Recent Research Articles from UNTHSC

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Notch1 signaling modulates neuronal progenitor activity in the subventricular zone in response to aging and focal ischemia.

Fri, 06/27/2014 - 4:05am
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Notch1 signaling modulates neuronal progenitor activity in the subventricular zone in response to aging and focal ischemia.

Aging Cell. 2013 Dec;12(6):978-87

Authors: Sun F, Mao X, Xie L, Ding M, Shao B, Jin K

Abstract
Neurogenesis diminishes with aging and ischemia-induced neurogenesis also occurs, but reduced in aged brain. Currently, the cellular and molecular pathways mediating these effects remain largely unknown. Our previous study has shown that Notch1 signaling regulates neurogenesis in subventricular zone (SVZ) of young adult brain after focal ischemia, but whether a similar effect occurs in aged normal and ischemic animals is unknown. Here, we used normal and ischemic aged rat brains to investigate whether Notch1 signaling was involved in the reduction of neurogenesis in response to aging and modulates neurogenesis in aged brains after focal ischemia. By Western blot, we found that Notch1 and Jagged1 expression in the SVZ of aged brain was significantly reduced compared with young adult brain. Consistently, the activated form of Notch1 (Notch intracellular domain; NICD) expression was also declined. Immunohistochemistry confirmed that expression and activation of Notch1 signaling in the SVZ of aged brain were reduced. Double or triple immunostaining showed that that Notch1 was mainly expressed in doublecortin (DCX)-positive cells, whereas Jagged1 was predominantly expressed in astroglial cells in the SVZ of normal aged rat brain. In addition, disruption or activation of Notch1 signaling altered the number of proliferating cells labeled by bromodeoxyuridine (BrdU) and DCX in the SVZ of aged brain. Moreover, ischemia-induced cell proliferation in the SVZ of aged brain was enhanced by activating the Notch1 pathway and was suppressed by inhibiting the Notch1 signaling. Reduced infarct volume and improved motor deficits were also observed in Notch1 activator-treated aged ischemic rats. Our data suggest that Notch1 signaling modulates the SVZ neurogenesis in aged brain in normal and ischemic conditions.

PMID: 23834718 [PubMed - indexed for MEDLINE]

Population data on 25 autosomal STRs for 500 unrelated Kuwaitis.

Thu, 06/26/2014 - 4:04am

Population data on 25 autosomal STRs for 500 unrelated Kuwaitis.

Forensic Sci Int Genet. 2014 Jun 2;12C:126-127

Authors: Al-Enizi M, Ge J, Salih A, Alenizi H, Al Jabber J, Ziab J, Al Harbi E, Isameal S, Budowle B

PMID: 24960412 [PubMed - as supplied by publisher]

MAPIT: development of a web-based intervention targeting substance abuse treatment in the criminal justice system.

Wed, 06/25/2014 - 4:04am
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MAPIT: development of a web-based intervention targeting substance abuse treatment in the criminal justice system.

J Subst Abuse Treat. 2014 Jan;46(1):60-5

Authors: Walters ST, Ondersma SJ, Ingersoll KS, Rodriguez M, Lerch J, Rossheim ME, Taxman FS

Abstract
Although drug and alcohol treatment are common requirements in the U.S. criminal justice system, only a minority of clients actually initiate treatment. This paper describes a two-session, web-based intervention to increase motivation for substance abuse treatment among clients using illicit substances. MAPIT (Motivational Assessment Program to Initiate Treatment) integrates the extended parallel process model, motivational interviewing, and social cognitive theory. The first session (completed near the start of probation) targets motivation to complete probation, to make changes in substance use (including treatment initiation), and to obtain HIV testing and care. The second session (completed approximately 30days after session 1) focuses on goal setting, coping strategies, and social support. Both sessions can generate emails or mobile texts to remind clients of their goals. MAPIT uses theory-based algorithms and a text-to-speech engine to deliver custom feedback and suggestions. In an initial test, participants indicated that the program was respectful, easy to use, and would be helpful in making changes in substance use. MAPIT is being tested in a randomized trial in two large U.S. probation agencies. MAPIT addresses the difficulties of many probation agencies to maximize client involvement in treatment, in a way that is cost effective and compatible with the existing service delivery system.

PMID: 23954392 [PubMed - indexed for MEDLINE]

mitoSAVE: Mitochondrial sequence analysis of variants in Excel.

Tue, 06/24/2014 - 4:04am
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mitoSAVE: Mitochondrial sequence analysis of variants in Excel.

Forensic Sci Int Genet. 2014 Jun 2;12C:122-125

Authors: King JL, Sajantila A, Budowle B

Abstract
The mitochondrial genome (mtGenome) contains genetic information amenable to numerous applications such as medical research, population and evolutionary studies, and human identity testing. However, inconsistent nomenclature assignment makes haplotype comparison difficult and can lead to false exclusion of potentially useful profiles. Massively Parallel Sequencing (MPS) is a platform for sequencing large datasets and potentially whole populations with relative ease. However, the data generated are not easily parsed and interpreted. With this in mind, mitoSAVE has been developed to enable fast conversion of Variant Call Format (VCF) files. mitoSAVE is an Excel-based workbook that converts data within the VCF into mtDNA haplotypes using phylogenetically-established nomenclature as well as rule-based alignments consistent with current forensic standards. mitoSAVE is formatted for human mitochondrial genome; however, it can easily be adapted to support other reasonably small genomes.

PMID: 24952129 [PubMed - as supplied by publisher]

Methamphetamine and HIV-1-induced neurotoxicity: Role of trace amine associated receptor 1 cAMP signaling in astrocytes.

Sun, 06/22/2014 - 4:04am

Methamphetamine and HIV-1-induced neurotoxicity: Role of trace amine associated receptor 1 cAMP signaling in astrocytes.

Neuropharmacology. 2014 Jun 17;

Authors: Cisneros IE, Ghorpade A

Abstract
Methamphetamine (METH) is abused by about 5% of the United States population with approximately 10-15% of human immunodeficiency virus-1 (HIV-1) patients reporting its use. METH abuse accelerates the onset and severity of HIV-associated neurocognitive disorders (HAND) and astrocyte-induced neurotoxicity. METH activates G-protein coupled receptors such as trace amine associated receptor 1 (TAAR1) increasing intracellular cyclic adenosine monophosphate (cAMP) levels in presynaptic cells of monoaminergic systems. In the present study, we investigated the effects of METH and HIV-1 on primary human astrocyte TAAR1 expression, function and glutamate clearance. Our results demonstrate combined conditions increased TAAR1 mRNA levels 7-fold and increased intracellular cAMP levels. METH and beta-phenylethylamine (β-PEA), known TAAR1 agonists, increased intracellular cAMP levels in astrocytes. Further, TAAR1 knockdown significantly reduced intracellular cAMP levels in response to METH/β-PEA, indicating signaling through astrocyte TAAR1. METH +/- HIV-1 decreased excitatory amino acid transporter-2 (EAAT-2) mRNA and significantly decreased glutamate clearance. RNA interference for TAAR1 prevented METH-mediated decreases in EAAT-2. TAAR1 knockdown significantly increased glutamate clearance, which was further heightened significantly by METH. Moreover, TAAR1 overexpression significantly decreased EAAT-2 levels and glutamate clearance that were further reduced by METH. Taken together, our data show that METH treatment activated TAAR1 leading to intracellular cAMP in human astrocytes and modulated glutamate clearance abilities. Furthermore, molecular alterations in astrocyte TAAR1 levels correspond to changes in astrocyte EAAT-2 levels and function. To our knowledge this is the first report implicating astrocyte TAAR1 as a novel receptor for METH during combined injury in the context of HAND.

PMID: 24950453 [PubMed - as supplied by publisher]

Caloric restriction and the aging process: a critique.

Sat, 06/21/2014 - 4:06am
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Caloric restriction and the aging process: a critique.

Free Radic Biol Med. 2014 Jun 2;

Authors: Sohal RS, Forster MJ

Abstract
The main objective of this review is to provide an appraisal of the current status of the relationship between energy intake and the life span of animals. The concept that a reduction in food intake, or caloric restriction (CR), retards the aging process, delays the age-associated decline in physiological fitness, and extends the life span of organisms of diverse phylogenetic groups is one of the leading paradigms in gerontology. However, emerging evidence disputes some of the primary tenets of this conception. One disparity is that the CR-related increase in longevity is not universal and may not even be shared among different strains of the same species. A further misgiving is that the control animals, fed ad libitum (AL), become overweight and prone to early onset of diseases and death, and thus may not be the ideal control animals for studies concerned with comparisons of longevity. Reexamination of body weight and longevity data from a study involving over 60,000 mice and rats, conducted by a National Institute on Aging-sponsored project, suggests that CR-related increase in life span of specific genotypes is directly related to the gain in body weight under the AL feeding regimen. Additionally, CR in mammals and "dietary restriction" in organisms such as Drosophila are dissimilar phenomena, albeit they are often presented to be the very same. The latter involves a reduction in yeast rather than caloric intake, which is inconsistent with the notion of a common, conserved mechanism of CR action in different species. Although specific mechanisms by which CR affects longevity are not well understood, existing evidence supports the view that CR increases the life span of those particular genotypes that develop energy imbalance owing to AL feeding. In such groups, CR lowers body temperature, rate of metabolism, and oxidant production and retards the age-related pro-oxidizing shift in the redox state.

PMID: 24941891 [PubMed - as supplied by publisher]

High glucose and diabetes enhanced store-operated Ca(2+) entry and increased expression of its signaling proteins in mesangial cells.

Sat, 06/21/2014 - 4:06am
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High glucose and diabetes enhanced store-operated Ca(2+) entry and increased expression of its signaling proteins in mesangial cells.

Am J Physiol Renal Physiol. 2014 May 1;306(9):F1069-80

Authors: Chaudhari S, Wu P, Wang Y, Ding Y, Yuan J, Begg M, Ma R

Abstract
The present study was conducted to determine whether and how store-operated Ca(2+) entry (SOCE) in glomerular mesangial cells (MCs) was altered by high glucose (HG) and diabetes. Human MCs were treated with either normal glucose or HG for different time periods. Cyclopiazonic acid-induced SOCE was significantly greater in the MCs with 7-day HG treatment and the response was completely abolished by GSK-7975A, a selective inhibitor of store-operated Ca(2+) channels. Similarly, the inositol 1,4,5-trisphosphate-induced store-operated Ca(2+) currents were significantly enhanced in the MCs treated with HG for 7 days, and the enhanced response was abolished by both GSK-7975A and La(3+). In contrast, receptor-operated Ca(2+) entry in MCs was significantly reduced by HG treatment. Western blotting showed that HG increased the expression levels of STIM1 and Orai1 in cultured MCs. A significant HG effect occurred at a concentration as low as 10 mM, but required a minimum of 7 days. The HG effect in cultured MCs was recapitulated in renal glomeruli/cortex of both type I and II diabetic rats. Furthermore, quantitative real-time RT-PCR revealed that a 6-day HG treatment significantly increased the mRNA expression level of STIM1. However, the expressions of STIM2 and Orai1 transcripts were not affected by HG. Taken together, these results suggest that HG/diabetes enhanced SOCE in MCs by increasing STIM1/Orai1 protein expressions. HG upregulates STIM1 by promoting its transcription but increases Orai1 protein through a posttranscriptional mechanism.

PMID: 24623143 [PubMed - indexed for MEDLINE]

Role of the p63-FoxN1 regulatory axis in thymic epithelial cell homeostasis during aging.

Fri, 06/20/2014 - 4:05am
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Role of the p63-FoxN1 regulatory axis in thymic epithelial cell homeostasis during aging.

Cell Death Dis. 2013;4:e932

Authors: Burnley P, Rahman M, Wang H, Zhang Z, Sun X, Zhuge Q, Su DM

Abstract
The p63 gene regulates thymic epithelial cell (TEC) proliferation, whereas FoxN1 regulates their differentiation. However, their collaborative role in the regulation of TEC homeostasis during thymic aging is largely unknown. In murine models, the proportion of TAp63(+), but not ΔNp63(+), TECs was increased with age, which was associated with an age-related increase in senescent cell clusters, characterized by SA-β-Gal(+) and p21(+) cells. Intrathymic infusion of exogenous TAp63 cDNA into young wild-type (WT) mice led to an increase in senescent cell clusters. Blockade of TEC differentiation via conditional FoxN1 gene knockout accelerated the appearance of this phenotype to early middle age, whereas intrathymic infusion of exogenous FoxN1 cDNA into aged WT mice brought only a modest reduction in the proportion of TAp63(+) TECs, but an increase in ΔNp63(+) TECs in the partially rejuvenated thymus. Meanwhile, we found that the increased TAp63(+) population contained a high proportion of phosphorylated-p53 TECs, which may be involved in the induction of cellular senescence. Thus, TAp63 levels are positively correlated with TEC senescence but inversely correlated with expression of FoxN1 and FoxN1-regulated TEC differentiation. Thereby, the p63-FoxN1 regulatory axis in regulation of postnatal TEC homeostasis has been revealed.

PMID: 24263106 [PubMed - indexed for MEDLINE]

Nanoparticle-mediated catalase delivery protects human neurons from oxidative stress.

Fri, 06/20/2014 - 4:05am
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Nanoparticle-mediated catalase delivery protects human neurons from oxidative stress.

Cell Death Dis. 2013;4:e903

Authors: Singhal A, Morris VB, Labhasetwar V, Ghorpade A

Abstract
Several neurodegenerative diseases and brain injury involve reactive oxygen species and implicate oxidative stress in disease mechanisms. Hydrogen peroxide (H2O2) formation due to mitochondrial superoxide leakage perpetuates oxidative stress in neuronal injury. Catalase, an H2O2-degrading enzyme, thus remains an important antioxidant therapy target. However, catalase therapy is restricted by its labile nature and inadequate delivery. Here, a nanotechnology approach was evaluated using catalase-loaded, poly(lactic co-glycolic acid) nanoparticles (NPs) in human neuronal protection against oxidative damage. This study showed highly efficient catalase encapsulation capable of retaining ~99% enzymatic activity. NPs released catalase rapidly, and antioxidant activity was sustained for over a month. NP uptake in human neurons was rapid and nontoxic. Although human neurons were highly sensitive to H2O2, NP-mediated catalase delivery successfully protected cultured neurons from H2O2-induced oxidative stress. Catalase-loaded NPs significantly reduced H2O2-induced protein oxidation, DNA damage, mitochondrial membrane transition pore opening and loss of cell membrane integrity and restored neuronal morphology, neurite network and microtubule-associated protein-2 levels. Further, catalase-loaded NPs improved neuronal recovery from H2O2 pre-exposure better than free catalase, suggesting possible applications in ameliorating stroke-relevant oxidative stress. Brain targeting of catalase-loaded NPs may find wide therapeutic applications for oxidative stress-associated acute and chronic neurodegenerative disorders.

PMID: 24201802 [PubMed - indexed for MEDLINE]

Combining Select Neuropsychological Assessment with Blood-Based Biomarkers to Detect Mild Alzheimer's Disease: A Molecular Neuropsychology Approach.

Fri, 06/13/2014 - 4:04am
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Combining Select Neuropsychological Assessment with Blood-Based Biomarkers to Detect Mild Alzheimer's Disease: A Molecular Neuropsychology Approach.

J Alzheimers Dis. 2014 Jun 10;

Authors: Edwards M, Balldin VH, Hall J, O'Bryant S

Abstract
Background: Current work has sought to establish a rapid and cost effective means of screening for Alzheimer's disease (AD) with the most recent findings showing utility of integrating blood-based biomarkers with cognitive measures. Objective: The current project sought to create a combined biomarker-cognitive profile to detect mild AD. Methods: Data was analyzed from 266 participants (129 AD cases [Early AD n = 93; Very Early AD n = 36]; 137 controls) enrolled in the Texas Alzheimer's Research and Care Consortium (TARCC). Non-fasting serum samples were collected from each participant and assayed via a multi-plex biomarker assay platform using electrochemiluminescence. Logistic Regression was utilized to detect early AD using two serum biomarkers (TNFα and IL7), demographic information (age), and one neuropsychological measure (Clock 4-point) as predictor variable. Disease severity was determined via Clinical Dementia Rating (CDR) scale global scores. Results: In the total sample (all levels of CDR scores), the combination of biomarkers, cognitive test score, and demographics yielded the obtained sensitivity (SN) of 0.94, specificity (SP) of 0.90, and an overall accuracy of 0.92. When examining early AD cases (i.e.m CDR = 0.5-1), the biomarker-cognitive profile yielded SN of 0.94, SP of 0.85, and an overall accuracy of 0.91. When restricted to very early AD cases (i.e., CDR = 0.5), the biomarker-cognitive profile yielded SN of 0.97 and SP of 0.72, with an overall accuracy of 0.91. Conclusions: The combination of demographics, two biomarkers, and one cognitive test created a biomarker-cognitive profile that was highly accurate in detecting the presence of AD, even in the very early stages.

PMID: 24916542 [PubMed - as supplied by publisher]

Rad5 template switch pathway of DNA damage tolerance determines synergism between cisplatin and NSC109268 in Saccharomyces cerevisiae.

Fri, 06/13/2014 - 4:04am
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Rad5 template switch pathway of DNA damage tolerance determines synergism between cisplatin and NSC109268 in Saccharomyces cerevisiae.

PLoS One. 2013;8(10):e77666

Authors: Jain D, Siede W

Abstract
The success of cisplatin (CP) based therapy is often hindered by acquisition of CP resistance. We isolated NSC109268 as a compound altering cellular sensitivity to DNA damaging agents. Previous investigation revealed an enhancement of CP sensitivity by NSC109268 in wild-type Saccharomyces cerevisiae and CP-sensitive and -resistant cancer cell lines that correlated with a slower S phase traversal. Here, we extended these studies to determine the target pathway(s) of NSC109268 in mediating CP sensitization, using yeast as a model. We reasoned that mutants defective in the relevant target of NSC109268 should be hypersensitive to CP and the sensitization effect by NSC109268 should be absent or strongly reduced. A survey of various yeast deletion mutants converged on the Rad5 pathway of DNA damage tolerance by template switching as the likely target pathway of NSC109268 in mediating cellular sensitization to CP. Additionally, cell cycle delays following CP treatment were not synergistically influenced by NSC109268 in the CP hypersensitive rad5Δ mutant. The involvement of the known inhibitory activities of NSC109268 on 20S proteasome and phosphatases 2Cα and 2A was tested. In the CP hypersensitive ptc2Δptc3Δpph3Δ yeast strain, deficient for 2C and 2A-type phosphatases, cellular sensitization to CP by NSC109268 was greatly reduced. It is therefore suggested that NSC109268 affects CP sensitivity by inhibiting the activity of unknown protein(s) whose dephosphorylation is required for the template switch pathway.

PMID: 24130896 [PubMed - indexed for MEDLINE]

American Society of Biomechanics Clinical Biomechanics Award 2012: plantar shear stress distributions in diabetic patients with and without neuropathy.

Thu, 06/12/2014 - 4:04am
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American Society of Biomechanics Clinical Biomechanics Award 2012: plantar shear stress distributions in diabetic patients with and without neuropathy.

Clin Biomech (Bristol, Avon). 2014 Feb;29(2):223-9

Authors: Yavuz M

Abstract
BACKGROUND: The exact pathology of diabetic foot ulcers remains to be resolved. Evidence suggests that plantar shear forces play a major role in diabetic ulceration. Unfortunately, only a few manuscripts exist on the clinical implications of plantar shear. The purpose of this study was to compare global and regional peak plantar stress values in three groups; diabetic patients with neuropathy, diabetic patients without neuropathy and healthy control subjects.
METHODS: Fourteen diabetic neuropathic patients, 14 non-neuropathic diabetic control and 11 non-diabetic control subjects were recruited. Subjects walked on a custom-built stress plate that quantified plantar pressures and shear. Four stress variables were analyzed; peak pressure, peak shear, peak pressure-time and shear-time integral.
FINDINGS: Global peak values of peak shear (p = 0.039), shear-time integral (p = 0.002) and pressure-time integral (p = 0.003) were significantly higher in the diabetic neuropathic group. The local peak shear stress and shear-time integral were also significantly higher in diabetic neuropathic patients compared to both control groups, in particular, at the hallux and central forefoot. The local peak pressure and pressure-time integral were significantly different between the three groups at the medial and lateral forefoot.
INTERPRETATION: Plantar shear and shear-time integral magnitudes were elevated in diabetic patients with peripheral neuropathy, which indicates the potential clinical significance of these factors in ulceration. It is thought that further investigation of plantar shear would lead to a better understanding of ulceration pathomechanics, which in turn will assist researchers in developing more effective preventive devices and strategies.

PMID: 24332719 [PubMed - indexed for MEDLINE]

HIV-1 Nef Is Transferred from Expressing T Cells to Hepatocytic Cells through Conduits and Enhances HCV Replication.

Wed, 06/11/2014 - 4:04am
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HIV-1 Nef Is Transferred from Expressing T Cells to Hepatocytic Cells through Conduits and Enhances HCV Replication.

PLoS One. 2014;9(6):e99545

Authors: Park IW, Fan Y, Luo X, Ryou MG, Liu J, Green L, He JJ

Abstract
HIV-1 infection enhances HCV replication and as a consequence accelerates HCV-mediated hepatocellular carcinoma (HCC). However, the precise molecular mechanism by which this takes place is currently unknown. Our data showed that infectious HIV-1 failed to replicate in human hepatocytic cell lines. No discernible virus replication was observed, even when the cell lines transfected with HIV-1 proviral DNA were co-cultured with Jurkat T cells, indicating that the problem of liver deterioration in the co-infected patient is not due to the replication of HIV-1 in the hepatocytes of the HCV infected host. Instead, HIV-1 Nef protein was transferred from nef-expressing T cells to hepatocytic cells through conduits, wherein up to 16% (average 10%) of the cells harbored the transferred Nef, when the hepatocytic cells were co-cultured with nef-expressing Jurkat cells for 24 h. Further, Nef altered the size and numbers of lipid droplets (LD), and consistently up-regulated HCV replication by 1.5∼2.5 fold in the target subgenomic replicon cells, which is remarkable in relation to the initially indolent viral replication. Nef also dramatically augmented reactive oxygen species (ROS) production and enhanced ethanol-mediated up-regulation of HCV replication so as to accelerate HCC. Taken together, these data indicate that HIV-1 Nef is a critical element in accelerating progression of liver pathogenesis via enhancing HCV replication and coordinating modulation of key intra- and extra-cellular molecules for liver decay.

PMID: 24911518 [PubMed - as supplied by publisher]

Association of body burden of mercury with liver function test status in the U.S. population.

Tue, 06/10/2014 - 4:04am
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Association of body burden of mercury with liver function test status in the U.S. population.

Environ Int. 2014 Jun 5;70C:88-94

Authors: Lin YS, Ginsberg G, Caffrey JL, Xue J, Vulimiri SV, Nath RG, Sonawane B

Abstract
The majority of mercury (Hg) exposure in the US population is from consumption of fish contaminated with methylmercury (MeHg). Since inorganic Hg is the predominant form excreted in the feces and urine, hepatic biotransformation is a critical step in its normal clearance. This study was set to test the hypothesis that compromised liver function is associated with body burden of Hg as indirectly reflected by Hg sampled in blood and urine. From the National Health and Nutrition Examination Survey (NHANES, 2003-2008), 3769 adults aged 20years and above were selected for analysis. Hepatic function was inferred from the three standard serum liver-related enzyme activities, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-glutamyltransferase (GGT). Multivariate regression models were used to examine the associations of interest. Although urinary Hg was significantly correlated with serum Hg, the blood-urinary Hg relationship was influenced by liver function, which is also a function of demographic and lifestyle factors (e.g., gender). Although the results were only marginally significant for examined enzymes (p=0.06-0.08), urinary Hg tended to be lower among subjects with elevated liver enzymes, as compared to those with normal enzyme measurements. Conversely, MeHg generally represents a higher fraction of the total circulating Hg among those with elevated liver enzyme levels, especially among participants with elevations in all three enzymes (p=0.01). In conclusion, this population-based study identified an association between liver function, serum Hg and urinary Hg. Urinalysis may not be the optimal approach to monitor Hg elimination toxicokinetics or Hg exposure, since the majority of Hg excretion is fecal and the fidelity of urinary excretion may depend on healthy liver function. Future prospective studies are warranted to expand these findings.

PMID: 24908642 [PubMed - as supplied by publisher]

Actual involvement vs preference for involvement as an indicator of shared decision making-reply.

Mon, 06/09/2014 - 4:05am
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Actual involvement vs preference for involvement as an indicator of shared decision making-reply.

JAMA Intern Med. 2014 Apr;174(4):644

Authors: Meltzer DO, Ruhnke GW, Tak HJ

PMID: 24711194 [PubMed - indexed for MEDLINE]

The HIV antiretroviral drug efavirenz has LSD-like properties.

Fri, 06/06/2014 - 4:04am
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The HIV antiretroviral drug efavirenz has LSD-like properties.

Neuropsychopharmacology. 2013 Nov;38(12):2373-84

Authors: Gatch MB, Kozlenkov A, Huang RQ, Yang W, Nguyen JD, González-Maeso J, Rice KC, France CP, Dillon GH, Forster MJ, Schetz JA

Abstract
Anecdotal reports have surfaced concerning misuse of the HIV antiretroviral medication efavirenz ((4S)-6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-2,4-dihydro-1H-3,1-benzoxazin-2-one) by HIV patients and non-infected teens who crush the pills and smoke the powder for its psychoactive effects. Molecular profiling of the receptor pharmacology of efavirenz pinpointed interactions with multiple established sites of action for other known drugs of abuse including catecholamine and indolamine transporters, and GABAA and 5-HT(2A) receptors. In rodents, interaction with the 5-HT(2A) receptor, a primary site of action of lysergic acid diethylamine (LSD), appears to dominate efavirenz's behavioral profile. Both LSD and efavirenz reduce ambulation in a novel open-field environment. Efavirenz occasions drug-lever responding in rats discriminating LSD from saline, and this effect is abolished by selective blockade of the 5-HT(2A) receptor. Similar to LSD, efavirenz induces head-twitch responses in wild-type, but not in 5-HT(2A)-knockout, mice. Despite having GABAA-potentiating effects (like benzodiazepines and barbiturates), and interactions with dopamine transporter, serotonin transporter, and vesicular monoamine transporter 2 (like cocaine and methamphetamine), efavirenz fails to maintain responding in rats that self-administer cocaine, and it fails to produce a conditioned place preference. Although its molecular pharmacology is multifarious, efavirenz's prevailing behavioral effect in rodents is consistent with LSD-like activity mediated via the 5-HT(2A) receptor. This finding correlates, in part, with the subjective experiences in humans who abuse efavirenz and with specific dose-dependent adverse neuropsychiatric events, such as hallucinations and night terrors, reported by HIV patients taking it as a medication.

PMID: 23702798 [PubMed - indexed for MEDLINE]

Protein Redox Modification as a Cellular Defense Mechanism against Tissue Ischemic Injury.

Wed, 06/04/2014 - 4:05am
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Protein Redox Modification as a Cellular Defense Mechanism against Tissue Ischemic Injury.

Oxid Med Cell Longev. 2014;2014:343154

Authors: Yan LJ

Abstract
Protein oxidative or redox modifications induced by reactive oxygen species (ROS) or reactive nitrogen species (RNS) not only can impair protein function, but also can regulate and expand protein function under a variety of stressful conditions. Protein oxidative modifications can generally be classified into two categories: irreversible oxidation and reversible oxidation. While irreversible oxidation usually leads to protein aggregation and degradation, reversible oxidation that usually occurs on protein cysteine residues can often serve as an "on and off" switch that regulates protein function and redox signaling pathways upon stress challenges. In the context of ischemic tolerance, including preconditioning and postconditioning, increasing evidence has indicated that reversible cysteine redox modifications such as S-sulfonation, S-nitrosylation, S-glutathionylation, and disulfide bond formation can serve as a cellular defense mechanism against tissue ischemic injury. In this review, I highlight evidence of cysteine redox modifications as protective measures in ischemic injury, demonstrating that protein redox modifications can serve as a therapeutic target for attenuating tissue ischemic injury. Prospectively, more oxidatively modified proteins will need to be identified that can play protective roles in tissue ischemic injury, in particular, when the oxidative modifications of such identified proteins can be enhanced by pharmacological agents or drugs that are available or to be developed.

PMID: 24883175 [PubMed - as supplied by publisher]

Did budget cuts in Medicaid disproportionate share hospital payment affect hospital quality of care?

Wed, 06/04/2014 - 4:05am
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Did budget cuts in Medicaid disproportionate share hospital payment affect hospital quality of care?

Med Care. 2014 May;52(5):415-21

Authors: Hsieh HM, Bazzoli GJ, Chen HF, Stratton LS, Clement DG

Abstract
BACKGROUND: Medicaid Disproportionate Share Hospital (DSH) payments are one of the major sources of financial support for hospitals providing care to low-income patients. However, Medicaid DSH payments will be redirected from hospitals to subsidize individual health insurance purchase through US national health reform.
OBJECTIVES: The purpose of this study is to examine the association between Medicaid DSH payment reductions and nursing-sensitive and birth-related quality of care among Medicaid/uninsured and privately insured patients.
METHODS: Economic theory of hospital behavior was used as a conceptual framework, and longitudinal data for California hospitals from 1996 to 2003 were examined. Hospital-fixed effects regression models were estimated. The unit of analysis is at the hospital level, examining 2 aggregated measures based on the payer category of discharged patients (ie, Medicaid/uninsured and privately insured).
PRINCIPAL FINDINGS: The overall study findings provide at best weak evidence of an association between net Medicaid DSH payments and hospital quality of care for either Medicaid/uninsured or the privately insured patients. The magnitudes of the effects are small and only a few have significant DSH effects.
CONCLUSIONS: Although this study does not find evidence suggesting that reducing Medicaid DSH payments had a strong negative impact on hospital quality of care for Medicaid/uninsured or privately insured patients, the results are not necessarily predictive of the impact national health care reform will have. Research is necessary to monitor hospital quality of care as this reform is implemented.

PMID: 24714580 [PubMed - indexed for MEDLINE]

Collaborative EDNAP exercise on the IrisPlex system for DNA-based prediction of human eye colour.

Tue, 06/03/2014 - 4:05am
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Collaborative EDNAP exercise on the IrisPlex system for DNA-based prediction of human eye colour.

Forensic Sci Int Genet. 2014 Jul;11C:241-251

Authors: Chaitanya L, Walsh S, Andersen JD, Ansell R, Ballantyne K, Ballard D, Banemann R, Bauer CM, Bento AM, Brisighelli F, Capal T, Clarisse L, Gross TE, Haas C, Hoff-Olsen P, Hollard C, Keyser C, Kiesler KM, Kohler P, Kupiec T, Linacre A, Minawi A, Morling N, Nilsson H, Norén L, Ottens R, Palo JU, Parson W, Pascali VL, Phillips C, Porto MJ, Sajantila A, Schneider PM, Sijen T, Söchtig J, Syndercombe-Court D, Tillmar A, Turanska M, Vallone PM, Zatkalíková L, Zidkova A, Branicki W, Kayser M

Abstract
The IrisPlex system is a DNA-based test system for the prediction of human eye colour from biological samples and consists of a single forensically validated multiplex genotyping assay together with a statistical prediction model that is based on genotypes and phenotypes from thousands of individuals. IrisPlex predicts blue and brown human eye colour with, on average, >94% precision accuracy using six of the currently most eye colour informative single nucleotide polymorphisms (HERC2 rs12913832, OCA2 rs1800407, SLC24A4 rs12896399, SLC45A2 (MATP) rs16891982, TYR rs1393350, and IRF4 rs12203592) according to a previous study, while the accuracy in predicting non-blue and non-brown eye colours is considerably lower. In an effort to vigorously assess the IrisPlex system at the international level, testing was performed by 21 laboratories in the context of a collaborative exercise divided into three tasks and organised by the European DNA Profiling (EDNAP) Group of the International Society of Forensic Genetics (ISFG). Task 1 involved the assessment of 10 blood and saliva samples provided on FTA cards by the organising laboratory together with eye colour phenotypes; 99.4% of the genotypes were correctly reported and 99% of the eye colour phenotypes were correctly predicted. Task 2 involved the assessment of 5 DNA samples extracted by the host laboratory from simulated casework samples, artificially degraded, and provided to the participants in varying DNA concentrations. For this task, 98.7% of the genotypes were correctly determined and 96.2% of eye colour phenotypes were correctly inferred. For Tasks 1 and 2 together, 99.2% (1875) of the 1890 genotypes were correctly generated and of the 15 (0.8%) incorrect genotype calls, only 2 (0.1%) resulted in incorrect eye colour phenotypes. The voluntary Task 3 involved participants choosing their own test subjects for IrisPlex genotyping and eye colour phenotype inference, while eye photographs were provided to the organising laboratory and judged; 96% of the eye colour phenotypes were inferred correctly across 100 samples and 19 laboratories. The high success rates in genotyping and eye colour phenotyping clearly demonstrate the reproducibility and the robustness of the IrisPlex assay as well as the accuracy of the IrisPlex model to predict blue and brown eye colour from DNA. Additionally, this study demonstrates the ease with which the IrisPlex system is implementable and applicable across forensic laboratories around the world with varying pre-existing experiences.

PMID: 24880832 [PubMed - as supplied by publisher]

PTEN degradation after ischemic stroke: a double-edged sword.

Mon, 06/02/2014 - 4:05am
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PTEN degradation after ischemic stroke: a double-edged sword.

Neuroscience. 2014 May 26;

Authors: Li W, Huang R, Chen Z, Yan LJ, Simpkins JW, Yang SH

Abstract
Tumor suppressor PTEN is highly expressed in neurons and PTEN inhibition has been reported to be neuroprotective against ischemic stroke in experimental models. On the other hand, PTEN deletion has been shown to lead to cognitive impairment. In current study, we examined the expression and functions of PTEN in ischemic stroke. We found rapid S-nitrosylation and degradation of PTEN after cerebral ischemia/reperfusion injury. PTEN degradation leads to activation of Akt. PTEN partial deletion or PTEN inhibition increased expression of GABAA receptor (GABAAR) γ2 subunit and enhanced GABAA receptor current. After cerebral ischemia, increased expression of GABAAR γ2 subunit was observed in the ischemia region and penumbra area. We also observed PTEN loss in astrocytes after cerebral ischemia. Astrocytic PTEN partial knockout increased astrocyte activation and exacerbated ischemic damage. We speculated that ischemic stroke induced neuronal PTEN degradation, hence enhanced GABAA receptor-medicated neuronal activity inhibition which could attenuate excitotoxicity and provide neuroprotection during the acute phase after stroke, while inhibit long term functional recovery and contribute vascular cognitive impairment after stroke. On the other hand, ischemic stroke induced astrocytic PTEN loss enhance ischemic damage and astrogliosis. Taken together, our study indicates that ischemic stroke induces rapid PTEN degradation in both neurons and astrocytes which play both protective and detrimental action in a spatiotemporal- and cell type-dependent manner. Our study provides critical insight for targeting PTEN signaling pathway for stroke treatment.

PMID: 24875179 [PubMed - as supplied by publisher]