Recent Research Articles from UNTHSC

Recent research articles indexed in PubMed from authors affiliated with the UNT Health Science Center.

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NCBI: db=pubmed; Term="University of North Texas Health Science Center"[All Fields] OR "Univ. of North Texas Health Science Center"[All Fields] OR "UNT Health Science Center"[All Fields] OR "Osteopathic Research Center"[All Fields] OR "University of North Texas System College of Pharmacy"[All Fields] OR "UNT System College of Pharmacy"[All Fields] OR "College of Pharmacy, University of North Texas System"[All Fields]
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The many faces of the trabecular meshwork cell.

Sat, 07/22/2017 - 07:34
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The many faces of the trabecular meshwork cell.

Exp Eye Res. 2017 May;158:112-123

Authors: Stamer WD, Clark AF

Abstract
With the combined purpose of facilitating useful vision over a lifetime, a number of ocular cells have evolved specialized features not found elsewhere in the body. The trabecular meshwork (TM) cell at the irido-corneal angle, which is a key regulator of intraocular pressure, is no exception. Examination of cells in culture isolated from the human TM has shown that they are unique in many ways, displaying characteristic features of several different cell types. Thus, these neural crest derived cells display expression patterns and behaviors typical of endothelia, fibroblasts, smooth muscle and macrophages, owing to the multiple roles and two distinct environments where they operate to maintain intraocular pressure homeostasis. In most individuals, TM cells function normally over a lifetime in the face of persistent stressors, including phagocytic, oxidative, mechanical and metabolic stress. Study of TM cells isolated from ocular hypertensive eyes has shown a compromised ability to perform their daily duties. This review highlights the many responsibilities of the TM cell and its challenges, progress in our understanding of TM biology over the past 30 years, as well as discusses unanswered questions about TM dysfunction that results in IOP dysregulation and glaucoma.

PMID: 27443500 [PubMed - indexed for MEDLINE]

Developing new targeting strategy for androgen receptor variants in castration resistant prostate cancer.

Thu, 07/20/2017 - 07:37

Developing new targeting strategy for androgen receptor variants in castration resistant prostate cancer.

Int J Cancer. 2017 Jul 19;:

Authors: Wang B, Lo UG, Wu K, Kapur P, Liu X, Huang J, Chen W, Hernandez E, Santoyo J, Ma SH, Pong RC, He D, Cheng YQ, Hsieh JT

Abstract
The presence of androgen receptor variant 7 (AR-V7) variants becomes a significant hallmark of castration resistant prostate cancer (CRPC) relapsed from hormonal therapy and is associated with poor survival of CRPC patients because of lacking a ligand-binding domain. Currently, it still lacks an effective agent to target AR-V7 or AR-Vs in general. Here, we showed a novel class of agents (thailanstatins, TSTs, spliceostatin A analogs) can significantly suppress the expression of AR-V7 mRNA and protein but in a less extent on the full-length AR expression. Mechanistically, TST-D is able to inhibit AR-V7 gene splicing by interfering the interaction between U2AF65 and SAP155 and preventing them from binding to polypyrimidine tract located between the branch point and the 3' splice site. In vivo, TST-D exhibits a potent tumor inhibitory effect on human CRPC xenografts leading to cell apoptosis. The machinery associated with AR gene splicing in CRPC is a potential target for drugs. Based on their potency in the suppression of AR-V7 responsible for the growth/survival of CRPC, TSTs representing a new class of anti-AR-V agents warrant further development into clinical application. This article is protected by copyright. All rights reserved.

PMID: 28722220 [PubMed - as supplied by publisher]

HIV Tat Impairs Neurogenesis through Functioning As a Notch Ligand and Activation of Notch Signaling Pathway.

Thu, 07/20/2017 - 07:37
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HIV Tat Impairs Neurogenesis through Functioning As a Notch Ligand and Activation of Notch Signaling Pathway.

J Neurosci. 2016 Nov 02;36(44):11362-11373

Authors: Fan Y, Gao X, Chen J, Liu Y, He JJ

Abstract
Alterations in adult neurogenesis have been noted in the brain of HIV-infected individuals and are likely linked to HIV-associated neurocognitive deficits, including those in learning and memory. But the underlying molecular mechanisms are not fully understood. In the study, we took advantage of doxycycline-inducible and astrocyte-specific HIV-1 Tat transgenic mice (iTat) and determined the relationship between Tat expression and neurogenesis. Tat expression in astrocytes was associated with fewer neuron progenitor cells (NPCs), fewer immature neurons, and fewer mature neurons in the dentate gyrus of the hippocampus of the mouse brain. In vitro NPC-derived neurosphere assays showed that Tat-containing conditioned media from astrocytes or recombinant Tat protein inhibited NPC proliferation and migration and altered NPC differentiation, while immunodepletion of Tat from Tat-containing conditioned media or heat inactivation of recombinant Tat abrogated those effects. Notch signaling downstream gene Hes1 promoter-driven luciferase reporter gene assay and Western blotting showed that recombinant Tat or Tat-containing conditioned media activated Hes1 transcription and protein expression, which were abrogated by Tat heat inactivation, immunodepletion, and cysteine mutation at position 30. Last, Notch signaling inhibitor N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT) significantly rescued Tat-impaired NPC differentiation in vitro and neurogenesis in vivo Together, these results show that Tat adversely affects NPCs and neurogenesis through Notch signaling and point to the potential of developing Notch signaling inhibitors as HIV/neuroAIDS therapeutics.
SIGNIFICANCE STATEMENT: HIV infection of the CNS causes cognitive and memory deficits, which have become more prevalent in the era of combination antiretroviral therapy (cART). Neurogenesis is impaired in HIV-infected individuals. But the underlying molecular mechanisms remain largely unknown. In this study, we have discovered that HIV Tat impairs neurogenesis through the Notch signaling pathway. These findings are particularly important because Tat protein has recently been detected in the brain of HIV-infected individuals with HIV replication in the periphery being effectively controlled by cART. The current study not only further highlights the importance of HIV Tat protein in HIV/neuroAIDS, but also presents a new strategy to develop novel HIV/neuroAIDS therapeutics, particularly in the era of cART.

PMID: 27807176 [PubMed - indexed for MEDLINE]

"Curcumin-loaded Poly (d, l-lactide-co-glycolide) nanovesicles induce antinociceptive effects and reduce pronociceptive cytokine and BDNF release in spinal cord after acute administration in mice".

Wed, 07/19/2017 - 19:39
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"Curcumin-loaded Poly (d, l-lactide-co-glycolide) nanovesicles induce antinociceptive effects and reduce pronociceptive cytokine and BDNF release in spinal cord after acute administration in mice".

Colloids Surf B Biointerfaces. 2017 Jul 10;158:379-386

Authors: Pieretti S, Ranjan AP, Di Giannuario A, Mukerjee A, Marzoli F, Di Giovannandrea R, Vishwanatha JK

Abstract
Given the poor bioavailability of curcumin, its antinociceptive effects are produced after chronic intravenous administration of high doses, while poly (d,l-lactide-co-glycolide)-loaded vesicles (PLGA) can improve drug delivery. This paper investigates the antinociceptive effects of curcumin-loaded PLGA nanovesicles (PLGA-CUR) administered via intravenous (i.v.) or intrathecal (i.t.) routes at low and high doses. The following models of pain were used: formalin test, zymosan-induced hyperalgesia and sciatic nerve ligation inducing neuropathic allodynia and hyperalgesia. PLGA-CUR administered intravenously was able to reduce the response to nociceptive stimuli in the formalin test and hyperalgesia induced by zymosan. Curcumin, instead, was inactive. Low-dose i.t. administration of PLGA-CUR significantly reduced allodynia produced by sciatic nerve ligation, whereas low doses of curcumin did not change the response to nociceptive stimuli. Long-lasting antinociceptive effects were observed when high doses of PLGA-CUR were administered intrathecally. At high doses, i.t. administration of curcumin only exerted rapid and transient antinociceptive effects. Measurement of cytokine and BDNF in the spinal cord of neuropathic mice demonstrate that the antinociceptive effects of PLGA-CUR depend on the reduction in cytokine release and BDNF in the spinal cord. The results demonstrate the effectiveness of PLGA-CUR and suggest that PLGA-CUR nanoformulation might be a new potential drug in the treatment of pain.

PMID: 28719859 [PubMed - as supplied by publisher]

Undiagnosed Liver Fibrosis in Patients Undergoing Pancreatoduodenectomy for Pancreatic Adenocarcinoma.

Wed, 07/19/2017 - 19:39
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Undiagnosed Liver Fibrosis in Patients Undergoing Pancreatoduodenectomy for Pancreatic Adenocarcinoma.

World J Surg. 2017 Jul 17;:

Authors: Gdowski A, Osman H, Butt U, Foster S, Jeyarajah DR

Abstract
BACKGROUND: Chronic obstruction of the biliary system may cause hepatic fibrosis and liver failure. The purpose of this study was to define the incidence of unrecognized liver fibrosis in patients undergoing pancreaticoduodenectomy (PD).
METHODS: Retrospective data were collected on patients undergoing PD during a 21-month period. Each patient had a core needle biopsy at the time of surgery by a hepatobiliary surgeon.
RESULTS: This study identified 36 consecutive patients who were referred to a tertiary center and underwent pancreatoduodenectomy during a period of 21 months. The majority of patients, 32 (88.8%), were diagnosed with pancreatic adenocarcinoma. Liver fibrosis was diagnosed in 23 (63.9%) patients. A total of 25 (69.4%) patients were found to have pathological evidence of cholestasis consistent with bile obstruction. Patients that were found to have evidence of obstruction had significantly increased odds that fibrosis stage 2 would be found on pathological diagnosis (OR 6.75, 95% CI 1.20-38.02, Fisher's exact test P value = 0.0312). There was no significant association in patients who were stented compared to non-stented patients and their diagnosis of high-grade fibrosis stage 2 (OR 1.5238, 95% CI 0.4019-5.7769, Fisher's exact test P value = 0.7360).
CONCLUSIONS: An astonishing 63.9% of patients who underwent PD were diagnosed with stage 1-4 liver fibrosis and half (47.2%) had fibrosis stage of 2 or more. Further, stent status had no significant impact on the degree of liver fibrosis. Liver fibrosis is currently underrecognized in patients undergoing PD, which is important for physicians to be conscious of as it is known that liver fibrosis increases morbidity and mortality.

PMID: 28717906 [PubMed - as supplied by publisher]

Systematic review of comparative effectiveness and health economics research relating to osteopathic manipulative treatment.

Tue, 07/18/2017 - 07:34

Systematic review of comparative effectiveness and health economics research relating to osteopathic manipulative treatment.

Musculoskelet Sci Pract. 2017 Jun;29:e16-e17

Authors: Licciardone JC

PMID: 28715303 [PubMed - in process]

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease.

Tue, 07/18/2017 - 07:34
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Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease.

Nat Genet. 2017 Jul 17;:

Authors: Sims R, van der Lee SJ, Naj AC, Bellenguez C, Badarinarayan N, Jakobsdottir J, Kunkle BW, Boland A, Raybould R, Bis JC, Martin ER, Grenier-Boley B, Heilmann-Heimbach S, Chouraki V, Kuzma AB, Sleegers K, Vronskaya M, Ruiz A, Graham RR, Olaso R, Hoffmann P, Grove ML, Vardarajan BN, Hiltunen M, Nöthen MM, White CC, Hamilton-Nelson KL, Epelbaum J, Maier W, Choi SH, Beecham GW, Dulary C, Herms S, Smith AV, Funk CC, Derbois C, Forstner AJ, Ahmad S, Li H, Bacq D, Harold D, Satizabal CL, Valladares O, Squassina A, Thomas R, Brody JA, Qu L, Sánchez-Juan P, Morgan T, Wolters FJ, Zhao Y, Garcia FS, Denning N, Fornage M, Malamon J, Naranjo MCD, Majounie E, Mosley TH, Dombroski B, Wallon D, Lupton MK, Dupuis J, Whitehead P, Fratiglioni L, Medway C, Jian X, Mukherjee S, Keller L, Brown K, Lin H, Cantwell LB, Panza F, McGuinness B, Moreno-Grau S, Burgess JD, Solfrizzi V, Proitsi P, Adams HH, Allen M, Seripa D, Pastor P, Cupples LA, Price ND, Hannequin D, Frank-García A, Levy D, Chakrabarty P, Caffarra P, Giegling I, Beiser AS, Giedraitis V, Hampel H, Garcia ME, Wang X, Lannfelt L, Mecocci P, Eiriksdottir G, Crane PK, Pasquier F, Boccardi V, Henández I, Barber RC, Scherer M, Tarraga L, Adams PM, Leber M, Chen Y, Albert MS, Riedel-Heller S, Emilsson V, Beekly D, Braae A, Schmidt R, Blacker D, Masullo C, Schmidt H, Doody RS, Spalletta G, Jr WTL, Fairchild TJ, Bossù P, Lopez OL, Frosch MP, Sacchinelli E, Ghetti B, Yang Q, Huebinger RM, Jessen F, Li S, Kamboh MI, Morris J, Sotolongo-Grau O, Katz MJ, Corcoran C, Dunstan M, Braddel A, Thomas C, Meggy A, Marshall R, Gerrish A, Chapman J, Aguilar M, Taylor S, Hill M, Fairén MD, Hodges A, Vellas B, Soininen H, Kloszewska I, Daniilidou M, Uphill J, Patel Y, Hughes JT, Lord J, Turton J, Hartmann AM, Cecchetti R, Fenoglio C, Serpente M, Arcaro M, Caltagirone C, Orfei MD, Ciaramella A, Pichler S, Mayhaus M, Gu W, Lleó A, Fortea J, Blesa R, Barber IS, Brookes K, Cupidi C, Maletta RG, Carrell D, Sorbi S, Moebus S, Urbano M, Pilotto A, Kornhuber J, Bosco P, Todd S, Craig D, Johnston J, Gill M, Lawlor B, Lynch A, Fox NC, Hardy J, ARUK Consortium, Albin RL, Apostolova LG, Arnold SE, Asthana S, Atwood CS, Baldwin CT, Barnes LL, Barral S, Beach TG, Becker JT, Bigio EH, Bird TD, Boeve BF, Bowen JD, Boxer A, Burke JR, Burns JM, Buxbaum JD, Cairns NJ, Cao C, Carlson CS, Carlsson CM, Carney RM, Carrasquillo MM, Carroll SL, Diaz CC, Chui HC, Clark DG, Cribbs DH, Crocco EA, DeCarli C, Dick M, Duara R, Evans DA, Faber KM, Fallon KB, Fardo DW, Farlow MR, Ferris S, Foroud TM, Galasko DR, Gearing M, Geschwind DH, Gilbert JR, Graff-Radford NR, Green RC, Growdon JH, Hamilton RL, Harrell LE, Honig LS, Huentelman MJ, Hulette CM, Hyman BT, Jarvik GP, Abner E, Jin LW, Jun G, Karydas A, Kaye JA, Kim R, Kowall NW, Kramer JH, LaFerla FM, Lah JJ, Leverenz JB, Levey AI, Li G, Lieberman AP, Lunetta KL, Lyketsos CG, Marson DC, Martiniuk F, Mash DC, Masliah E, McCormick WC, McCurry SM, McDavid AN, McKee AC, Mesulam M, Miller BL, Miller CA, Miller JW, Morris JC, Murrell JR, Myers AJ, O'Bryant S, Olichney JM, Pankratz VS, Parisi JE, Paulson HL, Perry W, Peskind E, Pierce A, Poon WW, Potter H, Quinn JF, Raj A, Raskind M, Reisberg B, Reitz C, Ringman JM, Roberson ED, Rogaeva E, Rosen HJ, Rosenberg RN, Sager MA, Saykin AJ, Schneider JA, Schneider LS, Seeley WW, Smith AG, Sonnen JA, Spina S, Stern RA, Swerdlow RH, Tanzi RE, Thornton-Wells TA, Trojanowski JQ, Troncoso JC, Van Deerlin VM, Van Eldik LJ, Vinters HV, Vonsattel JP, Weintraub S, Welsh-Bohmer KA, Wilhelmsen KC, Williamson J, Wingo TS, Woltjer RL, Wright CB, Yu CE, Yu L, Garzia F, Golamaully F, Septier G, Engelborghs S, Vandenberghe R, De Deyn PP, Fernadez CM, Benito YA, Thonberg H, Forsell C, Lilius L, Kinhult-Stählbom A, Kilander L, Brundin R, Concari L, Helisalmi S, Koivisto AM, Haapasalo A, Dermecourt V, Fievet N, Hanon O, Dufouil C, Brice A, Ritchie K, Dubois B, Himali JJ, Keene CD, Tschanz J, Fitzpatrick AL, Kukull WA, Norton M, Aspelund T, Larson EB, Munger R, Rotter JI, Lipton RB, Bullido MJ, Hofman A, Montine TJ, Coto E, Boerwinkle E, Petersen RC, Alvarez V, Rivadeneira F, Reiman EM, Gallo M, O'Donnell CJ, Reisch JS, Bruni AC, Royall DR, Dichgans M, Sano M, Galimberti D, St George-Hyslop P, Scarpini E, Tsuang DW, Mancuso M, Bonuccelli U, Winslow AR, Daniele A, Wu CK, GERAD/PERADES, CHARGE, ADGC, EADI, Peters O, Nacmias B, Riemenschneider M, Heun R, Brayne C, Rubinsztein DC, Bras J, Guerreiro R, Al-Chalabi A, Shaw CE, Collinge J, Mann D, Tsolaki M, Clarimón J, Sussams R, Lovestone S, O'Donovan MC, Owen MJ, Behrens TW, Mead S, Goate AM, Uitterlinden AG, Holmes C, Cruchaga C, Ingelsson M, Bennett DA, Powell J, Golde TE, Graff C, De Jager PL, Morgan K, Ertekin-Taner N, Combarros O, Psaty BM, Passmore P, Younkin SG, Berr C, Gudnason V, Rujescu D, Dickson DW, Dartigues JF, DeStefano AL, Ortega-Cubero S, Hakonarson H, Campion D, Boada M, Kauwe JK, Farrer LA, Van Broeckhoven C, Ikram MA, Jones L, Haines JL, Tzourio C, Launer LJ, Escott-Price V, Mayeux R, Deleuze JF, Amin N, Holmans PA, Pericak-Vance MA, Amouyel P, van Duijn CM, Ramirez A, Wang LS, Lambert JC, Seshadri S, Williams J, Schellenberg GD

Abstract
We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10(-4)) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10(-8)) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10(-10), odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10(-10), OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10(-14), OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

PMID: 28714976 [PubMed - as supplied by publisher]

Expansion of Microbial Forensics.

Tue, 07/18/2017 - 07:34
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Expansion of Microbial Forensics.

J Clin Microbiol. 2016 Aug;54(8):1964-74

Authors: Schmedes SE, Sajantila A, Budowle B

Abstract
Microbial forensics has been defined as the discipline of applying scientific methods to the analysis of evidence related to bioterrorism, biocrimes, hoaxes, or the accidental release of a biological agent or toxin for attribution purposes. Over the past 15 years, technology, particularly massively parallel sequencing, and bioinformatics advances now allow the characterization of microorganisms for a variety of human forensic applications, such as human identification, body fluid characterization, postmortem interval estimation, and biocrimes involving tracking of infectious agents. Thus, microbial forensics should be more broadly described as the discipline of applying scientific methods to the analysis of microbial evidence in criminal and civil cases for investigative purposes.

PMID: 26912746 [PubMed - indexed for MEDLINE]

Hookah use among adolescents: Differential cognitions about hookah and cigarettes.

Mon, 07/17/2017 - 07:36

Hookah use among adolescents: Differential cognitions about hookah and cigarettes.

Addict Behav. 2017 Jul 09;75:75-78

Authors: Barnett TE, Livingston MD

Abstract
Background Hookah use is prevalent among adolescent and young adult populations. The study assessed how positive cognitions toward cigarettes moderate the impact of positive hookah cognitions on past 30day hookah use among a representative sample of youth. Understanding cognitions about products can contribute to effective interventions. Methods Data from the 2015 Florida Youth Tobacco Survey was used to determine cognitions and use patterns among high school students. Weighted means and proportions were used for demographic comparisons for cognitions about products. t-Tests and chi-square analysis were conducted for differences between users and non-users. Logistic regressions were conducted for the modeling of interaction between hookah and cigarette cognition. Results Nearly one out of ten (9.6%) of adolescents reported current hookah use. Across all cognition measures, positive hookah cognitions were associated with current hookah use. Additionally, there was a pattern of hookah cognitions being more strongly associated with current hookah use among those students that did not endorse the equivalent cognition for traditional cigarettes. Conclusions Hookah cognitions were generally more associated with hookah use among youth who did not endorse positive cognitions for cigarettes compared to those that did endorse positive cognitions for cigarettes. This finding is novel given youth who feel negatively about cigarettes are more influenced by their hookah-specific cognitions. Youth who believe cigarettes pose harm may benefit from messaging about the harms of hookah. Interventions or prevention efforts that draw strong comparisons between cigarettes and hookah may be effective among youth.

PMID: 28711747 [PubMed - as supplied by publisher]

Association between thyroid dysfunction and dysglycaemia: a prospective cohort study.

Sun, 07/16/2017 - 07:35

Association between thyroid dysfunction and dysglycaemia: a prospective cohort study.

Diabet Med. 2017 Jul 14;:

Authors: Chang CH, Yeh YC, Shih SR, Lin JW, Chuang LM, Caffrey JL, Tu YK

Abstract
AIMS: To compare the incidence of hyperglycaemia among participants with low, elevated and normal serum thyroid-stimulating hormone concentration, as well as the incidence of abnormal thyroid function test results among participants with normal blood glucose and those with hyperglycaemia.
METHODS: In a prospective study, a cohort of 72 003 participants with normal, low and elevated serum thyroid-stimulating hormone concentration were followed from the study beginning to the first report of diabetes and prediabetes. A proportional hazards regression model was used to calculate the hazard ratios and 95% CIs for each outcome, adjusting for age, sex, education level, smoking, alcohol consumption and obesity. Analyses for the association between dysglycaemia and incident abnormal thyroid function test were also conducted.
RESULTS: During a median 2.6 year follow-up, the incident rates for dysglycaemia, particularly prediabetes, were substantially higher in participants with elevated thyroid-stimulating hormone concentrations at baseline, while the rates for participants with normal and low thyroid-stimulating hormone were similar. After controlling for risk factors, participants with elevated thyroid-stimulating hormone retained a 15% increase in risk of prediabetes (adjusted hazard ratio 1.16, 95% CI 1.05-1.28), but were not at greater risk of diabetes (adjusted hazard ratio 1.04, 95% CI 0.68-1.52). By contrast, participants with normal and low thyroid-stimulating hormone concentrations had similar dysglycaemia risks. Participants with diabetes and prediabetes were not at greater risks of developing abnormal thyroid function test results when compared with participants with euglycaemia.
CONCLUSIONS: People with elevated serum thyroid-stimulating hormone concentration are at greater risk of developing prediabetes. Whether this includes a greater risk of developing frank diabetes may require an extended period of follow-up to clarify. This article is protected by copyright. All rights reserved.

PMID: 28710779 [PubMed - as supplied by publisher]

Short-Term Alcohol Abstinence Improves Antibacterial Defenses of Chronic Alcohol-Consuming Mice against Gut Bacteria-Associated Sepsis Caused by Enterococcus faecalis Oral Infection.

Sat, 07/15/2017 - 07:38

Short-Term Alcohol Abstinence Improves Antibacterial Defenses of Chronic Alcohol-Consuming Mice against Gut Bacteria-Associated Sepsis Caused by Enterococcus faecalis Oral Infection.

Am J Pathol. 2017 Jul 11;:

Authors: Kobayashi M, Asai A, Ito I, Suzuki S, Higuchi K, Suzuki F

Abstract
The effects of short-term alcohol abstinence on host antibacterial resistance against Enterococcus faecalis oral infection was investigated in chronic alcohol-consuming mice [mice with 0.1 g/day of 20% ethanol consumption for 12 or 16 weeks (CAC-mice)]. These mice were highly susceptible to the infection; however, after 7 days of alcohol abstinence (aaCAC-mice), their antibacterial resistances were completely restored to the normal mouse level. Normal mice inoculated with CAC-mouse hepatic macrophages were shown to be susceptible to the infection, whereas the same macrophage preparation from aaCAC-mice did not impair the antibacterial resistance of normal mice. aaCAC-mouse liver macrophages protected nonobese diabetic-severe combined immunodeficiency IL-2Rγ(null) mice exposed to E. faecalis, whereas those from CAC-mice did not. Monocyte-derived (MD) M2b macrophages were predominantly isolated from CAC-mouse livers, but these cells were not significantly isolated from aaCAC-mouse livers. Hepatic MD macrophages from aaCAC-mice switched to M1 macrophages in response to bacterial antigen, whereas the same macrophage preparation from CAC-mice did not. M1 Kupffer cells, M2a Kupffer cells, and MD M2b macrophages were shown to be not bactericidal, whereas E. faecalis was killed effectively by M1 macrophages derived from aaCAC-mouse hepatic MD macrophages. These results indicate that MD M2b macrophages predominantly distributed in the liver are responsible for the impaired resistance of CAC-mice to E. faecalis oral infection, and aaCAC-mice without MD M2b macrophages in the livers are resistant to the infection.

PMID: 28708971 [PubMed - as supplied by publisher]

Dysregulated corticostriatal activity in open-field behavior and the head-twitch response induced by the hallucinogen 2,5-dimethoxy-4-iodoamphetamine.

Fri, 07/14/2017 - 07:36
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Dysregulated corticostriatal activity in open-field behavior and the head-twitch response induced by the hallucinogen 2,5-dimethoxy-4-iodoamphetamine.

Neuropharmacology. 2017 Feb;113(Pt A):502-510

Authors: Rangel-Barajas C, Estrada-Sánchez AM, Barton SJ, Luedtke RR, Rebec GV

Abstract
The substituted amphetamine, 2,5-dimethoxy-4-iodoamphetamine (DOI), is a hallucinogen that has been used to model a variety of psychiatric conditions. Here, we studied the effect of DOI on neural activity recorded simultaneously in the primary motor cortex (M1) and dorsal striatum of freely behaving FvB/N mice. DOI significantly decreased the firing rate of individually isolated neurons in M1 and dorsal striatum relative to pre-drug baseline. It also induced a bursting pattern of activity by increasing both the number of spikes within a burst and burst duration. In addition, DOI increased coincident firing between simultaneously recorded neuron pairs within the striatum and between M1 and dorsal striatum. Local field potential (LFP) activity also increased in coherence between M1 and dorsal striatum after DOI in the low frequency gamma band (30-50 Hz), while corticostriatal coherence in delta, theta, alpha, and beta activity decreased. We also assessed corticostriatal LFP activity in relation to the DOI-induced head-twitch response (HTR), a readily identifiable behavior used to assess potential treatments for the conditions it models. The HTR was associated with increased delta and decreased theta power in both M1 and dorsal striatum. Together, our results suggest that DOI dysregulates corticostriatal communication and that the HTR is associated with this dysregulation.

PMID: 27816502 [PubMed - indexed for MEDLINE]

5-(N, N-Hexamethylene) amiloride is a GABA-A ρ1 receptor positive allosteric modulator.

Fri, 07/14/2017 - 07:36
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5-(N, N-Hexamethylene) amiloride is a GABA-A ρ1 receptor positive allosteric modulator.

Channels (Austin). 2016 Nov;10(6):498-506

Authors: Snell HD, Gonzales EB

Abstract
Guanidine compounds act as ion channel modulators. In the case of Cys-loop receptors, the guanidine compound amiloride antagonized the heteromeric GABA-A, glycine, and nicotinic acetylcholine receptors. However, amiloride exhibits characteristics consistent with a positive allosteric modulator for the human GABA-A (hGABA-A) ρ1 receptor. Site-directed mutagenesis revealed that the positive allosteric modulation was influenced by the GABA-A ρ1 second transmembrane domain 15' position, a site implicated in ligand allosteric modulation of Cys-loop receptors. There are a variety of amiloride derivatives that provide opportunities to assess the significance of amiloride functional groups (e.g., the guanidine group, the pyrazine ring, etc.) in the modulation of the GABA-A ρ1 receptor activity. We utilized 3 amiloride derivatives (benzamil, phenamil, and 5-(N, N-Hexamethylene) amiloride) to assess the contribution of these groups toward the potentiation of the GABA-A ρ1 receptor. Benzamil and phenamil failed to potentiate on the wild type GABA-A ρ1 GABA-mediated current while HMA demonstrated efficacy only at the highest concentration studied. The hGABA-A ρ1 (I15'N) mutant receptor activity was potentiated by lower HMA concentrations compared to the wild type receptor. Our findings suggest that an exposed guanidine group on amiloride and amiloride derivatives is critical for modulating the GABA-A ρ1 receptor. The present study provides a conceptual framework for predicting which amiloride derivatives will demonstrate positive allosteric modulation of the GABA-A ρ1 receptor.

PMID: 27367557 [PubMed - indexed for MEDLINE]

Regulatory CD4+CD25+ T Cells Dampen Inflammatory Disease in Murine Mycoplasma Pneumonia and Promote IL-17 and IFN-γ Responses.

Fri, 07/14/2017 - 07:36
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Regulatory CD4+CD25+ T Cells Dampen Inflammatory Disease in Murine Mycoplasma Pneumonia and Promote IL-17 and IFN-γ Responses.

PLoS One. 2016;11(5):e0155648

Authors: Odeh AN, Simecka JW

Abstract
Mycoplasmas cause respiratory diseases characterized by persistent infection and chronic airway inflammation. Mycoplasma lung disease is immunopathologic, with CD4+ Th cells determining both disease severity and resistance to infection. Th2 cell responses promote immunopathology, while Th1 cells confer resistance to infection. However, regulatory CD4+ T cells may also have a role in the pathogenesis of mycoplasma respiratory diseases. We hypothesized Treg cells control the severity of the inflammatory lesions and may also promote persistence of infection. To examine this, BALB/c mice were depleted of CD25+ cells, and had increased disease severity due to Mycoplasma pulmonis infection. Increases in mycoplasma antibody responses and lymphocyte infiltration into lungs also occurred after CD25+ cell depletion. CD4+CD25+ regulatory T cells promoted IFN-γ and IL-17 mycoplasma-specific CD4+ T cell responses in vitro and in vivo, while dampening IL-13+ Th responses. Neither IL-10 nor TGF-ß expression was detected in CD4+CD25+ T cells from lymph nodes. Thus, a regulatory T cell population plays an important role in controlling damaging immune responses in mycoplasma respiratory disease but does not contribute to persistence of infection. It appears that a regulatory T cell population preferentially dampens Th2 cell-mediated inflammatory responses to mycoplasma through a mechanism independent of IL-10 or TGF-ß characteristic of "classic" Treg cells.

PMID: 27175511 [PubMed - indexed for MEDLINE]

Effect of adenovirus-mediated RNA interference of IL-1β expression on spinal cord injury in rats.

Fri, 07/14/2017 - 07:36
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Effect of adenovirus-mediated RNA interference of IL-1β expression on spinal cord injury in rats.

Spinal Cord. 2016 Oct;54(10):778-784

Authors: Lin WP, Lin JH, Cai B, Shi JX, Li WJ, Choudhury GR, Wu SQ, Wu JZ, Wu HP, Ke QF

Abstract
STUDY DESIGN: We introduced an adenoviral vector expressing interleukin-1β (IL-1β) small-hairpin RNA (shRNA) into the injured spinal cords to evaluate the therapeutic potential of IL-1β downregulation in a rat model of spinal cord injury (SCI).
OBJECTIVES: The purpose of this study was to investigate the possible protective effects of the IL-1β downregulation on traumatic SCI in rats.
SETTING: Department of Orthopedic Surgery, The Second Affiliated Hospital, Fujian Medical University, Quanzhou, People's Republic of China.
METHODS: An adenoviral shRNA targeting IL-1β was constructed and injected at the T12 section 7 days before SCI. The rats' motor functions were evaluated by the Basso-Beattie-Bresnahan (BBB) rating scale. Immunofluorescence, enzyme-linked immunosorbent assay, flow-cytometric analysis and western blots were also performed.
RESULTS: Animals downregulating IL-1β had significantly better recovery of locomotor function and less neuronal loss after SCI. In addition, IL-1β downregulation significantly decreased tumor necrosis factor-alpha (TNF-α) level and Bax expression, reduced the activity of caspase-3 and increased Bcl-2 expression after SCI.
CONCLUSION: This study demonstrated that the IL-1β downregulation may have potential therapeutic benefits for both reducing secondary damages and improving the outcomes after traumatic SCI.

PMID: 26902461 [PubMed - indexed for MEDLINE]

Dopamine agonist resistance-related endocan promotes angiogenesis and cells viability of prolactinomas.

Fri, 07/14/2017 - 07:36
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Dopamine agonist resistance-related endocan promotes angiogenesis and cells viability of prolactinomas.

Endocrine. 2016 Jun;52(3):641-51

Authors: Cai L, Leng ZG, Guo YH, Lin SJ, Wu ZR, Su ZP, Lu JL, Wei LF, Zhuge QC, Jin K, Wu ZB

Abstract
Dopamine agonists (DAs) are the first-line treatment of prolactinomas. They function through the dopamine 2 receptor (D2R) in the tumor cells. Endocan, also called endothelial cell-specific molecule-1 (ESM1), has been described as a marker of neoangiogenesis. However, whether ESM1 promotes the resistance of prolactinomas to DA therapy is largely unknown. In our study, 25 patients with prolactinomas were divided into resistant- and sensitive- groups according to the clinical response to bromocriptine. We found that ESM1-microvessel density of resistant prolactinomas was significantly higher than that of sensitive prolactinomas (47.9 ± 11.6, n = 8, vs 13.1 ± 2.8, n = 17, p = 0.0006), indicating that ESM1 was a DA resistance-related gene. Immunostaining showed that ESM1 was expressed in tumor vessels and sporadic tumor cells, and ESM1 was overlapped with the Smooth Muscle Actin (SMA) and von Willebrand Factor (VWF) in the tumor vessels. Silencing of ESM1 markedly suppressed the viability of GH3 and MMQ cells in vitro, and furthermore, significantly increased the sensitivity of GH3 and MMQ cells to DA treatment. Additionally, silencing of ESM1 down-regulated the angiogenesis-associated genes, such as VEGFR2, FGF2, CD34, CD31, VWF, and EGFR. Knockdown of ESM1 decreased endothelial tube formation of HUVECs, and significantly increased the sensitivity of HUVECs to Avastin treatment. Therefore, we first demonstrate that DA resistance-related ESM1 promotes the angiogenesis and tumor cells growth of prolactinomas, suggesting that ESM1 may be a novel therapeutic target for prolactinomas.

PMID: 26662185 [PubMed - indexed for MEDLINE]

Energetic redistribution in allostery to execute protein function.

Wed, 07/12/2017 - 07:35
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Energetic redistribution in allostery to execute protein function.

Proc Natl Acad Sci U S A. 2017 Jul 10;:

Authors: Liu J, Nussinov R

PMID: 28696318 [PubMed - as supplied by publisher]

Potassium as a pluripotency-associated element identified through inorganic element profiling in human pluripotent stem cells.

Wed, 07/12/2017 - 07:35
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Potassium as a pluripotency-associated element identified through inorganic element profiling in human pluripotent stem cells.

Sci Rep. 2017 Jul 10;7(1):5005

Authors: Lin VJT, Zolekar A, Shi Y, Koneru B, Dimitrijevich S, Di Pasqua AJ, Wang YC

Abstract
Despite their well-known function in maintaining normal cell physiology, how inorganic elements are relevant to cellular pluripotency and differentiation in human pluripotent stem cells (hPSCs) has yet to be systematically explored. Using total reflection X-ray fluorescence (TXRF) spectrometry and inductively coupled plasma mass spectrometry (ICP-MS), we analyzed the inorganic components of human cells with isogenic backgrounds in distinct states of cellular pluripotency. The elemental profiles revealed that the potassium content of human cells significantly differs when their cellular pluripotency changes. Pharmacological treatment that alters cell membrane permeability to potassium affected the maintenance and establishment of cellular pluripotency via multiple mechanisms in bona fide hPSCs and reprogrammed cells. Collectively, we report that potassium is a pluripotency-associated inorganic element in human cells and provide novel insights into the manipulation of cellular pluripotency in hPSCs by regulating intracellular potassium.

PMID: 28694442 [PubMed - in process]

Adiponectin: Its role in obesity-associated colon and prostate cancers.

Wed, 07/12/2017 - 07:35
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Adiponectin: Its role in obesity-associated colon and prostate cancers.

Crit Rev Oncol Hematol. 2017 Aug;116:125-133

Authors: Muppala S, Konduru SKP, Merchant N, Ramsoondar J, Rampersad CK, Rajitha B, Mukund V, Kancherla J, Hammond A, Barik TK, Mannarapu M, Alam A, Basha R, Bramhachari PV, Verma D, Sushma PS, Pattnaik S, Nagaraju GP

Abstract
Adipose tissue synthesizes many proteins and hormones collectively called adipokines, which are linked to a number of diseases, including cancer. Low levels of adiponectin are reported to be a risk factor for obesity-related cancers including colorectal and prostate cancers. Accordingly, obesity/lifestyle-related diseases, including certain cancers, may be treated by developing drugs that act specifically on adiponectin levels in circulation. Adiponectin may also serve as a clinical biomarker in obesity-related diseases. Adiponectin-based therapies are known to inhibit cancer advancement and thus may provide a therapeutic approach to delay cancer progression. Better understanding of the function of adiponectin is of great significance in the fight against cancer. This timely review is concentrated on the role of adiponectin and the impact of obesity on the development of cancers, especially colorectal and prostate cancers.

PMID: 28693794 [PubMed - in process]

Optimal Measurement Interval for Emergency Department Crowding Estimation Tools.

Mon, 07/10/2017 - 07:35

Optimal Measurement Interval for Emergency Department Crowding Estimation Tools.

Ann Emerg Med. 2017 Jul 06;:

Authors: Wang H, Ojha RP, Robinson RD, Jackson BE, Shaikh SA, Cowden CD, Shyamanand R, Leuck J, Schrader CD, Zenarosa NR

Abstract
STUDY OBJECTIVE: Emergency department (ED) crowding is a barrier to timely care. Several crowding estimation tools have been developed to facilitate early identification of and intervention for crowding. Nevertheless, the ideal frequency is unclear for measuring ED crowding by using these tools. Short intervals may be resource intensive, whereas long ones may not be suitable for early identification. Therefore, we aim to assess whether outcomes vary by measurement interval for 4 crowding estimation tools.
METHODS: Our eligible population included all patients between July 1, 2015, and June 30, 2016, who were admitted to the JPS Health Network ED, which serves an urban population. We generated 1-, 2-, 3-, and 4-hour ED crowding scores for each patient, using 4 crowding estimation tools (National Emergency Department Overcrowding Scale [NEDOCS], Severely Overcrowded, Overcrowded, and Not Overcrowded Estimation Tool [SONET], Emergency Department Work Index [EDWIN], and ED Occupancy Rate). Our outcomes of interest included ED length of stay (minutes) and left without being seen or eloped within 4 hours. We used accelerated failure time models to estimate interval-specific time ratios and corresponding 95% confidence limits for length of stay, in which the 1-hour interval was the reference. In addition, we used binomial regression with a log link to estimate risk ratios (RRs) and corresponding confidence limit for left without being seen.
RESULTS: Our study population comprised 117,442 patients. The time ratios for length of stay were similar across intervals for each crowding estimation tool (time ratio=1.37 to 1.30 for NEDOCS, 1.44 to 1.37 for SONET, 1.32 to 1.27 for EDWIN, and 1.28 to 1.23 for ED Occupancy Rate). The RRs of left without being seen differences were also similar across intervals for each tool (RR=2.92 to 2.56 for NEDOCS, 3.61 to 3.36 for SONET, 2.65 to 2.40 for EDWIN, and 2.44 to 2.14 for ED Occupancy Rate).
CONCLUSION: Our findings suggest limited variation in length of stay or left without being seen between intervals (1 to 4 hours) regardless of which of the 4 crowding estimation tools were used. Consequently, 4 hours may be a reasonable interval for assessing crowding with these tools, which could substantially reduce the burden on ED personnel by requiring less frequent assessment of crowding.

PMID: 28688771 [PubMed - as supplied by publisher]

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