Recent Research Articles from UNTHSC

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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]

Measurement Properties of the Sedentary Behavior Strategy Self-management Instrument in African-American Breast Cancer Survivors.

Tue, 01/13/2015 - 4:29am

Measurement Properties of the Sedentary Behavior Strategy Self-management Instrument in African-American Breast Cancer Survivors.

Am J Health Behav. 2015 Mar;39(2):175-182

Authors: Paxton RJ, Gao Y, Herrmann SD, Norman GJ

Abstract
OBJECTIVES: To examine the validity and reliability of a modified Sedentary Behavior Strategy Self-Management Scale (SBSMS) in a sample of breast cancer survivors.
METHODS: A total of 291 African-American (AA) breast cancer survivors completed the SBSMS, which was subjected to tests of reliability, structural validity, and tests of measurement equivalence/invariance (ME/I).
RESULTS: A revised measurement model fit the data and demonstrated internal reliability and structural validity. Tests for ME/I revealed that the revised model had appropriate levels of invariance among weight status, educational, and years out from diagnosis groups, but not among age groups.
CONCLUSION: The reliability and structural validity of the instrument was supported overall; however, revisions may be needed to support its validity in older AA breast cancer survivors.

PMID: 25564829 [PubMed - as supplied by publisher]

Preoperative decision making in the treatment of high-angle "vertical" femoral neck fractures in young adult patients. An expert opinion survey of the Orthopaedic Trauma Association's (OTA) membership.

Thu, 01/08/2015 - 4:29am
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Preoperative decision making in the treatment of high-angle "vertical" femoral neck fractures in young adult patients. An expert opinion survey of the Orthopaedic Trauma Association's (OTA) membership.

J Orthop Trauma. 2014 Sep;28(9):e221-5

Authors: Luttrell K, Beltran M, Collinge CA

Abstract
OBJECTIVE: To identify the current implant and diagnostic imaging preferences among orthopaedic trauma experts for the treatment of high-energy vertical femoral neck fractures in young adult patients.
DESIGN: Web-based survey.
SETTING: Not available.
PARTICIPANTS: Active members of the OTA.
METHODS: A cross-sectional expert opinion survey was administered to the active members of the OTA to determine their preferences for implant use and imaging in the surgical treatment of a vertical femoral neck fracture in a young adult patient (e.g., 60-degree Pauwels angle fracture in a healthy 30-year-old patient). Questions were also asked regarding the reason why this implant was selected, whether the surgeon felt that their choice was supported by the literature, and what imaging studies are routinely obtained to guide decision making. Data were collected using simple multiple-choice questions and/or a 5-point Likert item.
RESULTS: Two hundred seventy-two surgeons (47%) responded to the survey. The preferred constructs for a vertical femoral neck fracture in a healthy young patient were a sliding hip screw with or without an anti-rotation screw (47%), parallel cannulated screws with an off-axis screw (28%), and parallel cannulated screw constructs (15%). When asked if their designated construct "was clearly supported by the literature," 46% were either unsure or disagreed. Seventy percent of surgeons chose their preferred implant because it was "biomechanically most stable." Most surgeons required anteroposterior pelvis (70%) and standard hip (88%) radiographs; however only 29% of surgeons required a computed tomography (59% found computed tomography helpful but not required). Twenty-seven percent of surgeons have changed their implant choice intraoperatively.
CONCLUSIONS: Femoral neck fractures in young adult patients are a challenging problem with high rates of failed treatment. Many options for treatment exist and a consensus on the best method remains elusive. Our survey demonstrates the diversity and disagreement among OTA member "expert" orthopaedic traumatologists for the "best" treatment choice for this important clinical scenario. Our survey shows a divided level of confidence in the current literature and highlights the need for further study of this problem.
LEVEL OF EVIDENCE: Therapeutic Level V. See Instructions for Authors for a complete description of levels of evidence.

PMID: 25148589 [PubMed - indexed for MEDLINE]

The impact of APOE status on relationship of biomarkers of vascular risk and systemic inflammation to neuropsychiatric symptoms in Alzheimer's disease.

Thu, 01/08/2015 - 4:29am
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The impact of APOE status on relationship of biomarkers of vascular risk and systemic inflammation to neuropsychiatric symptoms in Alzheimer's disease.

J Alzheimers Dis. 2014;40(4):887-96

Authors: Hall JR, Wiechmann AR, Johnson LA, Edwards M, Barber RC, Cunningham R, Singh M, O'Bryant SE

Abstract
Research on the link between APOEε4 and neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) has been inconsistent. Previous work has shown a relationship between serum biomarkers of vascular risk and inflammation and NPS in AD. The current study investigated the impact of APOEε4 status on the relationship between biomarkers of cardiovascular risk, systemic inflammation, and NPS. The sample was drawn from the TARCC Longitudinal Research Cohort; the final sample of 190 consisted of 124 females and 66 males meeting the diagnostic criteria for mild to moderate AD. 115 individuals were APOEε4 carriers and 75 were non-carriers. Serum-based clinical biomarkers of vascular risk and biomarkers of inflammation related to AD were analyzed. NPS data was gathered from caretakers/family members using the Neuropsychiatric Inventory. The significant biomarkers differed for carriers and non-carriers with IL15 being a negative biomarker of total NPS accounting for 12% of the variance for carriers and IL18 and TNFα negative predictors for non-carriers (18% of variance). Patterns related to specific symptoms were similar. Stratification by gender revealed significant biomarkers of total NPS for female carriers were negative IL15 and IL1ra (18% of variance) and for female non-carriers were negative IL18 and positive homocysteine. Total cholesterol was a positive biomarker of total NPS for both male carriers (36% of variance) and non-carriers (negative TNFα and total cholesterol, 32% of variance). These findings suggest that dysregulation of inflammatory activity is related to NPS, that cholesterol is a significant factor in the occurrence of NPS, and that gender and APOE status need to be considered.

PMID: 24577461 [PubMed - indexed for MEDLINE]

Dehydrated Amnion/Chorion Membrane and Venous Leg Ulcers.

Wed, 01/07/2015 - 4:30am

Dehydrated Amnion/Chorion Membrane and Venous Leg Ulcers.

Wound Repair Regen. 2014 Dec 30;

Authors: Dickerson JE, Slade HB

PMID: 25556326 [PubMed - as supplied by publisher]

Characterization of [(3) H]LS-3-134, a novel arylamide phenylpiperazine D3 dopamine receptor selective radioligand.

Wed, 01/07/2015 - 4:30am
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Characterization of [(3) H]LS-3-134, a novel arylamide phenylpiperazine D3 dopamine receptor selective radioligand.

J Neurochem. 2014 Nov;131(4):418-31

Authors: Rangel-Barajas C, Malik M, Taylor M, Neve KA, Mach RH, Luedtke RR

Abstract
LS-3-134 is a substituted N-phenylpiperazine derivative that has been reported to exhibit: (i) high-affinity binding (Ki value 0.2 nM) at human D3 dopamine receptors, (ii) > 100-fold D3 versus D2 dopamine receptor subtype binding selectivity, and (iii) low-affinity binding (Ki  > 5000 nM) at sigma 1 and sigma 2 receptors. Based upon a forskolin-dependent activation of the adenylyl cyclase inhibition assay, LS-3-134 is a weak partial agonist at both D2 and D3 dopamine receptor subtypes (29% and 35% of full agonist activity, respectively). In this study, [(3) H]-labeled LS-3-134 was prepared and evaluated to further characterize its use as a D3 dopamine receptor selective radioligand. Kinetic and equilibrium radioligand binding studies were performed. This radioligand rapidly reaches equilibrium (10-15 min at 37°C) and binds with high affinity to both human (Kd  = 0.06 ± 0.01 nM) and rat (Kd  = 0.2 ± 0.02 nM) D3 receptors expressed in HEK293 cells. Direct and competitive radioligand binding studies using rat caudate and nucleus accumbens tissue indicate that [(3) H]LS-3-134 selectively binds a homogeneous population of binding sites with a dopamine D3 receptor pharmacological profile. Based upon these studies, we propose that [(3) H]LS-3-134 represents a novel D3 dopamine receptor selective radioligand that can be used for studying the expression and regulation of the D3 dopamine receptor subtype.

PMID: 25041389 [PubMed - indexed for MEDLINE]

Collaborative EDNAP exercise on the IrisPlex system for DNA-based prediction of human eye colour.

Wed, 01/07/2015 - 4:30am
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Collaborative EDNAP exercise on the IrisPlex system for DNA-based prediction of human eye colour.

Forensic Sci Int Genet. 2014 Jul;11:241-51

Authors: Chaitanya L, Walsh S, Andersen JD, Ansell R, Ballantyne K, Ballard D, Banemann R, Bauer CM, Bento AM, Brisighelli F, Capal T, Clarisse L, Gross TE, Haas C, Hoff-Olsen P, Hollard C, Keyser C, Kiesler KM, Kohler P, Kupiec T, Linacre A, Minawi A, Morling N, Nilsson H, Norén L, Ottens R, Palo JU, Parson W, Pascali VL, Phillips C, Porto MJ, Sajantila A, Schneider PM, Sijen T, Söchtig J, Syndercombe-Court D, Tillmar A, Turanska M, Vallone PM, Zatkalíková L, Zidkova A, Branicki W, Kayser M

Abstract
The IrisPlex system is a DNA-based test system for the prediction of human eye colour from biological samples and consists of a single forensically validated multiplex genotyping assay together with a statistical prediction model that is based on genotypes and phenotypes from thousands of individuals. IrisPlex predicts blue and brown human eye colour with, on average, >94% precision accuracy using six of the currently most eye colour informative single nucleotide polymorphisms (HERC2 rs12913832, OCA2 rs1800407, SLC24A4 rs12896399, SLC45A2 (MATP) rs16891982, TYR rs1393350, and IRF4 rs12203592) according to a previous study, while the accuracy in predicting non-blue and non-brown eye colours is considerably lower. In an effort to vigorously assess the IrisPlex system at the international level, testing was performed by 21 laboratories in the context of a collaborative exercise divided into three tasks and organised by the European DNA Profiling (EDNAP) Group of the International Society of Forensic Genetics (ISFG). Task 1 involved the assessment of 10 blood and saliva samples provided on FTA cards by the organising laboratory together with eye colour phenotypes; 99.4% of the genotypes were correctly reported and 99% of the eye colour phenotypes were correctly predicted. Task 2 involved the assessment of 5 DNA samples extracted by the host laboratory from simulated casework samples, artificially degraded, and provided to the participants in varying DNA concentrations. For this task, 98.7% of the genotypes were correctly determined and 96.2% of eye colour phenotypes were correctly inferred. For Tasks 1 and 2 together, 99.2% (1875) of the 1890 genotypes were correctly generated and of the 15 (0.8%) incorrect genotype calls, only 2 (0.1%) resulted in incorrect eye colour phenotypes. The voluntary Task 3 involved participants choosing their own test subjects for IrisPlex genotyping and eye colour phenotype inference, while eye photographs were provided to the organising laboratory and judged; 96% of the eye colour phenotypes were inferred correctly across 100 samples and 19 laboratories. The high success rates in genotyping and eye colour phenotyping clearly demonstrate the reproducibility and the robustness of the IrisPlex assay as well as the accuracy of the IrisPlex model to predict blue and brown eye colour from DNA. Additionally, this study demonstrates the ease with which the IrisPlex system is implementable and applicable across forensic laboratories around the world with varying pre-existing experiences.

PMID: 24880832 [PubMed - indexed for MEDLINE]

Developmental validation of the EX20+4 system.

Wed, 01/07/2015 - 4:30am
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Developmental validation of the EX20+4 system.

Forensic Sci Int Genet. 2014 Jul;11:207-13

Authors: Li S, Liu C, Liu H, Ge J, Budowle B, Liu C, Zheng W, Li F, Ge B

Abstract
The EX20+4Y System is a polymerase chain reaction (PCR)-based amplification kit that enables typing of 19 autosomal short tandem repeat (STR) loci (i.e., CSF1PO, D13S317, D16S539, D18S51, D21S11, D3S1358, D5S818, D7S820, D8S1179, FGA, TH01, TPOX, vWA, Penta D, Penta E, D2S1338, D19S433, D12S391, D6S1043), four widely used Y chromosome-specific STR (Y-STR) loci (DYS458, DYS456, DYS391, DYS635), and amelogenin. In this study, this multiplex system was validated for sensitivity of detection, DNA mixtures, inhibitor tolerance, species specificity based on the Scientific Working Group on DNA Analysis methods (SWGDAM) developmental validation guidelines, and the Chinese criteria for the human fluorescent STR multiplex PCR reagent. The results show that the EX20+4 System is a robust and reliable amplification kit which can be used for human identification testing.

PMID: 24815370 [PubMed - indexed for MEDLINE]

Erythropoietin: powerful protection of ischemic and post-ischemic brain.

Wed, 01/07/2015 - 4:30am
Related Articles

Erythropoietin: powerful protection of ischemic and post-ischemic brain.

Exp Biol Med (Maywood). 2014 Nov;239(11):1461-75

Authors: Nguyen AQ, Cherry BH, Scott GF, Ryou MG, Mallet RT

Abstract
Ischemic brain injury inflicted by stroke and cardiac arrest ranks among the leading causes of death and long-term disability in the United States. The brain consumes large amounts of metabolic substrates and oxygen to sustain its energy requirements. Consequently, the brain is exquisitely sensitive to interruptions in its blood supply, and suffers irreversible damage after 10-15 min of severe ischemia. Effective treatments to protect the brain from stroke and cardiac arrest have proven elusive, due to the complexities of the injury cascades ignited by ischemia and reperfusion. Although recombinant tissue plasminogen activator and therapeutic hypothermia have proven efficacious for stroke and cardiac arrest, respectively, these treatments are constrained by narrow therapeutic windows, potentially detrimental side-effects and the limited availability of hypothermia equipment. Mounting evidence demonstrates the cytokine hormone erythropoietin (EPO) to be a powerful neuroprotective agent and a potential adjuvant to established therapies. Classically, EPO originating primarily in the kidneys promotes erythrocyte production by suppressing apoptosis of proerythroid progenitors in bone marrow. However, the brain is capable of producing EPO, and EPO's membrane receptors and signaling components also are expressed in neurons and astrocytes. EPO activates signaling cascades that increase the brain's resistance to ischemia-reperfusion stress by stabilizing mitochondrial membranes, limiting formation of reactive oxygen and nitrogen intermediates, and suppressing pro-inflammatory cytokine production and neutrophil infiltration. Collectively, these mechanisms preserve functional brain tissue and, thus, improve neurocognitive recovery from brain ischemia. This article reviews the mechanisms mediating EPO-induced brain protection, critiques the clinical utility of exogenous EPO to preserve brain threatened by ischemic stroke and cardiac arrest, and discusses the prospects for induction of EPO production within the brain by the intermediary metabolite, pyruvate.

PMID: 24595981 [PubMed - indexed for MEDLINE]

Menu-labeling usage and its association with diet and exercise: 2011 BRFSS Sugar Sweetened Beverage and Menu Labeling module.

Wed, 01/07/2015 - 4:30am
Related Articles

Menu-labeling usage and its association with diet and exercise: 2011 BRFSS Sugar Sweetened Beverage and Menu Labeling module.

Prev Chronic Dis. 2014;11:130231

Authors: Bowers KM, Suzuki S

Abstract
INTRODUCTION: The primary objective of our study was to investigate the association between menu-labeling usage and healthy behaviors pertaining to diet (consumption of fruits, vegetables, sodas, and sugar-sweetened beverages) and exercise.
METHODS: Data from the 2011 Behavioral Risk Factor Surveillance System, Sugar Sweetened Beverage and Menu-Labeling module, were used. Logistic regression was used to determine the association between menu-labeling usage and explanatory variables that included fruit, vegetable, soda, and sugar-sweetened beverage consumption as well as exercise.
RESULTS: Nearly half (52%) of the sample indicated that they used menu labeling. People who used menu labeling were more likely to be female (odds ratio [OR], 2.29; 95% confidence interval [CI], 2.04-2.58), overweight (OR, 1.13; 95% CI, 1.00-1.29) or obese (OR, 1.29; 95% CI, 1.12-1.50), obtain adequate weekly aerobic exercise (OR, 1.18; 95% CI, 1.06-1.32), eat fruits (OR, 1.20; 95% CI, 1.12-1.29) and vegetables (OR, 1.12; 95% CI, 1.05-1.20), and drink less soda (OR, 0.76; 95% CI, 0.69-0.83).
CONCLUSION: Although obese and overweight people were more likely to use menu labeling, they were also adequately exercising, eating more fruits and vegetables, and drinking less soda. Menu labeling is intended to combat the obesity epidemic; however the results indicate an association between menu-labeling usage and certain healthy behaviors. Thus, efforts may be necessary to increase menu-labeling usage among people who are not partaking in such behaviors.

PMID: 24384303 [PubMed - indexed for MEDLINE]

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

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

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

Bioorg Med Chem Lett. 2014 Dec 17;

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

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

PMID: 25556097 [PubMed - as supplied by publisher]

Joint pain in a man with lung cancer.

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

Joint pain in a man with lung cancer.

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

Authors: Jernigan E, Siddiqi N, Peddi P

PMID: 25552621 [PubMed - in process]

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