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Locomotor and discriminative stimulus effects of four novel hallucinogens in rodents.

Recent Research Articles from UNTHSC - Fri, 05/26/2017 - 07:35
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Locomotor and discriminative stimulus effects of four novel hallucinogens in rodents.

Behav Pharmacol. 2017 May 19;:

Authors: Gatch MB, Dolan SB, Forster MJ

Abstract
There has been increasing use of novel synthetic hallucinogenic compounds, 2-(4-bromo-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine hydrochloride (25B-NBOMe), 2-(4-chloro-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine hydrochloride (25C-NBOMe), 2-(4-iodo-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine hydrochloride (25I-NBOMe), and N,N-diallyl-5-methoxy tryptamine (5-MeO-DALT), which have been associated with severe toxicities. These four compounds were tested for discriminative stimulus effects similar to a prototypical hallucinogen (-)-2,5-dimethoxy-4-methylamphetamine (DOM) and the entactogen (±)-3,4-methylenedioxymethamphetamine (MDMA). Locomotor activity in mice was tested to obtain dose range and time-course information. 25B-NBOMe, 25C-NBOMe, and 25I-NBOMe decreased locomotor activity. 5-MeO-DALT dose dependently increased locomotor activity, with a peak at 10 mg/kg. A higher dose (25 mg/kg) suppressed activity. 25B-NBOMe fully substituted (≥80%) in both DOM-trained and MDMA-trained rats at 0.5 mg/kg. However, higher doses produced much lower levels of drug-appropriate responding in both DOM-trained and MDMA-trained rats. 25C-NBOMe fully substituted in DOM-trained rats, but produced only 67% drug-appropriate responding in MDMA-trained rats at doses that suppressed responding. 25I-NBOMe produced 74-78% drug-appropriate responding in DOM-trained and MDMA-trained rats at doses that suppressed responding. 5-MeO-DALT fully substituted for DOM, but produced few or no MDMA-like effects. All of the compounds, except 25I-NBOMe, fully substituted for DOM, whereas only 25B-NBOMe fully substituted for MDMA. However, the failure of 25I-NBOMe to fully substitute for either MDMA or DOM was more likely because of its substantial rate-depressant effects than weak discriminative stimulus effects. All of the compounds are likely to attract recreational users for their hallucinogenic properties, but probably of much less interest as substitutes for MDMA. Although no acute adverse effects were observed at the doses tested, the substantial toxicities reported in humans, coupled with the high likelihood for illicit use, suggests that these compounds have the same potential for abuse as other, currently scheduled compounds.

PMID: 28537942 [PubMed - as supplied by publisher]

Statin-associated muscle symptoms and SLCO1B1 rs4149056 genotype in patients with familial hypercholesterolemia.

Recent Research Articles from UNTHSC - Fri, 05/26/2017 - 07:35
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Statin-associated muscle symptoms and SLCO1B1 rs4149056 genotype in patients with familial hypercholesterolemia.

Am Heart J. 2016 Sep;179:1-9

Authors: Khine H, Yuet WC, Adams-Huet B, Ahmad Z

Abstract
UNLABELLED: Patients with familial hypercholesterolemia (FH) may be at increased risk for statin-associated muscle symptoms because they require long-term treatment with high-intensity statin therapy. We sought to determine (1) whether other predisposing factors, including the well-known genetic variant associated with statin-associated muscle symptoms-solute carrier organic anion transporter family, member 1B1 (SLCO1B1) rs4149056-also increase the risk of statin-associated muscle symptoms in FH patients, and (2) the natural history and management for FH patients with statin-associated muscle symptoms.
METHODS: We queried electronic records (2004-2014) of 278 genetically screened FH patients (113 men, 165 women; mean [SD] pretreatment low-density lipoprotein cholesterol [LDL-C] 259 [72] mg/dL) recruited from lipid clinics in the Dallas, TX, area from 2004 to 2014. Statin-associated muscle symptoms were defined as muscle symptoms arising while taking a statin and interrupting therapy.
RESULTS: The risk of muscle symptoms was associated with age (odds ratio 1.6 [95% CI 1.2-2.2]), body mass index in non-African Americans (0.90 [0.83-0.97]), and hypertension (0.4 [0.2-0.9]). Simvastatin was the most commonly used statin, and it was the statin most associated with muscle symptoms. Among FH patients with muscle symptoms, 41% (n = 40) reestablished statin therapy ("eventually tolerant") and 29% (n = 28) never reestablished statin therapy ("never tolerant"). Rosuvastatin (43%) and pravastatin (30%) were the most common eventually tolerated statins, and eventually tolerant patients achieved lower treated LDL-C levels (eventually tolerant 127 vs never tolerant 192 mg/dL, P < .001). Never tolerant patients also developed muscle symptoms on nonstatins (16% vs 50%, P = .003). SLCO1B1 rs4149056 genotyping revealed 224 wild-type patients (TT) and 49 heterozygotes (TC). SLCO1B1 genotype was not associated with the risk of statin-associated muscle symptoms (odds ratio 1.40 [95% CI 0.74-2.64]).
CONCLUSION: Age, not SLCO1B1 rs4149056 genotype, was the strongest risk factor for statin-associated muscle symptoms in FH patients. After developing muscle symptoms, many patients reestablished statin therapy and achieved significant LDL-C reductions. Overall, 10% of all FH patients had statin-associated muscle symptoms and never reestablished statin therapy. Such patients developed muscle symptoms even on nonstatin lipid-lowering drugs and continued to have elevations in LDL-C. Further insight is needed into the relationship between FH and statin-associated muscle symptoms so all FH patients can be adequately treated.

PMID: 27595674 [PubMed - indexed for MEDLINE]

Identification and localization of lamina cribrosa cells in the human optic nerve head.

Recent Research Articles from UNTHSC - Fri, 05/26/2017 - 07:35
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Identification and localization of lamina cribrosa cells in the human optic nerve head.

Exp Eye Res. 2016 Jun;147:94-7

Authors: Tovar-Vidales T, Wordinger RJ, Clark AF

Abstract
One of the central features of glaucoma is progressive cupping and excavation of the optic nerve head (ONH). Unmyelinated retinal ganglion cell (RGC) axons exit the eye through the ONH, which is supported by the lamina cribrosa (LC) consisting of plates of connective tissue with channels for bundles of RGC axons. The LC progressively remodels during glaucoma, but the cellular and molecular mechanisms responsible for this remodeling are poorly understood. Two major cell types have been isolated and cultured from the human ONH, which differ in their characteristics. Glial fibrillary acidic protein (GFAP) positive ONH astrocytes are the major cell type and are reactive in glaucoma. GFAP negative LC cells are the second major cell type isolated from the human ONH, and in contrast to ONH astrocytes, are α-smooth muscle actin (α-SMA) positive. Although a number of in vitro studies have been conducted with LC cells, to date there has been no direct evidence for these cells in situ in the human ONH. We used GFAP and α-SMA immunofluorescent staining of human eyes to clearly demonstrate the presence of not only ONH astrocytes within the human ONH, but also LC cells within the cribriform (e.g. laminar) plates/beams of the LC region. Both of these cell types likely play important roles in the homeostatic maintenance of the ONH and pathogenic changes that occur in primary open angle glaucoma (POAG).

PMID: 27167365 [PubMed - indexed for MEDLINE]

Human trabecular meshwork cells express BMP antagonist mRNAs and proteins.

Recent Research Articles from UNTHSC - Fri, 05/26/2017 - 07:35
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Human trabecular meshwork cells express BMP antagonist mRNAs and proteins.

Exp Eye Res. 2016 Jun;147:156-60

Authors: Tovar-Vidales T, Fitzgerald AM, Clark AF

Abstract
Glaucoma patients have elevated aqueous humor and trabecular meshwork (TM) levels of transforming growth factor-beta2 (TGF-β2). TGF-β2 has been associated with increased extracellular matrix (ECM) deposition (i.e. fibronectin), which is attributed to the increased resistance of aqueous humor outflow through the TM. We have previously demonstrated that bone morphogenetic protein (BMP) 4 selectively counteracts the profibrotic effect of TGF-β2 with respect to ECM synthesis in the TM, and this action is reversed by the BMP antagonist gremlin. Thus, the BMP and TGF-β signaling pathways antagonize each other's antifibrotic and profibrotic roles. The purpose of this study was to determine whether cultured human TM cells: (a) express other BMP antagonists including noggin, chordin, BMPER, BAMBI, Smurf1 and 2, and (b) whether expression of these proteins is regulated by exogenous TGF-β2 treatment. Primary human trabecular meshwork (TM) cells were grown to confluency and treated with TGF-β2 (5 ng/ml) for 24 or 48 h in serum-free medium. Untreated cell served as controls. qPCR and Western immunoblots (WB) determined that human TM cells expressed mRNAs and proteins for the BMP antagonist proteins: noggin, chordin, BMPER, BAMBI, and Smurf1/2. Exogenous TGF-β2 decreased chordin, BMPER, BAMBI, and Smurf1 mRNA and protein expression. In contrast, TGF-β2 increased secreted noggin and Smurf2 mRNA and protein levels. BMP antagonist members are expressed in the human TM. These molecules may be involved in the normal function of the TM as well as TM pathogenesis. Altered expression of BMP antagonist members may lead to functional changes in the human TM.

PMID: 27167364 [PubMed - indexed for MEDLINE]

Changes in inflammatory biomarkers following spinal manipulation.

Recent Research Articles from UNTHSC - Wed, 05/24/2017 - 07:35
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Changes in inflammatory biomarkers following spinal manipulation.

Musculoskelet Sci Pract. 2017 May 17;:

Authors: Licciardone JC

PMID: 28533071 [PubMed - as supplied by publisher]

HIV-1 Tat Induces Unfolded Protein Response and Endoplasmic Reticulum Stress in Astrocytes and Causes Neurotoxicity through Glial Fibrillary Acidic Protein (GFAP) Activation and Aggregation.

Recent Research Articles from UNTHSC - Tue, 05/23/2017 - 07:34
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HIV-1 Tat Induces Unfolded Protein Response and Endoplasmic Reticulum Stress in Astrocytes and Causes Neurotoxicity through Glial Fibrillary Acidic Protein (GFAP) Activation and Aggregation.

J Biol Chem. 2016 Oct 21;291(43):22819-22829

Authors: Fan Y, He JJ

Abstract
HIV-1 Tat is a major culprit for HIV/neuroAIDS. One of the consistent hallmarks of HIV/neuroAIDS is reactive astrocytes or astrocytosis, characterized by increased cytoplasmic accumulation of the intermediate filament glial fibrillary acidic protein (GFAP). We have shown that that Tat induces GFAP expression in astrocytes and that GFAP activation is indispensable for astrocyte-mediated Tat neurotoxicity. However, the underlying molecular mechanisms are not known. In this study, we showed that Tat expression or GFAP expression led to formation of GFAP aggregates and induction of unfolded protein response (UPR) and endoplasmic reticulum (ER) stress in astrocytes. In addition, we demonstrated that GFAP up-regulation and aggregation in astrocytes were necessary but also sufficient for UPR/ER stress induction in Tat-expressing astrocytes and for astrocyte-mediated Tat neurotoxicity. Importantly, we demonstrated that inhibition of Tat- or GFAP-induced UPR/ER stress by the chemical chaperone 4-phenylbutyrate significantly alleviated astrocyte-mediated Tat neurotoxicity in vitro and in the brain of Tat-expressing mice. Taken together, these results show that HIV-1 Tat expression leads to UPR/ER stress in astrocytes, which in turn contributes to astrocyte-mediated Tat neurotoxicity, and raise the possibility of developing HIV/neuroAIDS therapeutics targeted at UPR/ER stress.

PMID: 27609520 [PubMed - indexed for MEDLINE]

HIV-1 Tat Promotes Lysosomal Exocytosis in Astrocytes and Contributes to Astrocyte-mediated Tat Neurotoxicity.

Recent Research Articles from UNTHSC - Tue, 05/23/2017 - 07:34
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HIV-1 Tat Promotes Lysosomal Exocytosis in Astrocytes and Contributes to Astrocyte-mediated Tat Neurotoxicity.

J Biol Chem. 2016 Oct 21;291(43):22830-22840

Authors: Fan Y, He JJ

Abstract
Tat interaction with astrocytes has been shown to be important for Tat neurotoxicity and HIV/neuroAIDS. We have recently shown that Tat expression leads to increased glial fibrillary acidic protein (GFAP) expression and aggregation and activation of unfolded protein response/endoplasmic reticulum (ER) stress in astrocytes and causes neurotoxicity. However, the exact molecular mechanism of astrocyte-mediated Tat neurotoxicity is not defined. In this study, we showed that neurotoxic factors other than Tat protein itself were present in the supernatant of Tat-expressing astrocytes. Two-dimensional gel electrophoresis and mass spectrometry revealed significantly elevated lysosomal hydrolytic enzymes and plasma membrane-associated proteins in the supernatant of Tat-expressing astrocytes. We confirmed that Tat expression and infection of pseudotyped HIV.GFP led to increased lysosomal exocytosis from mouse astrocytes and human astrocytes. We found that Tat-induced lysosomal exocytosis was tightly coupled to astrocyte-mediated Tat neurotoxicity. In addition, we demonstrated that Tat-induced lysosomal exocytosis was astrocyte-specific and required GFAP expression and was mediated by ER stress. Taken together, these results show for the first time that Tat promotes lysosomal exocytosis in astrocytes and causes neurotoxicity through GFAP activation and ER stress induction in astrocytes and suggest a common cascade through which aberrant astrocytosis/GFAP up-regulation potentiates neurotoxicity and contributes to neurodegenerative diseases.

PMID: 27609518 [PubMed - indexed for MEDLINE]

Current Alcohol Use is Associated with Sleep Patterns in First-Year College Students.

Recent Research Articles from UNTHSC - Tue, 05/23/2017 - 07:34
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Current Alcohol Use is Associated with Sleep Patterns in First-Year College Students.

Sleep. 2016 06 01;39(6):1321-6

Authors: Van Reen E, Roane BM, Barker DH, McGeary JE, Borsari B, Carskadon MA

Abstract
STUDY OBJECTIVES: To examine whether differences exist in self-reported sleep patterns and self-reported alcohol use for first-semester college students who do or do not report drinking during the last 6 months (mo) of high school.
METHODS: Participants were 878 first-year college students. Students completed a survey in late May/early June about alcohol use and consequences, during the last 6 mo of high school; they later completed a daily record of sleep behavior and alcohol use across the first 9 weeks of the first semester of college. High school drinking status (past 6 mo) was classified as positive (HS-6 mo+) or negative (HS-6mo-) based on any indication of drinking on the May/June survey. Collegiate drinking was determined from first-semester daily diary alcohol reports as non-drinkers (0 reported drinks), drinkers (one or fewer heavy episodic drinking episodes (HED)), and drinkers reporting more than one HED episode. Sleep patterns were compared for non-drinkers, drinkers, and HED with no high school drinking history (HS-6mo-/HED). In addition, a separate analysis compared sleep patterns for college HED with (HS-6mo+/HED) and without (HS-6mo-/HED) high school self-reported alcohol use.
RESULTS: Increased alcohol consumption in the first semester of college was associated with later bedtimes and rise times. We found no association of high school alcohol use and sleep in those with collegiate HED.
CONCLUSIONS: Later sleep timing in those with greater alcohol use, supports a connection between sleep patterns and alcohol use. Such an early appearance of this connection may herald the development of alcohol use disorder in some individuals.

PMID: 27070138 [PubMed - indexed for MEDLINE]

Breaking Up Sedentary Behavior: Perceptions From Cancer Survivors.

Recent Research Articles from UNTHSC - Tue, 05/23/2017 - 07:34
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Breaking Up Sedentary Behavior: Perceptions From Cancer Survivors.

Cancer Nurs. 2016 Jul-Aug;39(4):272-8

Authors: Paxton RJ, Anderson A, Sarkar S, Taylor WC

Abstract
BACKGROUND: Limited data exist on the benefits of, barriers to, and potential strategies to break up time spent sitting in cancer survivors. Such data will be meaningful given the consequences of prolonged sitting.
OBJECTIVES: The aim of this study was to conduct a mixed-method research study consisting of semistructured telephone interviews to identify recurrent themes associated with prolonged sitting in cancer survivors.
METHODS: African American breast cancer survivors (N = 31) were recruited from a local tumor registry. Telephone interviews were conducted and group consensus processes were used to identify recurrent themes. The a priori categories were benefits, barriers, and potential strategies to breaking up prolonged periods of sitting.
RESULTS: Recurrent themes contributing most to prolonged sitting were leisure time interest (45%: eg, watching television and reading) and health challenges (27%: eg, pain and fatigue). Most (66%) women perceived improved health as benefits to breaking up time spent sitting. Nonetheless, many (41%) survivors reported health (eg, pain and fatigue) as the biggest challenge to interrupt time spent sitting. Engaging in light intensity activities (eg, staying active, keep moving) was the most commonly reported strategy for breaking up prolonged sitting.
CONCLUSIONS: African American breast cancer survivors identified the benefits and barriers to breaking up time spent sitting as well as potential strategies to interrupt time-spent sitting.
IMPLICATIONS FOR PRACTICE: Clinicians are integral in promoting breaks from prolonged sitting throughout the initial phases of the cancer continuum. Successful studies will begin with early intervention in the clinical setting, with increasing intensity as survivors transition to the recovery phase.

PMID: 26713501 [PubMed - indexed for MEDLINE]

Genetically engineered probiotic for the treatment of phenylketonuria (PKU); assessment of a novel treatment in vitro and in the PAHenu2 mouse model of PKU.

Recent Research Articles from UNTHSC - Fri, 05/19/2017 - 07:39

Genetically engineered probiotic for the treatment of phenylketonuria (PKU); assessment of a novel treatment in vitro and in the PAHenu2 mouse model of PKU.

PLoS One. 2017;12(5):e0176286

Authors: Durrer KE, Allen MS, Hunt von Herbing I

Abstract
Phenylketonuria (PKU) is a genetic disease characterized by the inability to convert dietary phenylalanine to tyrosine by phenylalanine hydroxylase. Given the importance of gut microbes in digestion, a genetically engineered microbe could potentially degrade some ingested phenylalanine from the diet prior to absorption. To test this, a phenylalanine lyase gene from Anabaena variabilis (AvPAL) was codon-optimized and cloned into a shuttle vector for expression in Lactobacillus reuteri 100-23C (pHENOMMenal). Functional expression of AvPAL was determined in vitro, and subsequently tested in vivo in homozygous PAHenu2 (PKU model) mice. Initial trials of two PAHenu2 homozygous (PKU) mice defined conditions for freeze-drying and delivery of bacteria. Animals showed reduced blood phe within three to four days of treatment with pHENOMMenal probiotic, and blood phe concentrations remained significantly reduced (P < 0.0005) compared to untreated controls during the course of experiments. Although pHENOMMenal probiotic could be cultured from fecal samples at four months post treatment, it could no longer be cultivated from feces at eight months post treatment, indicating eventual loss of the microbe from the gut. Preliminary screens during experimentation found no immune response to AvPAL. Collectively these studies provide data for the use of a genetically engineered probiotic as a potential treatment for PKU.

PMID: 28520731 [PubMed - in process]

Extracellular Superoxide Dismutase Enhances Recruitment of Immature Neutrophils to the Liver.

Recent Research Articles from UNTHSC - Fri, 05/19/2017 - 07:39
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Extracellular Superoxide Dismutase Enhances Recruitment of Immature Neutrophils to the Liver.

Infect Immun. 2016 Dec;84(12):3302-3312

Authors: Break TJ, Witter AR, Indramohan M, Mummert ME, Dory L, Berg RE

Abstract
Listeria monocytogenes is a Gram-positive intracellular pathogen that causes spontaneous abortion in pregnant women, as well as septicemia, meningitis, and gastroenteritis, primarily in immunocompromised individuals. Although L. monocytogenes can usually be effectively treated with antibiotics, there is still around a 25% mortality rate with individuals who develop clinical listeriosis. Neutrophils are innate immune cells required for the clearance of pathogenic organisms, including L. monocytogenes The diverse roles of neutrophils during both infectious and noninfectious inflammation have recently gained much attention. However, the impact of reactive oxygen species, and the enzymes that control their production, on neutrophil recruitment and function is not well understood. Using congenic mice with varying levels of extracellular superoxide dismutase (ecSOD) activity, we have recently shown that the presence of ecSOD decreases clearance of L. monocytogenes while increasing the recruitment of neutrophils that are not protective in the liver. The data presented here show that ecSOD activity does not lead to a cell-intrinsic increase in neutrophil-homing potential or a decrease in protection against L. monocytogenes Instead, ecSOD activity enhances the production of neutrophil-attracting factors and protects hyaluronic acid (HA) from damage. Furthermore, neutrophils from the livers of ecSOD-expressing mice have decreased intracellular and surface-bound myeloperoxidase, are less capable of killing phagocytosed L. monocytogenes, and have decreased oxidative burst. Collectively, our data reveal that ecSOD activity modulates neutrophil recruitment and function in a cell-extrinsic fashion, highlighting the importance of the enzyme in protecting tissues from oxidative damage.

PMID: 27600509 [PubMed - indexed for MEDLINE]

Therapeutic drug monitoring of posaconazole oral suspension in paediatric patients younger than 13 years of age: a retrospective analysis and literature review.

Recent Research Articles from UNTHSC - Thu, 05/18/2017 - 07:40
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Therapeutic drug monitoring of posaconazole oral suspension in paediatric patients younger than 13 years of age: a retrospective analysis and literature review.

J Clin Pharm Ther. 2017 Feb;42(1):75-79

Authors: Jancel T, Shaw PA, Hallahan CW, Kim T, Freeman AF, Holland SM, Penzak SR

Abstract
WHAT IS KNOWN AND OBJECTIVE: Posaconazole is an extended-spectrum triazole antifungal with activity against a variety of clinically significant yeasts and moulds. Posaconazole is not currently approved by the U.S. Food and Drug Administration for use in children younger than 13 years of age. Our primary objective was to describe the dosing and observed trough concentrations with posaconazole oral suspension in paediatric patients at the National Institutes of Health Clinical Center (Bethesda, MD).
METHODS: This retrospective single-centre study reviewed paediatric patients younger than 13 years of age initiated on posaconazole oral suspension. Patients were included if they were initiated on posaconazole for prophylaxis or treatment for fungal infections from September 2006 through March 2013 with at least one trough concentration collected after at least 7 days of therapy.
RESULTS AND DISCUSSION: A total of 20 male patients were included, of whom 15 (75%) had chronic granulomatous disease. The median age of patients was 6·5 years (range: 2·8-10·7). A total of 79 posaconazole trough concentrations were measured in patients receiving posaconazole as prophylaxis (n = 8) or treatment (n = 12). Posaconazole dose referenced to total body weight ranged from 10·0 to 49·2 mg/kg/day. Posaconazole trough concentrations ranged from undetectable (<50 ng/mL) up to 3620 ng/mL and were ≥500, ≥700 and ≥1250 ng/mL in 95%, 60% and 25% of patients, respectively.
WHAT IS NEW AND CONCLUSIONS: Patients younger than 13 years of age had highly variable trough concentrations, and recommendations for the appropriate dosing of posaconazole oral suspension remain challenging. Until studies are conducted to determine the appropriate dosing of posaconazole in this patient population, therapeutic drug monitoring should be considered to ensure adequate posaconazole exposure.

PMID: 27982447 [PubMed - indexed for MEDLINE]

Reiteration of the Statistical Basis of DNA Source Attribution Determinations in View of the Attorney General's Directive on "Reasonable Scientific Certainty" Statements.

Recent Research Articles from UNTHSC - Wed, 05/17/2017 - 10:01
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Reiteration of the Statistical Basis of DNA Source Attribution Determinations in View of the Attorney General's Directive on "Reasonable Scientific Certainty" Statements.

J Forensic Sci. 2017 May 16;:

Authors: Moretti TR, Budowle B

PMID: 28508395 [PubMed - as supplied by publisher]

Evolving Relevance of Neuroproteomics in Alzheimer's Disease.

Recent Research Articles from UNTHSC - Wed, 05/17/2017 - 10:01
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Evolving Relevance of Neuroproteomics in Alzheimer's Disease.

Methods Mol Biol. 2017;1598:101-115

Authors: Lista S, Zetterberg H, O'Bryant SE, Blennow K, Hampel H

Abstract
Substantial progress in the understanding of the biology of Alzheimer's disease (AD) has been achieved over the past decades. The early detection and diagnosis of AD and other age-related neurodegenerative diseases, however, remain a challenging scientific frontier. Therefore, the comprehensive discovery (relating to all individual, converging or diverging biochemical disease mechanisms), development, validation, and qualification of standardized biological markers with diagnostic and prognostic functions with a precise performance profile regarding specificity, sensitivity, and positive and negative predictive value are warranted.Methodological innovations in the area of exploratory high-throughput technologies, such as sequencing, microarrays, and mass spectrometry-based analyses of proteins/peptides, have led to the generation of large global molecular datasets from a multiplicity of biological systems, such as biological fluids, cells, tissues, and organs. Such methodological progress has shifted the attention to the execution of hypothesis-independent comprehensive exploratory analyses (opposed to the classical hypothesis-driven candidate approach), with the aim of fully understanding the biological systems in physiology and disease as a whole. The systems biology paradigm integrates experimental biology with accurate and rigorous computational modelling to describe and foresee the dynamic features of biological systems. The use of dynamically evolving technological platforms, including mass spectrometry, in the area of proteomics has enabled to rush the process of biomarker discovery and validation for refining significantly the diagnosis of AD. Currently, proteomics-which is part of the systems biology paradigm-is designated as one of the dominant matured sciences needed for the effective exploratory discovery of prospective biomarker candidates expected to play an effective role in aiding the early detection, diagnosis, prognosis, and therapy development in AD.

PMID: 28508359 [PubMed - in process]

Altered levels of blood proteins in Alzheimer's disease longitudinal study: Results from Australian Imaging Biomarkers Lifestyle Study of Ageing cohort.

Recent Research Articles from UNTHSC - Wed, 05/17/2017 - 10:01
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Altered levels of blood proteins in Alzheimer's disease longitudinal study: Results from Australian Imaging Biomarkers Lifestyle Study of Ageing cohort.

Alzheimers Dement (Amst). 2017;8:60-72

Authors: Gupta VB, Hone E, Pedrini S, Doecke J, O'Bryant S, James I, Bush AI, Rowe CC, Villemagne VL, Ames D, Masters CL, Martins RN, AIBL Research Group

Abstract
INTRODUCTION: A blood-based biomarker panel to identify individuals with preclinical Alzheimer's disease (AD) would be an inexpensive and accessible first step for routine testing.
METHODS: We analyzed 14 biomarkers that have previously been linked to AD in the Australian Imaging Biomarkers lifestyle longitudinal study of aging cohort.
RESULTS: Levels of apolipoprotein J (apoJ) were higher in AD individuals compared with healthy controls at baseline and 18 months (P = .0003) and chemokine-309 (I-309) were increased in AD patients compared to mild cognitive impaired individuals over 36 months (P = .0008).
DISCUSSION: These data suggest that apoJ may have potential in the context of use (COU) of AD diagnostics, I-309 may be specifically useful in the COU of identifying individuals at greatest risk for progressing toward AD. This work takes an initial step toward identifying blood biomarkers with potential use in the diagnosis and prognosis of AD and should be validated across other prospective cohorts.

PMID: 28508031 [PubMed - in process]

Treatment of refractory epilepsy patients with autologous mesenchymal stem cells reduces seizure frequency: An open label study.

Recent Research Articles from UNTHSC - Sun, 05/14/2017 - 07:36

Treatment of refractory epilepsy patients with autologous mesenchymal stem cells reduces seizure frequency: An open label study.

Adv Med Sci. 2017 May 10;62(2):273-279

Authors: Hlebokazov F, Dakukina T, Ihnatsenko S, Kosmacheva S, Potapnev M, Shakhbazau A, Goncharova N, Makhrov M, Korolevich P, Misyuk N, Dakukina V, Shamruk I, Slobina E, Marchuk S

Abstract
PURPOSE: Existing anti-epileptic drugs (AED) have limited efficiency in many patients, necessitating the search for alternative approaches such as stem cell therapy. We report the use of autologous patient-derived mesenchymal stem cells (MSC) as a therapeutic agent in symptomatic drug-resistant epilepsy in a Phase I open label clinical trial (registered as NCT02497443).
PATIENTS AND METHODS: The patients received either standard treatment with AED (control group), or AED supplemented with single intravenous administration of undifferentiated autologous MSC (target dose of 1×10(6)cells/kg), followed by a single intrathecal injection of neurally induced autologous MSC (target dose of 0.1×10(6)cells/kg).
RESULTS: MSC injections were well tolerated and did not cause any severe adverse effects. Seizure frequency was designated as the main outcome and evaluated at 1 year time point. 3 out of 10 patients in MSC therapy group achieved remission (no seizures for one year and more), and 5 additional patients became responders to AEDs, while only 2 out of 12 patients became responders in control group (difference significant, P=0.0135).
CONCLUSIONS: MSC possess unique immunomodulatory properties and are a safe and promising candidate for cell therapy in AED resistant epilepsy patients.

PMID: 28500900 [PubMed - as supplied by publisher]

European survey on forensic applications of massively parallel sequencing.

Recent Research Articles from UNTHSC - Sat, 05/13/2017 - 07:33
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European survey on forensic applications of massively parallel sequencing.

Forensic Sci Int Genet. 2017 Apr 26;:

Authors: Alonso A, Müller P, Roewer L, Willuweit S, Budowle B, Parson W

PMID: 28495357 [PubMed - as supplied by publisher]

A pilot mobile integrated healthcare program for frequent utilizers of emergency department services.

Recent Research Articles from UNTHSC - Sat, 05/13/2017 - 07:33
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A pilot mobile integrated healthcare program for frequent utilizers of emergency department services.

Am J Emerg Med. 2017 Apr 27;:

Authors: Nejtek VA, Aryal S, Talari D, Wang H, O'Neill L

Abstract
PURPOSE: To examine whether or not a mobile integrated health (MIH) program may improve health-related quality of life while reducing emergency department (ED) transports, ED admissions, and inpatient hospital admissions in frequent utilizers of ED services.
METHODS: A small retrospective evaluation assessing pre- and post-program quality of life, ED transports, ED admissions, and inpatient hospital admissions was conducted in patients who frequently used the ED for non-emergent or emergent/primary care treatable conditions.
RESULTS: Pre- and post-program data available on 64 program completers are reported. Of those with mobility problems (n=42), 38% improved; those with problems performing usual activities (N=45), 58% reported improvement; and of those experiencing moderate to extreme pain or discomfort (N=48), 42% reported no pain or discomfort after program completion. Frequency of ED transports decreased (5.34±6.0 vs. 2.08±3.3; p <0.000), as did ED admissions (9.66±10.2 vs. 3.30±4.6; p<0.000), and inpatient hospital admissions (3.11±5.5 vs. 1.38±2.5; p=0.003).
CONCLUSION: Results suggest that MIH participation is associated with improved quality of life, reduced ED transports, ED admissions, and inpatient hospital admissions. The MIH program may have potential to improve health outcomes in patients who are frequent ED users for non-emergent or emergent/primary care treatable conditions by teaching them how to proactively manage their health and adhere to therapeutic regimens. Programmatic reasons for these improvements may include psychosocial bonding with participants who received in-home care, health coaching, and the MIH team's 24/7 availability that provided immediate healthcare access.

PMID: 28495031 [PubMed - as supplied by publisher]

Intermittent Hypoxia Training Blunts Cerebrocortical Presenilin 1 Overexpression and Amyloid β Accumulation in Ethanol-Withdrawn Rats.

Recent Research Articles from UNTHSC - Fri, 05/12/2017 - 07:36
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Intermittent Hypoxia Training Blunts Cerebrocortical Presenilin 1 Overexpression and Amyloid β Accumulation in Ethanol-Withdrawn Rats.

Am J Physiol Regul Integr Comp Physiol. 2017 May 10;:ajpregu.00050.2017

Authors: Ryou MG, Mallet RT, Metzger DB, Jung ME

Abstract
Abrupt cessation of chronic alcohol consumption triggers signaling cascades that harm vulnerable brain regions and produce neurobehavioral deficits. We have demonstrated that a program of intermittent, normobaric hypoxia training (IHT) in rats prevents neurobehavioral impairment resulting from abrupt ethanol withdrawal (EW). Moreover, EW induced expression of stress-activated protein kinase p38 and presenilin 1 (PS1), the γ-secretase component that produces the neurotoxic amyloid-β (Aβ) peptides, Aβ40 and Aβ42. We tested the hypotheses that (1) IHT limits EW-induced activation of the p38-PS1 axis, thereby attenuating γ-secretase activation and Aβ accumulation, and (2) EW disables heat shock protein 25 (HSP25), a p38 substrate, molecular chaperone and antioxidant, and provokes protein carbonylation in a manner suppressed by IHT. Adult male rats completed two cycles of 4 wk ethanol diet (0 or 6.5% w/v) and 3 wk EW. A 20 d IHT program of cyclic, 5-8 min exposures to 9.5-10% FIO2 was administered during the first EW phase. PS1, phosphorylated p38 (P-p38) and HSP25 were analyzed by immunoblot, PS1 messenger RNA by quantitative polymerase chain reaction, protein carbonyl content by spectrometry, and Aβ40 and Aβ42 contents by enzyme-linked immunosorbent assay, in prefrontal cortical extracts. IHT attenuated the EW-associated increases in PS1, P-p38, Aβ40, Aβ42 and protein carbonyl contents, but not that of PS1 messenger RNA, while preserving functionally competent HSP25 dimers in EW rats. Collectively, these findings demonstrate that IHT attenuates EW-activation of the p38-PS1-γ-secretase axis, thereby dampening Aβ accumulation, and prevents EW-induced oxidative protein damage.

PMID: 28490448 [PubMed - as supplied by publisher]

Rapid-eye-movement sleep-predominant central sleep apnea relieved by positive airway pressure: a case report.

Recent Research Articles from UNTHSC - Wed, 05/10/2017 - 07:33
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Rapid-eye-movement sleep-predominant central sleep apnea relieved by positive airway pressure: a case report.

Physiol Rep. 2017 May;5(9):

Authors: Jouett NP, Smith ML, Watenpaugh DE, Siddiqui M, Ahmad M, Siddiqui F

Abstract
Central Sleep Apnea (CSA) is characterized by intermittent apneas and hypopneas during sleep that result from absent central respiratory drive. CSA occurs almost exclusively during non-rapid-eye-movement (NREM) sleep due to enhanced neuronal ventilatory drive during REM sleep that makes central apneas highly unlikely to form. A 45-year-old obese African American female presented with co-existing Obstructive Sleep Apnea (OSA) and CSA, not in the form of mixed or complex sleep apnea. Peculiarly, her CSA occurred only during rapid-eye-movement (REM) sleep, which is exceedingly rare. The patient's CSA was resolved when appropriate positive airway pressure (PAP) was prescribed. Our patient remains stable and has reported significant benefit from PAP usage. We offer possible neuro-physiological mechanisms herein, including enhanced loop gain and/or malfunction or malformation of the pre-Botzinger nucleus or other neurological process, that could explain the unique findings of this case.

PMID: 28483860 [PubMed - in process]

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