Recent Research Articles from UNTHSC

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Coupling of neurogenesis and angiogenesis after ischemic stroke.

Tue, 03/10/2015 - 11:30am

Coupling of neurogenesis and angiogenesis after ischemic stroke.

Brain Res. 2015 Feb 28;

Authors: Ruan L, Wang B, ZhuGe Q, Jin K

Abstract
Stroke is a leading cause of mortality and severe long-term disability worldwide. Development of effective treatment or new therapeutic strategies for ischemic stroke patients is therefore crucial. Ischemic stroke promotes neurogenesis by several growth factors including FGF-2, IGF-1, BDNF, VEGF and chemokines including SDF-1, MCP-1. Stroke-induced angiogenesis is similarly regulated by many factors most notably, eNOS and CSE, VEGF/VEGFR2, and Ang-1/Tie2. Important findings in the last decade have revealed that neurogenesis is not the stand-alone consideration in the fight for full functional recovery from stroke. Angiogenesis has been also shown to be critical in improving post-stroke neurological functional recovery. More than that, recent evidence has shown a highly possible interplay or dependence between stroke-induced neurogenesis and angiogenesis. Moving forward, elucidating the underlying mechanisms of this coupling between stroke-induced neurogenesis and angiogenesis will be of great importance, which will provide the basis for neurorestorative therapy.

PMID: 25736182 [PubMed - as supplied by publisher]

Effects of multiple genetic loci on age at onset in late-onset Alzheimer disease: a genome-wide association study.

Tue, 03/10/2015 - 11:30am
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Effects of multiple genetic loci on age at onset in late-onset Alzheimer disease: a genome-wide association study.

JAMA Neurol. 2014 Nov;71(11):1394-404

Authors: Naj AC, Jun G, Reitz C, Kunkle BW, Perry W, Park YS, Beecham GW, Rajbhandary RA, Hamilton-Nelson KL, Wang LS, Kauwe JS, Huentelman MJ, Myers AJ, Bird TD, Boeve BF, Baldwin CT, Jarvik GP, Crane PK, Rogaeva E, Barmada MM, Demirci FY, Cruchaga C, Kramer PL, Ertekin-Taner N, Hardy J, Graff-Radford NR, Green RC, Larson EB, St George-Hyslop PH, Buxbaum JD, Evans DA, Schneider JA, Lunetta KL, Kamboh MI, Saykin AJ, Reiman EM, De Jager PL, Bennett DA, Morris JC, Montine TJ, Goate AM, Blacker D, Tsuang DW, Hakonarson H, Kukull WA, Foroud TM, Martin ER, Haines JL, Mayeux RP, Farrer LA, Schellenberg GD, Pericak-Vance MA, Alzheimer Disease Genetics Consortium, Albert MS, Albin RL, Apostolova LG, Arnold SE, Barber R, Barnes LL, Beach TG, Becker JT, Beekly D, Bigio EH, Bowen JD, Boxer A, Burke JR, Cairns NJ, Cantwell LB, Cao C, Carlson CS, Carney RM, Carrasquillo MM, Carroll SL, Chui HC, Clark DG, Corneveaux J, Cribbs DH, Crocco EA, DeCarli C, DeKosky ST, Dick M, Dickson DW, Duara R, Faber KM, Fallon KB, Farlow MR, Ferris S, Frosch MP, Galasko DR, Ganguli M, Gearing M, Geschwind DH, Ghetti B, Gilbert JR, Glass JD, Growdon JH, Hamilton RL, Harrell LE, Head E, Honig LS, Hulette CM, Hyman BT, Jicha GA, Jin LW, Karydas A, Kaye JA, Kim R, Koo EH, Kowall NW, Kramer JH, LaFerla FM, Lah JJ, Leverenz JB, Levey AI, Li G, Lieberman AP, Lin CF, Lopez OL, Lyketsos CG, Mack WJ, Martiniuk F, Mash DC, Masliah E, McCormick WC, McCurry SM, McDavid AN, McKee AC, Mesulam M, Miller BL, Miller CA, Miller JW, Murrell JR, Olichney JM, Pankratz VS, Parisi JE, Paulson HL, Peskind E, Petersen RC, Pierce A, Poon WW, Potter H, Quinn JF, Raj A, Raskind M, Reisberg B, Ringman JM, Roberson ED, Rosen HJ, Rosenberg RN, Sano M, Schneider LS, Seeley WW, Smith AG, Sonnen JA, Spina S, Stern RA, Tanzi RE, Thornton-Wells TA, Trojanowski JQ, Troncoso JC, Valladares O, Van Deerlin VM, Van Eldik LJ, Vardarajan BN, Vinters HV, Vonsattel JP, Weintraub S, Welsh-Bohmer KA, Williamson J, Wishnek S, Woltjer RL, Wright CB, Younkin SG, Yu CE, Yu L

Abstract
IMPORTANCE: Because APOE locus variants contribute to risk of late-onset Alzheimer disease (LOAD) and to differences in age at onset (AAO), it is important to know whether other established LOAD risk loci also affect AAO in affected participants.
OBJECTIVES: To investigate the effects of known Alzheimer disease risk loci in modifying AAO and to estimate their cumulative effect on AAO variation using data from genome-wide association studies in the Alzheimer Disease Genetics Consortium.
DESIGN, SETTING, AND PARTICIPANTS: The Alzheimer Disease Genetics Consortium comprises 14 case-control, prospective, and family-based data sets with data on 9162 participants of white race/ethnicity with Alzheimer disease occurring after age 60 years who also had complete AAO information, gathered between 1989 and 2011 at multiple sites by participating studies. Data on genotyped or imputed single-nucleotide polymorphisms most significantly associated with risk at 10 confirmed LOAD loci were examined in linear modeling of AAO, and individual data set results were combined using a random-effects, inverse variance-weighted meta-analysis approach to determine whether they contribute to variation in AAO. Aggregate effects of all risk loci on AAO were examined in a burden analysis using genotype scores weighted by risk effect sizes.
MAIN OUTCOMES AND MEASURES: Age at disease onset abstracted from medical records among participants with LOAD diagnosed per standard criteria.
RESULTS: Analysis confirmed the association of APOE with earlier AAO (P = 3.3 × 10(-96)), with associations in CR1 (rs6701713, P = 7.2 × 10(-4)), BIN1 (rs7561528, P = 4.8 × 10(-4)), and PICALM (rs561655, P = 2.2 × 10(-3)) reaching statistical significance (P < .005). Risk alleles individually reduced AAO by 3 to 6 months. Burden analyses demonstrated that APOE contributes to 3.7% of the variation in AAO (R(2) = 0.256) over baseline (R(2) = 0.221), whereas the other 9 loci together contribute to 2.2% of the variation (R(2) = 0.242).
CONCLUSIONS AND RELEVANCE: We confirmed an association of APOE (OMIM 107741) variants with AAO among affected participants with LOAD and observed novel associations of CR1 (OMIM 120620), BIN1 (OMIM 601248), and PICALM (OMIM 603025) with AAO. In contrast to earlier hypothetical modeling, we show that the combined effects of Alzheimer disease risk variants on AAO are on the scale of, but do not exceed, the APOE effect. While the aggregate effects of risk loci on AAO may be significant, additional genetic contributions to AAO are individually likely to be small.

PMID: 25199842 [PubMed - indexed for MEDLINE]

Association of hypothyroidism with low-level arsenic exposure in rural West Texas.

Thu, 03/05/2015 - 4:29am

Association of hypothyroidism with low-level arsenic exposure in rural West Texas.

Environ Res. 2015 Feb 23;138C:154-160

Authors: Gong G, Basom J, Mattevada S, Onger F

Abstract
It has been reported recently that a higher airborne arsenic level was correlated with higher urinary arsenic concentration and lower serum thyroxin level among urban policemen and rural highway workmen in Italy. The current study was to determine whether exposure to low-level arsenic groundwater (2-22µg/L) is associated with hypothyroidism among 723 participants (118 male and 267 female Hispanics; 108 male and 230 female non-Hispanic whites, NHW) living in rural West Texas counties. Arsenic and iodine levels in their groundwater used for drinking and or cooking were estimated by the inverse distance weighted (IDW) interpolation technique. Groundwater arsenic was ≥8µg/L in 36% of the subjects' wells while iodine concentration was <1µg/L in 91% of their wells. Logistic regression analysis showed that arsenic in groundwater ≥8µg/L and cumulative arsenic exposure (groundwater arsenic concentration multiplied by the number of years living in the current address) but not groundwater iodine concentration were significant predictors for hypothyroidism among Hispanics (p<0.05) but not NHW after adjusting for covariates such as age, gender, annual household income and health insurance coverage. The ethnic difference may be due to a marginally higher percentage of Hispanics (p=0.0622) who lived in areas with groundwater arsenic ≥8µg/L compared with NHW. The prevalence of hypothyroidism was significantly higher in Hispanics or NHW of this rural cohort than the national prevalence. Measures should be taken to reduce arsenic in drinking water in order to prevent hypothyroidism in rural areas.

PMID: 25721242 [PubMed - as supplied by publisher]

Efficacy of SMS text message interventions for smoking cessation: A meta-analysis.

Thu, 03/05/2015 - 4:29am

Efficacy of SMS text message interventions for smoking cessation: A meta-analysis.

J Subst Abuse Treat. 2015 Feb 2;

Authors: Spohr SA, Nandy R, Gandhiraj D, Vemulapalli A, Anne S, Walters ST

Abstract
BACKGROUND: Mobile technology provides new opportunities for health promotion communication. The purpose of this study was to conduct a current and extensive meta-analytic review of SMS (short message service) text message-based interventions for individual smoking cessation.
METHODS: Academic Search Complete, PsycINFO, PubMed, and Scopus were reviewed for articles meeting selection criteria: 1) randomized controlled trials, 2) measured smoking cessation, and 3) intervention primarily delivered through SMS text messaging. Three and 6month follow-up of 7-day point prevalence or continuous abstinence was considered from studies meeting criteria. All analyses were conducted with intention-to-treat. Both fixed and random effects models were used to calculate the global outcome measure and confidence intervals.
RESULTS: Thirteen studies were identified that met inclusion criteria. The studies were found to be homogeneous [Q12=10.89, p=0.54]. Odds ratios based on the random effects models suggested that interventions generally increased quit rates compared to controls, 1.35 [95% CI=1.23, 1.48]. Intervention efficacy was higher in studies with a 3month follow-up compared to 6month follow-up. Text plus programs (e.g., text messaging plus Web or in-person intervention modalities) performed only slightly better than text only programs. Pooled results also indicate message frequency schedule can affect quit rates, in which fixed schedules performed better than decreasing or variable schedules. The use of quit status assessment messages was not related to intervention efficacy.
CONCLUSION: Smoking quit rates for the text messaging intervention group were 35% higher compared to the control group quit rates. Results suggest that SMS text messaging may be a promising way to improve smoking cessation outcomes. This is significant given the relatively wide reach and low cost of text message interventions. Identifying the components that make interventions efficacious will help to increase the effectiveness of such interventions.

PMID: 25720333 [PubMed - as supplied by publisher]

Neuritin 1 promotes retinal ganglion cell survival and axonal regeneration following optic nerve crush.

Sat, 02/28/2015 - 12:29pm

Neuritin 1 promotes retinal ganglion cell survival and axonal regeneration following optic nerve crush.

Cell Death Dis. 2015;6:e1661

Authors: Sharma TP, Liu Y, Wordinger RJ, Pang IH, Clark AF

Abstract
Neuritin 1 (Nrn1) is an extracellular glycophosphatidylinositol-linked protein that stimulates axonal plasticity, dendritic arborization and synapse maturation in the central nervous system (CNS). The purpose of this study was to evaluate the neuroprotective and axogenic properties of Nrn1 on axotomized retinal ganglion cells (RGCs) in vitro and on the in vivo optic nerve crush (ONC) mouse model. Axotomized cultured RGCs treated with recombinant hNRN1 significantly increased survival of RGCs by 21% (n=6-7, P<0.01) and neurite outgrowth in RGCs by 141% compared to controls (n=15, P<0.05). RGC transduction with AAV2-CAG-hNRN1 prior to ONC promoted RGC survival (450%, n=3-7, P<0.05) and significantly preserved RGC function by 70% until 28 days post crush (dpc) (n=6, P<0.05) compared with the control AAV2-CAG-green fluorescent protein transduction group. Significantly elevated levels of RGC marker, RNA binding protein with multiple splicing (Rbpms; 73%, n=5-8, P<0.001) and growth cone marker, growth-associated protein 43 (Gap43; 36%, n=3, P<0.01) were observed 28 dpc in the retinas of the treatment group compared with the control group. Significant increase in Gap43 (100%, n=5-6, P<0.05) expression was observed within the optic nerves of the AAV2-hNRN1 group compared to controls. In conclusion, Nrn1 exhibited neuroprotective, regenerative effects and preserved RGC function on axotomized RGCs in vitro and after axonal injury in vivo. Nrn1 is a potential therapeutic target for CNS neurodegenerative diseases.

PMID: 25719245 [PubMed - as supplied by publisher]

In vitro protection by pyruvate against cadmium-induced cytotoxicity in hippocampal HT-22 cells.

Sat, 02/28/2015 - 12:29pm
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In vitro protection by pyruvate against cadmium-induced cytotoxicity in hippocampal HT-22 cells.

J Appl Toxicol. 2014 Aug;34(8):903-13

Authors: Poteet E, Winters A, Xie L, Ryou MG, Liu R, Yang SH

Abstract
Cadmium is a toxic metal with no biological function in higher-order mammals. Humans are exposed to cadmium environmental contamination and the mechanism underlying the cadmium's cytotoxicity is unclear. To better understand this mechanism, we employed murine hippocampal HT-22 cells to test the in vitro effects of cadmium toxicity. Our study indicated that cadmium inhibits both mitochondria oxidative phosphorylation and glycolysis. In turn, this causes depolarization of mitochondrial membrane potential, increase of superoxide production and decrease of ATP generation. Furthermore, we demonstrated that the detrimental action of cadmium in bioenergetics could be mitigated by pyruvate, an intermediate metabolic product. Pyruvate decreased superoxide production, maintained mitochondrial membrane potential, restored glycolysis, mitigated the decrease in cellular ATP and attenuated cadmium cytotoxicity. Our study provides the first evidence that pyruvate might offer promising therapy for cadmium poisoning.

PMID: 24037965 [PubMed - indexed for MEDLINE]

An Attachment-Based Description of the Medial Collateral and Spring Ligament Complexes.

Fri, 02/27/2015 - 4:29am

An Attachment-Based Description of the Medial Collateral and Spring Ligament Complexes.

Foot Ankle Int. 2015 Feb 23;

Authors: Cromeens BP, Kirchhoff CA, Patterson RM, Motley T, Stewart D, Fisher C, Reeves RE

Abstract
BACKGROUND: Anatomy of the medial collateral and spring ligament complexes has been the cause of confusion. The anatomic description is highly dependent on the source studied and little agreement exists between texts. In addition, inconsistent nomenclature has been used to describe the components. This study attempted to clarify confusion through the creation of a 3D ligament map using attachment-based dissection.
METHODS: Nine fresh foot and ankle specimens were observed. The medial collateral ligament and spring ligament complexes were dissected using their attachment sites as a guide to define individual components. Each component's perimeter and thickness was measured and each bony attachment was mapped using a microscribe 3D digitizer.
RESULTS: Five components were identified contributing to the ligament complexes of interest: the tibiocalcaneonavicular, superficial posterior tibiotalar, deep posterior tibiotalar, deep anterior tibiotalar, and inferoplantar longitudinal ligaments. The largest component by total attachment area was the tibiocalcaneonavicular ligament followed by the deep posterior tibiotalar ligament. The largest ligament surface area of attachment to the tibia and talus was the deep posterior tibiotalar ligament. The largest attachment to the navicular and calcaneus was the tibiocalcaneonavicular ligament, which appeared to function in holding these bones in proximity while supporting the head of the talus.
CONCLUSION: By defining complex components by their attachment sites, a novel, more functional and reproducible description of the medial collateral and spring ligament complexes was created.
CLINICAL RELEVANCE: The linear measurements and 3D maps may prove useful when attempting more anatomically accurate reconstructions.

PMID: 25712121 [PubMed - as supplied by publisher]

Stress Induces p38 MAPK-Mediated Phosphorylation and Inhibition of Drosha-Dependent Cell Survival.

Thu, 02/26/2015 - 4:29am

Stress Induces p38 MAPK-Mediated Phosphorylation and Inhibition of Drosha-Dependent Cell Survival.

Mol Cell. 2015 Feb 19;57(4):721-34

Authors: Yang Q, Li W, She H, Dou J, Duong DM, Du Y, Yang SH, Seyfried NT, Fu H, Gao G, Mao Z

Abstract
MicroRNAs (miRNAs) regulate the translational potential of their mRNA targets and control many cellular processes. The key step in canonical miRNA biogenesis is the cleavage of the primary transcripts by the nuclear RNase III enzyme Drosha. Emerging evidence suggests that the miRNA biogenic cascade is tightly controlled. However, little is known whether Drosha is regulated. Here, we show that Drosha is targeted by stress. Under stress, p38 MAPK directly phosphorylates Drosha at its N terminus. This reduces its interaction with DiGeorge syndrome critical region gene 8 and promotes its nuclear export and degradation by calpain. This regulatory mechanism mediates stress-induced inhibition of Drosha function. Reduction of Drosha sensitizes cells to stress and increases death. In contrast, increase in Drosha attenuates stress-induced death. These findings reveal a critical regulatory mechanism by which stress engages p38 MAPK pathway to destabilize Drosha and inhibit Drosha-mediated cellular survival.

PMID: 25699712 [PubMed - in process]

NKp44 and Natural Cytotoxicity Receptors as Damage-Associated Molecular Pattern Recognition Receptors.

Thu, 02/26/2015 - 4:29am

NKp44 and Natural Cytotoxicity Receptors as Damage-Associated Molecular Pattern Recognition Receptors.

Front Immunol. 2015;6:31

Authors: Horton NC, Mathew PA

Abstract
Natural killer (NK) cells are a key constituent of the innate immune system, protecting against bacteria, virally infected cells, and cancer. Recognition and protective function against such cells are dictated by activating and inhibitory receptors on the surface of the NK cell, which bind to specific ligands on the surface of target cells. Among the activating receptors is a small class of specialized receptors termed the natural cytotoxicity receptors (NCRs) comprised of NKp30, NKp46, and NKp44. The NCRs are key receptors in the recognition and termination of virally infected and tumor cells. Since their discovery over 10 years ago, ligands corresponding to the NCRs have largely remained elusive. Recent identification of the cellular ligands for NKp44 and NKp30 as exosomal proliferating cell nuclear antigen (PCNA) and HLA-B-associated transcript 3 (BAT3), respectively, implicate that NCRs may function as receptors for damage-associated molecular pattern (DAMP) molecules. In this review, we focus on NKp44, which surprisingly recognizes two distinct ligands resulting in either activation or inhibition of NK cell effector responses in response to tumor cells. The inhibitory function of NKp44 requires further study as it may play a pivotal role in placentation in addition to being exploited by tumors as a mechanism to escape NK cell killing. Finally, we suggest that the NCRs are a class of pattern recognition receptors, which recognize signals of genomic instability and cellular stress via interaction with the c-terminus of DAMP molecules localized to the surface of target cells by various co-ligands.

PMID: 25699048 [PubMed]

Pharmacological modulation of abnormal involuntary DOI-induced head twitch response movements in male DBA/2J mice: II. Effects of D3 dopamine receptor selective compounds.

Thu, 02/26/2015 - 4:29am

Pharmacological modulation of abnormal involuntary DOI-induced head twitch response movements in male DBA/2J mice: II. Effects of D3 dopamine receptor selective compounds.

Neuropharmacology. 2015 Feb 17;

Authors: Rangel-Barajas C, Malik M, Mach RH, Luedtke RR

Abstract
We recently reported on the characterization of the hallucinogen 2,5-dimethoxy-4-methylamphetamine's (DOI) ability to elicit a head twitch response (HTR) in DBA/2J mice and the ability of D2 vs. D3 dopamine receptor selective compounds to modulate that response. For these studies, the ability of D3 vs. D2 dopamine receptor selective compounds to attenuate the DOI-dependent HTR was examined. WC 10, a D3 dopamine receptor weak partial agonist with 40-fold binding selectivity for D3 vs. D2 dopamine receptors, produced a dose-dependent decrease in the DOI-induced HTR (IC50 = 3.7 mg/kg). WC 44, a D3 receptor selective full agonist, also inhibited the DOI-induced HTR (IC50 = 5.1 mg/kg). The effect of two D3 receptor selective partial agonists, LAX-4-136 and WW-III-55, were also evaluated. These analogs exhibit 150-fold and 800-fold D3 vs. D2 binding selectivity, respectively. Both compounds inhibited the HTR with similar potency but with different maximum efficacies. At 10 mg/kg WW-III-55 inhibited the HTR by 95%, while LAX-4-136 administration resulted in a 50% reduction. In addition, DOI (5 mg/kg) was administered at various times after LAX-4-136 or WW-III-55 administration to compare the duration of action. The homopiperazine analog LAX-4-136 exhibited greater stability. An assessment of our test compounds on motor performance and coordination was performed using a rotarod test. None of the D3 dopamine receptor selective compounds significantly altered latency to fall, suggesting that these compounds a) did not attenuate the DOI-dependent HTR due to sedative or adverse motor effects and b) may have antipsychotic/antihallucinogenic activity.

PMID: 25698528 [PubMed - as supplied by publisher]

Pathogenesis of chronic hyperglycemia: from reductive stress to oxidative stress.

Thu, 02/26/2015 - 4:29am
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Pathogenesis of chronic hyperglycemia: from reductive stress to oxidative stress.

J Diabetes Res. 2014;2014:137919

Authors: Yan LJ

Abstract
Chronic overnutrition creates chronic hyperglycemia that can gradually induce insulin resistance and insulin secretion impairment. These disorders, if not intervened, will eventually be followed by appearance of frank diabetes. The mechanisms of this chronic pathogenic process are complex but have been suggested to involve production of reactive oxygen species (ROS) and oxidative stress. In this review, I highlight evidence that reductive stress imposed by overflux of NADH through the mitochondrial electron transport chain is the source of oxidative stress, which is based on establishments that more NADH recycling by mitochondrial complex I leads to more electron leakage and thus more ROS production. The elevated levels of both NADH and ROS can inhibit and inactivate glyceraldehyde 3-phosphate dehydrogenase (GAPDH), respectively, resulting in blockage of the glycolytic pathway and accumulation of glycerol 3-phospate and its prior metabolites along the pathway. This accumulation then initiates all those alternative glucose metabolic pathways such as the polyol pathway and the advanced glycation pathways that otherwise are minor and insignificant under euglycemic conditions. Importantly, all these alternative pathways lead to ROS production, thus aggravating cellular oxidative stress. Therefore, reductive stress followed by oxidative stress comprises a major mechanism of hyperglycemia-induced metabolic syndrome.

PMID: 25019091 [PubMed - indexed for MEDLINE]

Development of biodegradable nanocarriers loaded with a monoclonal antibody.

Tue, 02/24/2015 - 4:30am

Development of biodegradable nanocarriers loaded with a monoclonal antibody.

Int J Mol Sci. 2015;16(2):3990-5

Authors: Gdowski A, Ranjan A, Mukerjee A, Vishwanatha J

Abstract
Treatments utilizing monoclonal antibody therapeutics against intracellular protein-protein interactions in cancer cells have been hampered by several factors, including poor intracellular uptake and rapid lysosomal degradation. Our current work examines the feasibility of encapsulating monoclonal antibodies within poly(lactic-co-glycolic acid) (PLGA) nanoparticles using a water/oil/water double emulsion solvent evaporation technique. This method can be used to prepare protective polymeric nanoparticles for transporting functional antibodies to the cytoplasmic compartment of cancer cells. Nanoparticles were formulated and then characterized using a number of physical and biological parameters. The average nanoparticle size ranged from 221 to 252 nm with a low polydispersity index. Encapsulation efficiency of 16%-22% and antibody loading of 0.3%-1.12% were observed. The antibody molecules were released from the nanoparticles in a sustained manner and upon release maintained functionality. Our studies achieved successful formulation of antibody loaded polymeric nanoparticles, thus indicating that a PLGA-based antibody nanoformulation is a promising intracellular delivery vehicle for a large number of new intracellular antibody targets in cancer cells.

PMID: 25690029 [PubMed - in process]

Elephant (Elephas maximus) Health and Management in Asia: Variations in Veterinary Perspectives.

Thu, 02/19/2015 - 4:29am
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Elephant (Elephas maximus) Health and Management in Asia: Variations in Veterinary Perspectives.

Vet Med Int. 2015;2015:614690

Authors: Miller D, Jackson B, Riddle HS, Stremme C, Schmitt D, Miller T

Abstract
There is a need to identify strategic investments in Asian elephant (Elephas maximus) health that will yield maximal benefits for overall elephant health and conservation. As an exploratory first step, a survey was administered to veterinarians from Asian elephant range countries at a workshop and via email to help prioritize health-related concerns that will mostly benefit elephants. Responses were received from 45 veterinarians from eight countries that had a range of experience with captive and wild elephants. The occurrence of medical conditions and responses to treatment varied among responses. However, injuries, parasitism, and gastrointestinal disease were reported as the most common syndromes responsible for elephant morbidity, whereas injury and infectious disease not due to parasitism were the most commonly reported sources of elephant mortality. Substandard nutrition, water quality and quantity deficiencies, and inadequate or absent shelter were among the factors listed as barriers to optimal elephant health. While this survey's results do not support definitive conclusions, they can be used to identify where and how subsequent investigations should be directed. Rigorous assessment of the relative costs and benefits of available options is required to ensure that investments in individual and population health yield the maximal benefits for elephants.

PMID: 25688328 [PubMed]

In reply to 'False-positive Xpert(®) MTB/RIF assays in previously treated patients'

Wed, 02/18/2015 - 4:30am

In reply to 'False-positive Xpert(®) MTB/RIF assays in previously treated patients'

Int J Tuberc Lung Dis. 2015 Mar;19(3):366-367

Authors: Steingart KR, Schiller I, Dendukuri N, Lalli M, Houben R, Churchyard G, White RG, Hoger S, Lykens K, Beavers S, Katz D, Miller T, Verma S, Verma G, Singh DV, Mokta J, Negi RS, Jhobta A, Kanga A, Flores-Suárez LF, Rivera LM, Rosales RM, Ruiz N, Saldaña RB

PMID: 25686149 [PubMed - as supplied by publisher]

Modeling cardiac arrest and resuscitation in the domestic pig.

Wed, 02/18/2015 - 4:30am

Modeling cardiac arrest and resuscitation in the domestic pig.

World J Crit Care Med. 2015 Feb 4;4(1):1-12

Authors: Cherry BH, Nguyen AQ, Hollrah RA, Olivencia-Yurvati AH, Mallet RT

Abstract
Cardiac arrest remains a leading cause of death and permanent disability worldwide. Although many victims are initially resuscitated, they often succumb to the extensive ischemia-reperfusion injury inflicted on the internal organs, especially the brain. Cardiac arrest initiates a complex cellular injury cascade encompassing reactive oxygen and nitrogen species, Ca(2+) overload, ATP depletion, pro- and anti-apoptotic proteins, mitochondrial dysfunction, and neuronal glutamate excitotoxity, which injures and kills cells, compromises function of internal organs and ignites a destructive systemic inflammatory response. The sheer complexity and scope of this cascade challenges the development of experimental models of and effective treatments for cardiac arrest. Many experimental animal preparations have been developed to decipher the mechanisms of damage to vital internal organs following cardiac arrest and cardiopulmonary resuscitation (CPR), and to develop treatments to interrupt the lethal injury cascades. Porcine models of cardiac arrest and resuscitation offer several important advantages over other species, and outcomes in this large animal are readily translated to the clinical setting. This review summarizes porcine cardiac arrest-CPR models reported in the literature, describes clinically relevant phenomena observed during cardiac arrest and resuscitation in pigs, and discusses numerous methodological considerations in modeling cardiac arrest/CPR. Collectively, published reports show the domestic pig to be a suitable large animal model of cardiac arrest which is responsive to CPR, defibrillatory countershocks and medications, and yields extensive information to foster advances in clinical treatment of cardiac arrest.

PMID: 25685718 [PubMed]

Nanofluidity of fatty acid hydrocarbon chains as monitored by benchtop time-domain nuclear magnetic resonance.

Tue, 02/17/2015 - 4:30am
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Nanofluidity of fatty acid hydrocarbon chains as monitored by benchtop time-domain nuclear magnetic resonance.

Biochemistry. 2014 Dec 9;53(48):7515-22

Authors: Robinson MD, Cistola DP

Abstract
The functional properties of lipid-rich assemblies such as serum lipoproteins, cell membranes, and intracellular lipid droplets are modulated by the fluidity of the hydrocarbon chain environment. Existing methods for monitoring hydrocarbon chain fluidity include fluorescence, electron spin resonance, and nuclear magnetic resonance (NMR) spectroscopy; each possesses advantages and limitations. Here we introduce a new approach based on benchtop time-domain (1)H NMR relaxometry (TD-NMR). Unlike conventional NMR spectroscopy, TD-NMR does not rely on the chemical shift resolution made possible by homogeneous, high-field magnets and Fourier transforms. Rather, it focuses on a multiexponential analysis of the time decay signal. In this study, we investigated a series of single-phase fatty acid oils, which allowed us to correlate (1)H spin-spin relaxation time constants (T2) with experimental measures of sample fluidity, as obtained using a viscometer. Remarkably, benchtop TD-NMR at 40 MHz was able to resolve two to four T2 components in biologically relevant fatty acids, assigned to nanometer-scale domains in different segments of the hydrocarbon chain. The T2 values for each domain were exquisitely sensitive to hydrocarbon chain structure; the largest values were observed for pure fatty acids or mixtures with the highest cis-double bond content. Moreover, the T2 values for each domain exhibited positive linear correlations with fluidity. The TD-NMR T2 and fluidity measurements appear to be monitoring the same underlying phenomenon: variations in hydrocarbon chain packing. The results from this study validate the use of benchtop TD-NMR T2 as a nanofluidity meter and demonstrate its potential for probing nanofluidity in other systems of biological interest.

PMID: 25409529 [PubMed - indexed for MEDLINE]

The spatial distribution of actin and mechanical cycle of myosin are different in right and left ventricles of healthy mouse hearts.

Tue, 02/17/2015 - 4:30am
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The spatial distribution of actin and mechanical cycle of myosin are different in right and left ventricles of healthy mouse hearts.

Biochemistry. 2014 Dec 9;53(48):7641-9

Authors: Nagwekar J, Duggal D, Rich R, Raut S, Fudala R, Gryczynski I, Gryczynski Z, Borejdo J

Abstract
The contraction of the right ventricle (RV) expels blood into the pulmonary circulation, and the contraction of the left ventricle (LV) pumps blood into the systemic circulation through the aorta. The respective afterloads imposed on the LV and RV by aortic and pulmonary artery pressures create very different mechanical requirements for the two ventricles. Indeed, differences have been observed in the contractile performance between left and right ventricular myocytes in dilated cardiomyopathy, in congestive heart failure, and in energy usage and speed of contraction at light loads in healthy hearts. In spite of these functional differences, it is commonly believed that the right and left ventricular muscles are identical because there were no differences in stress development, twitch duration, work performance, or power among the RV and LV in dogs. This report shows that on a mesoscopic scale [when only a few molecules are studied (here three to six molecules of actin) in ex vivo ventricular myofibrils], the two ventricles in rigor differ in the degree of orientational disorder of actin within in filaments and during contraction in the kinetics of the cross-bridge cycle.

PMID: 25488019 [PubMed - indexed for MEDLINE]

Pharmacology, benefits, unaddressed questions, and pragmatic issues of the newer oral anticoagulants for stroke prophylaxis in non-valvular atrial fibrillation and proposal of a management algorithm.

Sat, 02/14/2015 - 4:32am
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Pharmacology, benefits, unaddressed questions, and pragmatic issues of the newer oral anticoagulants for stroke prophylaxis in non-valvular atrial fibrillation and proposal of a management algorithm.

Int J Cardiol. 2014 Jul 1;174(3):471-83

Authors: Rosanio S, Keylani AM, D'Agostino DC, DeLaughter CM, Vitarelli A

Abstract
This systematic review aims to provide an update on pharmacology, efficacy and safety of the newer oral direct thrombin and factor Xa inhibitors, which have emerged for the first time in ~60 years as cogent alternatives to warfarin for stroke prophylaxis in non-valvular atrial fibrillation. We also discuss on four of the most common clinical scenarios with several unsolved questions and areas of uncertainty that may play a role in physicians' reluctance to prescribe the newer oral anticoagulants such as 1) patients with renal failure; 2) the elderly; 3) patients presenting with atrial fibrillation and acute coronary syndromes and/or undergoing coronary stenting; and 4) patients planning to receive AF ablation with the use of pulmonary vein isolation. New aspects presented in current guidelines are covered and we also propose an evidence-based anticoagulation management algorithm.

PMID: 24814537 [PubMed - indexed for MEDLINE]

A review of creatine supplementation in age-related diseases: more than a supplement for athletes.

Fri, 02/13/2015 - 4:30am
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A review of creatine supplementation in age-related diseases: more than a supplement for athletes.

F1000Res. 2014;3:222

Authors: Smith RN, Agharkar AS, Gonzales EB

Abstract
Creatine is an endogenous compound synthesized from arginine, glycine and methionine. This dietary supplement can be acquired from food sources such as meat and fish, along with athlete supplement powders. Since the majority of creatine is stored in skeletal muscle, dietary creatine supplementation has traditionally been important for athletes and bodybuilders to increase the power, strength, and mass of the skeletal muscle. However, new uses for creatine have emerged suggesting that it may be important in preventing or delaying the onset of neurodegenerative diseases associated with aging. On average, 30% of muscle mass is lost by age 80, while muscular weakness remains a vital cause for loss of independence in the elderly population. In light of these new roles of creatine, the dietary supplement's usage has been studied to determine its efficacy in treating congestive heart failure, gyrate atrophy, insulin insensitivity, cancer, and high cholesterol. In relation to the brain, creatine has been shown to have antioxidant properties, reduce mental fatigue, protect the brain from neurotoxicity, and improve facets/components of neurological disorders like depression and bipolar disorder. The combination of these benefits has made creatine a leading candidate in the fight against age-related diseases, such as Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, long-term memory impairments associated with the progression of Alzheimer's disease, and stroke. In this review, we explore the normal mechanisms by which creatine is produced and its necessary physiology, while paying special attention to the importance of creatine supplementation in improving diseases and disorders associated with brain aging and outlining the clinical trials involving creatine to treat these diseases.

PMID: 25664170 [PubMed]

Angiotensin II induces membrane trafficking of natively expressed transient receptor potential vanilloid type 4 channels in hypothalamic 4B cells.

Fri, 02/13/2015 - 4:30am
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Angiotensin II induces membrane trafficking of natively expressed transient receptor potential vanilloid type 4 channels in hypothalamic 4B cells.

Am J Physiol Regul Integr Comp Physiol. 2014 Oct 15;307(8):R945-55

Authors: Saxena A, Bachelor M, Park YH, Carreno FR, Nedungadi TP, Cunningham JT

Abstract
Transient receptor potential vanilloid family type 4 (TRPV4) channels are expressed in central neuroendocrine neurons and have been shown to be polymodal in other systems. We previously reported that in the rodent, a model of dilutional hyponatremia associated with hepatic cirrhosis, TRPV4 expression is increased in lipid rafts from the hypothalamus and that this effect may be angiotensin dependent. In this study, we utilized the immortalized neuroendocrine rat hypothalamic 4B cell line to more directly test the effects of angiotensin II (ANG II) on TRPV4 expression and function. Our results demonstrate the expression of corticotropin-releasing factor (CRF) transcripts, for sex-determining region Y (SRY) (male genotype), arginine vasopressin (AVP), TRPV4, and ANG II type 1a and 1b receptor in 4B cells. After a 1-h incubation in ANG II (100 nM), 4B cells showed increased TRPV4 abundance in the plasma membrane fraction, and this effect was prevented by the ANG II type 1 receptor antagonist losartan (1 μM) and by a Src kinase inhibitor PP2 (10 μM). Ratiometric calcium imaging experiments demonstrated that ANG II incubation potentiated TRPV4 agonist (GSK 1016790A, 20 nM)-induced calcium influx (control 18.4 ± 2.8% n = 5 and ANG II 80.5 ± 2.4% n = 5). This ANG II-induced increase in calcium influx was also blocked by 1 μM losartan and 10 μM PP2 (losartan 26.4 ± 3.8% n = 5 and PP2 19.7 ± 3.9% n = 5). Our data suggests that ANG II can increase TRPV4 channel membrane expression in 4B cells through its action on AT1R involving a Src kinase pathway.

PMID: 25080500 [PubMed - indexed for MEDLINE]

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