Recent Research Articles from UNTHSC

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Synthesis, pharmacological evaluation and molecular modeling studies of triazole containing dopamine D3 receptor ligands.

Tue, 01/06/2015 - 12:29am

Synthesis, pharmacological evaluation and molecular modeling studies of triazole containing dopamine D3 receptor ligands.

Bioorg Med Chem Lett. 2014 Dec 17;

Authors: Peng X, Wang Q, Mishra Y, Xu J, Reichert DE, Malik M, Taylor M, Luedtke RR, Mach RH

Abstract
A series of 2-methoxyphenyl piperazine analogues containing a triazole ring were synthesized and their in vitro binding affinities at human dopamine D2 and D3 receptors were evaluated. Compounds 5b, 5c, 5d, and 4g, demonstrate high affinity for dopamine D3 receptors and moderate selectivity for the dopamine D3 versus D2 receptor subtypes. To further examine their potential as therapeutic agents, their intrinsic efficacy at both D2 and D3 receptors was determined using a forskolin-dependent adenylyl cyclase inhibition assay. Affinity at dopamine D4 and serotonin 5-HT1A receptors was also determined. In addition, information from previous molecular modeling studies of the binding of a panel of 163 structurally-related benzamide analogues at dopamine D2 and D3 receptors was applied to this series of compounds. The results of the modeling studies were consistent with our previous experimental data. More importantly, the modeling study results explained why the replacement of the amide linkage with the hetero-aromatic ring leads to a reduction in the affinity of these compounds at D3 receptors.

PMID: 25556097 [PubMed - as supplied by publisher]

Joint pain in a man with lung cancer.

Sun, 01/04/2015 - 4:29am

Joint pain in a man with lung cancer.

Cleve Clin J Med. 2015 Jan;82(1):18-9

Authors: Jernigan E, Siddiqi N, Peddi P

PMID: 25552621 [PubMed - in process]

Organizational downsizing and depressive symptoms in the European recession: the experience of workers in France, Hungary, Sweden and the United kingdom.

Fri, 01/02/2015 - 4:30am
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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 - indexed for MEDLINE]

Astragaloside IV prevents damage to human mesangial cells through the inhibition of the NADPH oxidase/ROS/Akt/NF‑κB pathway under high glucose conditions.

Thu, 01/01/2015 - 4:30am
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Astragaloside IV prevents damage to human mesangial cells through the inhibition of the NADPH oxidase/ROS/Akt/NF‑κB pathway under high glucose conditions.

Int J Mol Med. 2014 Jul;34(1):167-76

Authors: Sun L, Li W, Li W, Xiong L, Li G, Ma R

Abstract
Glomerular hypertrophy and hyperfiltration are the two major pathological characteristics of the early stages of diabetic nephropathy (DN), which are respectively related to mesangial cell (MC) proliferation and a decrease in calcium influx conducted by canonical transient receptor potential cation channel 6 (TRPC6). The marked increase in the production of reactive oxygen species (ROS) induced by hyperglycemia is the main sponsor of multiple pathological pathways in DN. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is an important source of ROS production in MCs. Astragaloside IV (AS‑IV) is an active ingredient of Radix Astragali which has a potent antioxidative effect. In this study, we aimed to investigate whether high glucose (HG)‑induced NADPH oxidase activation and ROS production contribute to MC proliferation and the downregulation of TRPC6 expression; we also wished to determine the effects of AS‑IV on MCs under HG conditions. Using a human glomerular mesangial cell line, we found that treatment with AS‑IV for 48 h markedly attenuated HG‑induced proliferation and the hypertrophy of MCs in a dose‑dependent manner. The intracellular ROS level was also markedly reduced following treatment with AS‑IV. In addition, the enhanced activity of NADPH oxidase and the expression level of NADPH oxidase 4 (Nox4) protein were decreased. Treatment with AS‑IV also inhibited the phosphorylation level of Akt and IκBα in the MCs. In addition, TRPC6 protein expression and the intracellular free calcium concentration were also markedly reduced following treatment with AS‑IV under HG conditions. These results suggest that AS‑IV inhibits HG‑induced mesangial cell proliferation and glomerular contractile dysfunction through the NADPH oxidase/ROS/Akt/nuclear factor‑κB (NF‑κB) pathway, providing a new perspective for the clinical treatment of DN.

PMID: 24718766 [PubMed - indexed for MEDLINE]

Platelet Activation after Presyncope by Lower Body Negative Pressure in Humans.

Wed, 12/31/2014 - 4:30am

Platelet Activation after Presyncope by Lower Body Negative Pressure in Humans.

PLoS One. 2014;9(12):e116174

Authors: Zaar M, Fedyk CG, Pidcoke HF, Scherer MR, Ryan KL, Rickards CA, Hinojosa-Laborde C, Convertino VA, Cap AP

Abstract
Central hypovolemia elevates hemostatic activity which is essential for preventing exsanguination after trauma, but platelet activation to central hypovolemia has not been described. We hypothesized that central hypovolemia induced by lower body negative pressure (LBNP) activates platelets. Eight healthy subjects were exposed to progressive central hypovolemia by LBNP until presyncope. At baseline and 5 min after presyncope, hemostatic activity of venous blood was evaluated by flow cytometry, thrombelastography, and plasma markers of coagulation and fibrinolysis. Cell counts were also determined. Flow cytometry revealed that LBNP increased mean fluorescence intensity of PAC-1 by 1959±455 units (P<0.001) and percent of fluorescence-positive platelets by 27±18%-points (P = 0.013). Thrombelastography demonstrated that coagulation was accelerated (R-time decreased by 0.8±0.4 min (P = 0.001)) and that clot lysis increased (LY60 by 6.0±5.8%-points (P = 0.034)). Plasma coagulation factor VIII and von Willebrand factor ristocetin cofactor activity increased (P = 0.011 and P = 0.024, respectively), demonstrating increased coagulation activity, while von Willebrand factor antigen was unchanged. Plasma protein C activity and tissue-type plasminogen activator increased (P = 0.007 and P = 0.017, respectively), and D-dimer increased by 0.03±0.02 mg l-1 (P = 0.031), demonstrating increased fibrinolytic activity. Plasma prothrombin time and activated partial thromboplastin time were unchanged. Platelet count increased by 15±13% (P = 0.014) and red blood cells by 9±4% (P = 0.002). In humans, LBNP-induced presyncope activates platelets, as evidenced by increased exposure of active glycoprotein IIb/IIIa, accelerates coagulation. LBNP activates fibrinolysis, similar to hemorrhage, but does not alter coagulation screening tests, such as prothrombin time and activated partial thromboplastin time. LBNP results in increased platelet counts, but also in hemoconcentration.

PMID: 25546432 [PubMed - as supplied by publisher]

Neither the HIV Protease Inhibitor Lopinavir-Ritonavir nor the Antimicrobial Trimethoprim-Sulfamethoxazole Prevent Malaria Relapse in Plasmodium cynomolgi-Infected Non-Human Primates.

Wed, 12/31/2014 - 4:30am

Neither the HIV Protease Inhibitor Lopinavir-Ritonavir nor the Antimicrobial Trimethoprim-Sulfamethoxazole Prevent Malaria Relapse in Plasmodium cynomolgi-Infected Non-Human Primates.

PLoS One. 2014;9(12):e115506

Authors: Hobbs CV, Dixit S, Penzak SR, Sahu T, Orr-Gonzalez S, Lambert L, Zeleski K, Chen J, Neal J, Borkowsky W, Wu Y, Duffy PE

Abstract
Plasmodium vivax malaria causes significant morbidity and mortality worldwide, and only one drug is in clinical use that can kill the hypnozoites that cause P. vivax relapses. HIV and P. vivax malaria geographically overlap in many areas of the world, including South America and Asia. Despite the increasing body of knowledge regarding HIV protease inhibitors (HIV PIs) on P. falciparum malaria, there are no data regarding the effects of these treatments on P. vivax's hypnozoite form and clinical relapses of malaria. We have previously shown that the HIV protease inhibitor lopinavir-ritonavir (LPV-RTV) and the antibiotic trimethoprim sulfamethoxazole (TMP-SMX) inhibit Plasmodium actively dividing liver stages in rodent malarias and in vitro in P. falciparum, but effect against Plasmodium dormant hypnozoite forms remains untested. Separately, although other antifolates have been tested against hypnozoites, the antibiotic trimethoprim sulfamethoxazole, commonly used in HIV infection and exposure management, has not been evaluated for hypnozoite-killing activity. Since Plasmodium cynomolgi is an established animal model for the study of liver stages of malaria as a surrogate for P. vivax infection, we investigated the antimalarial activity of these drugs on Plasmodium cynomolgi relapsing malaria in rhesus macaques. Herein, we demonstrate that neither TMP-SMX nor LPV-RTV kills hypnozoite parasite liver stage forms at the doses tested. Because HIV and malaria geographically overlap, and more patients are being managed for HIV infection and exposure, understanding HIV drug impact on malaria infection is important.

PMID: 25541998 [PubMed - in process]

Molecular mechanisms of maternal vascular dysfunction in preeclampsia.

Wed, 12/31/2014 - 4:30am

Molecular mechanisms of maternal vascular dysfunction in preeclampsia.

Trends Mol Med. 2014 Dec 2;

Authors: Goulopoulou S, Davidge ST

Abstract
In preeclampsia, as a heterogeneous syndrome, multiple pathways have been proposed for both the causal as well as the perpetuating factors leading to maternal vascular dysfunction. Postulated mechanisms include imbalance in the bioavailability and activity of endothelium-derived contracting and relaxing factors and oxidative stress. Studies have shown that placenta-derived factors [antiangiogenic factors, microparticles (MPs), cell-free nucleic acids] are released into the maternal circulation and act on the vascular wall to modify the secretory capacity of endothelial cells and alter the responsiveness of vascular smooth muscle cells to constricting and relaxing stimuli. These molecules signal their deleterious effects on the maternal vascular wall via pathways that provide the molecular basis for novel and effective therapeutic interventions.

PMID: 25541377 [PubMed - as supplied by publisher]

Angiotensin II Type 1a Receptors in Subfornical Organ contributes towards Chronic Intermittent Hypoxia associated sustained increase in Mean Arterial Pressure.

Wed, 12/31/2014 - 4:30am

Angiotensin II Type 1a Receptors in Subfornical Organ contributes towards Chronic Intermittent Hypoxia associated sustained increase in Mean Arterial Pressure.

Am J Physiol Heart Circ Physiol. 2014 Dec 24;:ajpheart.00747.2014

Authors: Saxena A, Little JT, Nedungadi TP, Cunningham JT

Abstract
Sleep apnea is associated with hypertension. The mechanisms contributing to sustained increase in mean arterial pressure (MAP) even during normoxic awake-state remain unknown. Rats exposed to chronic intermittent hypoxia for 7 days, a model of the hypoxemia associated with sleep apnea, exhibit sustained increases in MAP even during the normoxic dark phase. Activation of the renin-angiotensin system (RAS) has been implicated in CIH hypertension. Since the subfornical organ (SFO) serves as a primary target for the central actions of circulating ANG II, we tested the effects of ANG II type1a receptor (AT1aR) knockdown in SFO on the sustained increase in mean arterial pressure in this CIH model. Adeno-associated virus carrying GFP and shRNA against either AT1aR or a scrambled control sequence (SCM) was stereotaxically injected in the SFO of rats. After recovery, MAP, heart rate, respiratory rate, and activity were continuously recorded using radio-telemetry. In the normoxic groups, the recorded variables did not deviate from the baseline values. Both CIH groups exhibited significant increases in MAP during CIH exposures (p<0.05). During the normoxic dark phase in the CIH groups, only the SCM injected group exhibited a sustained increase in MAP (p<0.05). The AT1aR-CIH group showed significant decreases in FosB/∆FosB staining in the median preoptic nucleus and the paraventricular nuclei of the hypothalamus as compared to the SCM-CIH group. Our data indicate that AT1aRs in the SFO are critical for the sustained elevation in MAP and increased FosB/∆FosB expression in forebrain autonomic nuclei associated with CIH.

PMID: 25539713 [PubMed - as supplied by publisher]

Protein redox modification as a cellular defense mechanism against tissue ischemic injury.

Wed, 12/31/2014 - 4:30am
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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 - indexed for MEDLINE]

Chemotherapeutic effect of tamoxifen on temozolomide-resistant gliomas.

Tue, 12/30/2014 - 4:31am

Chemotherapeutic effect of tamoxifen on temozolomide-resistant gliomas.

Anticancer Drugs. 2014 Dec 22;

Authors: He W, Liu R, Yang S, Yuan F

Abstract
Tamoxifen, a selective estrogen receptor modulator, is widely used in the chemotherapy of estrogen receptor-positive breast cancer. Recent studies have indicated that tamoxifen might have a potential chemotherapeutic effect on glioma. In the present study, we determined the chemotherapeutic action of tamoxifen on human glioma cell lines. Methylation of 06-methylguanine-DNA methyltransferase was identified in A172, U251, and BT325 glioma cell lines, but not in the U87 cell line. Consistently, A172, U251, and BT325 cell lines are resistant to temozolomide. Tamoxifen induced significant cytotoxic action in A172, U251, BT325, and U87 cell lines. Further, Hoechst 33342 staining and apoptosis flow cytometric analysis demonstrated that tamoxifen induced apoptosis in the BT325 cell line. Mitochondrial complex analysis indicated that tamoxifen, but not other estrogen receptor modulators, dose-dependently inhibits complex I activity. In summary, our study suggests that tamoxifen might have a chemotherapeutic effect on temozolomide-resistant glioma through its direct action on mitochondrial complex I inhibition and could provide further evidence to support future clinical trials of tamoxifen for the treatment of glioblastoma.

PMID: 25535979 [PubMed - as supplied by publisher]

Rarity of the Alzheimer Disease-Protective APP A673T Variant in the United States.

Wed, 12/24/2014 - 4:29am

Rarity of the Alzheimer Disease-Protective APP A673T Variant in the United States.

JAMA Neurol. 2014 Dec 22;

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

Abstract
Importance: Recently, a rare variant in the amyloid precursor protein gene (APP) was described in a population from Iceland. This variant, in which alanine is replaced by threonine at position 673 (A673T), appears to protect against late-onset Alzheimer disease (AD). We evaluated the frequency of this variant in AD cases and cognitively normal controls to determine whether this variant will significantly contribute to risk assessment in individuals in the United States.
Objective: To determine the frequency of the APP A673T variant in a large group of elderly cognitively normal controls and AD cases from the United States and in 2 case-control cohorts from Sweden.
Design, Setting, and Participants: Case-control association analysis of variant APP A673T in US and Swedish white individuals comparing AD cases with cognitively intact elderly controls. Participants were ascertained at multiple university-associated medical centers and clinics across the United States and Sweden by study-specific sampling methods. They were from case-control studies, community-based prospective cohort studies, and studies that ascertained multiplex families from multiple sources.
Main Outcomes and Measures: Genotypes for the APP A673T variant were determined using the Infinium HumanExome V1 Beadchip (Illumina, Inc) and by TaqMan genotyping (Life Technologies).
Results: The A673T variant genotypes were evaluated in 8943 US AD cases, 10 480 US cognitively normal controls, 862 Swedish AD cases, and 707 Swedish cognitively normal controls. We identified 3 US individuals heterozygous for A673T, including 1 AD case (age at onset, 89 years) and 2 controls (age at last examination, 82 and 77 years). The remaining US samples were homozygous for the alanine (A673) allele. In the Swedish samples, 3 controls were heterozygous for A673T and all AD cases were homozygous for the A673 allele. We also genotyped a US family previously reported to harbor the A673T variant and found a mother-daughter pair, both cognitively normal at ages 72 and 84 years, respectively, who were both heterozygous for A673T; however, all individuals with AD in the family were homozygous for A673.
Conclusions and Relevance: The A673T variant is extremely rare in US cohorts and does not play a substantial role in risk for AD in this population. This variant may be primarily restricted to Icelandic and Scandinavian populations.

PMID: 25531812 [PubMed - as supplied by publisher]

Effect of glycyrrhizin on pseudomonal skin infections in human-mouse chimeras.

Wed, 12/24/2014 - 4:29am
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Effect of glycyrrhizin on pseudomonal skin infections in human-mouse chimeras.

PLoS One. 2014;9(1):e83747

Authors: Yoshida S, Lee JO, Nakamura K, Suzuki S, Hendon DN, Kobayashi M, Suzuki F

Abstract
In our previous studies, peripheral blood lineage(-)CD34(+)CD31(+) cells (CD31(+) IMC) appearing in severely burned patients have been characterized as inhibitor cells for the production of β-defensins (HBDs) by human epidermal keratinocytes (NHEK). In this study, the effect of glycyrrhizin on pseudomonal skin infections was studied in a chimera model of thermal injury. Two different chimera models were utilized. Patient chimeras were created in murine antimicrobial peptide-depleted NOD-SCID IL-2rγ(null) mice that were grafted with unburned skin tissues of severely burned patients and inoculated with the same patient peripheral blood CD31(+) IMC. Patient chimera substitutes were created in the same mice that were grafted with NHEK and inoculated with experimentally induced CD31(+) IMC. In the results, both groups of chimeras treated with glycyrrhizin resisted a 20 LD50 dose of P. aeruginosa skin infection, while all chimeras in both groups treated with saline died within 3 days of the infection. Human antimicrobial peptides were detected from the grafted site tissues of both groups of chimeras treated with glycyrrhizin, while the peptides were not detected in the same area tissues of controls. HBD-1 was produced by keratinocytes in transwell-cultures performed with CD31(+) IMC and glycyrrhizin. Also, inhibitors (IL-10 and CCL2) of HBD-1 production by keratinocytes were not detected in cultures of patient CD31(+) IMC treated with glycyrrhizin. These results indicate that sepsis stemming from pseudomonal grafted site infections in a chimera model of burn injury is controllable by glycyrrhizin. Impaired antimicrobial peptide production at the infection site of severely burned patients may be restored after treatment with glycyrrhizin.

PMID: 24497916 [PubMed - indexed for MEDLINE]

High sensitivity multiplex short tandem repeat loci analyses with massively parallel sequencing.

Tue, 12/23/2014 - 4:32am

High sensitivity multiplex short tandem repeat loci analyses with massively parallel sequencing.

Forensic Sci Int Genet. 2014 Dec 3;16C:38-47

Authors: Zeng X, King JL, Stoljarova M, Warshauer DH, LaRue BL, Sajantila A, Patel J, Storts DR, Budowle B

Abstract
STR typing in forensic genetics has been performed traditionally using capillary electrophoresis (CE). However, CE-based method has some limitations: a small number of STR loci can be used; stutter products, dye artifacts and low level alleles. Massively parallel sequencing (MPS) has been considered a viable technology in recent years allowing high-throughput coverage at a relatively affordable price. Some of the CE-based limitations may be overcome with the application of MPS. In this study, a prototype multiplex STR System (Promega) was amplified and prepared using the TruSeq DNA LT Sample Preparation Kit (Illumina) in 24 samples. Results showed that the MinElute PCR Purification Kit (Qiagen) was a better size selection method compared with recommended diluted bead mixtures. The library input sensitivity study showed that a wide range of amplicon product (6-200ng) could be used for library preparation without apparent differences in the STR profile. PCR sensitivity study indicated that 62pg may be minimum input amount for generating complete profiles. Reliability study results on 24 different individuals showed that high depth of coverage (DoC) and balanced heterozygote allele coverage ratios (ACRs) could be obtained with 250pg of input DNA, and 62pg could generate complete or nearly complete profiles. These studies indicate that this STR multiplex system and the Illumina MiSeq can generate reliable STR profiles at a sensitivity level that competes with current widely used CE-based method.

PMID: 25528025 [PubMed - as supplied by publisher]

Cell-cell contact viral transfer contributes to HIV infection and persistence in astrocytes.

Mon, 12/22/2014 - 4:30am

Cell-cell contact viral transfer contributes to HIV infection and persistence in astrocytes.

J Neurovirol. 2014 Dec 19;

Authors: Luo X, He JJ

Abstract
Astrocytes are the most abundant cells in the central nervous system and play important roles in human immunodeficiency virus (HIV)/neuro-acquired immunodeficiency syndrome. Detection of HIV proviral DNA, RNA, and early gene products but not late structural gene products in astrocytes in vivo and in vitro indicates that astrocytes are susceptible to HIV infection albeit in a restricted manner. We as well as others have shown that cell-free HIV is capable of entering CD4- astrocytes through human mannose receptor-mediated endocytosis. In this study, we took advantage of several newly developed fluorescence protein-based HIV reporter viruses and further characterized HIV interaction with astrocytes. First, we found that HIV was successfully transferred to astrocytes from HIV-infected CD4+ T cells in a cell-cell contact- and gp120-dependent manner. In addition, we demonstrated that, compared to endocytosis-mediated cell-free HIV entry and subsequent degradation of endocytosed virions, the cell-cell contact between astrocytes and HIV-infected CD4+ T cells led to robust HIV infection of astrocytes but retained the restricted nature of viral gene expression. Furthermore, we showed that HIV latency was established in astrocytes. Lastly, we demonstrated that infectious progeny HIV was readily recovered from HIV latent astrocytes in a cell-cell contact-mediated manner. Taken together, our studies point to the importance of the cell-cell contact-mediated HIV interaction with astrocytes and provide direct evidence to support the notion that astrocytes are HIV latent reservoirs in the central nervous system.

PMID: 25522787 [PubMed - as supplied by publisher]

The link between sleep disturbance and depression among Mexican Americans: a Project FRONTIER study.

Mon, 12/22/2014 - 4:30am
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The link between sleep disturbance and depression among Mexican Americans: a Project FRONTIER study.

J Clin Sleep Med. 2014 Apr 15;10(4):427-31

Authors: Roane BM, Johnson L, Edwards M, Hall J, Al-Farra S, O'Bryant SE

Abstract
OBJECTIVE: To examine the link between disturbed sleep and depression scores in Mexican Americans and non-Hispanic Whites.
METHODS: Data were analyzed for 566 participants (45% Mexican Americans) who were part of a rural healthcare study, Project FRONTIER. Mean age was 55.5 years for Mexican Americans (70% female) and 65.6 years for non-Hispanic Whites (69% female). Self-reported sleep disturbance was entered as the predictor, GDS-30 total and factor scores as the outcome variables, and age, sex, education, BMI, and medical diagnoses (hyperlipidemia, diabetes mellitus, and hypertension) entered as covariates.
RESULTS: Mexican Americans reported higher rates of sleep disturbances (25%) than non-Hispanic whites (17%). Sleep disturbances were significantly associated with GDS-30 total scores and the factors Dysphoria and Cognitive Impairment in both Mexican Americans and non-Hispanic whites.
CONCLUSIONS: In this study, Mexican Americans reported higher rates of sleep disturbances than non-Hispanic whites. Disturbed sleep was positively associated with depression and the factor scores for Dysphoria and Cognitive Impairment in both groups. Given the paucity of research on sleep disorders in Mexican Americans, identifying what sleep disorders are present and the impact treating these sleep disorders have on depression warrant further investigation.

PMID: 24733989 [PubMed - indexed for MEDLINE]

Acute intermittent optogenetic stimulation of nucleus tractus solitarius neurons induces sympathetic long-term facilitation.

Sat, 12/20/2014 - 4:30am

Acute intermittent optogenetic stimulation of nucleus tractus solitarius neurons induces sympathetic long-term facilitation.

Am J Physiol Regul Integr Comp Physiol. 2014 Dec 17;:ajpregu.00381.2014

Authors: Yamamoto K, Lalley PM, Mifflin SW

Abstract
Acute intermittent hypoxia (AIH) induces sympathetic and phrenic long-term facilitation (LTF), defined as a sustained increase in nerve discharge. We investigated the effects of AIH and acute intermittent optogenetic stimulation (AIO) of neurons labeled with AAV-CaMKIIa - hChR2(H134R) - mCherry in the nucleus of the solitary tract (NTS) of anesthetized, vagotomized, mechanically ventilated rats. We measured renal sympathetic nerve activity (RSNA), phrenic nerve activity (PNA), power spectral density and coherence, and we made cross-correlation measurements to determine how AIO and AIH affected synchronization between PNA and RSNA. Sixty min after AIH produced by ventilation with 10% oxygen in balanced nitrogen, RSNA and PNA amplitude increased by 80% and by 130%, respectively (P<0.01). Sixty min after AIO stimulation, RSNA and PNA amplitude increased by 60% and 100%, respectively, (P<0.01). These results suggest that acute intermittent stimulation of NTS neurons can induce renal sympathetic and phrenic LTF in the absence of hypoxia or chemoreceptor afferent activation. We also found that while acute intermittent optogenetic and hypoxic stimulations increased respiratory-related RSNA modulation (P<0.01), they did not increase synchronization between central respiratory drive and RSNA. We conclude that mechanisms that induce LTF originate within the caudal NTS and extend to other interconnecting neuronal elements of the central nervous cardiorespiratory network.

PMID: 25519734 [PubMed - as supplied by publisher]

Oxidative stress, testosterone, and cognition among Caucasian and Mexican-American men with and without Alzheimer's disease.

Fri, 12/19/2014 - 4:29am
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Oxidative stress, testosterone, and cognition among Caucasian and Mexican-American men with and without Alzheimer's disease.

J Alzheimers Dis. 2014;40(3):563-73

Authors: Cunningham RL, Singh M, O'Bryant SE, Hall JR, Barber RC

Abstract
BACKGROUND: The use of testosterone among aging men has been increasing, but results from studies addressing the effectiveness of testosterone replacement therapy have been equivocal.
OBJECTIVE: Given our prior pre-clinical studies that reported a major influence of oxidative stress on testosterone's neuroprotective effects, we investigated whether the negative effects of testosterone on brain function were predicted by oxidative load.
METHODS: In order to test our hypothesis, we determined whether circulating total testosterone and luteinizing hormone correlated with cognition in a subset of the Texas Alzheimer's Research & Care Consortium (TARCC) cohort, consisting of Caucasian (n = 116) and Mexican-American (n = 117) men. We also assessed whether oxidative stress (as indexed by homocysteine levels) modified this relationship between sex hormones and cognition, and whether the levels of two antioxidants, superoxide dismutase-1 and glutathione S-transferase (GST), varied as a function of circulating testosterone.
RESULTS: In a low oxidative stress environment, testosterone was positively associated with the level of the antioxidant, GST, while no deleterious effects on cognitive function were noted. In contrast, under conditions of high oxidative stress (homocysteine levels >12 μmol/L), testosterone and luteinizing hormone were associated with cognitive impairment, but only among Caucasians. The ethnic difference was attributed to significantly higher GST levels among Mexican-Americans.
CONCLUSION: While testosterone may be beneficial under conditions of low oxidative stress, testosterone appears to have negative consequences under conditions of elevated oxidative stress, but only in Caucasians. Mexican-Americans, however, were protected from any deleterious effects of testosterone, potentially due to higher levels of endogenous antioxidant defenses such as GST.

PMID: 24496073 [PubMed - indexed for MEDLINE]

Two-week normobaric intermittent-hypoxic exposures stabilize cerebral perfusion during hypocapnia and hypercapnia.

Thu, 12/18/2014 - 4:29am

Two-week normobaric intermittent-hypoxic exposures stabilize cerebral perfusion during hypocapnia and hypercapnia.

Exp Biol Med (Maywood). 2014 Dec 11;

Authors: Zhang P, Shi X, Downey HF

Abstract
The effect of moderately extended, intermittent-hypoxia (IH) on cerebral perfusion during changes in CO2 was unknown. Thus, we assessed the changes in cerebral vascular conductance (CVC) and cerebral tissue oxygenation (ScO2) during experimental hypocapnia and hypercapnia following 14-day normobaric exposures to IH (10% O2). CVC was estimated from the ratio of mean middle cerebral arterial blood flow velocity (transcranial Doppler sonography) to mean arterial pressure (tonometry), and ScO2 in the prefrontal cortex was monitored by near-infrared spectroscopy. Changes in CVC and ScO2 during changes in partial pressure of end-tidal CO2 (PETCO2, mass spectrometry) induced by 30-s paced-hyperventilation (hypocapnia) and during 6-min CO2 rebreathing (hypercapnia) were compared before and after 14-day IH exposures in eight young nonsmokers. Repetitive IH exposures reduced the ratio of %ΔCVC/ΔPETCO2 during hypocapnia (1.00 ± 0.13 vs 1.94 ± 0.35 vs %/mmHg, P = 0.026) and the slope of ΔCVC/ΔPETCO2 during hypercapnia (1.79 ± 0.37 vs 2.97 ± 0.64 %/mmHg, P = 0.021), but had no significant effect on ΔScO2/ΔPETCO2. The ventilatory response to hypercapnia during CO2 rebreathing was significantly diminished following 14-day IH exposures (0.83 ± 0.07 vs 1.14 ± 0.09 L/min/mmHg, P = 0.009). We conclude that repetitive normobaric IH exposures significantly diminish variations of cerebral perfusion in response to hypercapnia and hypocapnia without compromising cerebral tissue oxygenation. This IH-induced blunting of cerebral vasoreactivity during CO2 variations helps buffer excessive oscillations of cerebral underperfusion and overperfusion while sustaining cerebral O2 homeostasis.

PMID: 25504012 [PubMed - as supplied by publisher]

A News Media Analysis of the Economic and Reputational Penalties of the Hospital Readmissions Reduction Program.

Thu, 12/18/2014 - 4:29am

A News Media Analysis of the Economic and Reputational Penalties of the Hospital Readmissions Reduction Program.

Inquiry. 2014;51

Authors: Winborn MS, Alencherril J, Pagán JA

Abstract
Section 3025 of the Affordable Care Act (ACA) of 2010 established the Hospital Readmissions Reduction Program (HRRP), an initiative designed to penalize hospitals with excess 30-day readmissions. This study investigates whether readmission penalties under HRRP impose significant reputational effects on hospitals. Data extracted from 2012 to 2013 news stories suggest that the higher the actual penalty, the higher the perceived cost of the penalty, the more likely it is that hospitals will state they have no control over the low-income patients they serve or that they will describe themselves as safety net providers. The downside of being singled out as a low-quality hospital deserving a relatively high penalty seems to be larger than the upside of being singled out as a high-quality hospital facing a relatively low penalty. Although the financial burden of the penalties seems to be low, hospitals may be reacting to the fact that information about excess readmissions and readmission penalties is being released widely and is scrutinized by the news media and the general public.

PMID: 25500753 [PubMed - as supplied by publisher]

Arsenic exposure, hyperuricemia, and gout in US adults.

Thu, 12/18/2014 - 4:29am

Arsenic exposure, hyperuricemia, and gout in US adults.

Environ Int. 2014 Dec 11;76C:32-40

Authors: Kuo CC, Weaver V, Fadrowski JJ, Lin YS, Guallar E, Navas-Acien A

Abstract
BACKGROUND: There is very limited information on the association between arsenic and serum uric acid levels or gout. The aim of this study was to investigate the association of arsenic with hyperuricemia and gout in US adults.
METHODS: A cross-sectional study was conducted in 5632 adults aged 20years or older from the National Health and Nutrition Examination Survey (NHANES) 2003-2010 with determinations of serum uric acid and urine total arsenic and dimethylarsinate (DMA). Hyperuricemia was defined as serum uric acid higher than 7.0mg/dL for men and 6.0mg/dL for women. Gout was defined based on self-reported physician diagnosis and medication use.
RESULTS: After adjustment for sociodemographic factors, comorbidities and arsenobetaine levels, the increase in the geometric means of serum uric acid associated with one interquartile range increase in total arsenic and DMA levels was 3% (95% CI 2-5) and 3% (2-5), respectively, in men and 1% (0-3) and 2% (0-4), respectively, in women. In men, the adjusted odds ratio for hyperuricemia comparing the highest to lowest quartiles of total arsenic was 1.84 (95% CI, 1.26-2.68) and for DMA it was 1.41 (95% CI, 1.01-1.96). The corresponding odds ratios in women were 1.26 (0.77, 2.07) and 1.49 (0.96, 2.31), respectively. The odds ratio for gout comparing the highest to lowest tertiles was 5.46 (95% CI, 1.70-17.6) for total arsenic and 1.98 (0.64-6.15) for DMA among women older than 40years old. Urine arsenic was not associated with gout in men.
CONCLUSION: Low level arsenic exposures may be associated with the risk of hyperuricemia in men and with the prevalence of gout in women. Prospective research focusing on establishing the direction of the relationship among arsenic, hyperuricemia, and gout is needed.

PMID: 25499256 [PubMed - as supplied by publisher]

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