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Activity of Meropenem-Vaborbactam Against Carbapenem-resistant Enterobacteriaceae in a Murine Model of Pyelonephritis.

Recent Research Articles from UNTHSC - Thu, 10/19/2017 - 07:36
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Activity of Meropenem-Vaborbactam Against Carbapenem-resistant Enterobacteriaceae in a Murine Model of Pyelonephritis.

Antimicrob Agents Chemother. 2017 Oct 16;:

Authors: Weiss WJ, Pulse ME, Nguyen P, Peterson K, Silva J, Simecka JW, Valtierra D, Sabet M, Griffith DC

Abstract
The recently approved combination of meropenem-vaborbactam (Vabomere™) is highly active against Gram-negative pathogens, especially KPC-producing, carbapenem-resistant Enterobacteriaceae We evaluated the efficacy of meropenem-vaborbactam against three clinically relevant isolates in a murine polynephritis model. Data indicated that the combination of meropenem-vaborbactam significantly increased the bacterial killing compared to the untreated controls. These data suggest that this combination may have utility in the treatment of complicated urinary tract infections due to KPC-producing, carbapenem-resistant Enterobacteriaceae.

PMID: 29038270 [PubMed - as supplied by publisher]

Baseline factors affecting closure of venous leg ulcers.

Recent Research Articles from UNTHSC - Thu, 10/19/2017 - 07:36
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Baseline factors affecting closure of venous leg ulcers.

J Vasc Surg Venous Lymphat Disord. 2017 Nov;5(6):829-835.e1

Authors: Marston WA, Ennis WJ, Lantis JC, Kirsner RS, Galiano RD, Vanscheidt W, Eming SA, Malka M, Cargill DI, Dickerson JE, Slade HB, HP802-247 Study Group

Abstract
OBJECTIVE: The objective of this study was to characterize factors associated with closure of venous leg ulcers (VLUs) in a pooled analysis of subjects from three randomized clinical trials.
METHODS: Closure of VLUs after treatment with HP802-247, an allogeneic living cell therapy consisting of growth-arrested human keratinocytes and fibroblasts, vs standard therapy with compression bandaging was evaluated in three phase 3 clinical trials of similar design. Two trials enrolled subjects with VLUs ranging from 2 cm(2) to 12 cm(2) in area with 12-week treatment periods; the third trial enrolled subjects with VLUs between >12 cm(2) and ≤36 cm(2) with a 16-week treatment period. The first trial went to completion but failed to demonstrate a benefit to therapy with HP802-247 compared with placebo, and because of this, the remaining trials were terminated before completion. On the basis of no differences in outcomes between groups, subjects from both HP802-247 and control groups were pooled across all three studies. Cox proportional hazards regression analysis was employed to evaluate factors associated with VLU closure.
RESULTS: This analysis included data from 716 subjects with VLU. Factors evaluated for association with healing included age, gender, race, diabetes, glycated hemoglobin level, body mass index, treatment (HP802-247 vs compression alone), and ulcer characteristics including location and area and duration at baseline. In an initial model including all of these putative factors, the following were significant at the P < .10 level: diagnosis of diabetes mellitus, gender, wound location (ankle or leg), baseline wound area, and wound duration at baseline. In a final model including only these factors, all but diabetes mellitus were significant at the P < .05 level. Effect sizes were as follows (hazard ratio [95% confidence interval]): female gender (1.384 [1.134-1.690]), wound location on the leg (1.490 [1.187-1.871]), smaller wound area at baseline (0.907 [0.887-0.927]), and shorter wound duration at baseline (0.971 [0.955-0.987]).
CONCLUSIONS: Factors associated with VLU lesions including location, area, and duration were important predictors of healing. Women were more likely than men to achieve wound closure. Factors including body mass index, the presence of diabetes mellitus, and higher concentrations of glycated hemoglobin were not significant independent predictors of wound closure in this analysis.

PMID: 29037354 [PubMed - in process]

Destination Brain: the Past, Present, and Future of Therapeutic Gene Delivery.

Recent Research Articles from UNTHSC - Thu, 10/19/2017 - 07:36
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Destination Brain: the Past, Present, and Future of Therapeutic Gene Delivery.

J Neuroimmune Pharmacol. 2017 Mar;12(1):51-83

Authors: Joshi CR, Labhasetwar V, Ghorpade A

Abstract
Neurological diseases and disorders (NDDs) present a significant societal burden and currently available drug- and biological-based therapeutic strategies have proven inadequate to alleviate it. Gene therapy is a suitable alternative to treat NDDs compared to conventional systems since it can be tailored to specifically alter select gene expression, reverse disease phenotype and restore normal function. The scope of gene therapy has broadened over the years with the advent of RNA interference and genome editing technologies. Consequently, encouraging results from central nervous system (CNS)-targeted gene delivery studies have led to their transition from preclinical to clinical trials. As we shift to an exciting gene therapy era, a retrospective of available literature on CNS-associated gene delivery is in order. This review is timely in this regard, since it analyzes key challenges and major findings from the last two decades and evaluates future prospects of brain gene delivery. We emphasize major areas consisting of physiological and pharmacological challenges in gene therapy, function-based selection of a ideal cellular target(s), available therapy modalities, and diversity of viral vectors and nanoparticles as vehicle systems. Further, we present plausible answers to key questions such as strategies to circumvent low blood-brain barrier permeability and most suitable CNS cell types for targeting. We compare and contrast pros and cons of the tested viral vectors in the context of delivery systems used in past and current clinical trials. Gene vector design challenges are also evaluated in the context of cell-specific promoters. Key challenges and findings reported for recent gene therapy clinical trials, assessing viral vectors and nanoparticles are discussed from the perspective of bench to bedside gene therapy translation. We conclude this review by tying together gene delivery challenges, available vehicle systems and comprehensive analyses of neuropathogenesis to outline future prospects of CNS-targeted gene therapies.

PMID: 28160121 [PubMed - indexed for MEDLINE]

Pathways between physical activity and quality of life in African-American breast cancer survivors.

Recent Research Articles from UNTHSC - Thu, 10/19/2017 - 07:36
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Pathways between physical activity and quality of life in African-American breast cancer survivors.

Support Care Cancer. 2017 Feb;25(2):489-495

Authors: Meadows R, Bonner T, Dobhal M, Borra S, Killion JA, Paxton R

Abstract
INTRODUCTION: Several studies have indicated that the relationship between physical activity and quality of life is not directed but mediated through various pathways. The purpose of this study was to assess the role of cancer-related fatigue, disability, and functional status as potential mediators in African-American breast cancer survivors.
METHODS: African-American breast cancer survivors (N = 135, mean age = 63) aged 55 years and older participated in a web-based survey consisting of measures assessing physical activity, functional status, cancer-related fatigue, disability, quality of life, and sociodemographic and medical characteristics. Structural equation modeling was used to assess the structural relationships among the constructs.
RESULTS: The initial structural model fit the data and revealed a significant relationship between physical activity and quality of life (β = 0.34, P < 0.01). Subsequent structural models with proposed complementary and mediating paths of fatigue, function, and disability fit the data. The adjusted model indicated that physical activity was no longer associated with quality of life (β = 0.11, P > 0.05) and mediated through pathways of functional status and fatigue (total β = 0.16, P < 0.01). The final adjusted model accounted for 32 % of the variance in quality of life.
CONCLUSION: Our data suggest that physical activity may be indirectly related to quality of life through pathways consisting of fatigue and functional status. Further longitudinal studies are needed to test the pathways through which varying levels of physical activity influence cancer-related and quality of life outcomes in minority cancer survivors.

PMID: 27709312 [PubMed - indexed for MEDLINE]

Probabilistic Modeling Approach to Reducing Healthcare Costs With Reflex Testing.

Recent Research Articles from UNTHSC - Tue, 10/17/2017 - 07:34

Probabilistic Modeling Approach to Reducing Healthcare Costs With Reflex Testing.

Lab Med. 2017 Sep 23;:

Authors: Prakash S, Hamby T, Leung-Pineda V, Wilson DP

Abstract
Objective: Statistical methods can be utilized to optimize the order for reflex diagnostic testing to attenuate patient and hospital costs without affecting quality of care. Our objective is to demonstrate the method of developing an order for testing and to apply this method to an illustrative example.
Methods: An algorithm was developed for minimizing costs for any given number of diagnostic tests, and it was retrospectively applied to a sample.
Results: The actual scenario of using both tests on all patients was compared to 2 other hypothetical reflex testing approaches: all patients are given 1 test, and those patients who tested negative were then given the second test. The 2 scenarios would have saved 37.1% and 17.4% in testing costs, respectively.
Conclusion: These calculations could be applied to numerous situations to reduce costs for patients and hospitals. We propose that this methodology would be best used in conjunction with any existing quality improvement initiatives.

PMID: 29036315 [PubMed - as supplied by publisher]

Development and Characterization of Methylene Blue Oleate Salt-Loaded Polymeric Nanoparticles and their Potential Application as a Treatment for Glioblastoma.

Recent Research Articles from UNTHSC - Tue, 10/17/2017 - 07:34
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Development and Characterization of Methylene Blue Oleate Salt-Loaded Polymeric Nanoparticles and their Potential Application as a Treatment for Glioblastoma.

J Nanomed Nanotechnol. 2017 Aug;8(4):

Authors: Castañeda-Gill JM, Ranjan AP, Vishwanatha JK

Abstract
Glioblastoma (GBM) is an aggressive, grade IV brain tumor that develops from astrocytes located within the cerebrum, resulting in poor prognosis and survival rates following an accepted treatment regimen of surgery, radiation, and temozolomide. Thus, development of new therapeutics is necessary. During the last two decades, methylene blue (MB) has received increased attention as a potential neurotherapeutic due to its duality in brain cancers and neurodegenerative diseases. While MB is capable of easily permeating the blood-brain barrier, its therapeutic concentrations in GBM are known to induce off-target cytotoxicity and thus, another mode of drug delivery must be considered. To this end, encapsulation of formerly unusable compounds into nanoparticles (NPs) made from the biodegradable/biocompatible, FDA approved co-polymer poly (lactide-co-glycolide) (PLGA) has been more commonplace when developing novel therapeutics. In this study, we formulated and characterized Pluronic F68-coated PLGA NPs containing a sodium oleate conjugate of MB (MBOS) via solvent displacement. Conjugation of sodium oleate to MB was shown to reduce its release from PLGA NPs compared to unmodified MB, leading to potential improvements in drug accumulation and therapeutic effectiveness. Our drug-loaded NP preparations, which were ~170 nm in size and had drug loading values of ~2%, were shown to reduce cell viability and cell compartment-specific, as well as overall cell, functions equivalenty, if not more so, when compared to free drug in two GBM cell lines. Following bio-distribution analysis of free MBOS compared to its nano-encapsulated counterpart, drug-loaded NPs were shown to more effectively permeate the BBB, which could lead to improvements in therapeutic effectiveness upon further examination in a tumor-bearing mouse model. Based on these results, we believe that the further development and eventual utilization of this nanoformulation could lead to an effective GBM therapy that could extend patient survival rates.

PMID: 29034126 [PubMed]

Characteristics of drinking events associated with heavy episodic drinking among adolescents in the United States.

Recent Research Articles from UNTHSC - Tue, 10/17/2017 - 07:34
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Characteristics of drinking events associated with heavy episodic drinking among adolescents in the United States.

Drug Alcohol Depend. 2017 Oct 10;181:50-57

Authors: Rossheim ME, Stephenson CJ, Thombs DL, Livingston MD, Walters ST, Suzuki S, Barry AE, Weiler RM

Abstract
PURPOSE: To examine associations between characteristics of drinking events and the quantity of alcohol consumed by adolescents in the United States.
METHODS: Analyses relied on 2011-2015 data from the National Survey on Drug Use and Health (NSDUH). The study sample included 8110 adolescents, ages 12-17years old, who drank alcohol in the past 30days. A logistic regression model, weighted for national estimation, was constructed to examine factors associated with heavy episodic drinking (HED; 5+ drinks for males, 4+ drinks for females) during the underage drinker's most recent drinking event. These models were adjusted for study year and individual characteristics, including past year drinking frequency, age of drinking onset, and demographic variables.
RESULTS: Buying alcohol off-premise or from another person and being given alcohol from non-parent social sources were associated with greater odds of HED compared to being given alcohol by one of their parents. Drinking alcohol at someone else's house or multiple locations were associated with heavier alcohol consumption compared to drinking at one's own home. Being older and an earlier age of alcohol onset were associated with greater odds of HED.
CONCLUSIONS: This study identifies contextual factors associated with HED by adolescents. Compared to global association studies, the findings from these event-specific analyses provide strong evidence of the environmental conditions that contribute to HED in American adolescents. Although no level of alcohol consumption is safe for adolescents, knowledge of event-level risk factors can inform targeted interventions.

PMID: 29032025 [PubMed - as supplied by publisher]

Constitutive Ret signaling leads to long-lasting expression of amphetamine-induced place conditioning via elevation of mesolimbic dopamine.

Recent Research Articles from UNTHSC - Tue, 10/17/2017 - 07:34
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Constitutive Ret signaling leads to long-lasting expression of amphetamine-induced place conditioning via elevation of mesolimbic dopamine.

Neuropharmacology. 2017 Oct 12;:

Authors: Kopra J, Villarta-Aguilera M, Savolainen M, Weingerl S, Myöhänen TT, Rannanpää S, Salvatore MF, Andressoo JO, Piepponen TP

Abstract
Addictive drugs enhance dopamine release in the striatum, which can lead to compulsive drug-seeking after repeated exposure. Glial cell line-derived neurotrophic factor (GDNF) is an important regulator of midbrain dopamine neurons, and may play a mechanistic role in addiction-related behaviors. To elucidate the components of GDNF-signaling that contribute to addiction-related behaviors of place preference and its extinction, we utilized two genetically modified GDNF mouse models in an amphetamine-induced conditioned place preference (CPP) paradigm and evaluated how the behavioral findings correlate with dopamine signaling in the dorsal and ventral striatum. We utilized two knock-in mouse strains to delineate contributions of GDNF and Ret signaling using MEN2B mice (constitutively active GDNF receptor Ret), and GDNF hypermorphic mice (enhanced endogenous GDNF expression). The duration of amphetamine-induced CPP was greatly enhanced in MEN2B mice, but not in the GDNF hypermorphic mice. The enhanced duration of CPP was correlated with increased tyrosine hydroxylase (TH) expression and dopamine content in the ventral striatum. Together, our results suggest that downstream components of GDNF signaling, in this case Ret, may mediate persistent drug-seeking behavior through increased TH expression and dopamine levels in the mesolimbic dopamine neurons.

PMID: 29031851 [PubMed - as supplied by publisher]

Methylene Blue Ameliorates Ischemia/Reperfusion-Induced Cerebral Edema: An MRI and Transmission Electron Microscope Study.

Recent Research Articles from UNTHSC - Sun, 10/15/2017 - 13:40
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Methylene Blue Ameliorates Ischemia/Reperfusion-Induced Cerebral Edema: An MRI and Transmission Electron Microscope Study.

Acta Neurochir Suppl. 2016;121:227-36

Authors: Fang Q, Yan X, Li S, Sun Y, Xu L, Shi Z, Wu M, Lu Y, Dong L, Liu R, Yuan F, Yang SH

Abstract
The neuroprotective effect of methylene blue (MB) has been identified against various brain disorders, including ischemic stroke. In the present study, we evaluated the effects of MB on postischemic brain edema using magnetic resonance imaging (MRI) and transmission electron microscopy (TEM). Adult male rats were subjected to transient focal cerebral ischemia induced by 1 h middle cerebral artery occlusion (MCAO), followed by reperfusion. MB was infused intravenously immediately after reperfusion (3 mg/kg) and again at 3 h post-occlusion (1.5 mg/kg). Normal saline was administered as vehicle control. Sequential MRIs, including apparent diffusion coefficient (ADC) and T2-weighted imaging (T2WI), were obtained at 0.5, 2.5, and 48 h after the onset of stroke. Separated groups of animals were sacrificed at 2.5 and 48 h after stroke for ultrastructural analysis by TEM. In addition, final lesion volumes were analyzed by triphenyltetrazolium chloride (TTC) staining at 48 h after stroke. Ischemic stroke induced ADC lesion volume at 0.5 h during MCAOs that were temporally recovered at 1.5 h after reperfusion. No significant difference in ADC-defined lesion was observed between vehicle and MB treatment groups. At 48 h after stroke, MB significantly reduced ADC lesion and T2WI lesion volume and attenuated cerebral swelling. Consistently, MB treatment significantly decreased TTC-defined lesion volume at 48 h after stroke. TEM revealed remarkable swollen astrocytes, astrocytic perivascular end-feet, and concurrent shrunken neurons in the penumbra at 2.5 and 48 h after MCAO. MB treatment attenuated astrocyte swelling, the perivascular astrocytic foot process, and endothelium and also alleviated neuron degeneration. This study demonstrated that MB could decrease postischemic brain edema and provided additional evidence that future clinical investigation of MB for the treatment of ischemic stroke is warrented.

PMID: 26463954 [PubMed - indexed for MEDLINE]

Direct costs for nonsurgical management of Chronic Pancreatitis in a tertiary care teaching hospital.

Recent Research Articles from UNTHSC - Fri, 10/13/2017 - 07:34

Direct costs for nonsurgical management of Chronic Pancreatitis in a tertiary care teaching hospital.

Expert Rev Pharmacoecon Outcomes Res. 2017 Oct 12;:1-6

Authors: Kamat N, Pai G, Mallayasamy SR, Kamath A, S R

Abstract
BACKGROUND: Chronic pancreatitis (CP) is a leading cause of hospitalization among gastrointestinal diseases resulting in considerable financial burden to patients. However the direct costs for nonsurgical management in CP remains unexplored.
METHODS: A cross sectional study was carried out (2011-14) in the Department of Gastroenterology, Kasturba Hospital, Manipal, India. Demographic and clinical data on laboratory investigations, interventions and follow up were obtained from the medical records department. Item costs were derived from the hospital electronic billing section. Cost was expressed as median annual cost per patient.
RESULTS: 65 (male 48; 73.8%) patients were included. Their median age was 31 (range 12-68) years. The annual median (IQR) total cost per patient was INR 88,892 (70,550.5-116,004); [USD 1410(1119-1841); € 1155(916-1507)], comprising of INR 61,089 (39,102.5-90,360.5) [USD 970 (621-1434); € 793(508-1174)] for outpatient management and INR 32,450 (11,016-46,958) [USD 515 (175-745); €421(143-610)] for hospitalization. 69.5% of the treatment cost was attributed to outpatient treatment. Drugs contributed to 54%, hospitalization incurred 30.5%, investigations 12% and professional fees (3.5%) of the total cost. Pancreatic enzyme replacement therapy (PERT) cost contributed to three-quarters of drug therapy. Use of rabeprazole as against pantoprazole reduced the overall annual cost of therapy by 4%.
CONCLUSIONS: This study depicts the first nonsurgical management of accrued direct costs associated with CP due to expensive medications. Due to the high cost for PERT, its usefulness needs proper validation by cost benefit analysis.

PMID: 29022830 [PubMed - as supplied by publisher]

Implantable Medical Device Website Efficacy in Informing Consumers Weighing Benefits/Risks of Health Care Options.

Recent Research Articles from UNTHSC - Fri, 10/13/2017 - 07:34
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Implantable Medical Device Website Efficacy in Informing Consumers Weighing Benefits/Risks of Health Care Options.

J Health Commun. 2016;21(sup2):121-126

Authors: Wagner T, Lindstadt C, Jeon Y, Mackert M

Abstract
As more individuals turn to the Internet for health-related information and technology increases the availability and use of implantable medical devices (IMDs), the websites marketing these devices will increase. Healthy People 2020 mandates increased understandability and usability of health-related websites. This project used social cognitive theory (SCT) and health literacy constructs from the Institute of Medicine and National Institutes of Health to analyze eight IMD websites. Despite current recommendations, none of the websites considered for this study offered content of an appropriate reading level in conjunction with the United States average of eighth grade, and 75% of the sites failed to satisfy more than one health literacy construct. Most of the websites lacked many of the SCT constructs. More attention is needed to improve the usability of these and future IMD websites to simultaneously meet the goal of marketing IMDs and the Healthy People 2020 goals to educate patients and promote public health.

PMID: 27662117 [PubMed - indexed for MEDLINE]

Recreational Cannabis Legalization and Opioid-Related Deaths in Colorado, 2000-2015.

Recent Research Articles from UNTHSC - Thu, 10/12/2017 - 07:37

Recreational Cannabis Legalization and Opioid-Related Deaths in Colorado, 2000-2015.

Am J Public Health. 2017 Nov;107(11):1827-1829

Authors: Livingston MD, Barnett TE, Delcher C, Wagenaar AC

Abstract
OBJECTIVES: To examine the association between Colorado's legalization of recreational cannabis use and opioid-related deaths.
METHODS: We used an interrupted time-series design (2000-2015) to compare changes in level and slope of monthly opioid-related deaths before and after Colorado stores began selling recreational cannabis. We also describe the percent change in opioid-related deaths by comparing the unadjusted model-smoothed number of deaths at the end of follow-up with the number of deaths just prior to legalization.
RESULTS: Colorado's legalization of recreational cannabis sales and use resulted in a 0.7 deaths per month (b = -0.68; 95% confidence interval = -1.34, -0.03) reduction in opioid-related deaths. This reduction represents a reversal of the upward trend in opioid-related deaths in Colorado.
CONCLUSIONS: Legalization of cannabis in Colorado was associated with short-term reductions in opioid-related deaths. As additional data become available, research should replicate these analyses in other states with legal recreational cannabis.

PMID: 29019782 [PubMed - in process]

Administration of 5-methoxyindole-2-carboxylic acid that potentially targets mitochondrial dihydrolipoamide dehydrogenase confers cerebral preconditioning against ischemic stroke injury.

Recent Research Articles from UNTHSC - Thu, 10/12/2017 - 07:37

Administration of 5-methoxyindole-2-carboxylic acid that potentially targets mitochondrial dihydrolipoamide dehydrogenase confers cerebral preconditioning against ischemic stroke injury.

Free Radic Biol Med. 2017 Oct 07;:

Authors: Wu J, Li R, Li W, Ren M, Thangthaeng N, Sumien N, Liu R, Yang S, Simpkins JW, Forster MJ, Yan LJ

Abstract
The objective of this study was to investigate a possible role of mitochondrial dihydrolipoamide dehydrogenase (DLDH) as a chemical preconditioning target for neuroprotection against ischemic injury. We used 5-methoxyindole-2-carboxylic acid (MICA), a reportedly reversible DLDH inhibitor, as the preconditioning agent and administered MICA to rats mainly via dietary intake. Upon completion of 4 week's MICA treatment, rats underwent 1h transient ischemia and 24h reperfusion followed by tissue collection. Our results show that MICA protected the brain against ischemic stroke injury as the infarction volume of the brain from the MICA-treated group was significantly smaller than that from the control group. Data were then collected without or with stroke surgery following MICA feeding. It was found that in the absence of stroke following MICA feeding, DLDH activity was lower in the MICA treated group than in the control group, and this decreased activity could be partly due to DLDH protein sulfenation. Moreover, DLDH inhibition by MICA was also found to upregulate the expression of NAD(P)H-ubiquinone oxidoreductase 1(NQO1) via the Nrf2 signaling pathway. In the presence of stroke following MICA feeding, decreased DLDH activity and increased Nrf2 signaling were also observed along with increased NQO1 activity, decreased oxidative stress, decreased cell death, and increased mitochondrial ATP output. We also found that MICA had a delayed preconditioning effect four weeks post MICA treatment. Our study indicates that administration of MICA confers chemical preconditioning and neuroprotection against ischemic stroke injury.

PMID: 29017857 [PubMed - as supplied by publisher]

Fast STR allele identification with STRait Razor 3.0.

Recent Research Articles from UNTHSC - Thu, 10/12/2017 - 07:37
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Fast STR allele identification with STRait Razor 3.0.

Forensic Sci Int Genet. 2017 Sep;30:18-23

Authors: Woerner AE, King JL, Budowle B

Abstract
The short tandem repeat allele identification tool (STRait Razor), a program used to characterize the haplotypes of short tandem repeats (STRs) in massively parallel sequencing (MPS) data, was redesigned. STRait Razor v3.0 performs ∼660× faster allele identification than its previous version (v2s), a speedup that is largely due to a novel indexing strategy used to perform "fuzzy" (approximate) string matching of anchor sequences. Written in a portable compiled language, C++, STRait Razor v3.0 functions on all major operating systems including Microsoft Windows, and it has cross-platform multithreading support. In silico estimates of precision and accuracy of STRait Razor v3.0 were 100% in this evaluation and results were highly concordant with those of Strait Razor v2s. STRait Razor v3.0 adds several key features that simplify the haplotype reporting process, including simple filters to remove low frequency haplotypes as well as merging haplotypes within a locus encoded on opposite strands of the DNA molecule.

PMID: 28605651 [PubMed - indexed for MEDLINE]

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

Recent Research Articles from UNTHSC - Wed, 10/11/2017 - 07:42

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

Neurotox Res. 2017 Oct 09;:

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 - as supplied by publisher]

Can Ceftazidime-Avibactam and Aztreonam Overcome β-Lactam Resistance Conferred by Metallo-β-Lactamases in Enterobacteriaceae?

Recent Research Articles from UNTHSC - Wed, 10/11/2017 - 07:42
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Can Ceftazidime-Avibactam and Aztreonam Overcome β-Lactam Resistance Conferred by Metallo-β-Lactamases in Enterobacteriaceae?

Antimicrob Agents Chemother. 2017 Apr;61(4):

Authors: Marshall S, Hujer AM, Rojas LJ, Papp-Wallace KM, Humphries RM, Spellberg B, Hujer KM, Marshall EK, Rudin SD, Perez F, Wilson BM, Wasserman RB, Chikowski L, Paterson DL, Vila AJ, van Duin D, Kreiswirth BN, Chambers HF, Fowler VG, Jacobs MR, Pulse ME, Weiss WJ, Bonomo RA

Abstract
Based upon knowledge of the hydrolytic profile of major β-lactamases found in Gram-negative bacteria, we tested the efficacy of the combination of ceftazidime-avibactam (CAZ-AVI) with aztreonam (ATM) against carbapenem-resistant enteric bacteria possessing metallo-β-lactamases (MBLs). Disk diffusion and agar-based antimicrobial susceptibility testing were initially performed to determine the in vitro efficacy of a unique combination of CAZ-AVI and ATM against 21 representative Enterobacteriaceae isolates with a complex molecular background that included blaIMP, blaNDM, blaOXA-48, blaCTX-M, blaAmpC, and combinations thereof. Time-kill assays were conducted, and the in vivo efficacy of this combination was assessed in a murine neutropenic thigh infection model. By disk diffusion assay, all 21 isolates were resistant to CAZ-AVI alone, and 19/21 were resistant to ATM. The in vitro activity of CAZ-AVI in combination with ATM against diverse Enterobacteriaceae possessing MBLs was demonstrated in 17/21 isolates, where the zone of inhibition was ≥21 mm. All isolates demonstrated a reduction in CAZ-AVI agar dilution MICs with the addition of ATM. At 2 h, time-kill assays demonstrated a ≥4-log10-CFU decrease for all groups that had CAZ-AVI with ATM (8 μg/ml) added, compared to the group treated with CAZ-AVI alone. In the murine neutropenic thigh infection model, an almost 4-log10-CFU reduction was noted at 24 h for CAZ-AVI (32 mg/kg every 8 h [q8h]) plus ATM (32 mg/kg q8h) versus CAZ-AVI (32 mg/kg q8h) alone. The data presented herein require us to carefully consider this new therapeutic combination to treat infections caused by MBL-producing Enterobacteriaceae.

PMID: 28167541 [PubMed - indexed for MEDLINE]

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

Recent Research Articles from UNTHSC - Wed, 10/11/2017 - 07:42
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Biomechanical behavior of novel composite PMMA-CaP bone cements in an anatomically accurate cadaveric vertebroplasty model.

J Orthop Res. 2017 Sep;35(9):2067-2074

Authors: Aghyarian S, Hu X, Haddas R, Lieberman IH, Kosmopoulos V, Kim HKW, 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 two 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 three 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. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2067-2074, 2017.

PMID: 27891670 [PubMed - indexed for MEDLINE]

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

Recent Research Articles from UNTHSC - Wed, 10/11/2017 - 07:42
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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. 2017 Jan;13(1):45-58

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 - indexed for MEDLINE]

HIV-1 Tat-shortened neurite outgrowth through regulation of microRNA-132 and its target gene expression.

Recent Research Articles from UNTHSC - Wed, 10/11/2017 - 07:42
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HIV-1 Tat-shortened neurite outgrowth through regulation of microRNA-132 and its target gene expression.

J Neuroinflammation. 2016 Sep 15;13(1):247

Authors: Rahimian P, He JJ

Abstract
BACKGROUND: Synaptodendritic damage is a pathological hallmark of HIV-associated neurocognitive disorders, and HIV-1 Tat protein is known to cause such injury in the central nervous system. In this study, we aimed to determine the molecular mechanisms of Tat-induced neurite shortening, specifically the roles of miR-132, an important regulator of neurite morphogenesis in this process.
METHODS: The relationship between Tat expression and miR-132 expression was first determined using reverse transcription quantitative PCR (qRT-PCR) in Tat-transfected astrocytes and neurons, astrocytes from Tat-transgenic mice, and HIV-infected astrocytes. qRT-PCR and Western blotting were performed to determine Tat effects on expression of miR-132 target genes methyl CpG-binding protein 2, Rho GTPase activator p250GAP, and brain-derived neurotrophic factor. Exosomes were isolated from Tat-expressing astrocytes, and exosomal microRNA (miRNA) uptake into neurons was studied using miRNA labeling and flow cytometry. The lactate dehydrogenase release was used to determine the cytotoxicity, while immunostaining was used to determine neurite lengths and synapse formation. Tat basic domain deletion mutant and miR-132 mimic and inhibitor were used to determine the specificity of the relationship between Tat and miR-132 and its effects on astrocytes and neurons and the underlying mechanisms of Tat-induced miR-132 expression.
RESULTS: Tat significantly induced miR-132 expression, ensuing down-regulation of miR-132 target genes in astrocytes and neurons. miR-132 induction was associated with phosphorylation of cAMP response element-binding protein and required the basic domain of Tat. miRNA-132 induction had no effects on astrocyte activation or survival but was involved in the direct neurotoxicity of Tat. miR-132 was present in astrocyte-derived exosomes and was taken up by neurons, causing neurite shortening.
CONCLUSIONS: Tat-induced miR-132 expression contributes to both direct and astrocyte-mediated Tat neurotoxicity and supports the important roles of miR-132 in controlling neurite outgrowth.

PMID: 27634380 [PubMed - indexed for MEDLINE]

CRISPR-Cas9-based treatment of myocilin-associated glaucoma.

Recent Research Articles from UNTHSC - Thu, 10/05/2017 - 07:39

CRISPR-Cas9-based treatment of myocilin-associated glaucoma.

Proc Natl Acad Sci U S A. 2017 Oct 02;:

Authors: Jain A, Zode G, Kasetti RB, Ran FA, Yan W, Sharma TP, Bugge K, Searby CC, Fingert JH, Zhang F, Clark AF, Sheffield VC

Abstract
Primary open-angle glaucoma (POAG) is a leading cause of irreversible vision loss worldwide, with elevated intraocular pressure (IOP) a major risk factor. Myocilin (MYOC) dominant gain-of-function mutations have been reported in ∼4% of POAG cases. MYOC mutations result in protein misfolding, leading to endoplasmic reticulum (ER) stress in the trabecular meshwork (TM), the tissue that regulates IOP. We use CRISPR-Cas9-mediated genome editing in cultured human TM cells and in a MYOC mouse model of POAG to knock down expression of mutant MYOC, resulting in relief of ER stress. In vivo genome editing results in lower IOP and prevents further glaucomatous damage. Importantly, using an ex vivo human organ culture system, we demonstrate the feasibility of human genome editing in the eye for this important disease.

PMID: 28973933 [PubMed - as supplied by publisher]

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