Recent Research Articles from UNTHSC

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Urine osmolality in the US population: implications for environmental biomonitoring.

Wed, 02/04/2015 - 4:35am
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Urine osmolality in the US population: implications for environmental biomonitoring.

Environ Res. 2015 Jan;136:482-90

Authors: Yeh HC, Lin YS, Kuo CC, Weidemann D, Weaver V, Fadrowski J, Neu A, Navas-Acien A

Abstract
BACKGROUND: For many environmental chemicals, concentrations in spot urine samples are considered valid surrogates of exposure and internal dose. To correct for urine dilution, spot urine concentrations are commonly adjusted for urinary creatinine. There are, however, several concerns about the use of urine creatinine. While urine osmolality is an attractive alternative; its characteristics and determinants in the general population remain unknown. Our objective was to describe the determinants of urine osmolality and to contrast the difference between osmolality and creatinine in urine.
METHODS: From the National Health and Nutrition Examination Survey (NHANES) (2009-2010), 10,769 participants aged 16 years or older with measured urine osmolality and creatinine were used in the analysis. Very dilute and very concentrated urine was defined as urine creatinine lower than 0.3g/l and higher than 3g/l, respectively. Linear and logistic regression analyses were performed to investigate the associations of interest.
RESULTS: Urine osmolality and creatinine were highly correlated (Pearson correlation coefficient=0.75) and their respective median values were 648 mOsm/kg and 1.07 g/l. The prevalence of very dilute and very concentrated urine samples was 8.1% and 3.1%, respectively. Factors associated in the same direction with both urine osmolality and urine creatinine included age, sex, race, body mass index (BMI), hypertension, water intake, and blood osmolality. The magnitude of associations expressed as percent change was significantly stronger with creatinine than osmolality. Compared to urine creatinine, urine osmolality did not vary by diabetes status but was affected by daily total protein intake. Participants with chronic kidney disease (CKD) had significantly higher urine creatinine concentrations but lower urine osmolality. Both very dilute and concentrated urine were associated with a diverse array of sociodemographic, medical conditions, and dietary factors. For instance, females were approximately 3.3 times more likely to have urine over-dilution than male [the adjusted odds ratios (95% CI)=3.27 (2.10-5.10)].
CONCLUSION: Although the determinants of urine osmolality were generally similar to those of urine creatinine, the relative influence of socio-demographic and medical conditions was less on urine osmolality than on urine creatinine. Protocols for spot urine sample collection could recommend avoiding excessive and insufficient water intake before urine sampling to improve urine adequacy. The feasibility of adopting urine osmolality adjustment and water intake recommendations before providing spot urine samples for environmental biomonitoring merits further investigation.

PMID: 25460670 [PubMed - indexed for MEDLINE]

Antioxidant activity, antitumor effect, and antiaging property of proanthocyanidins extracted from kunlun chrysanthemum flowers.

Tue, 02/03/2015 - 4:29am
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Antioxidant activity, antitumor effect, and antiaging property of proanthocyanidins extracted from kunlun chrysanthemum flowers.

Oxid Med Cell Longev. 2015;2015:983484

Authors: Jing S, Zhang X, Yan LJ

Abstract
The objective of the present study was to evaluate the antioxidant activity, antitumor effect, and antiaging property of proanthocyanidins from Kunlun Chrysanthemum flowers (PKCF) grown in Xinjiang. In vitro antioxidant experiments results showed that the total antioxidant activity and the scavenging capacity of hydroxyl radicals ((•)OH) and 1,1-diphenyl-2-picrylhydrazyl (DPPH(•)) radicals increased in a concentration-dependent manner and were stronger than those of vitamin C. To investigate the antioxidant activity of PKCF in vivo, we used serum, liver, and kidney from mouse for the measurement of superoxide dismutase (SOD), malondialdehyde (MDA), and total antioxidant capacity (T-AOC). Results indicated that PKCF had antioxidative effect in vivo which significantly improved the activity of SOD and T-AOC and decreased MDA content. To investigate the antitumor activity of PKCF, we used H22 cells, HeLa cells, and Eca-109 cells with Vero cells as control. Inhibition ratio and IC50 values were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay; PKCF showed great inhibitory activity on H22 cells and HeLa cells. We also used fruit flies as a model for analyzing the anti-aging property of PKCF. Results showed that PKCF has antiaging effect on Drosophila. Results of the present study demonstrated that PKCF could be a promising agent that may find applications in health care, medicine, and cosmetics.

PMID: 25628774 [PubMed - in process]

Pharmacological modulation of abnormal involuntary DOI-induced head twitch response in male DBA/2J mice: I. Effects of D2/D3 and D2 dopamine receptor selective compounds.

Tue, 02/03/2015 - 4:29am
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Pharmacological modulation of abnormal involuntary DOI-induced head twitch response in male DBA/2J mice: I. Effects of D2/D3 and D2 dopamine receptor selective compounds.

Neuropharmacology. 2014 Aug;83:18-27

Authors: Rangel-Barajas C, Malik M, Vangveravong S, Mach RH, Luedtke RR

Abstract
Because of the complexity and heterogeneity of human neuropsychiatric disorders, it has been difficult to identify animal models that mimic the symptoms of these neuropathologies and can be used to screen for antipsychotic agents. For this study we selected the murine 5HT2A/2C receptor agonist-induced head twitch response (HTR) induced by the administration of 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), which has been proposed as an animal model of symptoms associated with a variety of behavioral and psychiatric conditions. We investigated the DOI-induced HTR in male DBA/2J mice using a panel of D2-like (D2, D3 and D4) and D2 dopamine receptor selective compounds. When DBA/2J mice were administered a daily dose of DOI (5 mg/kg), tolerance to the DOI occurs. However, administrations of the same dose of DOI every other day (48 h) or on a weekly basis did not lead to tolerance and the ability to induce tolerance after daily administration of DOI remains intact after repeated weekly administration of DOI. Subsequently, a panel of D2-like dopamine receptor antagonists was found to effectively inhibit the DOI-induced HTR in DBA/2J mice. However, the benzamide eticlopride, which is a high affinity D2-like antagonist, was a notable exception. SV 293, SV-III-130s and N-methylbenperidol, which exhibit a high affinity for D2 versus the D3 dopamine receptor subtypes (60- to 100-fold binding selectivity), were also found to inhibit the HTR in DBA/2J mice. This observation suggests a functional interaction between dopaminergic and serotonergic systems through D2 dopamine receptors and the 5-HT2A serotonin receptors in vivo.

PMID: 24680675 [PubMed - indexed for MEDLINE]

The therapeutic promise of positive allosteric modulation of nicotinic receptors.

Tue, 02/03/2015 - 4:29am
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The therapeutic promise of positive allosteric modulation of nicotinic receptors.

Eur J Pharmacol. 2014 Mar 15;727:181-5

Authors: Uteshev VV

Abstract
In the central nervous system, deficits in cholinergic neurotransmission correlate with decreased attention and cognitive impairment, while stimulation of neuronal nicotinic acetylcholine receptors improves attention, cognitive performance and neuronal resistance to injury as well as produces robust analgesic and anti-inflammatory effects. The rational basis for the therapeutic use of orthosteric agonists and positive allosteric modulators (PAMs) of nicotinic receptors arises from the finding that functional nicotinic receptors are ubiquitously expressed in neuronal and non-neuronal tissues including brain regions highly vulnerable to traumatic and ischemic types of injury (e.g., cortex and hippocampus). Moreover, functional nicotinic receptors do not vanish in age-, disease- and trauma-related neuropathologies, but their expression and/or activation levels decline in a subunit- and brain region-specific manner. Therefore, augmenting the endogenous cholinergic tone by nicotinic agents is possible and may offset neurological impairments associated with cholinergic hypofunction. Importantly, because neuronal damage elevates extracellular levels of choline (a selective agonist of α7 nicotinic acetylcholine receptors) near the site of injury, α7-PAM-based treatments may augment pathology-activated α7-dependent auto-therapies where and when they are most needed (i.e., in the penumbra, post-injury). Thus, nicotinic-PAM-based treatments are expected to augment the endogenous cholinergic tone in a spatially and temporally restricted manner creating the potential for differential efficacy and improved safety as compared to exogenous orthosteric nicotinic agonists that activate nicotinic receptors indiscriminately. In this review, I will summarize the existing trends in therapeutic applications of nicotinic PAMs.

PMID: 24530419 [PubMed - indexed for MEDLINE]

Sigma-1 receptor stimulation protects retinal ganglion cells from ischemia-like insult through the activation of extracellular-signal-regulated kinases 1/2.

Tue, 02/03/2015 - 4:29am
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Sigma-1 receptor stimulation protects retinal ganglion cells from ischemia-like insult through the activation of extracellular-signal-regulated kinases 1/2.

Exp Eye Res. 2014 Nov;128:156-69

Authors: Mueller BH, Park Y, Ma HY, Dibas A, Ellis DZ, Clark AF, Yorio T

Abstract
Sigma-1 receptor (σ-1) activation and mitogen-activated protein kinases (MAPKs) have been shown to protect retinal ganglion cells (RGCs) from cell death. The purpose of this study was to determine if σ-1 receptor stimulation with pentazocine could promote neuroprotection under conditions of an ischemia-like insult (oxygen glucose deprivation (OGD)) through the phosphorylation of extracellular signal regulated kinase (pERK)1/2. Primary RGCs were isolated from P3-P7 Sprague-Dawley rats and purified by sequential immunopanning using Thy1.1 antibodies. RGCs were cultured for 7 days before subjecting the cells to an OGD insult (0.5% oxygen in glucose-free medium) for 6 h. During the OGD, RGCs were treated with pentazocine (σ-1 receptor agonist) with or without BD 1047 (σ-1 receptor antagonist). In other experiments, primary RGCs were treated with pentazocine in the presence or absence of an MEK1/2 inhibitor, PD098059. Cell survival/death was assessed by staining with the calcein-AM/ethidium homodimer reagent. Levels of pERK1/2, total ERK1/2, and beta tubulin expression were determined by immunoblotting and immunofluorescence staining. RGCs subjected to OGD for 6 h induced 50% cell death in primary RGCs (p < 0.001) and inhibited pERK1/2 expression by 65% (p < 0.001). Cell death was attenuated when RGCs were treated with pentazocine under OGD (p < 0.001) and pERK1/2 expression was increased by 1.6 fold (p < 0.05) compared to OGD treated RGCs without pentazocine treatment. The co-treatment of PD098059 (MEK1/2 inhibitor) with pentazocine significantly abolished the protective effects of pentazocine on the RGCs during this OGD insult. Activation of the σ-1 receptor is a neuroprotective target that can protect RGCs from an ischemia-like insult. These results also established a direct relationship between σ-1 receptor stimulation and the neuroprotective effects of the ERK1/2 pathway in purified RGCs subjected to OGD. These findings suggest that activation of the σ-1 receptor may be a therapeutic target for neuroprotection particularly relevant to ocular neurodegenerative diseases that effect RGCs.

PMID: 25305575 [PubMed - indexed for MEDLINE]

Autosomal and Y-STR analysis of degraded DNA from the 120-year-old skeletal remains of Ezekiel Harper.

Fri, 01/30/2015 - 4:30am
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Autosomal and Y-STR analysis of degraded DNA from the 120-year-old skeletal remains of Ezekiel Harper.

Forensic Sci Int Genet. 2014 Mar;9:33-41

Authors: Ambers A, Gill-King H, Dirkmaat D, Benjamin R, King J, Budowle B

Abstract
The 120-year-old skeletal remains of Confederate Civil War soldier Captain Ezekiel "Zeke" Harper were exhumed by court order in January 2011 for DNA analysis. The goal of the DNA testing was to support or refute whether Captain Harper had fathered a son (Earl J. Maxwell) with his Native American maid prior to his murder in 1892. Bones with adequate structural integrity (left tibia, right tibia, right femur, mandible, four teeth) were retrieved from the burial site and sent to the Institute of Applied Genetics in Fort Worth, Texas for analysis. Given the age and condition of the remains, three different extraction methods were used to maximize the probability of DNA recovery. The majority of the DNA isolates from over fifty separate bone sections yielded partial autosomal STR genotypes and partial Y-STR haplotypes. After comparing the partial results for concordance, consensus profiles were generated for comparison to reference samples from alleged family members. Considering the genetic recombination that occurs in autosomal DNA over the generations within a family, Y-STR analysis was determined to be the most appropriate and informative approach for determining potential kinship. Two of Earl J. Maxwell's grandsons submitted buccal samples for comparison. The Y-STR haplotypes obtained from both of these reference samples were identical to each other and to the alleles in Ezekiel Harper's consensus profile at all 17 loci examined. This Y-STR haplotype was not found in either of two major Y-STR population databases (U.S. Y-STR database and YHRD). The fact that the Y-STR haplotype obtained from Ezekiel's skeletal remains and Earl's grandsons is not found in either population database demonstrates its rarity and further supports a paternal lineage relationship among them. Results of the genetic analyses are consistent with the hypothesis that Earl J. Maxwell is the son of Ezekiel Harper.

PMID: 24528577 [PubMed - indexed for MEDLINE]

Neuroglobin Overexpression Inhibits AMPK Signaling and Promotes Cell Anabolism.

Wed, 01/28/2015 - 4:30am
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Neuroglobin Overexpression Inhibits AMPK Signaling and Promotes Cell Anabolism.

Mol Neurobiol. 2015 Jan 24;

Authors: Cai B, Li W, Mao X, Winters A, Ryou MG, Liu R, Greenberg DA, Wang N, Jin K, Yang SH

Abstract
Neuroglobin (Ngb) is a recently discovered globin with preferential localization to neurons. Growing evidence indicates that Ngb has distinct physiological functions separate from the oxygen storage and transport roles of other globins, such as hemoglobin and myoglobin. We found increased ATP production and decreased glycolysis in Ngb-overexpressing immortalized murine hippocampal cell line (HT-22), in parallel with inhibition of AMP-activated protein kinase (AMPK) signaling and activation of acetyl-CoA carboxylase (ACC). In addition, lipid and glycogen content was increased in Ngb-overexpressing HT-22 cells. AMPK signaling was also inhibited in the brain and heart from Ngb-overexpressing transgenic mice. Although Ngb overexpression did not change glycogen content in whole brain, glycogen synthase was activated in cortical neurons of Ngb-overexpressing mouse brain and Ngb overexpression primary neurons. Moreover, lipid and glycogen content was increased in hearts derived from Ngb-overexpressing mice. These findings suggest that Ngb functions as a metabolic regulator and enhances cellular anabolism through the inhibition of AMPK signaling.

PMID: 25616953 [PubMed - as supplied by publisher]

The unique protein kinase Cη: implications for breast cancer (review).

Wed, 01/28/2015 - 4:30am
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The unique protein kinase Cη: implications for breast cancer (review).

Int J Oncol. 2014 Aug;45(2):493-8

Authors: Pal D, Basu A

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

PMID: 24841225 [PubMed - indexed for MEDLINE]

STAT3 and its Phosphorylation are Involved in HIV-1 Tat-induced Transactivation of Glial Fibrillary Acidic Protein.

Tue, 01/27/2015 - 4:31am

STAT3 and its Phosphorylation are Involved in HIV-1 Tat-induced Transactivation of Glial Fibrillary Acidic Protein.

Curr HIV Res. 2015 Jan 20;

Authors: Fan Y, Timani KA, He JJ

Abstract
Human immunodeficiency virus type 1 (HIV-1) Tat protein is a major pathogenic factor in HIV-associated neurological diseases; it exhibits direct neurotoxicity and indirect astrocyte-mediated neurotoxicity. We have shown that Tat alone is capable of activating glial fibrillary acidic protein (GFAP) expression and inducing astrocytosis involving sequential activation of early growth response protein 1 (Egr-1) and p300. In this study, we determined the roles of signal transducer and activator of transcription 3 (STAT3) in Tat-induced GFAP transactivation. STAT3 expression and phosphorylation led to significant increases in GFAP transcription and protein expression. Tat expression was associated with increased STAT3 expression and phosphorylation in Tat-expressing astrocytes and HIV-infected astrocytes. GFAP, Egr-1 and p300 transcription and protein expression all showed positive response to STAT3 and its phosphorylation. Importantly, knockdown of STAT3 resulted in significant decreases in Tat-induced GFAP and Egr-1 transcription and protein expression. Taken together, these findings show that STAT3 is involved in and acts upstream of Egr1 and p300 in the Tat-induced GFAP transactivation cascade and suggest important roles of STAT3 in controlling astrocyte proliferation and activation in the HIV-infected central nervous system.

PMID: 25613134 [PubMed - as supplied by publisher]

Diagnosis and treatment of bipolar disorders in adults: a review of the evidence on pharmacologic treatments.

Sat, 01/24/2015 - 12:31am

Diagnosis and treatment of bipolar disorders in adults: a review of the evidence on pharmacologic treatments.

Am Health Drug Benefits. 2014 Dec;7(9):489-99

Authors: Jann MW

Abstract
BACKGROUND: Patients with bipolar disorder are exceptionally challenging to manage because of the dynamic, chronic, and fluctuating nature of their disease. Typically, the symptoms of bipolar disorder first appear in adolescence or early adulthood, and are repeated over the patient's lifetime, expressed as unpredictable recurrences of hypomanic/manic or depressive episodes. The lifetime prevalence of bipolar disorder in adults is reported to be approximately 4%, and its management was estimated to cost the US healthcare system in 2009 $150 billion in combined direct and indirect costs.
OBJECTIVE: To review the published literature and describe the personal and societal burdens associated with bipolar disorder, the impact of delays in accurate diagnosis, and the evidence for the clinical effectiveness of available pharmacologic therapies.
METHODS: The studies in this comprehensive review were selected for inclusion based on clinical relevance, importance, and robustness of data related to diagnosis and treatment of bipolar disorder. The search terms that were initially used on MEDLINE/PubMed and Google Scholar were restricted to 1994 through 2014 and included "bipolar disorder," "mania," "bipolar depression," "mood stabilizer," "atypical antipsychotics," and "antidepressants." High-quality, recent reviews of major relevant topics were included to supplement the primary studies.
DISCUSSION: Substantial challenges facing patients with bipolar disorder, in addition to their severe mood symptoms, include frequent incidence of psychiatric (eg, anxiety disorders, alcohol or drug dependence) and general medical comorbidities (eg, diabetes, cardiovascular disease, obesity, migraine, and hepatitis C virus infection). It has been reported that more than 75% of patients take their medication less than 75% of the time, and the rate of suicide (0.4%) among patients with bipolar disorder is more than 20 times greater than in the general US population. Mood stabilizers are the cornerstone of treatment of bipolar disorder, but atypical antipsychotics are broadly as effective; however, differences in efficacy exist between individual agents in the treatment of the various phases of bipolar disorder, including treatment of acute mania or acute depression symptoms, and in the prevention of relapse.
CONCLUSION: The challenges involved in managing bipolar disorder over a patient's lifetime are the result of the dynamic, chronic, and fluctuating nature of this disease. Diligent selection of a treatment that takes into account its efficacy in the various phases of the disorder, along with the safety profile identified in clinical trials and in the real world can help ameliorate the impact of this devastating condition.

PMID: 25610528 [PubMed]

The Relationship Between Drug Use, Drug-related Arrests, and Chronic Pain Among Adults on Probation.

Fri, 01/23/2015 - 4:30am

The Relationship Between Drug Use, Drug-related Arrests, and Chronic Pain Among Adults on Probation.

J Subst Abuse Treat. 2014 Dec 30;

Authors: Reingle Gonzalez JM, Walters ST, Lerch J, Taxman FS

Abstract
The intersection between chronic health conditions, drug use, and treatment seeking behavior among adults in the criminal justice system has been largely understudied. This study examined whether chronic pain was associated with opiate use, other illicit drug use, and drug-related arrests in a sample of substance-using probationers. We expected that probationers with chronic pain-related diagnoses would report more opiate use and drug-related arrests. This study used baseline data from 250 adults on probation in Baltimore, Maryland and Dallas, Texas who were participating in a larger clinical trial. Eighteen percent of probationers in this sample reported suffering from chronic pain. In bivariate analyses, probationers with chronic pain reported more drug-related arrests (t=-1.81; p<0.05) than those without chronic pain. Multivariate analyses support the hypothesis that probationers who reported chronic pain were marginally more likely to use opiates (OR=2.37; 95% CI .89-1.05) and non-opiate illicit drugs (OR=3.11; 95% CI 1.03-9.39) compared to offenders without chronic pain. In summary, these findings suggest that adults under probation supervision who suffer from chronic pain may be involved in criminal activity (specifically, drug-related criminal activity) in an effort to self-medicate their physical health condition(s). Screening probationers for chronic pain in the probation setting and referring these adults to pain management treatment may be an important step in advancing public safety.

PMID: 25595302 [PubMed - as supplied by publisher]

Lenticular cytoprotection, part 2: Link between glycogen synthase kinase-3β, epithelial to mesenchymal transition, and mitochondrial depolarization.

Sun, 01/18/2015 - 4:30am

Lenticular cytoprotection, part 2: Link between glycogen synthase kinase-3β, epithelial to mesenchymal transition, and mitochondrial depolarization.

Mol Vis. 2014;20:1758-75

Authors: Neelam S, Brooks MM, Cammarata PR

Abstract
PURPOSE: The inhibition of GSK-3β blocks mitochondrial membrane permeability transition (mMPT) for HLE-B3 cells in atmospheric oxygen. GSK-3β, as part of a multifactorial complex, also regulates nuclear levels of β-catenin, a known coordinator of cell survival and adhesion. The purpose of these studies was to demonstrate a novel, but likely disadvantageous, link between β-catenin's influence on the expression of the pro-survival protein, vascular endothelial growth factor (VEGF), resulting in enhanced lens epithelial cell mitochondrial protection against depolarization and nuclear β-catenin as an inducer of epithelial to mesenchymal transition (EMT).
METHODS: Virally transformed human lens epithelial cells (HLE-B3) were treated with SB216763, a specific inhibitor of GSK-3β catalytic activity and XAV939, a specific β-catenin inhibitor that bars the translocation of β-catenin from cytoplasm to the nucleus. Western blot analysis was employed to detect the levels of cytoplasmic and nuclear β-catenin and phospho-β-catenin, pBcl-2 and the EMT proteins, α-smooth muscle actin (α-SMA), and fibronectin. ELISA was used to measure the levels of VEGF in cell culture supernatants. JC-1 analysis was performed to analyze the influence of either SB216763 or XAV939 on mitochondrial depolarization.
RESULTS: Cultured lens epithelial cells maintained in hypoxia (1% oxygen) and subsequently reintroduced into atmospheric oxygen and treated with the GSK-3β inhibitor SB216763 illustrated a marked inhibition of phosphorylation of glycogen synthase (downstream substrate of GSK-3β) and significant increase in nuclear translocation of β-catenin. The augmented nuclear β-catenin levels positively correlated with increased expression of α-SMA and fibronectin, both marker proteins indicative of EMT. The enhanced nuclear β-catenin activity also elicited increased VEGF and pBcl-2 expression, resulting in increased resistance to mitochondrial depolarization. Treatment of the cells with the β-catenin inhibitor XAV939 resulted in decreased expression of nuclear β-catenin, VEGF levels, pBcl-2, and EMT proteins, as well as increased mitochondrial depolarization.
CONCLUSIONS: The data support a model whereby the onset of epithelial to mesenchymal transition may circuitously benefit from the enhanced synthesis of VEGF by setting up a potentially harmful situation whereby the resulting mesenchymal cell population may be more resistant to mitochondrial depolarization than the lens epithelial cell population from which it originated. These findings support the potential therapeutic relevance of developing strategies to undermine the progression of normal cells to mesenchymal transition without subverting cell viability.

PMID: 25593505 [PubMed - in process]

Factors Contributing to 50-ft Walking Speed and Observed Ethnic Differences in Older Community-Dwelling Mexican Americans and European Americans.

Sun, 01/18/2015 - 4:30am

Factors Contributing to 50-ft Walking Speed and Observed Ethnic Differences in Older Community-Dwelling Mexican Americans and European Americans.

Phys Ther. 2015 Jan 15;

Authors: Quiben MU, Hazuda HP

Abstract
BACKGROUND: Mexican Americans (MAs) comprise the most rapidly growing segment of the US older population and are reported to have poorer functional health than European Americans (EAs), but few studies have examined factors contributing to ethnic differences in walking speed (WS) between MAs and EAs.
OBJECTIVE: To examine factors that contribute to WS and observed ethnic differences in WS in older MAs and EAs using the disablement process model (DPM) as a guide.
DESIGN: Observational, cross-sectional study METHODS: Subjects were 703 MA and EA older adults (65+ years) who completed the baseline examination of the San Antonio Longitudinal Study of Aging (SALSA). Hierarchical regression models were performed to identify the contribution of contextual, lifestyle/anthropometric, disease, and impairment variables to WS and to ethnic differences in WS.
RESULTS: The ethic difference in unadjusted mean WS (MAs: 1.17 m/s, EAs: 1.29 m/s; p<.001) was fully explained by adjustment for contextual (age, sex, education, income) and lifestyle/anthropometric (BMI, height, physical activity [PA]) variables; adjusted mean WS in both ethnic groups was 1.23 m/s. Contextual variables explained 20.3% of the variance in WS, lifestyle/anthropometric variables explained an additional 8.4%. Diseases (diabetes, stroke, COPD) explained an additional 1.9% of the variance in WS; impairments (FEV1, upper leg pain, lower-extremity strength and ROM) contributed an additional 5.5%. Thus, both non-modifiable (contextual, height) and modifiable (impairments, BMI, PA) factors contributed to WS in older MAs and EAs.
LIMITATIONS: Conducted in a single geographic area; included only MA Hispanics.
CONCLUSIONS: WS in older MAs and EAs is influenced by modifiable and non-modifiable factors, underscoring the importance of the DPM framework which incorporates both factors into the physical therapy patient/client management process.

PMID: 25592187 [PubMed - as supplied by publisher]

Chemokine CXCL8 promotes HIV-1 replication in human monocyte-derived macrophages and primary microglia via nuclear factor-κB pathway.

Sat, 01/17/2015 - 4:37am
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Chemokine CXCL8 promotes HIV-1 replication in human monocyte-derived macrophages and primary microglia via nuclear factor-κB pathway.

PLoS One. 2014;9(3):e92145

Authors: Mamik MK, Ghorpade A

Abstract
BACKGROUND: Chemokine CXCL8 is an important neutrophil chemoattractant implicated in various neurodegenerative disorders. Cytokine/chemokine imbalance, with an increase in proinflammatory cytokines like interleukin-1β and tumor necrosis factor-α within the central nervous system, is a hallmark of human immunodeficiency virus (HIV)-1 infection. We previously reported that HIV-1 infection is linked to upregulation of CXCL8 in brain tissues and human astrocytes. Chemokines play crucial roles in trafficking of leukocytes and trafficking of HIV-1-infected across the blood-brain barrier play an important role in HIV-1 central nervous system disease. In the post-antiretroviral therapy era, low level of productive replication of HIV-1 in brain is a critical component of neuropathogenesis regulation. The present study investigated the effect of CXCL8 on productive infection of HIV-1 in human monocytes-derived macrophages (MDM) and primary human microglia.
RESULTS: Human MDM and microglia were infected with the blood or brain derived HIV-1 isolates, HIV-1ADA or HIV-1JRFL. Treatment with CXCL8 significantly upregulated HIV-1p24 levels in supernatants of both HIV-1-infected MDM as well as microglia. In addition, the formation of 2-long terminal repeat (LTR) circles, a measure of viral genome integration, was significantly higher in CXCL8-treated, HIV-1-infected MDM and microglia. Transient transfection of U937 cells with HIV-1 LTR luciferase reporter construct resulted in increased promoter activity when treated with CXCL8. Moreover, increased nuclear translocation of nuclear factor-κB was seen in HIV-1-infected MDM following CXCL8 treatment. Blocking CXCL8 receptors CXCR1 and CXCR2 abrogated the CXCL8-mediated enhanced HIV-1 replication.
CONCLUSION: Our results show that CXCL8 mediates productive infection of HIV-1 in MDM and microglia via receptors CXCR1 and CXCR2. These results demonstrate that CXCL8 exerts its downstream effects by increasing translocation of nuclear factor-κB into the nucleus, thereby promoting HIV-1 LTR activity.

PMID: 24662979 [PubMed - indexed for MEDLINE]

Protons and Psalmotoxin-1 reveal nonproton ligand stimulatory sites in chicken acid-sensing ion channel: Implication for simultaneous modulation in ASICs.

Sat, 01/17/2015 - 4:37am
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Protons and Psalmotoxin-1 reveal nonproton ligand stimulatory sites in chicken acid-sensing ion channel: Implication for simultaneous modulation in ASICs.

Channels (Austin). 2014;8(1):49-61

Authors: Smith RN, Gonzales EB

Abstract
Acid-sensing ion channels (ASICs) are proton-sensitive, sodium-selective channels expressed in the nervous system that sense changes in extracellular pH. These ion channels are sensitive to an increasing number of nonproton ligands that include natural venom peptides and guanidine compounds. In the case of chicken ASIC1, the spider toxin Psalmotoxin-1 (PcTx1) activates the channel, resulting in an inward current. Furthermore, a growing class of ligands containing a guanidine group has been identified that stimulate peripheral ASICs (ASIC3), but exert subtle influence on other ASIC subtypes. The effects of the guanidine compounds on cASIC1 have not been the focus of previous study. Here, we investigated the interaction of the guanidine compound 2-guanidine-4-methylquinazoline (GMQ) on cASIC1 proton activation and PcTx1 stimulation. Exposure of expressed cASIC1 to PcTx1 resulted in biphasic currents consisting of a transient peak followed by an irreversible cASIC1 PcTx1 persistent current. This cASIC1 PcTx1 persistent current may be the result of locking the cASIC1 protein into a desensitized transition state. The guanidine compound GMQ increased the apparent affinity of protons on cASIC1 and decreased the half-maximal constant of the cASIC1 steady-state desensitization profile. Furthermore, GMQ stimulated the cASIC1 PcTx1 persistent current in a concentration-dependent manner, which resulted in a non-desensitizing inward current. Our data suggests that GMQ may have multiple sites within cASIC1 and may act as a "molecular wedge" that forces the PcTx1-desensitized ASIC into an open state. Our findings indicate that guanidine compounds, such as GMQ, may alter acid-sensing ion channel activity in combination with other stimuli, and that additional ASIC subtypes (along with ASIC3) may serve to sense and mediate signals from multiple stimuli.

PMID: 24262969 [PubMed - indexed for MEDLINE]

Fibrocaps for surgical hemostasis: two randomized, controlled phase II trials.

Fri, 01/16/2015 - 4:30am

Fibrocaps for surgical hemostasis: two randomized, controlled phase II trials.

J Surg Res. 2014 Dec 10;

Authors: Verhoef C, Singla N, Moneta G, Muir W, Rijken A, Lockstadt H, de Wilt JH, O-Yurvati A, Zuckerman LA, Frohna P, Porte RJ

Abstract
BACKGROUND: Fibrocaps, a ready-to-use, dry-powder fibrin sealant containing human plasma-derived thrombin and fibrinogen, is being developed as an adjunct for surgical hemostasis.
MATERIALS AND METHODS: Safety and efficacy of Fibrocaps applied directly or by spray device, in combination with gelatin sponge, was compared with that of gelatin sponge-alone in two randomized, single-blind controlled trials: FC-002 US (United States) and FC-002 NL (the Netherlands). A total of 126 adult patients were randomized (Fibrocaps: n = 47 [FC-002 US], n = 39 [FC-002 NL]; gelatin sponge alone: n = 23 [FC-002 US], n = 17 [FC-002 NL). One bleeding site was treated during a surgical procedure (n = 125). Time to hemostasis (primary end point) was measured, with a 28-d safety follow-up. Four surgical indications included hepatic resection (n = 58), spinal procedures (n = 37), peripheral vascular procedures (n = 30), and soft tissue dissection (n = 1).
RESULTS: Mean (standard deviation) time to hemostasis was significantly shorter after Fibrocaps treatment than after gelatin sponge alone (FC-002 US: 1.9 [1.3] versus 4.8 min [3.1], P < 0.001; FC-002 NL: 2.2 [1.3] versus 4.4 min [3.1], P = 0.004). The incidence of hemostasis was greater after Fibrocaps compared with that of gelatin sponge alone within 3 min (FC-002 US: 83% versus 35%, P < 0.001; FC-002 NL: 77% versus 53%, P = 0.11), 5 min (94% versus 61%, P = 0.001; 95% versus 71%, P = 0.022), and 10 min (100% versus 78%, P = 0.003; 100% versus 82%, P = 0.025). Adverse events were consistent with surgical procedures performed and patients' underlying diseases and generally similar between treatment arms; most were mild or moderate in severity. Non-neutralizing antithrombin antibodies were detected in 5% of Fibrocaps-treated patients on day 29.
CONCLUSIONS: Fibrocaps had good safety and efficacy profiles, supporting continuing clinical development as a novel fibrin sealant.

PMID: 25586331 [PubMed - as supplied by publisher]

Extracellular pH modulates GABAergic neurotransmission in rat hypothalamus.

Fri, 01/16/2015 - 4:30am
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Extracellular pH modulates GABAergic neurotransmission in rat hypothalamus.

Neuroscience. 2014 Jun 20;271:64-76

Authors: Chen ZL, Huang RQ

Abstract
Changes in extracellular pH have a modulatory effect on GABAA receptor function. It has been reported that pH sensitivity of the GABA receptor is dependent on subunit composition and GABA concentration. Most of previous investigations focused on GABA-evoked currents, which only reflect the postsynaptic receptors. The physiological relevance of pH modulation of GABAergic neurotransmission is not fully elucidated. In the present studies, we examined the influence of extracellular pH on the GABAA receptor-mediated inhibitory neurotransmission in rat hypothalamic neurons. The inhibitory postsynaptic currents (IPSCs), tonic currents, and the GABA-evoked currents were recorded with whole-cell patch techniques on the hypothalamic slices from Sprague-Dawley rats at 15-26 postnatal days. The amplitude and frequency of spontaneous GABA IPSCs were significantly increased while the external pH was changed from 7.3 to 8.4. In the acidic pH (6.4), the spontaneous GABA IPSCs were reduced in amplitude and frequency. The pH induced changes in miniature GABA IPSCs (mIPSCs) similar to that in spontaneous IPSCs. The pH effect on the postsynaptic GABA receptors was assessed with exogenously applied varying concentrations of GABA. The tonic currents and the currents evoked by sub-saturating concentration of GABA ([GABA]) (10 μM) were inhibited by acidic pH and potentiated by alkaline pH. In contrast, the currents evoked by saturating [GABA] (1mM) were not affected by pH changes. We also investigated the influence of pH buffers and buffering capacity on pH sensitivity of GABAA receptors on human recombinant α1β2γ2 GABAA receptors stably expressed in HEK 293 cells. The pH influence on GABAA receptors was similar in HEPES- and MES-buffered media, and not dependent on protonated buffers, suggesting that the observed pH effect on GABA response is a specific consequence of changes in extracellular protons. Our data suggest that the hydrogen ions suppress the GABAergic neurotransmission, which is mediated by both presynaptic and postsynaptic mechanisms.

PMID: 24780768 [PubMed - indexed for MEDLINE]

U.S. population estimates and correlates of sexual abuse of community-dwelling older adults.

Fri, 01/16/2015 - 4:30am
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U.S. population estimates and correlates of sexual abuse of community-dwelling older adults.

J Elder Abuse Negl. 2014;26(4):398-413

Authors: Cannell MB, Manini T, Spence-Almaguer E, Maldonado-Molina M, Andresen EM

Abstract
We describe the annual prevalence of sexual abuse among community-dwelling older adults in the United States. We also describe factors associated with experiencing sexual abuse. We used data from 24,343 older adults from the 2005 Behavioral Risk Factor Surveillance System pooled across 18 states. We estimated prevalence of sexual abuse, bivariate distributions, and odds ratio associations across demographic, health, and contextual factors. Our results show that 0.9% of older adults reported experiencing sexual abuse in the previous year. This represents approximately 90,289 community-dwelling older adults. We also report on factors associated with experiencing recent sexual abuse. There was a significant gender by binge drinking interaction, with a stronger association among women. There is a need for health promotion efforts targeted specifically toward older adults, encouraging them to seek services, if possible, after exposure to sexual abuse.

PMID: 24410194 [PubMed - indexed for MEDLINE]

Treatment for Preventing Tuberculosis in Children and Adolescents: A Randomized Clinical Trial of a 3-Month, 12-Dose Regimen of a Combination of Rifapentine and Isoniazid.

Thu, 01/15/2015 - 4:30am

Treatment for Preventing Tuberculosis in Children and Adolescents: A Randomized Clinical Trial of a 3-Month, 12-Dose Regimen of a Combination of Rifapentine and Isoniazid.

JAMA Pediatr. 2015 Jan 12;

Authors: Villarino ME, Scott NA, Weis SE, Weiner M, Conde MB, Jones B, Nachman S, Oliveira R, Moro RN, Shang N, Goldberg SV, Sterling TR, for the International Maternal Pediatric and Adolescents AIDS Clinical Trials Group (IMPAACT) and the Tuberculosis Trials Consortium (TBTC)

Abstract
Importance: Three months of a once-weekly combination of rifapentine and isoniazid for treatment of latent tuberculosis infection is safe and effective for persons 12 years or older. Published data for children are limited.
Objectives: To compare treatment safety and assess noninferiority treatment effectiveness of combination therapy with rifapentine and isoniazid vs 9 months of isoniazid treatment for latent tuberculosis infection in children.
Design, Setting, and Participants: A pediatric cohort nested within a randomized, open-label clinical trial conducted from June 11, 2001, through December 17, 2010, with follow-up through September 5, 2013, in 29 study sites in the United States, Canada, Brazil, Hong Kong (China), and Spain. Participants were children (aged 2-17 years) who were eligible for treatment of latent tuberculosis infection.
Interventions: Twelve once-weekly doses of the combination drugs, given with supervision by a health care professional, for 3 months vs 270 daily doses of isoniazid, without supervision by a health care professional, for 9 months.
Main Outcomes and Measures: We compared rates of treatment discontinuation because of adverse events (AEs), toxicity grades 1 to 4, and deaths from any cause. The equivalence margin for the comparison of AE-related discontinuation rates was 5%. Tuberculosis disease diagnosed within 33 months of enrollment was the main end point for testing effectiveness. The noninferiority margin was 0.75%.
Results: Of 1058 children enrolled, 905 were eligible for evaluation of effectiveness. Of 471 in the combination-therapy group, 415 (88.1%) completed treatment vs 351 of 434 (80.9%) in the isoniazid-only group (P = .003). The 95% CI for the difference in rates of discontinuation attributed to an AE was -2.6 to 0.1, which was within the equivalence range. In the safety population, 3 of 539 participants (0.6%) who took the combination drugs had a grade 3 AE vs 1 of 493 (0.2%) who received isoniazid only. Neither arm had any hepatotoxicity, grade 4 AEs, or treatment-attributed death. None of the 471 in the combination-therapy group developed tuberculosis vs 3 of 434 (cumulative rate, 0.74%) in the isoniazid-only group, for a difference of -0.74% and an upper bound of the 95% CI of the difference of +0.32%, which met the noninferiority criterion.
Conclusions and Relevance: Treatment with the combination of rifapentine and isoniazid was as effective as isoniazid-only treatment for the prevention of tuberculosis in children aged 2 to 17 years. The combination-therapy group had a higher treatment completion rate than did the isoniazid-only group and was safe.
Trial Registration: clinicaltrials.gov Identifier: NCT00023452.

PMID: 25580725 [PubMed - as supplied by publisher]

The Effects of Sigma-1 Receptor Selective Ligands on Muscarinic Receptor Antagonist Induced Cognitive Deficits in Mice.

Thu, 01/15/2015 - 4:30am
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The Effects of Sigma-1 Receptor Selective Ligands on Muscarinic Receptor Antagonist Induced Cognitive Deficits in Mice.

Br J Pharmacol. 2015 Jan 9;

Authors: Malik M, Rangel-Barajas C, Sumien N, Su C, Singh M, Chen Z, Huang RQ, Meunier J, Maurice T, Mach RH, Luedtke RR

Abstract
BACKGROUND AND PURPOSE: Cognitive deficits in patients with Alzheimer's Disease, Parkinson's Disease, traumatic brain injury and stroke often involve alterations in cholinergic signaling. Currently available therapeutic drugs provide only symptomatic relief. Therefore, novel therapeutic strategies are needed to retard and/or arrest the progressive loss of memory.
EXPERIMENTAL APPROACH: Scopolamine-induced memory impairment provides a rapid and reversible phenotypic screening paradigm for cognition enhancement drug discovery. Male C57BL/6J mice administered scopolamine (1mg/kg) were used to evaluate the ability of LS-1-137, a novel sigma-1 receptor selective agonist, to improve the cognitive deficits associated with muscarinic antagonist administration.
KEY RESULTS: LS-1-137 is a high affinity (Ki = 3.2 nM) sigma-1 receptor agonist that is 80-fold selective for sigma-1 compared to sigma-2 receptor. LS-1-137 binds with low affinity at D2-like (D2, D3 and D4) dopamine and muscarinic receptors. LS-1-137 was found to partially reverse the learning deficits associated with scopolamine administration using a water maze test and an active avoidance task. LS-1-137 treatment was also found to trigger the release of BDNF from rat astrocytes.
CONCLUSIONS AND IMPLICATIONS: The sigma-1 receptor selective compound such as LS-1-137 may represent a novel candidate cognitive enhancer for the treatment of cholinergic muscarinic-dependent cognitive deficits.

PMID: 25573298 [PubMed - as supplied by publisher]

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