Recent Research Articles from UNTHSC

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Updated: 32 min 52 sec ago

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]

Exosome-associated hepatitis C virus in cell cultures and patient plasma.

Fri, 02/13/2015 - 4:30am
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Exosome-associated hepatitis C virus in cell cultures and patient plasma.

Biochem Biophys Res Commun. 2014 Dec 12;455(3-4):218-22

Authors: Liu Z, Zhang X, Yu Q, He JJ

Abstract
Hepatitis C virus (HCV) infects its target cells in the form of cell-free viruses and through cell-cell contact. Here we report that HCV is associated with exosomes. Using highly purified exosomes and transmission electron microscopic imaging, we demonstrated that HCV occurred in both exosome-free and exosome-associated forms. Exosome-associated HCV was infectious and resistant to neutralization by an anti-HCV neutralizing antibody. There were more exosome-associated HCV than exosome-free HCV detected in the plasma of HCV-infected patients. These results suggest exosome-associated HCV as an alternative form for HCV infection and transmission.

PMID: 25449270 [PubMed - indexed for MEDLINE]

The Critical Need to Promote Research of Aging and Aging-related Diseases to Improve Health and Longevity of the Elderly Population.

Wed, 02/11/2015 - 4:31am
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The Critical Need to Promote Research of Aging and Aging-related Diseases to Improve Health and Longevity of the Elderly Population.

Aging Dis. 2015 Feb;6(1):1-5

Authors: Jin K, Simpkins JW, Ji X, Leis M, Stambler I

Abstract
Due to the aging of the global population and the derivative increase in aging-related non-communicable diseases and their economic burden, there is an urgent need to promote research on aging and aging-related diseases as a way to improve healthy and productive longevity for the elderly population. To accomplish this goal, we advocate the following policies: 1) Increasing funding for research and development specifically directed to ameliorate degenerative aging processes and to extend healthy and productive lifespan for the population; 2) Providing a set of incentives for commercial, academic, public and governmental organizations to foster engagement in such research and development; and 3) Establishing and expanding coordination and consultation structures, programs and institutions involved in aging-related research, development and education in academia, industry, public policy agencies and at governmental and supra-governmental levels.

PMID: 25657847 [PubMed]

Autonomic neural control of heart rate during dynamic exercise: revisited.

Fri, 02/06/2015 - 4:30am
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Autonomic neural control of heart rate during dynamic exercise: revisited.

J Physiol. 2014 Jun 15;592(Pt 12):2491-500

Authors: White DW, Raven PB

Abstract
UNLABELLED: The accepted model of autonomic control of heart rate (HR) during dynamic exercise indicates that the initial increase is entirely attributable to the withdrawal of parasympathetic nervous system (PSNS) activity and that subsequent increases in HR are entirely attributable to increases in cardiac sympathetic activity. In the present review, we sought to re-evaluate the model of autonomic neural control of HR in humans during progressive increases in dynamic exercise workload. We analysed data from both new and previously published studies involving baroreflex stimulation and pharmacological blockade of the autonomic nervous system. Results indicate that the PSNS remains functionally active throughout exercise and that increases in HR from rest to maximal exercise result from an increasing workload-related transition from a 4 : 1 vagal-sympathetic balance to a 4 : 1 sympatho-vagal balance. Furthermore, the beat-to-beat autonomic reflex control of HR was found to be dependent on the ability of the PSNS to modulate the HR as it was progressively restrained by increasing workload-related sympathetic nerve activity.
IN CONCLUSION: (i) increases in exercise workload-related HR are not caused by a total withdrawal of the PSNS followed by an increase in sympathetic tone; (ii) reciprocal antagonism is key to the transition from vagal to sympathetic dominance, and (iii) resetting of the arterial baroreflex causes immediate exercise-onset reflexive increases in HR, which are parasympathetically mediated, followed by slower increases in sympathetic tone as workloads are increased.

PMID: 24756637 [PubMed - indexed for MEDLINE]

High therapeutic potential of positive allosteric modulation of α7 nAChRs in a rat model of traumatic brain injury: Proof-of-concept.

Thu, 02/05/2015 - 4:32am

High therapeutic potential of positive allosteric modulation of α7 nAChRs in a rat model of traumatic brain injury: Proof-of-concept.

Brain Res Bull. 2015 Jan 31;

Authors: Gatson JW, Simpkins JW, Uteshev VV

Abstract
There are currently no clinically-efficacious drug therapies to treat brain damage secondary to traumatic brain injury (TBI). In this proof-of-concept study, we used a controlled cortical impact model of TBI in young adult rats to explore a novel promising approach that utilizes PNU-120596, a previously-reported highly selective Type-II positive allosteric modulator (α7-PAM) of α7 nicotinic acetylcholine receptors (nAChRs). α7-PAMs enhance and prolong α7 nAChR activation, but do not activate α7 nAChRs when administered without an agonist. The rational basis for the use of an α7-PAM as a post-TBI treatment is tripartite and arises from: 1) the intrinsic ability of brain injury to elevate extracellular levels of choline (a ubiquitous cell membrane-building material and a selective endogenous agonist of α7 nAChRs) due to the breakdown of cell membranes near the site and time of injury; 2) the ubiquitous expression of functional α7 nAChRs in neuronal and glial/immune brain cells; and 3) the potent neuroprotective and anti-inflammatory effects of α7 nAChR activation. Therefore, both neuroprotective and anti-inflammatory effects can be achieved post-TBI by targeting only a single player (i.e., the α7 nAChR) using α7-PAMs to enhance the activation of α7 nAChRs by injury-elevated extracellular choline. Our data support this hypothesis and demonstrate that subcutaneous administration of PNU-120596 post-TBI in young adult rats significantly reduces both brain cell damage and reactive gliosis. Therefore, our results introduce post-TBI systemic administration of α7-PAMs as a promising therapeutic intervention that could significantly restrict brain injury post-TBI and facilitate recovery of TBI patients.

PMID: 25647232 [PubMed - as supplied by publisher]

Population genetics of 23 Y-STR markers in Kuwaiti population.

Thu, 02/05/2015 - 4:32am

Population genetics of 23 Y-STR markers in Kuwaiti population.

Forensic Sci Int Genet. 2015 Jan 17;16C:203-204

Authors: Taqi Z, Alenizi M, Alenizi H, Ismael S, Dukhyil AA, Nazir M, Sanqoor S, Al Harbi E, Al-Jaber J, Theyab J, Moura-Neto RS, Budowle B

PMID: 25643873 [PubMed - as supplied by publisher]

AMPA Receptor Desensitization is the Determinant of AMPA Receptor Mediated Excitotoxicity in Purified Retinal Ganglion Cells.

Thu, 02/05/2015 - 4:32am

AMPA Receptor Desensitization is the Determinant of AMPA Receptor Mediated Excitotoxicity in Purified Retinal Ganglion Cells.

Exp Eye Res. 2015 Jan 30;

Authors: Park YH, Mueller BH, McGrady NR, Ma HY, Yorio T

Abstract
The ionotropic glutamate receptors (iGLuR) have been hypothesized to play a role in neuronal pathogenesis by mediating excitotoxic death. Previous studies on iGluR in the retina have focused on two broad classes of receptors: NMDA and non-NMDA receptors including the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptor (AMPAR) and kainate receptor. In this study, we examined the role of receptor desensitization on the specific excitotoxic effects of AMPAR activation on primary retinal ganglion cells (RGCs). Purified rat RGCs were isolated from postnatal day 4-7 Sprague-Dawley rats. Calcium imaging was used to identify the functionality of the AMPARs and selectivity of the s-AMPA agonist. Phosphorylated CREB and ERK1/2 expression were performed following s-AMPA treatment. s-AMPA excitotoxicity was determined by JC-1 mitochondrial membrane depolarization assay, caspase3/7 luciferase activity assay, immunoblot analysis for α-fodrin, and Live (calcein AM)/Dead (ethidium homodimer-1) assay. RGC cultures of 98% purity, lacking Iba1 and GFAP expression were used for the present studies. Isolated prenatal RGCs expressed calcium permeable AMPAR and s-AMPA (100μM) treatment of cultured RGCs significantly increased phosphorylation of CREB but not that of ERK1/2. A prolonged (6 hours) AMPAR activation in purified RGCs using s-AMPA (100μM) did not depolarize the RGC mitochondrial membrane potential. In addition, treatment of cultured RGCs with s-AMPA, both in the presence and absence of trophic factors (BDNF and CNTF), did not increase caspase 3/7 activities or the cleavage of α-fodrin (neuronal apoptosis marker), as compared to untreated controls. Lastly, a significant increase in cell survival of RGCs was observed after s-AMPA treatment as compared to control untreated RGCs. However, preventing the desensitization of AMPAR with the treatment with either kainic acid (100μM) or the combination of s-AMPA and cyclothiazide (50μM) significantly reduced cell survivability. Activation of the AMPAR in RGCs does not appear to activate a signaling cascade to apoptosis, suggesting that RGCs in vitro are not susceptible to AMPA excitotoxicity as previously hypothesized. Conversely, preventing AMPAR desensitization through differential agonist activation caused AMPAR mediated excitotoxicity. Activation of the AMPAR in increasing CREB phosphorylation was dependent on the presence of calcium, which may help explain this action in increasing RGC survival.

PMID: 25643624 [PubMed - as supplied by publisher]

Indoor air pollution from solid fuels and peripheral blood DNA methylation: findings from a population study in Warsaw, Poland.

Thu, 02/05/2015 - 4:32am
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Indoor air pollution from solid fuels and peripheral blood DNA methylation: findings from a population study in Warsaw, Poland.

Environ Res. 2014 Oct;134:325-30

Authors: Tao MH, Zhou J, Rialdi AP, Martinez R, Dabek J, Scelo G, Lissowska J, Chen J, Boffetta P

Abstract
DNA methylation is a potential mechanism linking indoor air pollution to adverse health effects. Fetal and early-life environmental exposures have been associated with altered DNA methylation and play a critical role in progress of diseases in adulthood. We investigated whether exposure to indoor air pollution from solid fuels at different lifetime periods was associated with global DNA methylation and methylation at the IFG2/H19 imprinting control region (ICR) in a population-based sample of non-smoking women from Warsaw, Poland. Global methylation and IFG2/H19 ICR methylation were assessed in peripheral blood DNA from 42 non-smoking women with Luminometric Methylation Assay (LUMA) and quantitative pyrosequencing, respectively. Linear regression models were applied to estimate associations between indoor air pollution and DNA methylation in the blood. Compared to women without exposure, the levels of LUMA methylation for women who had ever exposed to both coal and wood were reduced 6.70% (95% CI: -13.36, -0.04). Using both coal and wood before age 20 was associated with 6.95% decreased LUMA methylation (95% CI: -13.79, -0.11). Further, the negative correlations were more significant with exposure to solid fuels for cooking before age 20. There were no clear associations between indoor solid fuels exposure before age 20 and through the lifetime and IFG2/H19 ICR methylation. Our study of non-smoking women supports the hypothesis that exposure to indoor air pollution from solid fuels, even early-life exposure, has the capacity to modify DNA methylation that can be detected in peripheral blood.

PMID: 25199973 [PubMed - indexed for MEDLINE]

Low serum zinc is associated with elevated risk of cadmium nephrotoxicity.

Thu, 02/05/2015 - 4:32am
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Low serum zinc is associated with elevated risk of cadmium nephrotoxicity.

Environ Res. 2014 Oct;134:33-8

Authors: Lin YS, Ho WC, Caffrey JL, Sonawane B

Abstract
BACKGROUND: Despite animal evidence suggests that zinc modulates cadmium nephrotoxicity, limited human data are available.
OBJECTIVE: To test the hypothesis that low serum zinc concentrations may increase the risk of cadmium-mediated renal dysfunction in humans.
METHODS: Data from 1545 subjects aged 20 or older in the National Health and Nutrition Examination Survey (NHANES), 2011-2012 were analyzed. Renal function was defined as impaired when estimated glomerular filtration rate (eGFR) fell below 60 ml/min/1.73 m(2) and/or the urinary albumin-to-creatinine ratio surpassed 2.5 in men and 3.5mg/mmol in women.
RESULTS: Within the study cohort, 117 subjects had reduced eGFR and 214 had elevated urinary albumin. After adjusting for potential confounders, subjects with elevated blood cadmium (>0.53 μg/L) were more likely to have a reduced eGFR (odds ratio [OR]=2.21, 95% confidence interval [CI]: 1.09-4.50) and a higher urinary albumin (OR=2.04, 95% CI: 1.13-3.69) than their low cadmium (<0.18 μg/L) peers. In addition, for any given cadmium exposure, low serum zinc is associated with elevated risk of reduced eGFR (OR=3.38, 95% CI: 1.39-8.28). A similar increase in the odds ratio was observed between declining serum zinc and albuminuria but failed to reach statistical significance. Those with lower serum zinc/blood cadmium ratios were likewise at a greater risk of renal dysfunction (p<0.01).
CONCLUSIONS: This study results suggest that low serum zinc concentrations are associated with an increased risk of cadmium nephrotoxicity. Elevated cadmium exposure is global public health issue and the assessment of zinc nutritional status may be an important covariate in determining its effective renal toxicity.

PMID: 25042034 [PubMed - indexed for MEDLINE]

Development of reusable logic for determination of statin exposure-time from electronic health records.

Wed, 02/04/2015 - 4:35am
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Development of reusable logic for determination of statin exposure-time from electronic health records.

J Biomed Inform. 2014 Jun;49:206-12

Authors: Miller AW, McCarty CA, Broeckel U, Hytopoulos V, Cross DS

Abstract
OBJECTIVE: We aim to quantify HMG-CoA reductase inhibitor (statin) prescriber-intended exposure-time using a generalizable algorithm that interrogates data stored in the electronic health record (EHR).
MATERIALS AND METHODS: This study was conducted using the Marshfield Clinic (MC) Personalized Medicine Research Project (PMRP) a central Wisconsin-based population and biobank with, on average, 30 years of electronic health data available in the independently-developed MC Cattails MD EHR. Individuals with evidence of statin exposure were identified from the electronic records, and manual chart abstraction of all mentions of prescribed statins was completed. We then performed electronic chart abstraction of prescriber-intended exposure time for statins, using previously identified logic to capture pill-splitting events, normalizing dosages to atorvastatin-equivalent dose. Four models using iterative training sets were tested to capture statin end-dates. Calculated cumulative provider-intended exposures were compared to manually abstracted gold-standard measures of ordered statin prescriptions, and aggregate model results (totals) for training and validation populations were compared. The most successful model was the one with the smallest discordance between modeled and manually abstracted Atorvastatin 10mg/year Equivalents (AEs).
RESULTS: Of the approximately 20,000 patients enrolled in the PMRP, 6243 were identified with statin exposure during the study period (1997-2011), 59.8% of whom had been prescribed multiple statins over an average of approximately 11 years. When the best-fit algorithm was implemented and validated by manual chart review for the statin-ordered population, it was found to capture 95.9% of the correlation between calculated and expected statin provider-intended exposure time for a random validation set, and the best-fit model was able to predict intended statin exposure to within a standard deviation of 2.6 AEs, with a standard error of +0.23 AEs.
CONCLUSION: We demonstrate that normalized provider-intended statin exposure time can be estimated using a combination of structured clinical data sources, including a medications ordering system and a clinical appointment coordination system, supplemented with text data from clinical notes.

PMID: 24637142 [PubMed - indexed for MEDLINE]

Neuronal ablation of p-Akt at Ser473 leads to altered 5-HT1A/2A receptor function.

Wed, 02/04/2015 - 4:35am
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Neuronal ablation of p-Akt at Ser473 leads to altered 5-HT1A/2A receptor function.

Neurochem Int. 2014 Jul;73:113-21

Authors: Saunders C, Siuta M, Robertson SD, Davis AR, Sauer J, Matthies HJ, Gresch PJ, Airey DC, Lindsley CW, Schetz JA, Niswender KD, Veenstra-Vanderweele JM, Galli A

Abstract
The serotonergic system regulates a wide range of behavior, including mood and impulsivity, and its dysregulation has been associated with mood disorders, autism spectrum disorder, and addiction. Diabetes is a risk factor for these conditions. Insulin resistance in the brain is specifically associated with susceptibility to psychostimulant abuse. Here, we examined whether phosphorylation of Akt, a key regulator of the insulin signaling pathway, controls serotonin (5-HT) signaling. To explore how impairment in Akt function regulates 5-HT homeostasis, we used a brain-specific rictor knockout (KO) mouse model of impaired neuronal phosphorylation of Akt at Ser473. Cortical 5-HT1A and 5-HT2A receptor binding was significantly elevated in rictor KO mice. Concomitant with this elevated receptor expression, the 5-HT1A receptor agonist 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) led to an increased hypothermic response in rictor KO mice. The increased cortical 5-HT1A receptor density was associated with higher 5-HT1A receptor levels on the cortical cell surface. In contrast, rictor KO mice displayed significantly reduced head-twitch response (HTR) to the 5-HT2A/C agonist 2,5-dimethoxy-4-iodoamphetamine (DOI), with evidence of impaired 5-HT2A/C receptor signaling. In vitro, pharmacological inhibition of Akt significantly increased 5-HT1A receptor expression and attenuated DOI-induced 5-HT2A receptor signaling, thereby lending credence to the observed in vivo cross-talk between neuronal Akt signaling and 5-HT receptor regulation. These data reveal that defective central Akt function alters 5-HT signaling as well as 5-HT-associated behaviors, demonstrating a novel role for Akt in maintaining neuronal 5-HT receptor function.

PMID: 24090638 [PubMed - indexed for MEDLINE]

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