Recent Research Articles from UNTHSC

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

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Updated: 20 min 55 sec ago

Needlephilia versus Needlephobia.

Fri, 12/29/2017 - 08:07
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Needlephilia versus Needlephobia.

Skinmed. 2017;15(6):413-414

Authors: Abramovits W, Babaniji D, Vincent KD

PMID: 29282176 [PubMed - in process]

Dissociation of Striatal Dopamine and Tyrosine Hydroxylase Expression from Aging-Related Motor Decline: Evidence from Calorie Restriction Intervention.

Wed, 12/27/2017 - 07:41
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Dissociation of Striatal Dopamine and Tyrosine Hydroxylase Expression from Aging-Related Motor Decline: Evidence from Calorie Restriction Intervention.

J Gerontol A Biol Sci Med Sci. 2017 Dec 12;73(1):11-20

Authors: Salvatore MF, Terrebonne J, Cantu MA, McInnis TR, Venable K, Kelley P, Kasanga EA, Latimer B, Owens CL, Pruett BS, Yu Y, Luedtke R, Forster MJ, Sumien N, Ingram DK

Abstract
The escalating increase in retirees living beyond their eighth decade brings increased prevalence of aging-related impairments, including locomotor impairment (Parkinsonism) that may affect ~50% of those reaching age 80, but has no confirmed neurobiological mechanism. Lifestyle strategies that attenuate motor decline, and its allied mechanisms, must be identified. Aging studies report little to moderate loss of striatal dopamine (DA) or tyrosine hydroxylase (TH) in nigrostriatal terminals, in contrast to ~70%-80% loss associated with bradykinesia onset in Parkinson's disease. These studies evaluated the effect of ~6 months 30% calorie restriction (CR) on nigrostriatal DA regulation and aging-related locomotor decline initiated at 12 months of age in Brown-Norway Fischer F1 hybrid rats. The aging-related decline in locomotor activity was prevented by CR. However, striatal DA or TH expression was decreased in the CR group, but increased in substantia nigra versus the ad libitum group or 12-month-old cohort. In a 4- to 6-month-old cohort, pharmacological TH inhibition reduced striatal DA ~30%, comparable with decreases reported in aged rats and the CR group, without affecting locomotor activity. The dissociation of moderate striatal DA reduction from locomotor activity seen in both studies suggests that aging-related decreases in striatal DA are dissociated from locomotor decline.

PMID: 28637176 [PubMed - indexed for MEDLINE]

Examining the Use of Sodium Nitroprusside in Coronary Artery Bypass Grafting: Is the Benefit Worth the Cost?

Tue, 12/26/2017 - 07:34
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Examining the Use of Sodium Nitroprusside in Coronary Artery Bypass Grafting: Is the Benefit Worth the Cost?

Hosp Pharm. 2017 Jul;52(7):502-507

Authors: Gibson CM, Davis S, Bradford D

Abstract
Purpose: Sodium nitroprusside is a vasodilator frequently used in the coronary artery bypass grafting (CABG) setting. However, the price of a 50-mg vial of sodium nitroprusside increased from $5.00 in 2003 to up to $900 in 2016. The purpose of this review is to help health systems balance high-quality patient care with economic responsibility. Methods: A MEDLINE literature search was performed using the search terms "nitroprusside" and "coronary artery bypass." All English-language trials in human subjects assessing the use of sodium nitroprusside in the setting of CABG were evaluated. The references of these studies were also reviewed. Results: In the setting of CABG, sodium nitroprusside attenuates conduit vasospasm and reduces the incidence of inflammation, atrial fibrillation, and acute kidney injury after surgery. However, other vasodilators are more effective at maintaining postoperative blood pressure at goal. Conclusions: Despite its cost, sodium nitroprusside may be an appropriate agent to use during CABG operations, but other agents should be considered for treatment of postoperative hypertension.

PMID: 29276280 [PubMed - in process]

Sex-related differences in oxidative stress and neurodegeneration.

Sun, 12/24/2017 - 07:46
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Sex-related differences in oxidative stress and neurodegeneration.

Steroids. 2017 Dec 20;:

Authors: Tenkorang MA, Snyder B, Cunningham RL

Abstract
Oxidative stress has been implicated in a number of neurodegenerative diseases spanning various fields of research. Reactive oxygen species can be beneficial or harmful, depending on their concentration. High levels of reactive oxygen species can lead to oxidative stress, which is an imbalance between free radicals and antioxidants. Increased oxidative stress can result in cell loss. Interestingly, sex differences have been observed in oxidative stress generation, which may underlie sex differences observed in neurodegenerative disorders. An enhanced knowledge of the role of sex hormones on oxidative stress signaling and cell loss can yield valuable information, leading to sex-based mechanistic approaches to neurodegeneration.

PMID: 29274405 [PubMed - as supplied by publisher]

Erratum to "Population and performance analyses of four major populations with Illumina's FGx Forensic Genomics System" [Forensic Sci. Int.: Genet. 30 (2017) 81-92].

Sun, 12/24/2017 - 07:46
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Erratum to "Population and performance analyses of four major populations with Illumina's FGx Forensic Genomics System" [Forensic Sci. Int.: Genet. 30 (2017) 81-92].

Forensic Sci Int Genet. 2017 Dec 19;:

Authors: Churchill JD, Novroski NMM, King JL, Seah LH, Budowle B

PMID: 29273514 [PubMed - as supplied by publisher]

Function of ubiquitin (Ub) specific protease 15 (USP15) in HIV-1 replication and viral protein degradation.

Sat, 12/23/2017 - 07:34
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Function of ubiquitin (Ub) specific protease 15 (USP15) in HIV-1 replication and viral protein degradation.

Virus Res. 2016 Sep 02;223:161-9

Authors: Pyeon D, Timani KA, Gulraiz F, He JJ, Park IW

Abstract
HIV-1 Nef is necessary and may be sufficient for HIV-1-associated AIDS pathogenicity, in that knockout of Nef alone can protect HIV-infected patients from AIDS. We therefore investigated the feasibility of physical knockout of Nef, using the host ubiquitin proteasome system in HIV-1-infected cells. Our co-immunoprecipitation analysis demonstrated that Nef interacted with ubiquitin specific protease 15 (USP15), and that USP15, which is known to stabilize cellular proteins, degraded Nef. Nef could also cause decay of USP15, although Nef-mediated degradation of USP15 was weaker than USP15-mediated Nef degradation. Direct interaction between Nef and USP15 was essential for the observed reciprocal decay of the proteins. Further, USP15 degraded not only Nef but also HIV-1 structural protein, Gag, thereby substantially inhibiting HIV-1 replication. However, Gag did not degrade USP15, indicating that the Nef and USP15 complex, in distinction to other viral proteins, play an integral role in coordinating viral protein degradation and hence HIV-1 replication. Moreover, Nef and USP15 globally suppressed ubiquitylation of cellular proteins, indicating that these proteins are major determinants for the stability of cellular as well as viral proteins. Taken together, these data indicate that Nef and USP15 are vital in regulating degradation of viral and cellular proteins and thus HIV-1 replication, and specific degradation of viral, not cellular proteins, by USP15 points to USP15 as a candidate therapeutic agent to combat AIDS by eliminating viral proteins from the infected cells via USP15-mediated proteosomal degradation.

PMID: 27460547 [PubMed - indexed for MEDLINE]

Effects of Alcohol Interventions on Other Drug Use in the Cherokee Nation.

Fri, 12/22/2017 - 07:49

Effects of Alcohol Interventions on Other Drug Use in the Cherokee Nation.

Am J Public Health. 2017 Dec 21;:e1-e3

Authors: Livingston MD, Komro KA, Wagenaar AC, Kominsky TK, Pettigrew DW, Garrett BA

Abstract
OBJECTIVES: To evaluate effects of 2 alcohol prevention interventions-Communities Mobilizing for Change on Alcohol (CMCA), a community organizing intervention designed to reduce youth alcohol access, and CONNECT, an individual-level screening and brief intervention approach-on other drug use outcomes.
METHODS: We conducted a community intervention trial with quarterly surveys over 3 years (2012-2015) of high school students living within the jurisdictional service area of the Cherokee Nation in Oklahoma. We used generalized estimating equations and linear probability models to examine intervention spillover effects on other drug use.
RESULTS: We found significant reductions in drug use other than alcohol attributable to CMCA and CONNECT. CMCA was associated with a 35% reduction in chewing tobacco use, a 39% reduction in marijuana use, and a 48% reduction in prescription drug misuse. CONNECT was associated with a 26% reduction in marijuana use and a 31% reduction in prescription drug misuse.
CONCLUSIONS: Nonalcohol drug use was consistently reduced as a result of 2 theoretically and operationally distinct alcohol prevention strategies. Evaluations of alcohol prevention efforts should continue to include other drug use to understand the broader effects of such interventions. (Am J Public Health. Published online ahead of print December 21, 2017: e1-e3. doi:10.2105/AJPH.2017.304188).

PMID: 29267057 [PubMed - as supplied by publisher]

Spotlight on solithromycin in the treatment of community-acquired bacterial pneumonia: design, development, and potential place in therapy.

Fri, 12/22/2017 - 07:49
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Spotlight on solithromycin in the treatment of community-acquired bacterial pneumonia: design, development, and potential place in therapy.

Drug Des Devel Ther. 2017;11:3559-3566

Authors: Donald BJ, Surani S, Deol HS, Mbadugha UJ, Udeani G

Abstract
Community-acquired bacterial pneumonia (CABP) is a leading cause of death worldwide. However, antibacterial agents used to treat common pathogens in CABP are marked by adverse drug events and increasing antimicrobial resistance. Solithromycin is a new ketolide antibiotic, based on the macrolide antibiotic structure, being studied for use in CABP. It has efficacy in vitro against the common causative pathogens in CABP including Streptococcus pneumoniae, Haemophilus influenzae, and atypical pathogens. In Phase II and Phase III clinical trials, it has been demonstrated efficacious as a single agent for treatment of CABP with an apparently milder adverse event profile than alternative agents.

PMID: 29263651 [PubMed - in process]

Magnesium intake and mortality due to liver diseases: Results from the Third National Health and Nutrition Examination Survey Cohort.

Fri, 12/22/2017 - 07:49
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Magnesium intake and mortality due to liver diseases: Results from the Third National Health and Nutrition Examination Survey Cohort.

Sci Rep. 2017 Dec 20;7(1):17913

Authors: Wu L, Zhu X, Fan L, Kabagambe EK, Song Y, Tao M, Zhong X, Hou L, Shrubsole MJ, Liu J, Dai Q

Abstract
People with fatty liver disease are at high risk of magnesium deficiency. Meanwhile, low magnesium status is linked to both chronic inflammation and insulin resistance. However, no study has investigated the association between intake of magnesium and risk of mortality due to liver diseases. We evaluated the association between total magnesium intake and mortality due to liver diseases in the Third National Health and Nutrition Examination Study (NHANES III) cohort, which included 13,504 participants who completed liver ultrasound examination for hepatic steatosis. Overall magnesium intake was associated with a reduced risk of mortality due to liver disease at borderline significance (P = 0.05). In fully-adjusted analyses, every 100 mg increase in intake of magnesium was associated with a 49% reduction in the risk for mortality due to liver diseases. Although interactions between magnesium intake and alcohol use and hepatic steatosis at baseline were not significant (P > 0.05), inverse associations between magnesium intake and liver disease mortality were stronger among alcohol drinkers and those with hepatic steatosis. Our findings suggest higher intakes of magnesium may be associated with a reduced risk of mortality due to liver disease particularly among alcohol drinkers and those with hepatic steatosis. Further studies are warranted to confirm the findings.

PMID: 29263344 [PubMed - in process]

Ontogenetic and functional modularity in the rodent mandible.

Fri, 12/22/2017 - 07:49
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Ontogenetic and functional modularity in the rodent mandible.

Zoology (Jena). 2017 Oct;124:61-72

Authors: Menegaz RA, Ravosa MJ

Abstract
The material properties of diets consumed by juvenile individuals are known to affect adult morphological outcomes. However, much of the current experimental knowledge regarding dietary effects on masticatory form is derived from studies in which individuals are fed a non-variable diet for the duration of their postweaning growth period. Thus, it remains unclear how intra-individual variation in diet, due to ontogenetic variation in feeding behaviors or seasonal resource fluctuations, affects the resulting adult morphology. Furthermore, the mandible is composed of multiple developmental and functional subunits, and the extent to which growth and plasticity among these modules is correlated may be misestimated by studies that examine non-variable masticatory function in adults only. To address these gaps in our current knowledge, this study raised Sprague Dawley rats (n=42) in four dietary cohorts from weaning to skeletal maturity. Two cohorts were fed a stable ("annual") diet of either solid or powdered pellets. The other two cohorts were fed a variable ("seasonal") diet consisting of solid/powdered pellets for the first half of the study, followed by a shift to the opposite diet. Results of longitudinal morphometric analyses indicate that variation in the mandibular corpus is more prominent at immature ontogenetic stages, likely due to processes of dental eruption and the growth of tooth roots. Furthermore, adult morphology is influenced by both masticatory function and the ontogenetic timing of this function, e.g., the consumption of a mechanically resistant diet. The morphology of the coronoid process was found to separate cohorts on the basis of their early weanling diet, suggesting that the coronoid process/temporalis muscle module may have an early plasticity window related to high growth rates during this life stage. Conversely, the morphology of the angular process was found to be influenced by the consumption of a mechanically resistant diet at any point during the growth period, but with a tendency to reflect the most recent diet. The prolonged plasticity window of the angular process/pterygomasseteric muscle module may be related to delayed ossification and muscular maturation within this module. The research presented here highlights the importance of more naturalistic models of mammalian feeding, and underscores the need for a better understanding of the processes of both morphological and behavioral maturation that follow weaning.

PMID: 28774721 [PubMed - indexed for MEDLINE]

Molecular mechanisms of serotonergic action of the HIV-1 antiretroviral efavirenz.

Fri, 12/22/2017 - 07:49
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Molecular mechanisms of serotonergic action of the HIV-1 antiretroviral efavirenz.

Pharmacol Res. 2016 Aug;110:10-24

Authors: Dalwadi DA, Kim S, Amdani SM, Chen Z, Huang RQ, Schetz JA

Abstract
Efavirenz is highly effective at suppressing HIV-1, and the WHO guidelines list it as a component of the first-line antiretroviral (ARV) therapies for treatment-naïve patients. Though the pharmacological basis is unclear, efavirenz is commonly associated with a risk for neuropsychiatric adverse events (NPAEs) when taken at the prescribed dose. In many patients these NPAEs appear to subside after several weeks of treatment, though long-term studies show that in some patients the NPAEs persist. In a recent study focusing on the abuse potential of efavirenz, its receptor psychopharmacology was reported to include interactions with a number of established molecular targets for known drugs of abuse, and it displayed a prevailing behavioral profile in rodents resembling an LSD-like activity. In this report, we discovered interactions with additional serotonergic targets that may be associated with efavirenz-induced NPAEs. The most robust interactions were with 5-HT3A and 5-HT6 receptors, with more modest interactions noted for the 5-HT2B receptor and monoamine oxidase A. From a molecular mechanistic perspective, efavirenz acts as a 5-HT6 receptor inverse agonist of Gs-signaling, 5-HT2A and 5-HT2C antagonist of Gq-signaling, and a blocker of the 5-HT3A receptor currents. Efavirenz also completely or partially blocks agonist stimulation of the M1 and M3 muscarinic receptors, respectively. Schild analysis suggests that efavirenz competes for the same site on the 5-HT2A receptor as two known hallucinogenic partial agonists (±)-DOI and LSD. Prolonged exposure to efavirenz reduces 5-HT2A receptor density and responsiveness to 5-HT. Other ARVs such as zidovudine, nevirapine and emtricitabine did not share the same complex pharmacological profile as efavirenz, though some of them weakly interact with the 5-HT6 receptor or modestly block GABAA currents.

PMID: 27157251 [PubMed - indexed for MEDLINE]

Sex differences in sleep apnea and comorbid neurodegenerative diseases.

Thu, 12/21/2017 - 07:34
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Sex differences in sleep apnea and comorbid neurodegenerative diseases.

Steroids. 2017 Dec 16;:

Authors: Snyder B, Cunningham RL

Abstract
Sleep apnea is a disorder, which increasingly affects people worldwide. Whether the associated hypoxic events during sleep are central or obstructive in origin, the end result is excessive daytime sleepiness and an increased risk for several comorbidities, such as cardiovascular and neurodegenerative disorders. Sleep apnea is diagnosed more frequently in men than women, suggesting a role of sex hormones in the pathology of the disease. Furthermore, there are sex differences in the development and progression of comorbid diseases associated with sleep apnea. Therefore, treatment of sleep apnea may be clinically relevant for prevention of subsequent sex-specific comorbid disorders. While the impact sleep apnea has on cardiovascular events has been the subject of many research studies, the role of sleep apnea in neurodegeneration is less established. Here we review known risk factors for sleep apnea and the implications of the observed sex differences in this disease. We also summarize the evidence and mechanisms for how sleep apnea may contribute to the onset of neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease.

PMID: 29258810 [PubMed - as supplied by publisher]

Water T2 as an early, global and practical biomarker for metabolic syndrome: an observational cross-sectional study.

Thu, 12/21/2017 - 07:34
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Water T2 as an early, global and practical biomarker for metabolic syndrome: an observational cross-sectional study.

J Transl Med. 2017 Dec 19;15(1):258

Authors: Robinson MD, Mishra I, Deodhar S, Patel V, Gordon KV, Vintimilla R, Brown K, Johnson L, O'Bryant S, Cistola DP

Abstract
BACKGROUND: Metabolic syndrome (MetS) is a highly prevalent condition that identifies individuals at risk for type 2 diabetes mellitus and atherosclerotic cardiovascular disease. Prevention of these diseases relies on early detection and intervention in order to preserve pancreatic β-cells and arterial wall integrity. Yet, the clinical criteria for MetS are insensitive to the early-stage insulin resistance, inflammation, cholesterol and clotting factor abnormalities that characterize the progression toward type 2 diabetes and atherosclerosis. Here we report the discovery and initial characterization of an atypical new biomarker that detects these early conditions with just one measurement.
METHODS: Water T2, measured in a few minutes using benchtop nuclear magnetic resonance relaxometry, is exquisitely sensitive to metabolic shifts in the blood proteome. In an observational cross-sectional study of 72 non-diabetic human subjects, the association of plasma and serum water T2 values with over 130 blood biomarkers was analyzed using bivariate, multivariate and logistic regression.
RESULTS: Plasma and serum water T2 exhibited strong bivariate correlations with markers of insulin, lipids, inflammation, coagulation and electrolyte balance. After correcting for confounders, low water T2 values were independently and additively associated with fasting hyperinsulinemia, dyslipidemia and subclinical inflammation. Plasma water T2 exhibited 100% sensitivity and 87% specificity for detecting early insulin resistance in normoglycemic subjects, as defined by the McAuley Index. Sixteen normoglycemic subjects with early metabolic abnormalities (22% of the study population) were identified by low water T2 values. Thirteen of the 16 did not meet the harmonized clinical criteria for metabolic syndrome and would have been missed by conventional screening for diabetes risk. Low water T2 values were associated with increases in the mean concentrations of 6 of the 16 most abundant acute phase proteins and lipoproteins in plasma.
CONCLUSIONS: Water T2 detects a constellation of early abnormalities associated with metabolic syndrome, providing a global view of an individual's metabolic health. It circumvents the pitfalls associated with fasting glucose and hemoglobin A1c and the limitations of the current clinical criteria for metabolic syndrome. Water T2 shows promise as an early, global and practical screening tool for the identification of individuals at risk for diabetes and atherosclerosis.

PMID: 29258604 [PubMed - in process]

Autoimmune therapeutic chloroquine lowers blood pressure and improves endothelial function in spontaneously hypertensive rats.

Thu, 12/21/2017 - 07:34
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Autoimmune therapeutic chloroquine lowers blood pressure and improves endothelial function in spontaneously hypertensive rats.

Pharmacol Res. 2016 Nov;113(Pt A):384-394

Authors: McCarthy CG, Wenceslau CF, Goulopoulou S, Ogbi S, Matsumoto T, Webb RC

Abstract
It has been suggested that hypertension results from a loss of immunological tolerance and the resulting autoimmunity may be an important underlying factor of its pathogenesis. This stems from the observations that many of the features involved in autoimmunity are also implicated in hypertension. Furthermore, the underlying presence of hypertension and cardiovascular disease are frequently observed in patients with autoimmune diseases. Antimalarial agents such as chloroquine are generally among the first line treatment options for patients with autoimmune diseases; however, whether they can improve a hypertensive phenotype in a genetic model of essential hypertension remains to be clarified. Therefore, we hypothesized that chloroquine treatment would improve endothelial function and lower blood pressure in spontaneously hypertensive rats (SHR). We treated adult SHR and Wistar-Kyoto rats (12 weeks old), as well as a group of young SHR (5 weeks old), with chloroquine (40mg/kg/day via intraperitoneal injection) for 21 days. Chloroquine lowered blood pressure in adult SHR, but did not impede the development of high blood pressure in young SHR. In isolated mesenteric resistance arteries from SHR of both ages, chloroquine treatment inhibited cyclooxygenase-dependent contraction to acetylcholine, lowered vascular and systemic generation of reactive oxygen species, and improved nitric oxide bioavailability. Overall, these data reveal the anti-hypertensive mechanisms of chloroquine in the vasculature, which may be important for lowering risk of cardiovascular disease in patients with autoimmune diseases. Furthermore, it adds to the growing body of evidence suggesting that autoimmunity underlies hypertension.

PMID: 27639600 [PubMed - indexed for MEDLINE]

Spectral and temporal properties of calls reveal deficits in ultrasonic vocalizations of adult Fmr1 knockout mice.

Wed, 12/20/2017 - 07:36
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Spectral and temporal properties of calls reveal deficits in ultrasonic vocalizations of adult Fmr1 knockout mice.

Behav Brain Res. 2017 Aug 14;332:50-58

Authors: Hodges SL, Nolan SO, Reynolds CD, Lugo JN

Abstract
The Fmr1 knockout (KO) mouse has commonly been used to investigate communication impairments, one of the key diagnostic symptoms observed in Fragile X syndrome (FXS) and Autism spectrum disorder (ASD). Many studies have found alterations in ultrasonic vocalizations (USVs) in neonatal Fmr1 KO mice, however, there is limited research investigating whether these deficits continue into adulthood. In the present study, we examine differences in female urine-induced ultrasonic vocalizations, scent marking behavior, odor discrimination, and open field activity in adult male Fmr1 KO and wildtype (WT) mice. Overall, we found extensive alterations between genotypes in both spectral and temporal properties of ultrasonic vocalizations. There was no difference in the average number of calls emitted by both genotypes, however, Fmr1 KO mice emitted calls of a higher frequency, decreased amplitude, and shorter duration than WT mice. Spectrographic analyses revealed statistically significant differences between genotypes in the types of calls emitted. Contrastingly, we found no differences in scent marking behavior, a form of social communication, or in odor discrimination and activity levels of the mice. The results corroborate previous studies emphasizing the importance of qualitative differences observed in vocalization behavior of Fmr1 KO mice, rather than quantitative measurements such as number of calls emitted. Overall, the study confirms the presence of abnormalities in vocalization behavior in adult Fmr1 KO mice that we believe are consistent with communication deficits seen in the syndrome.

PMID: 28552599 [PubMed - indexed for MEDLINE]

Transethnic genome-wide scan identifies novel Alzheimer's disease loci.

Tue, 12/19/2017 - 07:34
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Transethnic genome-wide scan identifies novel Alzheimer's disease loci.

Alzheimers Dement. 2017 Jul;13(7):727-738

Authors: Jun GR, Chung J, Mez J, Barber R, Beecham GW, Bennett DA, Buxbaum JD, Byrd GS, Carrasquillo MM, Crane PK, Cruchaga C, De Jager P, Ertekin-Taner N, Evans D, Fallin MD, Foroud TM, Friedland RP, Goate AM, Graff-Radford NR, Hendrie H, Hall KS, Hamilton-Nelson KL, Inzelberg R, Kamboh MI, Kauwe JSK, Kukull WA, Kunkle BW, Kuwano R, Larson EB, Logue MW, Manly JJ, Martin ER, Montine TJ, Mukherjee S, Naj A, Reiman EM, Reitz C, Sherva R, St George-Hyslop PH, Thornton T, Younkin SG, Vardarajan BN, Wang LS, Wendlund JR, Winslow AR, Alzheimer's Disease Genetics Consortium, Haines J, Mayeux R, Pericak-Vance MA, Schellenberg G, Lunetta KL, Farrer LA

Abstract
INTRODUCTION: Genetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood.
METHODS: We conducted a transethnic genome-wide association study (GWAS) for late-onset AD in Stage 1 sample including whites of European Ancestry, African-Americans, Japanese, and Israeli-Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset.
RESULTS: Genome-wide significant (GWS) associations in single-nucleotide polymorphism (SNP)-based tests (P < 5 × 10-8) were identified for SNPs in PFDN1/HBEGF, USP6NL/ECHDC3, and BZRAP1-AS1 and for the interaction of the (apolipoprotein E) APOE ε4 allele with NFIC SNP. We also obtained GWS evidence (P < 2.7 × 10-6) for gene-based association in the total sample with a novel locus, TPBG (P = 1.8 × 10-6).
DISCUSSION: Our findings highlight the value of transethnic studies for identifying novel AD susceptibility loci.

PMID: 28183528 [PubMed - indexed for MEDLINE]

Losartan reduces the immediate and sustained increases in muscle sympathetic nerve activity after hyperacute intermittent hypoxia.

Tue, 12/19/2017 - 07:34
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Losartan reduces the immediate and sustained increases in muscle sympathetic nerve activity after hyperacute intermittent hypoxia.

J Appl Physiol (1985). 2017 Apr 01;122(4):884-892

Authors: Jouett NP, Moralez G, Raven PB, Smith ML

Abstract
Obstructive sleep apnea (OSA) is characterized by intermittent hypoxemia, which produces elevations in sympathetic nerve activity (SNA) and associated hypertension in experimental models that persist beyond the initial exposure. We tested the hypotheses that angiotensin receptor blockade in humans using losartan attenuates the immediate and immediately persistent increases in 1) SNA discharge and 2) mean arterial pressure (MAP) after hyperacute intermittent hypoxia training (IHT) using a randomized, placebo-controlled, repeated-measures experimental design. We measured ECG and photoplethysmographic arterial pressure in nine healthy human subjects, while muscle SNA (MSNA) was recorded in seven subjects using microneurography. Subjects were exposed to a series of hypoxic apneas in which they inhaled two to three breaths of nitrogen, followed by a 20-s apnea and 40 s of room air breathing every minute for 20 min. Hyperacute IHT produced substantial and persistent elevations in MSNA burst frequency (baseline: 15.3 ± 1.8, IHT: 24 ± 1.5, post-IHT 20.0 ± 1.3 bursts/min, all P < 0.01) and MAP (baseline: 89.2 ± 3.3, IHT: 92.62 ± 3.1, post-IHT: 93.83 ± 3.1 mmHg, all P < 0.02). Losartan attenuated the immediate and sustained increases in MSNA (baseline: 17.3 ± 2.5, IHT: 18.6 ± 2.2, post-IHT 20.0 ± 1.3 bursts/min, all P < 0.001) and MAP (baseline: 81.9 ± 2.6, IHT: 81.1 ± 2.8, post-IHT: 81.3 ± 3.0 mmHg, all P > 0.70). This investigation confirms the role of angiotensin II type 1a receptors in the immediate and persistent sympathoexcitatory and pressor responses to IHT.NEW & NOTEWORTHY This study demonstrates for the first time in humans that losartan, an angiotensin receptor blocker (ARB), abrogates the acute and immediately persistent increases in muscle sympathetic nerve activity and arterial pressure in response to acute intermittent hypoxia. This investigation, along with others, provides important beginning translational evidence for using ARBs in treatment of the intermittent hypoxia observed in obstructive sleep apnea patients.

PMID: 28082332 [PubMed - indexed for MEDLINE]

Targeting specificity protein 1 transcription factor and survivin using tolfenamic acid for inhibiting Ewing sarcoma cell growth.

Fri, 12/15/2017 - 07:34
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Targeting specificity protein 1 transcription factor and survivin using tolfenamic acid for inhibiting Ewing sarcoma cell growth.

Invest New Drugs. 2017 Apr;35(2):158-165

Authors: Shelake S, Sankpal UT, Paul Bowman W, Wise M, Ray A, Basha R

Abstract
Transcription factor Specificity protein 1 (Sp1) and its downstream target survivin (inhibitor of apoptosis protein), play major roles in the pathogenesis of various cancers. Ewing Sarcoma (ES) is a common soft tissue/bone tumor in adolescent and young adults. Overexpression of survivin is also linked to the aggressiveness and poor prognosis of ES. Small molecule Tolfenamic acid (TA) inhibits Sp1 and survivin in cancer cells. In this investigation, we demonstrate a strategy to target Sp1 and survivin using TA and positive control Mithramycin A (Mit) to inhibit ES cell growth. Knock down of Sp1 using small interfering RNA (siRNA) resulted in significant (p < 0.05) inhibition of CHLA-9 and TC-32 cell growth as assessed by CellTiter-Glo assay kit. TA or Mit treatment caused dose/time-dependent inhibition of cell viability, and this inhibition was correlated with a decrease in Sp1 and survivin protein levels in ES cells. Quantitative PCR results showed that Mit treatment decreased the mRNA expression of both survivin and Sp1, whereas TA diminished only survivin but not Sp1. Proteasome inhibitor restored TA-induced inhibition of Sp1 protein expression suggesting that TA might cause proteasome-dependent degradation. Gel shift assay using ES cell nuclear extract and biotinylated Sp1 consensus oligonucleotides confirmed that both TA and Mit decreased DNA-binding activity of Sp1. These results demonstrate that both Mit and TA reduce expression of Sp1 and survivin, disrupt Sp1 DNA-binding and inhibit ES cell proliferation. This investigation suggests that targeting Sp1 and survivin could be an effective strategy for inhibiting ES cell growth.

PMID: 28025760 [PubMed - indexed for MEDLINE]

WISE 2005: Aerobic and resistive countermeasures prevent paraspinal muscle deconditioning during 60-day bed rest in women.

Fri, 12/15/2017 - 07:34
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WISE 2005: Aerobic and resistive countermeasures prevent paraspinal muscle deconditioning during 60-day bed rest in women.

J Appl Physiol (1985). 2016 May 15;120(10):1215-22

Authors: Holt JA, Macias BR, Schneider SM, Watenpaugh DE, Lee SM, Chang DG, Hargens AR

Abstract
Microgravity-induced lumbar paraspinal muscle deconditioning may contribute to back pain commonly experienced by astronauts and may increase the risk of postflight injury. We hypothesized that a combined resistive and aerobic exercise countermeasure protocol that included spinal loading would mitigate lumbar paraspinal muscle deconditioning during 60 days of bed rest in women. Sixteen women underwent 60-day, 6° head-down-tilt bed rest (BR) and were randomized into control and exercise groups. During bed rest the control group performed no exercise. The exercise group performed supine treadmill exercise within lower body negative pressure (LBNP) for 3-4 days/wk and flywheel resistive exercise for 2-3 days/wk. Paraspinal muscle cross-sectional area (CSA) was measured using a lumbar spine MRI sequence before and after BR. In addition, isokinetic spinal flexion and extension strengths were measured before and after BR. Data are presented as means ± SD. Total lumbar paraspinal muscle CSA decreased significantly more in controls (10.9 ± 3.4%) than in exercisers (4.3 ± 3.4%; P < 0.05). The erector spinae was the primary contributor (76%) to total lumbar paraspinal muscle loss. Moreover, exercise attenuated isokinetic spinal extension loss (-4.3 ± 4.5%), compared with controls (-16.6 ± 11.2%; P < 0.05). In conclusion, LBNP treadmill and flywheel resistive exercises during simulated microgravity mitigate decrements in lumbar paraspinal muscle structure and spine function. Therefore spaceflight exercise countermeasures that attempt to reproduce spinal loads experienced on Earth may mitigate spinal deconditioning during long-duration space travel.

PMID: 26893030 [PubMed - indexed for MEDLINE]

Assessing a traditional case-based application exercise and a student question creation exercise on student performance and perceptions.

Thu, 12/14/2017 - 07:39
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Assessing a traditional case-based application exercise and a student question creation exercise on student performance and perceptions.

Curr Pharm Teach Learn. 2017 Jul;9(4):689-697

Authors: Tatachar A, Kominski C

Abstract
BACKGROUND AND PURPOSE: To compare the impact of a traditional case-based application exercise with a student question creation exercise on a) student exam performance, b) student perceptions of enjoyment, competence, understanding, effort, interest in continuing participation, and interest in the subject.
EDUCATIONAL ACTIVITY AND SETTING: Subjects were 84 second-year pharmacy students in a pharmacotherapy course. The research focus was active learning involving the topic of chronic kidney disease-mineral bone disorder. Student teams were randomly assigned to either case-based or student question creation exercises using PeerWise. Student performance was assessed by a pre- and posttest and on block and final exams. After completion, an online survey assessed student perceptions of both exercises.
FINDINGS: Statistically significant differences were revealed in favor of the student question creation group on enjoyment and interest in the subject matter. No statistically differences were found between the traditional case-based group and the student question creation group on gain score from pre-test to posttest. The student question creation group performed slightly better than the case-based application group on two of the five questions on the block exam but none of these differences reached statistical significance.
DISCUSSION AND CONCLUSIONS: Students randomly assigned to groups that created and reviewed questions exhibited slightly improved summative exam performance and reported significantly more positive perceptions than students engaging in a more traditional case-based learning activity. Student question creation has demonstrated potential as a useful learning activity. Despite inherent difficulties in designing studies involving educational research in a controlled environment, students who have submitted, created, rated, and answered peers' questions have overall performed well.

PMID: 29233444 [PubMed - in process]

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