K, Ottinger MA, Prokai L

Abstract
Estrogens are neuroprotective, and studies suggest that they may mitigate the pathology and symptoms of Alzheimer's disease (AD) in female models. However, central estrogen effects have not been examined in males in the context of AD. The purpose of this follow-up study was to assess the benefits of a brain-selective 17β-estradiol estrogen prodrug, 10β,17β-hydroxyestra-1,4-dien-3-one (DHED), also in the male APPswe/PS1dE9 double-transgenic mouse model of the disease. After continuously exposing 6-month old animals to DHED for two months, their brains showed decreased amyloid precursor and amyloid-β protein levels. The DHED-treated APPswe/PS1dE9 double transgenic subjects also exhibited enhanced performance in a cognitive task, while 17β-estradiol treatment did not reach statistical significance. Taken together, data presented here suggest that DHED may also have therapeutic benefit in males and warrant further investigations to fully elucidate the potential of targeted estrogen therapy for a gender-independent treatment of early-stage AD.

PMID: 29183688 [PubMed - indexed for MEDLINE]

The Role of Dental Providers in Preventing HPV-Related Diseases: A Systems Perspective.

Sun, 02/03/2019 - 07:48

The Role of Dental Providers in Preventing HPV-Related Diseases: A Systems Perspective.

J Dent Educ. 2019 Feb;83(2):161-172

Authors: Daley EM, Vamos CA, Thompson E, Vázquez-Otero C, Griner SB, Merrell L, Kline N, Walker K, Driscoll A, Petrila J

Abstract
Successfully educating dental providers and patients about the link between human papillomavirus (HPV) and oropharyngeal cancer requires coordinated efforts to increase HPV-related prevention practices. The aim of this study was to identify, using a systems perspective, the multi-level determinants related to how dental providers can promote HPV prevention in dental practices. Data for this qualitative study were collected in 2015-16 from focus groups with dentists (four focus groups, n=33), focus groups with dental hygienists (four focus groups, n=48), and in-depth interviews with dental opinion leaders (n=13). Results were triangulated and mapped along micro, meso, and macro system levels. At the micro level, participants identified patient characteristics and low self-efficacy as influential determinants when discussing HPV prevention. At the meso level, relationships among dentists, dental hygienists, and the physical practice environment were factors affecting dental providers' HPV prevention efforts. At the macro level, professional organizations impacted how dental providers interacted with their patients on this topic. These results suggest that improving HPV prevention among dental providers requires a multi-level approach that considers the distinctive context of dental settings, dental training, and perceptions of professional roles. The findings suggested that the macro- and meso-level determinants may be challenging to modify due to the distinctive culture and practice models of dentistry. Nevertheless, the association between HPV and oral cancer requires an expansion of prevention strategies used in dental practices. Improving dental providers' self-efficacy to communicate HPV prevention through continuing education and integration of skill-guided training in dental and dental hygiene curricula could facilitate this process.

PMID: 30709991 [PubMed - in process]

The Use of V.A.C. VERAFLO CLEANSE CHOICE in the Burn Population.

Sat, 02/02/2019 - 16:30
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The Use of V.A.C. VERAFLO CLEANSE CHOICE in the Burn Population.

Cureus. 2018 Nov 26;10(11):e3632

Authors: Matthews MR, Hechtman A, Quan AN, Foster KN, Fernandez LG

Abstract
Negative pressure wound therapy (NPWT) is routinely used in the treatment of acute and chronic wounds. The technology continues to evolve with improved results NPWT is routinely used at the Arizona Burn Center and the addition of the V.A.C. VERAFLO CLEANSE CHOICETM with its reticulated open foam device has been used with promising results in a variety of complicated wounds. We present a case series involving the use of this negative pressure wound therapy device and irrigation in burn and necrotizing soft tissue patients treated at the Arizona Burn Center.

PMID: 30705791 [PubMed]

Leukocyte expression profiles reveal gene sets with prognostic value for seizure-free outcome following stereotactic laser amygdalohippocampotomy.

Sat, 02/02/2019 - 16:30
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Leukocyte expression profiles reveal gene sets with prognostic value for seizure-free outcome following stereotactic laser amygdalohippocampotomy.

Sci Rep. 2019 Jan 31;9(1):1086

Authors: Sprissler R, Bina R, Kasoff W, Witte MH, Bernas M, Walter C, Labiner DM, Lau B, Hammer MF, Weinand ME

Abstract
Among patients with intractable epilepsy, the most commonly performed surgical procedure is craniotomy for amygdalohippocampectomy (AH). Stereotactic laser amygdalohippocampotomy (SLAH) has also been recently employed as a minimally invasive treatment for intractable temporal lobe epilepsy (TLE). Among patients treated with AH and SLAH approximately 65% and 54% of patients become seizure-free, respectively. Therefore, selection criteria for surgical candidates with improved prognostic value for post-operative seizure-free outcome are greatly needed. In this study, we perform RNA sequencing (RNA-Seq) on whole blood leukocyte samples taken from 16 patients with intractable TLE prior to SLAH to test the hypothesis that pre-operative leukocyte RNA expression profiles are prognostic for post-operative seizure outcome. Multidimensional scaling analysis of the RNA expression data indicated separate clustering of patients with seizure free (SF) and non-seizure-free (NSF) outcomes. Differential expression (DE) analysis performed on SF versus NSF groups revealed 24 significantly differentially expressed genes (≥2.0-fold change, p-value < 0.05, FDR <0.05). Network and pathway analyses identified differential activation of pathways involved in lipid metabolism, morphology of oligodendrocytes, inflammatory response, and development of astrocytes. These results suggest that pre-operative leukocyte expression profiles have prognostic value for seizure outcome following SLAH.

PMID: 30705324 [PubMed - in process]

Identification of long non-coding RNA-related and -coexpressed mRNA biomarkers for hepatocellular carcinoma.

Sat, 02/02/2019 - 16:30
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Identification of long non-coding RNA-related and -coexpressed mRNA biomarkers for hepatocellular carcinoma.

BMC Med Genomics. 2019 Jan 31;12(Suppl 1):25

Authors: Zhang F, Ding L, Cui L, Barber R, Deng B

Abstract
BACKGROUND: While changes in mRNA expression during tumorigenesis have been used widely as molecular biomarkers for the diagnosis of a number of cancers, the approach has limitations. For example, traditional methods do not consider the regulatory and positional relationship between mRNA and lncRNA. The latter has been largely shown to possess tumor suppressive or oncogenic properties. The combined analysis of mRNA and lncRNA is likely to facilitate the identification of biomarkers with higher confidence.
RESULTS: Therefore, we have developed an lncRNA-related method to identify traditional mRNA biomarkers. First we identified mRNAs that are differentially expressed in Hepatocellular Carcinoma (HCC) by comparing cancer and matched adjacent non-tumorous liver tissues. Then, we performed mRNA-lncRNA relationship and coexpression analysis and obtained 41 lncRNA-related and -coexpressed mRNA biomarkers. Next, we performed network analysis, gene ontology analysis and pathway analysis to unravel the functional roles and molecular mechanisms of these lncRNA-related and -coexpressed mRNA biomarkers. Finally, we validated the prediction and performance of the 41 lncRNA-related and -coexpressed mRNA biomarkers using Support Vector Machine model with five-fold cross-validation in an independent HCC dataset from RNA-seq.
CONCLUSIONS: Our results suggested that mRNAs expression profiles coexpressed with positionally related lncRNAs can provide important insights into early diagnosis and specific targeted gene therapy of HCC.

PMID: 30704465 [PubMed - in process]

Diversification of bent-toed geckos (Cyrtodactylus) on Sumatra and west Java.

Fri, 02/01/2019 - 07:27
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Diversification of bent-toed geckos (Cyrtodactylus) on Sumatra and west Java.

Mol Phylogenet Evol. 2019 Jan 28;:

Authors: O'Connell KA, Smart U, Sidik I, Riyanto A, Kurniawan N, Smith EN

Abstract
Complex geological processes often drive biotic diversification on islands. The islands of Sumatra and Java have experienced dramatic historical changes, including isolation by marine incursions followed by periodic connectivity with the rest of Sundaland across highland connections. To determine how this geological history influenced island invasions, we investigated the colonization history and diversification of bent-toed geckos (genus Cyrtodactylus) on Sumatra and west Java. We used mitochondrial and nuclear sequence data to explore species boundaries, estimate phylogenetic relationships and divergence times, and to reconstruct ancestral range evolution. We found that Sumatran and Javan Cyrtodactylus were closely related to species from the Thai-Malay Peninsula, rather than from Borneo, and that Cyrtodactylus most likely dispersed to Sumatra three times during the late Oligocene and early Miocene. Similarly, Cyrtodactylus invaded west Java from Sumatra once in the early Miocene. Our results suggest that despite isolation by marine incursions during much of the Miocene, Cyrtodactylus dispersed to and from Sumatra and west Java likely via land bridges, and that in situ diversification occurred several times on Sumatra.

PMID: 30703515 [PubMed - as supplied by publisher]

Methamphetamine Augments Concurrent Astrocyte Mitochondrial Stress, Oxidative Burden, and Antioxidant Capacity: Tipping the Balance in HIV-Associated Neurodegeneration.

Fri, 02/01/2019 - 07:27
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Methamphetamine Augments Concurrent Astrocyte Mitochondrial Stress, Oxidative Burden, and Antioxidant Capacity: Tipping the Balance in HIV-Associated Neurodegeneration.

Neurotox Res. 2018 02;33(2):433-447

Authors: Borgmann K, Ghorpade A

Abstract
Methamphetamine (METH) use, with and without human immunodeficiency virus (HIV)-1 comorbidity, exacerbates neurocognitive decline. Oxidative stress is a probable neurotoxic mechanism during HIV-1 central nervous system infection and METH abuse, as viral proteins, antiretroviral therapy and METH have each been shown to induce mitochondrial dysfunction. However, the mechanisms regulating mitochondrial homeostasis and overall oxidative burden in astrocytes are not well understood in the context of HIV-1 infection and METH abuse. Here, we report METH-mediated dysregulation of astrocyte mitochondrial morphology and function during prolonged exposure to low levels of METH. Mitochondria became larger and more rod shaped with METH when assessed by machine learning, segmentation analyses. These changes may be mediated by elevated mitofusin expression coupled with inhibitory phosphorylation of dynamin-related protein-1, which regulate mitochondrial fusion and fission, respectively. While METH decreased oxygen consumption and ATP levels during acute exposure, chronic treatment of 1 to 2 weeks significantly enhanced both when tested in the absence of METH. Together, these changes significantly increased not only expression of antioxidant proteins, augmenting the astrocyte's oxidative capacity, but also oxidative damage. We propose that targeting astrocytes to reduce their overall oxidative burden and expand their antioxidant capacity could ultimately tip the balance from neurotoxicity towards neuroprotection.

PMID: 28993979 [PubMed - indexed for MEDLINE]

Current Strategies for Brain Drug Delivery.

Thu, 01/31/2019 - 07:28
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Current Strategies for Brain Drug Delivery.

Theranostics. 2018;8(6):1481-1493

Authors: Dong X

Abstract
The blood-brain barrier (BBB) has been a great hurdle for brain drug delivery. The BBB in healthy brain is a diffusion barrier essential for protecting normal brain function by impeding most compounds from transiting from the blood to the brain; only small molecules can cross the BBB. Under certain pathological conditions of diseases such as stroke, diabetes, seizures, multiple sclerosis, Parkinson's disease and Alzheimer disease, the BBB is disrupted. The objective of this review is to provide a broad overview on current strategies for brain drug delivery and related subjects from the past five years. It is hoped that this review could inspire readers to discover possible approaches to deliver drugs into the brain. After an initial overview of the BBB structure and function in both healthy and pathological conditions, this review re-visits, according to recent publications, some questions that are controversial, such as whether nanoparticles by themselves could cross the BBB and whether drugs are specifically transferred to the brain by actively targeted nanoparticles. Current non-nanoparticle strategies are also reviewed, such as delivery of drugs through the permeable BBB under pathological conditions and using non-invasive techniques to enhance brain drug uptake. Finally, one particular area that is often neglected in brain drug delivery is the influence of aging on the BBB, which is captured in this review based on the limited studies in the literature.

PMID: 29556336 [PubMed - indexed for MEDLINE]

Identification of Binding Sites for Efflux Pump Inhibitors of the AcrAB-TolC Component AcrA.

Wed, 01/30/2019 - 07:28
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Identification of Binding Sites for Efflux Pump Inhibitors of the AcrAB-TolC Component AcrA.

Biophys J. 2019 Jan 12;:

Authors: Darzynkiewicz ZM, Green AT, Abdali N, Hazel A, Fulton RL, Kimball J, Gryczynski Z, Gumbart JC, Parks JM, Smith JC, Zgurskaya HI

Abstract
The overexpression of multidrug efflux pumps is an important mechanism of clinical resistance in Gram-negative bacteria. Recently, four small molecules were discovered that inhibit efflux in Escherichia coli and interact with the AcrAB-TolC efflux pump component AcrA. However, the binding site(s) for these molecules was not determined. Here, we combine ensemble docking and molecular dynamics simulations with tryptophan fluorescence spectroscopy, site-directed mutagenesis, and antibiotic susceptibility assays to probe binding sites and effects of binding of these molecules. We conclude that clorobiocin and SLU-258 likely bind at a site located between the lipoyl and β-barrel domains of AcrA.

PMID: 30691677 [PubMed - as supplied by publisher]

Is Long-Acting Reversible Contraceptive Use Increasing? Assessing Trends Among U.S. College Women, 2008-2013.

Wed, 01/30/2019 - 07:28
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Is Long-Acting Reversible Contraceptive Use Increasing? Assessing Trends Among U.S. College Women, 2008-2013.

Matern Child Health J. 2018 Nov;22(11):1639-1646

Authors: Logan RG, Thompson EL, Vamos CA, Griner SB, Vázquez-Otero C, Daley EM

Abstract
Objective To assess LARC use trends among college women (18-24 years) and identify groups that have increased LARC use. Methods Data were extracted from the National College Health Assessment-II (NCHA-II) fall 2008-2013 surveys. Logistic regression statistics were used to assess LARC use. Results Although LARC use increased from 2008 to 2013 (aOR = 2.62; 95% CI 2.23-3.07), less than half of the sample (44%) reported using contraception at last vaginal sex. Only 2.5% of college women in this study reported using a LARC method; of LARC users, 90% reported using an intrauterine device. Nearly all sociodemographic factors were significantly associated with increases in LARC use including: age, sexual orientation, and insurance status. Conclusions LARC use significantly increased among college women. However, less effective methods such as condoms and short-acting reversible contraceptives are used more frequently. Promoting LARC use for women who desire to effectively prevent pregnancy can reduce unintended pregnancy and improve health outcomes for women while in college. Future work should examine the importance of individual and lifestyle factors that influence college women's decision to choose a LARC method and seek to eliminate barriers to college women choosing a contraceptive method they believe works best for them.

PMID: 29936659 [PubMed - indexed for MEDLINE]

Characteristics of Cognitively Normal Mexican-Americans with Cognitive Complaints.

Fri, 01/25/2019 - 07:28
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Characteristics of Cognitively Normal Mexican-Americans with Cognitive Complaints.

J Alzheimers Dis. 2018;61(4):1485-1492

Authors: Hall JR, Wiechmann A, Johnson LA, Edwards M, O'Bryant SE

Abstract
BACKGROUND: Subjective cognitive complaints in cognitively normal adults have been linked to later cognitive decline and dementia. Research on the characteristics of this group has been conducted on a variety of clinical and community-based populations. The current study focuses on the rapidly expanding population of Mexican-American elders.
OBJECTIVE: The objective of the study is the determination of characteristics of cognitively normal Mexican-Americans with cognitive complaints.
METHODS: Data on 319 cognitively normal participants in a large-scale community-based study of elderly Mexican-Americans (HABLE) were analyzed comparing those with cognitive complaints with those without on clinical characteristics, affective status, neuropsychological functioning, and proteomic markers.
RESULTS: Those expressing concern about cognitive decline scored lower on the MMSE, were more likely to have significantly more affective symptoms, higher levels of diabetic markers, poorer performance on attention and executive functioning, and a different pattern of inflammatory markers.
CONCLUSION: Although longitudinal research is needed to determine the impact of these differences on later cognition, possible targets for early intervention with Mexican-Americans were identified.

PMID: 29376872 [PubMed - indexed for MEDLINE]

Pharmacological, Toxicological and Dose-Range Assessment of OG716, a Novel Lantibiotic for the Treatment of Clostridium difficile Associated Infection (CDI).

Thu, 01/24/2019 - 07:28
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Pharmacological, Toxicological and Dose-Range Assessment of OG716, a Novel Lantibiotic for the Treatment of Clostridium difficile Associated Infection (CDI).

Antimicrob Agents Chemother. 2019 Jan 22;:

Authors: Pulse ME, Weiss WJ, Kers JA, DeFusco AW, Park JH, Handfield M

Abstract
Lantibiotics present an attractive scaffold for the development of novel antibiotics. We report here a novel lantibiotic for the treatment of C. difficile infection. The lead compounds were selected from a library of over 700 single and multiple substitution variants of the lantibiotic Mutacin 1140 (MU1140). The best performers in vitro and in vivo, were further challenged orally in the Golden Syrian hamster model of Clostridium difficile associated disease CDAD in a dose-response format, resulting in selection of OG716 as the lead compound. This lantibiotic was characterized by an ED50 of 23.85 mg/Kg/day (10.97 μmole/Kg/day) in this model. Upon oral administration of the maximum feasible dose (≥1,918 mg/Kg/day), no observable toxicities and side effects were noted and no effect on intestinal motility was observed. Compartmentalization to the GI tract was confirmed. MU1140-derived variants offer a large pipeline for the development of novel antibiotics in several indications and are particularly attractive considering their novel mechanism of action. Based on the currently available data, OG716 has an acceptable profile for further development for the treatment of CDAD.

PMID: 30670434 [PubMed - as supplied by publisher]

Transforming growth factor β2 (TGFβ2) signaling plays a key role in glucocorticoid-induced ocular hypertension.

Wed, 01/23/2019 - 10:29
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Transforming growth factor β2 (TGFβ2) signaling plays a key role in glucocorticoid-induced ocular hypertension.

J Biol Chem. 2018 06 22;293(25):9854-9868

Authors: Kasetti RB, Maddineni P, Patel PD, Searby C, Sheffield VC, Zode GS

Abstract
Elevation of intraocular pressure (IOP) is a serious adverse effect of glucocorticoid (GC) therapy. Increased extracellular matrix (ECM) accumulation and endoplasmic reticulum (ER) stress in the trabecular meshwork (TM) is associated with GC-induced IOP elevation. However, the molecular mechanisms by which GCs induce ECM accumulation and ER stress in the TM have not been determined. Here, we show that a potent GC, dexamethasone (Dex), activates transforming growth factor β (TGFβ) signaling, leading to GC-induced ECM accumulation, ER stress, and IOP elevation. Dex increased both the precursor and bioactive forms of TGFβ2 in conditioned medium and activated TGFβ-induced SMAD signaling in primary human TM cells. Dex also activated TGFβ2 in the aqueous humor and TM of a mouse model of Dex-induced ocular hypertension. We further show that Smad3-/- mice are protected from Dex-induced ocular hypertension, ER stress, and ECM accumulation. Moreover, treating WT mice with a selective TGFβ receptor kinase I inhibitor, LY364947, significantly decreased Dex-induced ocular hypertension. Of note, knockdown of the ER stress-induced activating transcription factor 4 (ATF4), or C/EBP homologous protein (CHOP), completely prevented Dex-induced TGFβ2 activation and ECM accumulation in TM cells. These observations suggested that chronic ER stress promotes Dex-induced ocular hypertension via TGFβ signaling. Our results indicate that TGFβ2 signaling plays a central role in GC-induced ocular hypertension and provides therapeutic targets for GC-induced ocular hypertension.

PMID: 29743238 [PubMed - indexed for MEDLINE]

Baicalin reverses the impairment of synaptogenesis induced by dopamine burden via the stimulation of GABAAR-TrkB interaction in minimal hepatic encephalopathy.

Wed, 01/23/2019 - 10:29
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Baicalin reverses the impairment of synaptogenesis induced by dopamine burden via the stimulation of GABAAR-TrkB interaction in minimal hepatic encephalopathy.

Psychopharmacology (Berl). 2018 04;235(4):1163-1178

Authors: Ding S, Zhuge W, Hu J, Yang J, Wang X, Wen F, Wang C, Zhuge Q

Abstract
BACKGROUND: It has been reported that D1 receptor (D1R) activation reduces GABAA receptor (GABAAR) current, and baicalin (BAI) displays therapeutic efficacy in diseases involving cognitive impairment.
METHODS: We investigated the mechanisms by which BAI could improve DA-induced minimal hepatic encephalopathy (MHE) using immunoblotting, immunofluorescence, and co-immunoprecipitation.
RESULTS: BAI did not induce toxicity on the primary cultured neurons. And no obvious toxicity of BAI to the brain was found in rats. DA activated D1R/dopamine and adenosine 3'5'-monophosphate-regulated phospho-protein (DARPP32) to reduce the GABAAR current; BAI treatment did not change the D1R/DARPP32 levels but blocked DA-induced reduction of GABAAR levels in primary cultured neurons. DA decreased the interaction of GABAAR with TrkB and the expression of downstream AKT, which was blocked by BAI treatment. Moreover, BAI reversed the decrease in the expression of GABAAR/TrkB/AKT and prevented the impairment of synaptogenesis and memory deficits in MHE rats.
CONCLUSIONS: These results suggest that BAI has neuroprotective and synaptoprotective effects on MHE which are not related to upstream D1R/DARPP32 signaling, but to the targeting of downstream GABAAR signaling to TrkB.

PMID: 29404643 [PubMed - indexed for MEDLINE]

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