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]
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Pyruvate enhancement of cardiac performance: Cellular mechanisms and clinical application.

Wed, 09/05/2018 - 07:29
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Pyruvate enhancement of cardiac performance: Cellular mechanisms and clinical application.

Exp Biol Med (Maywood). 2018 01;243(2):198-210

Authors: Mallet RT, Olivencia-Yurvati AH, Bünger R

Abstract
Cardiac contractile function is adenosine-5'-triphosphate (ATP)-intensive, and the myocardium's high demand for oxygen and energy substrates leaves it acutely vulnerable to interruptions in its blood supply. The myriad cardioprotective properties of the natural intermediary metabolite pyruvate make it a potentially powerful intervention against the complex injury cascade ignited by myocardial ischemia-reperfusion. A readily oxidized metabolic substrate, pyruvate augments myocardial free energy of ATP hydrolysis to a greater extent than the physiological fuels glucose, lactate and fatty acids, particularly when it is provided at supra-physiological plasma concentrations. Pyruvate also exerts antioxidant effects by detoxifying reactive oxygen and nitrogen intermediates, and by increasing nicotinamide adenine dinucleotide phosphate reduced form (NADPH) production to maintain glutathione redox state. These enhancements of free energy and antioxidant defenses combine to augment sarcoplasmic reticular Ca2+ release and re-uptake central to cardiac mechanical performance and to restore β-adrenergic signaling of ischemically stunned myocardium. By minimizing Ca2+ mismanagement and oxidative stress, pyruvate suppresses inflammation in post-ischemic myocardium. Thus, pyruvate administration stabilized cardiac performance, augmented free energy of ATP hydrolysis and glutathione redox systems, and/or quelled inflammation in a porcine model of cardiopulmonary bypass, a canine model of cardiac arrest-resuscitation, and a caprine model of hypovolemia and hindlimb ischemia-reperfusion. Pyruvate's myriad benefits in preclinical models provide the mechanistic framework for its clinical application as metabolic support for myocardium at risk. Phase one trials have demonstrated pyruvate's safety and efficacy for intravenous resuscitation for septic shock, intracoronary infusion for heart failure and as a component of cardioplegia for cardiopulmonary bypass. The favorable outcomes of these trials, which argue for expanded, phase three investigations of pyruvate therapy, mirror findings in isolated, perfused hearts, underscoring the pivotal role of preclinical research in identifying clinical interventions for cardiovascular diseases. Impact statement This article reviews pyruvate's cardioprotective properties as an energy-yielding metabolic fuel, antioxidant and anti-inflammatory agent in mammalian myocardium. Preclinical research has shown these properties make pyruvate a powerful intervention to curb the complex injury cascade ignited by ischemia and reperfusion. In ischemically stunned isolated hearts and in large mammal models of cardiopulmonary bypass, cardiac arrest-resuscitation and hypovolemia, intracoronary pyruvate supports recovery of myocardial contractile function, intracellular Ca2+ homeostasis and free energy of ATP hydrolysis, and its antioxidant actions restore β-adrenergic signaling and suppress inflammation. The first clinical trials of pyruvate for cardiopulmonary bypass, fluid resuscitation and intracoronary intervention for congestive heart failure have been reported. Receiver operating characteristic analyses show remarkable concordance between pyruvate's beneficial functional and metabolic effects in isolated, perfused hearts and in patients recovering from cardiopulmonary bypass in which they received pyruvate- vs. L-lactate-fortified cardioplegia. This research exemplifies the translation of mechanism-oriented preclinical studies to clinical application and outcomes.

PMID: 29154687 [PubMed - indexed for MEDLINE]

Limb remote ischemic conditioning increases Notch signaling activity and promotes arteriogenesis in the ischemic rat brain.

Wed, 09/05/2018 - 07:29
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Limb remote ischemic conditioning increases Notch signaling activity and promotes arteriogenesis in the ischemic rat brain.

Behav Brain Res. 2018 03 15;340:87-93

Authors: Ren C, Li S, Wang B, Han R, Li N, Gao J, Li X, Jin K, Ji X

Abstract
BACKGROUND AND PURPOSE: We tested the hypothesis that limb remote ischemic conditioning (LRIC) treatment promotes arteriogenesis and increases Notch signaling activity during stroke recovery.
METHODS: Adult male Sprague Dawley rats were subjected to middle cerebral artery occlusion (MCAO). LRIC was applied after the onset of focal ischemia (per-conditioning), followed by repeated short episodes of remote ischemia 24h after reperfusion (post-conditioning). Cerebral blood flow (CBF) was measured by Laser Doppler Flowmetry. Immunohistochemistry was used to reveal α-smooth muscle actin (α-SMA) immunopositive cells in the arteries of the brain. The cerebral angioarchitecture was visualized with a latex perfusion technique.
RESULTS: LRIC treatment significantly elevated local cerebral blood flow and increased arteriogenesis as indicated by increased arterial diameter and vascular smooth muscle cell proliferation in the ischemic brain. The increased arteriogenesis significantly correlated with the functional outcome after stroke. Furthermore, LRIC treatment upregulated the expressions of Notch1 and Notch intracellular domain (NICD) in arteries surrounding the ischemic area.
CONCLUSION: These results suggest that the therapeutic effects of LRIC may involve the promotion of arteriogenesis during the recovery phase after focal cerebral ischemia and that Notch1 signaling seems to be an important player in limb remote ischemia-mediated arteriogenesis.

PMID: 27780723 [PubMed - indexed for MEDLINE]

NIST interlaboratory studies involving DNA mixtures (MIX13): A modern analysis.

Tue, 09/04/2018 - 07:28
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NIST interlaboratory studies involving DNA mixtures (MIX13): A modern analysis.

Forensic Sci Int Genet. 2018 Aug 27;37:172-179

Authors: Buckleton JS, Bright JA, Cheng K, Budowle B, Coble MD

Abstract
MIX13 was an interlaboratory exercise directed by NIST in 2013. The goal of the exercise was to evaluate the general state of interpretation methods in use at the time across the forensic community within the US and Canada and to measure the consistency in mixture interpretation. The findings were that there was a large variation in analysts' interpretations between and within laboratories. Within this work, we sought to evaluate the same mock mixture cases analyzed in MIX13 but with a more current view of the state-of-the-science. Each of the five cases were analyzed using the Identifiler™ multiplex and interpreted with the combined probability of inclusion, CPI, and four different modern probabilistic genotyping systems. Cases 1-4 can be interpreted without difficulty by any of the four PG systems examined. Cases 1 and 4 could also be interpreted successfully with the CPI by assuming two donors. Cases 2 and 3 cannot be interpreted successfully with the CPI because of potential of allele dropout. Case 3 demonstrated the need to consider relevant background information before interpretation of the profile. This case does not show that there is some barrier to interpretation caused by relatedness beyond the increased allelic overlap that can occur. Had this profile been of better template it might have been interpreted using the CPI despite the (potential) relatedness of contributors. Case 5 suffers from over-engineering. It is unclear whether reference 5C, a non-donor, can be excluded by manual methods. Inclusion of reference 5C should be termed an adventitious match not a false inclusion. Beyond this statement this case does not contribute to the interlaboratory study of analyst/laboratory interpretation method performance, instead, it explores the limits of DNA analysis. Taken collectively the analysis of these five cases demonstrates the benefits of changing from CPI to a PG system.

PMID: 30176439 [PubMed - as supplied by publisher]

Potential highly polymorphic short tandem repeat markers for enhanced forensic identity testing.

Tue, 09/04/2018 - 07:28
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Potential highly polymorphic short tandem repeat markers for enhanced forensic identity testing.

Forensic Sci Int Genet. 2018 Aug 23;37:162-171

Authors: Novroski NMM, Woerner AE, Budowle B

Abstract
Due to their polymorphic nature, short tandem repeats (STRs) are well-studied and routinely used genetic markers for forensic DNA typing. However, even the largest STR multiplexes are limited in their ability to parse out individuals in a DNA mixture sample, due to alleles shared by size detected by capillary electrophoresis and challenges in resolving minor alleles from stutter, and inherent heterozygote imbalance. In this study, STRs were explored in public datasets that displayed sequence variation and may have limited allele length spread. STRs were first selected using fundamental criteria of high heterozygosity, tetra-, penta-, or hexanucleotide repeat length, and overall relative narrow allele spread (based on length). All candidates were further scrutinized for chemistry compatibility. The resulting STRs were multiplexed and sequenced by massively parallel sequencing in a limited sample population set. Each candidate STR was evaluated for analytical performance and desired biological properties. The findings presented describe a refined set of 53 potential highly polymorphic STR markers (high sequence diversity and heterozygosity; reduced allele spread) that may be suitable to supplement the current core marker set(s) for possible enhanced characterization of complex DNA profiles.

PMID: 30176438 [PubMed - as supplied by publisher]

Machine Learning Applications in Head and Neck Radiation Oncology: Lessons From Open-Source Radiomics Challenges.

Tue, 09/04/2018 - 07:28
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Machine Learning Applications in Head and Neck Radiation Oncology: Lessons From Open-Source Radiomics Challenges.

Front Oncol. 2018;8:294

Authors: Elhalawani H, Lin TA, Volpe S, Mohamed ASR, White AL, Zafereo J, Wong AJ, Berends JE, AboHashem S, Williams B, Aymard JM, Kanwar A, Perni S, Rock CD, Cooksey L, Campbell S, Yang P, Nguyen K, Ger RB, Cardenas CE, Fave XJ, Sansone C, Piantadosi G, Marrone S, Liu R, Huang C, Yu K, Li T, Yu Y, Zhang Y, Zhu H, Morris JS, Baladandayuthapani V, Shumway JW, Ghosh A, Pöhlmann A, Phoulady HA, Goyal V, Canahuate G, Marai GE, Vock D, Lai SY, Mackin DS, Court LE, Freymann J, Farahani K, Kaplathy-Cramer J, Fuller CD

Abstract
Radiomics leverages existing image datasets to provide non-visible data extraction via image post-processing, with the aim of identifying prognostic, and predictive imaging features at a sub-region of interest level. However, the application of radiomics is hampered by several challenges such as lack of image acquisition/analysis method standardization, impeding generalizability. As of yet, radiomics remains intriguing, but not clinically validated. We aimed to test the feasibility of a non-custom-constructed platform for disseminating existing large, standardized databases across institutions for promoting radiomics studies. Hence, University of Texas MD Anderson Cancer Center organized two public radiomics challenges in head and neck radiation oncology domain. This was done in conjunction with MICCAI 2016 satellite symposium using Kaggle-in-Class, a machine-learning and predictive analytics platform. We drew on clinical data matched to radiomics data derived from diagnostic contrast-enhanced computed tomography (CECT) images in a dataset of 315 patients with oropharyngeal cancer. Contestants were tasked to develop models for (i) classifying patients according to their human papillomavirus status, or (ii) predicting local tumor recurrence, following radiotherapy. Data were split into training, and test sets. Seventeen teams from various professional domains participated in one or both of the challenges. This review paper was based on the contestants' feedback; provided by 8 contestants only (47%). Six contestants (75%) incorporated extracted radiomics features into their predictive model building, either alone (n = 5; 62.5%), as was the case with the winner of the "HPV" challenge, or in conjunction with matched clinical attributes (n = 2; 25%). Only 23% of contestants, notably, including the winner of the "local recurrence" challenge, built their model relying solely on clinical data. In addition to the value of the integration of machine learning into clinical decision-making, our experience sheds light on challenges in sharing and directing existing datasets toward clinical applications of radiomics, including hyper-dimensionality of the clinical/imaging data attributes. Our experience may help guide researchers to create a framework for sharing and reuse of already published data that we believe will ultimately accelerate the pace of clinical applications of radiomics; both in challenge or clinical settings.

PMID: 30175071 [PubMed]

Successful long-term, adjunctive use of guaifenesin in a patient with a complex atopic medical history and primary immune deficiency: A case report.

Tue, 09/04/2018 - 07:28
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Successful long-term, adjunctive use of guaifenesin in a patient with a complex atopic medical history and primary immune deficiency: A case report.

Respir Med Case Rep. 2018;25:145-146

Authors: Lanier BQ, Miller J

Abstract
We report the case of a 45 year old female patient who suffered from recurrent respiratory infections, asthma, allergies and atopic dermatitis since childhood and multiple autoimmune and chronic respiratory conditions as an adult, who has achieved symptoms remission through a combination of immunotherapy and the daily use of over-the-counter high-dose guaifenesin.

PMID: 30175035 [PubMed]

Factors associated with human papillomavirus (HPV) test acceptability in primary screening for cervical cancer: A mixed methods research synthesis.

Mon, 09/03/2018 - 07:30
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Factors associated with human papillomavirus (HPV) test acceptability in primary screening for cervical cancer: A mixed methods research synthesis.

Prev Med. 2018 Aug 30;:

Authors: Tatar O, Thompson E, Naz A, Perez S, Shapiro GK, Wade K, Zimet G, Gilca V, Janda M, Kahn J, Daley E, Rosberger Z

Abstract
Primary screening for cervical cancer is transitioning from the longstanding Pap smear towards implementation of an HPV-DNA test, which is more sensitive than Pap cytology in detecting high-risk lesions and offers greater protection against invasive cervical carcinomas. Based on these results, many countries are recommending and implementing HPV testing-based screening programs. Understanding what factors (e.g., knowledge, attitudes) will impact on HPV test acceptability by women is crucial for ensuring adequate public health practices to optimize cervical screening uptake. We used mixed methods research synthesis to provide a categorization of the relevant factors related to HPV primary screening for cervical cancer and describe their influence on women's acceptability of HPV testing. We searched Medline, Embase, PsycINFO, CINAHL, Global Health and Web of Science for journal articles between January 1, 1980 and October 31, 2017 and retained 22 empirical articles. Our results show that while most factors associated with HPV test acceptability are included in the Health Belief Model and/or Theory of Planned Behavior (e.g., attitudes, knowledge), other important factors are not encompassed by these theoretical frameworks (e.g., health behaviors, negative emotional reactions related HPV testing). The direction of influence of psychosocial factors on HPV test acceptability was synthesized based on 14 quantitative studies as: facilitators (e.g., high perceived HPV test benefits), barriers (e.g., negative attitudes towards increased screening intervals), contradictory evidence (e.g., sexual history) and no impact (e.g., high perceived severity of HPV infection). Further population-based studies are needed to confirm the impact of these factors on HPV-based screening acceptability.

PMID: 30172799 [PubMed - as supplied by publisher]

AT1a influences GABAa mediated inhibition through the regulation of KCC2 expression.

Thu, 08/30/2018 - 07:29
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AT1a influences GABAa mediated inhibition through the regulation of KCC2 expression.

Am J Physiol Regul Integr Comp Physiol. 2018 Aug 29;:

Authors: Farmer GE, Balapattabi K, Bachelor ME, Little JT, Cunningham JT

Abstract
The median preoptic nucleus (MnPO) is an integrative site involved in body fluid homeostasis, cardiovascular control, thermoregulation, and sleep homeostasis. Angiotensin II (ANG II), a neuropeptide shown to have excitatory effects on MnPO neurons, is of particular interest with regard to its role in body fluid homeostasis and cardiovascular control. The current study investigated the role of angiotensin type 1 (AT1a) receptor activation on neuronal excitability in the MnPO. Male Sprague-Dawley rats were infused with an adeno-associated virus with a shRNA against the AT1a receptor or a scrambled control. In vitro loose patch voltage clamp recordings of spontaneous action potential activity were made from labeled MnPO neurons in response to brief focal application of ANG II or the GABAA receptor agonist muscimol. Tissue punches from MnPO were taken to asses mRNA and protein expression. AT1a receptor knockdown neurons were insensitive to ANG II and showed a marked reduction in GABAA mediated inhibition. The reduction in GABAA mediated inhibition was not associated with reductions in mRNA or protein expression of GABAA β-subunits. Knockdown of the AT1a receptor was associated with a reduction in the potassium-chloride cotransporter KCC2 mRNA as well as a reduction in pS940 KCC2 protein. The impaired GABAA mediated inhibition in AT1a knockdown neurons was recovered by bath application of phospholipase C (PLC) and protein kinase C (PKC) activators. The following study indicates that AT1a receptor activation mediates the excitability of MnPO neurons, in part, through the regulation of KCC2.

PMID: 30156863 [PubMed - as supplied by publisher]

Application of a Health Literacy Framework to Explore Patients' Knowledge of the Link between HPV and Cancer.

Wed, 08/29/2018 - 07:29

Application of a Health Literacy Framework to Explore Patients' Knowledge of the Link between HPV and Cancer.

J Health Commun. 2018 Aug 28;:1-8

Authors: Best AL, Logan RG, Vázquez-Otero C, Fung W, Chee V, Thompson EL, Villalona S, Thompson LMA, Gwede CK, Daley EM

Abstract
The human papillomavirus (HPV) is a sexually transmitted infection and causes most oropharyngeal (e.g., throat) and anogenital (e.g., anal, cervical) cancers. Research indicates low knowledge about the link between HPV and cancer among the general population, and similar low knowledge of HPV among individuals diagnosed with HPV-associated cancers. This is important because HPV status can have implications for treatment, prognosis, and future sexual decisions. Using a health literacy framework, this study explored how patients diagnosed with HPV-associated cancers accessed, understood, appraised, and applied HPV information. We conducted 27 in-depth interviews with patients seeking care at a comprehensive cancer center; and data were analyzed using applied thematic analysis. Findings revealed that patients' primary source of HPV information was medical providers (access); and many patients exhibited limited understanding of HPV and its role in their cancer diagnosis (understand). Most patients (17 of 27) did not mention HPV as the cause of their cancer. Many patients displayed difficulty connecting HPV with their lifestyles (appraise); and few discussed plans to engage in HPV prevention practices going forward (apply). Future research should focus on strategies to improve understanding of HPV which could increase vaccine uptake, reduce stigma, and enhance informed decision-making among HPV-associated cancer patients.

PMID: 30153087 [PubMed - as supplied by publisher]

MicroRNA-21 Ablation Exacerbates Aldosterone-Mediated Cardiac Injury, Remodeling and Dysfunction.

Wed, 08/29/2018 - 07:29

MicroRNA-21 Ablation Exacerbates Aldosterone-Mediated Cardiac Injury, Remodeling and Dysfunction.

Am J Physiol Endocrinol Metab. 2018 Aug 28;:

Authors: Syed M, Ball JP, Mathis KW, Hall ME, Ryan MJ, Rothenberg ME, Yanes Cardozo LL, Romero DG

Abstract
Primary aldosteronism is characterized by excess aldosterone secretion by the adrenal gland independent of the renin-angiotensin system and accounts for ~10% of hypertensive patients. Excess aldosterone causes cardiac hypertrophy, fibrosis, inflammation and hypertension. The molecular mechanisms that trigger the onset and progression of aldosterone-mediated cardiac injury remain incompletely understood. MicroRNAs (miRNAs) are endogenous, small, non-coding RNAs that have been implicated in multiple cardiac pathologies; however, their regulation and role in aldosterone-mediated cardiac injury and dysfunction remains mostly unknown. We previously reported that miR-21 is the most upregulated miRNA by excess aldosterone in the left ventricle in a rat experimental model of primary aldosteronism. To elucidate the role of miR-21 in aldosterone-mediated cardiac injury and dysfunction, miR-21 knockout mice and their WT littermates were treated with aldosterone infusion and salt in the drinking water for 2 or 8 weeks. miR-21 genetic ablation exacerbated aldosterone/salt-mediated cardiac hypertrophy and cardiomyocyte cross-sectional area. Furthermore, miR-21 genetic ablation increased the cardiac expression of fibrosis and inflammation markers and fetal gene program. miR-21 genetic ablation increased aldosterone/salt-mediated cardiac dysfunction but did not affect aldosterone/salt-mediated hypertension. miR-21 target gene Sprouty 2 may be implicated in the cardiac effects of miR-21 genetic ablation. Our study shows that miR-21 genetic ablation exacerbates aldosterone/salt-mediated cardiac hypertrophy, injury and dysfunction blood pressure independently. These results suggest that miR-21 plays a protective role in the cardiac pathology triggered by excess aldosterone. Furthermore, miR-21 supplementation may be a novel therapeutic approach to abolish or mitigate excess aldosterone-mediated cardiovascular deleterious effects in primary aldosteronism.

PMID: 30153065 [PubMed - as supplied by publisher]

Pharmacy resident-led student mentoring program: A focus on developing mentoring skills.

Wed, 08/29/2018 - 07:29
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Pharmacy resident-led student mentoring program: A focus on developing mentoring skills.

Curr Pharm Teach Learn. 2017 Nov;9(6):1123-1128

Authors: Howard ML, Steuber TD, Nisly SA, Wilhoite J, Saum L

Abstract
BACKGROUND AND PURPOSE: Formalized mentoring programs are often credited for influencing professional development of mentees. Unfortunately, little information exists regarding advancement of mentoring skills. We report the development and evaluation of a program to cultivate mentoring skills in pharmacy residents.
EDUCATIONAL ACTIVITY AND SETTING: Advanced pharmacy practice experience students and pharmacy residents were contacted for program participation. Resident mentors were paired with a student mentee for the program. Mentors were provided resources and support throughout the program. Sessions were held to facilitate mentoring relationships and to discuss professional development topics. Pre- and post-perception surveys were administered to mentors to measure changes in mentoring comfort and ability. Only matched pre- and post-surveys were included for analysis. The program was held and evaluated over two separate academic years FINDINGS: Fifty-three residents mentored 54 students over two cycles of the program. Mentors' matched perception surveys (n = 26) reported increased comfort in mentoring (p < 0.001), increased confidence in delivery of subjective content (p < 0.001), increased comfort in providing written and oral feedback (p = 0.013), and increased effectiveness in provision of written and oral feedback (p = 0.004 and p = 0.013 respectively). Mentors also reported heightened belief that serving as a student mentor will be beneficial to their long-term career goals (p = 0.034).
DISCUSSION AND SUMMARY: Overall, this formal resident-led student mentoring program improved resident comfort serving in a mentoring role.

PMID: 29233381 [PubMed - indexed for MEDLINE]

Pharmacy residents as primary educators within a professional pharmacy elective.

Wed, 08/29/2018 - 07:29
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Pharmacy residents as primary educators within a professional pharmacy elective.

Curr Pharm Teach Learn. 2017 Sep;9(5):862-868

Authors: Howard ML, Steuber TD, Walton AM, Nisly SA

Abstract
BACKGROUND AND PURPOSE: The purpose of this study was to evaluate the impact of a course change from a faculty-led professional pharmacy elective to a primarily pharmacy resident-led course on student satisfaction and learning.
EDUCATIONAL ACTIVITY AND SETTING: In 2014, pharmacy residents were transitioned into primary teaching roles in a drug-induced diseases elective to increase student exposure to residents and different teaching styles. Student learning roles did not change. Course evaluations and grades were compared between the resident-led year and prior year.
FINDINGS: There was no significant difference between overall course grades during the resident-led year (94.2 ± 36.6 in 2014 vs. 94.1 ± 2.7 in 2013; p=0.975). Course evaluations were similar to the previous year and students provided favorable feedback.
DISCUSSION AND SUMMARY: This pharmacy resident-led elective allowed for resident integration in to an interactive professional elective. Student satisfaction with the course remained similar to the previous year and overall course grades did not differ.

PMID: 29233316 [PubMed - indexed for MEDLINE]

Development, implementation, and evaluation of a service-learning series for pharmacy students using a public health tool.

Wed, 08/29/2018 - 07:29
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Development, implementation, and evaluation of a service-learning series for pharmacy students using a public health tool.

Curr Pharm Teach Learn. 2017 Sep;9(5):828-834

Authors: Bullock KC

Abstract
BACKGROUND AND PURPOSE: The purpose of this article is to describe the utility of the Assessment, Development, Assurance: Pharmacist's Tool (ADAPT) during the design, delivery, and assessment of service-learning events by pharmacy students.
EDUCATIONAL ACTIVITY AND SETTING: The ADAPT instrument was used to develop a series of five service-learning events that featured a health promotion program delivered by 19 pharmacy students and attended by over 200 senior citizens at local senior centers. Student competence was assessed prior to participating in the service-learning activities and each student completed a reflection following the event. Senior center directors evaluated both the quality of the health promotion program as well as the interaction with the sponsoring college of pharmacy.
FINDINGS: Pharmacy students reported achievement of health promotion learning objectives based on self-evaluations. Responses to reflections also indicate that students gained insight to and appreciation for several of the public health essential services, which are the basis of the ADAPT instrument. Feedback from the senior center directors was consistently positive.
DISCUSSION AND SUMMARY: Use of the ADAPT instrument helped to facilitate the delivery of a high-quality, comprehensive service-learning series at local senior centers that had a solid public health foundation. Colleges and schools of pharmacy should strongly consider consulting the tool prior to planning any future health promotion activities for students.

PMID: 29233311 [PubMed - indexed for MEDLINE]

Improving diagnosis by improving education: a policy brief on education in healthcare professions.

Mon, 08/27/2018 - 07:29
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Improving diagnosis by improving education: a policy brief on education in healthcare professions.

Diagnosis (Berl). 2018 Aug 27;:

Authors: Graber ML, Rencic J, Rusz D, Papa F, Croskerry P, Zierler B, Harkless G, Giuliano M, Schoenbaum S, Colford C, Cahill M, Olson APJ

PMID: 30145580 [PubMed - as supplied by publisher]

A Review of the Opioid Analgesic Benzhydrocodone-Acetaminophen.

Sat, 08/25/2018 - 07:28
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A Review of the Opioid Analgesic Benzhydrocodone-Acetaminophen.

Cureus. 2018 Jun 20;10(6):e2844

Authors: Mustafa AA, Rajan R, Suarez JD, Alzghari SK

Abstract
There is an undeniable opioid crisis in the United States that has caused significant negative consequences including many lives lost due to opioid overdoses. Currently, researchers are searching for alternatives for pain management as well as developing abuse-deterrent agents. In February 2018, the Food and Drug Administration (FDA) approved benzhydrocodone and acetaminophen (Apadaz™) for the short-term (no more than 14 days) management of acute pain severe enough to require an opioid analgesic and where alternative treatments are inadequate. This article looks further into this oral opioid prodrug and assesses its clinical pharmacology, pharmacokinetics, clinical trials and safety considerations that led to approval. Even though this prodrug provides a novel approach to analgesia, it was not classified as an abuse-deterrent agent and therefore still has the potential for abuse and misuse. This new agent potentially runs a higher risk of augmenting the opioid crisis rather than curtailing it. Innovative approaches to discover opioid alternatives are warranted.

PMID: 30140595 [PubMed]

Optimization and scale up of microfluidic nanolipomer production method for preclinical and potential clinical trials.

Sat, 08/25/2018 - 07:28
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Optimization and scale up of microfluidic nanolipomer production method for preclinical and potential clinical trials.

J Nanobiotechnology. 2018 Feb 12;16(1):12

Authors: Gdowski A, Johnson K, Shah S, Gryczynski I, Vishwanatha J, Ranjan A

Abstract
BACKGROUND: The process of optimization and fabrication of nanoparticle synthesis for preclinical studies can be challenging and time consuming. Traditional small scale laboratory synthesis techniques suffer from batch to batch variability. Additionally, the parameters used in the original formulation must be re-optimized due to differences in fabrication techniques for clinical production. Several low flow microfluidic synthesis processes have been reported in recent years for developing nanoparticles that are a hybrid between polymeric nanoparticles and liposomes. However, use of high flow microfluidic synthetic techniques has not been described for this type of nanoparticle system, which we will term as nanolipomer. In this manuscript, we describe the successful optimization and functional assessment of nanolipomers fabricated using a microfluidic synthesis method under high flow parameters.
RESULTS: The optimal total flow rate for synthesis of these nanolipomers was found to be 12 ml/min and flow rate ratio 1:1 (organic phase: aqueous phase). The PLGA polymer concentration of 10 mg/ml and a DSPE-PEG lipid concentration of 10% w/v provided optimal size, PDI and stability. Drug loading and encapsulation of a representative hydrophobic small molecule drug, curcumin, was optimized and found that high encapsulation efficiency of 58.8% and drug loading of 4.4% was achieved at 7.5% w/w initial concentration of curcumin/PLGA polymer. The final size and polydispersity index of the optimized nanolipomer was 102.11 nm and 0.126, respectively. Functional assessment of uptake of the nanolipomers in C4-2B prostate cancer cells showed uptake at 1 h and increased uptake at 24 h. The nanolipomer was more effective in the cell viability assay compared to free drug. Finally, assessment of in vivo retention in mice of these nanolipomers revealed retention for up to 2 h and were completely cleared at 24 h.
CONCLUSIONS: In this study, we have demonstrated that a nanolipomer formulation can be successfully synthesized and easily scaled up through a high flow microfluidic system with optimal characteristics. The process of developing nanolipomers using this methodology is significant as the same optimized parameters used for small batches could be translated into manufacturing large scale batches for clinical trials through parallel flow systems.

PMID: 29433518 [PubMed - indexed for MEDLINE]

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

Fri, 08/24/2018 - 07:29
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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 - in process]

The Probabilistic Genotyping Software STRmix: Utility and Evidence for its Validity.

Thu, 08/23/2018 - 07:28
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The Probabilistic Genotyping Software STRmix: Utility and Evidence for its Validity.

J Forensic Sci. 2018 Aug 21;:

Authors: Buckleton JS, Bright JA, Gittelson S, Moretti TR, Onorato AJ, Bieber FR, Budowle B, Taylor DA

Abstract
Forensic DNA interpretation is transitioning from manual interpretation based usually on binary decision-making toward computer-based systems that model the probability of the profile given different explanations for it, termed probabilistic genotyping (PG). Decision-making by laboratories to implement probability-based interpretation should be based on scientific principles for validity and information that supports its utility, such as criteria to support admissibility. The principles behind STRmix™ are outlined in this study and include standard mathematics and modeling of peak heights and variability in those heights. All PG methods generate a likelihood ratio (LR) and require the formulation of propositions. Principles underpinning formulations of propositions include the identification of reasonably assumed contributors. Substantial data have been produced that support precision, error rate, and reliability of PG, and in particular, STRmix™. A current issue is access to the code and quality processes used while coding. There are substantial data that describe the performance, strengths, and limitations of STRmix™, one of the available PG software.

PMID: 30132900 [PubMed - as supplied by publisher]

High Salt Loading Increases Brain Derived Neurotrophic Factor in Supraoptic Vasopressin Neurons.

Wed, 08/22/2018 - 07:29
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High Salt Loading Increases Brain Derived Neurotrophic Factor in Supraoptic Vasopressin Neurons.

J Neuroendocrinol. 2018 Aug 21;:e12639

Authors: Balapattabi K, Little JT, Farmer GE, Cunningham JT

Abstract
High salt loading (SL) is associated with inappropriate arginine vasopressin (AVP) release and increased mean arterial pressure. Previous work has shown that chronic high salt intake impairs baroreceptor inhibition of rat AVP neurons through Brain-Derived Neurotrophic Factor (BDNF) dependent activation of tyrosine receptor kinase B (TrkB) and downregulation of K+ /Cl- co-transporter KCC2. This mechanism diminishes the GABAA inhibition of AVP neurons in the supraoptic nucleus (SON) by increasing intracellular chloride ([Cl]i ). However, the source of BDNF leading to this ionic plasticity is unknown. Here we used adeno-associated viral vectors with shRNA against BDNF to test if SON is the source of BDNF contributing to increased AVP release and elevated mean arterial pressure in high salt loaded rats. Virally mediated BDNF knockdown (shBDNF) in the SON of salt loaded rats significantly blocked the increases in BDNF mRNA and AVP hnRNA expression. The observed increase in the activation of TrkB receptor during salt loading is consistent with previous studies. Western blot analysis of SON punches revealed that tyrosine phosphorylation of TrkB (pTrkBY515 ) was significantly decreased in Salt shBDNF rats compared to the Salt SCR rats. Injections of shBDNF in the SON also significantly prevented the increase in plasma AVP concentration associated with salt loading. However, the salt loading induced increase in mean arterial pressure was not decreased with BDNF knockdown in the SON. Average daily fluid intake and urine output were significantly elevated in both Salt SCR and Salt shBDNF rats compared to the euhydrated controls. Daily average urine sodium concentration was significantly higher in shBDNF injected Salt rats than the other groups. These findings indicate that BDNF produced in the SON contributes to the increased AVP secretion during high salt loading but not for the subsequent increase in mean arterial pressure. This article is protected by copyright. All rights reserved.

PMID: 30129982 [PubMed - as supplied by publisher]

Inhibition of Noncanonical Murine Double Minute 2 Homolog Abrogates Ocular Inflammation through NF-κB Suppression.

Wed, 08/22/2018 - 07:29
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Inhibition of Noncanonical Murine Double Minute 2 Homolog Abrogates Ocular Inflammation through NF-κB Suppression.

Am J Pathol. 2018 Sep;188(9):2087-2096

Authors: Fan Y, Zhang W, Ni A, Mahato B, Chavala SH

Abstract
Uveitis is estimated to account for 10% of all cases of blindness in the United States, including 30,000 new cases of legal blindness each year. Intraocular and oral corticosteroids are the effective mainstay treatment, but they carry the risk of serious long-term ocular and systemic morbidity. New noncorticosteroid therapies with a favorable side effect profile are necessary for the treatment of chronic uveitis, given the paucity of existing treatment choices. We have previously demonstrated that Nutlin-3, a small-molecule inhibitor of murine double minute 2 (MDM2) homolog, suppresses pathologic retinal angiogenesis through a p53-dependent mechanism, but the noncanonical p53-independent functions have not been adequately elucidated. Herein, we demonstrate an unanticipated function of MDM2 inhibition, where Nutlin-3 potently abrogates lipopolysaccharide-induced ocular inflammation. Furthermore, we identified a mechanism by which transcription and translation of NF-κB is mediated by MDM2, independent of p53, in ocular inflammation. Small-molecule MDM2 inhibition is a novel noncorticosteroid strategy for inhibiting ocular inflammation, which may potentially benefit patients with chronic uveitis.

PMID: 30126549 [PubMed - in process]

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