Recent Research Articles from UNTHSC

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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]

Exome sequencing identifies somatic gain-of-function PPM1D mutations in brainstem gliomas.

Tue, 06/03/2014 - 4:05am
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Exome sequencing identifies somatic gain-of-function PPM1D mutations in brainstem gliomas.

Nat Genet. 2014 Jun 1;

Authors: Zhang L, Chen LH, Wan H, Yang R, Wang Z, Feng J, Yang S, Jones S, Wang S, Zhou W, Zhu H, Killela PJ, Zhang J, Wu Z, Li G, Hao S, Wang Y, Webb JB, Friedman HS, Friedman AH, McLendon RE, He Y, Reitman ZJ, Bigner DD, Yan H

Abstract
Gliomas arising in the brainstem and thalamus are devastating tumors that are difficult to surgically resect. To determine the genetic and epigenetic landscape of these tumors, we performed exomic sequencing of 14 brainstem gliomas (BSGs) and 12 thalamic gliomas. We also performed targeted mutational analysis of an additional 24 such tumors and genome-wide methylation profiling of 45 gliomas. This study led to the discovery of tumor-specific mutations in PPM1D, encoding wild-type p53-induced protein phosphatase 1D (WIP1), in 37.5% of the BSGs that harbored hallmark H3F3A mutations encoding p.Lys27Met substitutions. PPM1D mutations were mutually exclusive with TP53 mutations in BSG and attenuated p53 activation in vitro. PPM1D mutations were truncating alterations in exon 6 that enhanced the ability of PPM1D to suppress the activation of the DNA damage response checkpoint protein CHK2. These results define PPM1D as a frequent target of somatic mutation and as a potential therapeutic target in brainstem gliomas.

PMID: 24880341 [PubMed - as supplied by publisher]

Protease-Activated Receptor 2 is Upregulated by Acanthamoeba Plasminogen Activator and Induces Proinflammatory Cytokine in Corneal Epithelial Cells.

Mon, 06/02/2014 - 4:05am
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Protease-Activated Receptor 2 is Upregulated by Acanthamoeba Plasminogen Activator and Induces Proinflammatory Cytokine in Corneal Epithelial Cells.

Invest Ophthalmol Vis Sci. 2014 May 29;

Authors: Alizadeh H, Tripathi T, Abdi M

Abstract
PURPOSE. Acanthamoeba plasminogen activator (aPA), is a serine protease elaborated by Acanthamoeba trophozoites and is involved in pathogenesis of Acanthamoeba keratitis (AK). The aim of this study was to explore if aPA stimulates proinflammatory cytokine in human corneal epithelial (HCE) cells via the protease-activated receptors (PARs) pathway. METHOD. HCE cells were incubated with or without aPA, PAR1-agonists (Thrombin, and TRAP-6), and PAR2-agonists (SLIGRL-NH2, AC-55541) for 24 and 48 hours. Inhibition of PAR1 and PAR2 involved pre-incubating the HCE cells for 1 hour with the antagonist of PAR1 (SCH79797) and PAR2 (FSLLRY-NH2) with or without aPA. HCE cells also were pre-incubated with PAR1 and PAR2 antagonists and then incubated with or without PAR 1 agonists and PAR 2 agonists. Expression of PAR1 and PAR2 was examined by qRT-PCR, flow cytometry, and immunocytochemistry. IL-8 expression was quantified by qRT-PCR and ELISA. RESULTS. HCE cells constitutively expressed, PAR1, and PAR2 mRNA. aPA and PAR2-agonists significantly upregulated PAR2 mRNA expression respectively (P<0.05). PAR2-antagonist significantly inhibited aPA and PAR2-agonists-induced PAR2 mRNA expression in HCE cells P<0.05). PAR1-agonists, but not aPA, significantly upregulated PAR1 mRNA expression, which was significantly inhibited by PAR1-antagonist in HCE cells. aPA and PAR2-agonists stimulated IL-8 mRNA expression and protein production, which is significantly diminished by PAR2-antagonist (P<0.5). PAR1-antagonist did not alter aPA-stimulated IL-8 mRNA expression and protein production in HCE cells. CONCLUSIONS. aPA specifically induces expression and production of IL-8 in HCE cells via PAR2 pathway and PAR2-antagonists may be used as a therapeutic target in AK.

PMID: 24876278 [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]

Detergent screening of the human voltage-gated ion channel (Hv1) using fluorescence-detection size exclusion chromatography.

Sat, 05/31/2014 - 4:07am
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Detergent screening of the human voltage-gated ion channel (Hv1) using fluorescence-detection size exclusion chromatography.

Protein Sci. 2014 May 23;

Authors: Agharkar A, Rzadkowolski J, McBroom M, Gonzales EB

Abstract
The human voltage-gated proton channel (Hv1) is a membrane protein consisting of four transmembrane domains and internal amino- and carboxy-termini. The protein is activated by membrane depolarization, similar to other voltage-sensitive proteins. However, the Hv1 proton channel lacks a traditional ion pore. The human Hv1 proton channel has been implicated in mediating sperm capacitance, stroke, and most recently as a biomarker/mediator of cancer metastasis. Recently, the three-dimensional structures for homologues of this voltage-gated proton channel were reported. However, it is not clear what artificial environment is needed to facilitate the isolation and purification of the human Hv1 proton channel for structural study. In the present study, we generated a chimeric protein that placed an enhanced green fluorescent protein (EGFP) to the amino-terminus of the human Hv1 proton channel (termed EGFP-Hv1). The chimeric protein was expressed in a baculovirus expression system using Sf9 cells and subjected to detergent screening using fluorescence-detection size exclusion chromatography (FSEC). The EGFP-Hv1 proton channel can be solubilized in the zwitterionic detergent Anzergent 3-12 and the nonionic n-dodecyl-β-D-maltoside (DDM) with little protein aggregation and a prominent monomeric protein peak at 48 hours post infection. Furthermore, we demonstrate that the chimeric protein exhibits a monomeric protein peak, which is distinguishable from protein aggregates, at the final size exclusion chromatography purification step. Taken together, we can conclude that solubilization in DDM will provide a useable final product for further structural characterization of the full-length human Hv1 proton channel.

PMID: 24863684 [PubMed - as supplied by publisher]

Editorial comment: Symposium: 2012 Musculoskeletal Infection Society.

Sat, 05/31/2014 - 4:07am
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Editorial comment: Symposium: 2012 Musculoskeletal Infection Society.

Clin Orthop Relat Res. 2013 Oct;471(10):3098-9

Authors: Nana A, Wongworawat MD

PMID: 23836244 [PubMed - indexed for MEDLINE]

Genome-guided discovery of diverse natural products from Burkholderia sp.

Sat, 05/31/2014 - 4:07am
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Genome-guided discovery of diverse natural products from Burkholderia sp.

J Ind Microbiol Biotechnol. 2014 Feb;41(2):275-84

Authors: Liu X, Cheng YQ

Abstract
Burkholderia species have emerged as a new source of diverse natural products. This mini-review covers all of the natural products discovered in recent years from Burkholderia sp. by genome-guided approaches--these refer to the use of bacterial genome sequence as an entry point for in silico structural prediction, wet lab experimental design, and execution. While reliable structural prediction based on cryptic biosynthetic gene cluster sequence was not always possible due to noncanonical domains and/or module organization of a deduced biosynthetic pathway, a molecular genetic method was often employed to detect or alter the expression level of the gene cluster to achieve an observable phenotype, which facilitated downstream natural product purification and identification. Those examples of natural product discovery from Burkholderia sp. provide practical guidance for future exploration of Gram-negative bacteria as a new source of natural products.

PMID: 24212473 [PubMed - indexed for MEDLINE]

Targeted Nanoparticles for Pediatric Leukemia Therapy.

Wed, 05/28/2014 - 4:04am
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Targeted Nanoparticles for Pediatric Leukemia Therapy.

Front Oncol. 2014;4:101

Authors: Basha R, Sabnis N, Heym K, Bowman WP, Lacko AG

Abstract
The two major forms of leukemia, acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), account for about one-third of the malignancies diagnosed in children. Despite the marked successes in ALL and AML treatment, concerns remain regarding the occurrence of resistant disease in subsets of patients, the residual effects of therapy that often persist for decades beyond the cessation of treatment. Therefore, new approaches are needed to reduce or to avoid off target toxicities, associated with chemotherapy and their long-term residual effects. Recently, nanotechnology has been employed to enhance cancer therapy, via improving the bioavailability and therapeutic efficacy of anti-cancer agents. While in the last several years, numerous review articles appeared detailing the size, composition, assembly, and performance evaluation of different types of drug carrying nanoparticles, the description and evaluation of lipoprotein-based drug carriers have been conspicuously absent from most of these major reviews. The current review focuses on such information regarding nanoparticles with an emphasis on high density lipoprotein-based drug delivery systems to examine their potential role(s) in the enhanced treatment of children with leukemia.

PMID: 24860784 [PubMed - as supplied by publisher]

Astrocyte Elevated Gene-1 is a Novel Modulator of HIV-1-Associated Neuroinflammation via Regulation of Nuclear Factor-κB Signaling and Excitatory Amino Acid Transporter-2 Repression.

Tue, 05/27/2014 - 4:04am
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Astrocyte Elevated Gene-1 is a Novel Modulator of HIV-1-Associated Neuroinflammation via Regulation of Nuclear Factor-κB Signaling and Excitatory Amino Acid Transporter-2 Repression.

J Biol Chem. 2014 May 22;

Authors: Vartak-Sharma N, Gelman BB, Joshi C, Borgmann K, Ghorpade A

Abstract
Astrocyte Elevated Gene-1 (AEG-1), a novel HIV-1 and TNF-α inducible oncogene, has generated significant interest in the field of cancer research as a therapeutic target for many metastatic aggressive tumors. However, little is known about its role in astrocyte responses during HIV-1 CNS infection, and whether it contributes towards the development of HIV-1-associated neurocognitive disorders (HAND). Therefore, in this study, we investigated changes in AEG-1 CNS expression in HIV-1 infected brain tissues, and elucidated a potential mechanism of AEG-1-mediated regulation of HIV-1-associated neuroinflammation. Immunoblotting and immunohistochemical analyses of HIV-1 seropositive and HIV-1 encephalitic human brain tissues revealed significantly elevated levels of AEG-1 protein. Immunohistochemical analyses of HIV-1 Tat transgenic mouse brain tissues also showed a marked increase in AEG-1 staining. Similar to in vivo observations, cultured astrocytes expressing HIV-1 Tat also revealed AEG-1 and cytokine upregulation. Astrocytes treated with HAND-relevant stimuli, TNF-α, IL-1β and HIV-1, also significantly induced AEG-1 expression and nuclear translocation via activation of the nuclear factor (NF)-κB pathway. Co-immunoprecipitation studies demonstrated IL-1β or TNF-α-induced AEG-1 interaction with NF-κB p65 subunit. AEG-1 knockdown decreased NF-κB activation, nuclear translocation and transcriptional output in TNF-α-treated astrocytes. Moreover, IL-1β treatment of AEG-1 overexpressing astrocytes significantly lowered expression of excitatory amino acid transporter-2 (EAAT2), increased expression of EAAT2 repressor, YY1, and reduced glutamate clearance, a major transducer of excitotoxic neuronal damage. Findings from this study identify a novel transcriptional cofactor function of AEG-1 and further implicate AEG-1 in HIV-1-associated neuroinflammation.

PMID: 24855648 [PubMed - as supplied by publisher]

Nomenclature update and allele repeat structure for the markers DYS518 and DYS449.

Tue, 05/27/2014 - 4:04am
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Nomenclature update and allele repeat structure for the markers DYS518 and DYS449.

Forensic Sci Int Genet. 2014 May 19;

Authors: Mulero J, Ballantyne J, Ballantyne K, Budowle B, Coble M, Gusmão L, Roewer L, Kayser M

PMID: 24854343 [PubMed - as supplied by publisher]

Utility of amplification enhancers in low copy number DNA analysis.

Sat, 05/24/2014 - 4:07am
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Utility of amplification enhancers in low copy number DNA analysis.

Int J Legal Med. 2014 May 22;

Authors: Marshall PL, King JL, Budowle B

Abstract
One parameter that impacts the robustness and reliability of forensic DNA analyses is the amount of template DNA used in the polymerase chain reaction (PCR). With short tandem repeat (STR) typing, low copy number (LCN) DNA samples can present exaggerated stochastic effects during the PCR that result in heterozygote peak height imbalance, allele drop out, and increased stutter. Despite these effects, there has been little progress toward decreasing the formation of stutter products and heterozygote peak imbalance effects during PCR. In an attempt to develop a more robust system that is less refractory to stochastic effects, the PCR additives, betaine, DMSO, PEG, and PCRboost®, were investigated on low-quantity DNA samples. The effects of the additives were assessed by evaluating STR typing results. Of the four additives, the only positive effects were observed with betaine treatment. Betaine, at a final concentration of 1.25 mol/L, was found to improve the robustness of the amplification, specifically by decreasing stutter in a dual locus system. In contrast, the addition of 1.25 mol/L betaine to commercial STR amplification kits did not affect stutter ratios. However, the addition of betaine did lead to increased yield of PCR products in all commercial kits tested. The results support that betaine can improve amplification efficiency of LCN DNA samples.

PMID: 24848516 [PubMed - as supplied by publisher]

Psychological Distress and Emergency Department Utilization in the United States: Evidence from the Medical Expenditure Panel Survey.

Fri, 05/23/2014 - 4:05am
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Psychological Distress and Emergency Department Utilization in the United States: Evidence from the Medical Expenditure Panel Survey.

Acad Emerg Med. 2014 May;21(5):510-519

Authors: Stockbridge EL, Wilson FA, Pagán JA

Abstract
OBJECTIVES: Psychological distress not only has substantial health and social consequences, but is also associated with emergency department (ED) use. Previous studies have typically used cross-sectional data to focus on the relation between serious psychological distress and dichotomized ED utilization measures, without assessing the volume of ED use or examining nonserious levels of psychological distress. The objective of this study was to explore the association between ED utilization volume and the full spectrum of psychological distress.
METHODS: Data from Panel 14 of the Medical Expenditure Panel Survey (MEPS; 2009-2010, n = 9,743) provided a nationally representative sample of U.S. individuals. ED utilization volume and three specifications of the Kessler Psychological Distress Scale (K6) were analyzed: a dichotomous serious/no serious psychological distress measure, a five-category ordinal measure, and a scale measure with a range of 0 to 24. Negative binomial-logit hurdle regression models were used to analyze how the different specifications of the K6 psychological distress measure were related to ED use.
RESULTS: Adults with serious psychological distress in 2009 had 1.59 (95% confidence interval [CI] = 1.15 to 2.20) times greater adjusted odds of having one or more ED visits in 2010 than those without serious psychological distress. Nonserious psychological distress levels in 2009 were also associated with increased adjusted odds of having at least one ED visit in 2010. The K6 scores showed a dose-response relationship in terms of the adjusted odds of having one or more ED visits. The adjusted odds ratios (ORs) were 1.86 (95% CI = 1.37 to 2.54) for adults with K6 scores at or above 11, OR 1.76 (95% CI = 1.38 to 2.25) for adults with K6 scores between 6 and 10, OR 1.33 (95% CI = 1.05 to 1.68) for adults with K6 scores between 3 and 5, and OR 1.17 (95% CI = 0.92 to 1.48) for adults with K6 scores of 1 or 2. In addition, the adjusted odds of having one or more ED visits in 2010 significantly increased with increasing psychological distress in 2009 (OR = 1.04, 95% CI = 1.03 to 1.06). Each additional point added to the K6 scale results in an increase in the adjusted odds of an ED visit.
CONCLUSIONS: Even a low level of psychological distress, and not just serious psychological distress, may be an early indicator of future ED use. These results highlight the need to develop novel responses to better manage or avert ED use not only for adults with serious psychological distress but also for those who are experiencing even mild symptoms of psychological distress.

PMID: 24842501 [PubMed - as supplied by publisher]

Organizational downsizing and depressive symptoms in the European recession: the experience of workers in france, hungary, sweden and the United kingdom.

Fri, 05/23/2014 - 4:05am
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Organizational downsizing and depressive symptoms in the European recession: the experience of workers in france, hungary, sweden and the United kingdom.

PLoS One. 2014;9(5):e97063

Authors: Brenner MH, Andreeva E, Theorell T, Goldberg M, Westerlund H, Leineweber C, Hanson LL, Imbernon E, Bonnaud S

Abstract
BACKGROUND: Organizational downsizing has become highly common during the global recession of the late 2000s with severe repercussions on employment. We examine whether the severity of the downsizing process is associated with a greater likelihood of depressive symptoms among displaced workers, internally redeployed workers and lay-off survivors.
METHODS: A cross-sectional survey involving telephone interviews was carried out in France, Hungary, Sweden and the United Kingdom. The study analyzes data from 758 workers affected by medium- and large-scale downsizing, using multiple logistic regression.
MAIN RESULTS: Both unemployment and surviving layoffs were significantly associated with depressive symptoms, as compared to reemployment, but the perceived procedural justice of a socially responsible downsizing process considerably mitigated the odds of symptoms. Perception of high versus low justice was assessed along several downsizing dimensions. In the overall sample, chances to have depressive symptoms were significantly reduced if respondents perceived the process as transparent and understandable, fair and unbiased, well planned and democratic; if they trusted the employer's veracity and agreed with the necessity for downsizing. The burden of symptoms was significantly greater if the process was perceived to be chaotic. We further tested whether perceived justice differently affects the likelihood of depressive symptoms among distinct groups of workers. Findings were that the odds of symptoms largely followed the same patterns of effects across all groups of workers. Redeploying and supporting surplus employees through the career change process-rather than forcing them to become unemployed-makes a substantial difference as to whether they will suffer from depressive symptoms.
CONCLUSIONS: While depressive symptoms affect both unemployed and survivors, a just and socially responsible downsizing process is important for the emotional health of workers.

PMID: 24841779 [PubMed - in process]

The unique protein kinase Cη: Implications for breast cancer (Review).

Fri, 05/23/2014 - 4:05am
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The unique protein kinase Cη: Implications for breast cancer (Review).

Int J Oncol. 2014 May 19;

Authors: Pal D, Basu A

Abstract
Deregulation of key signal transduction pathways that govern important cellular processes leads to cancer. The development of effective therapeutics for cancer warrants a comprehensive understanding of the signaling pathways that are deregulated in cancer. The protein kinase C (PKC) family has served as an attractive target for cancer therapy for decades owing to its crucial roles in several cellular processes. PKCη is a novel member of the PKC family that plays critical roles in various cellular processes such as growth, proliferation, differentiation and cell death. The regulation of PKCη appears to be unique compared to other PKC isozymes, and there are conflicting reports regarding its role in cancer. This review focuses on the unique aspects of PKCη in terms of its structure, regulation and subcellular distribution and speculates on how these features could account for its distinct functions. We have also discussed the functional implications of PKCη in cancer with particular emphasis on breast cancer.

PMID: 24841225 [PubMed - as supplied by publisher]