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: 2 hours 37 min ago

Kienböck Disease: Moving Forward.

Sat, 03/11/2017 - 07:34
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Kienböck Disease: Moving Forward.

J Hand Surg Am. 2016 May;41(5):630-8

Authors: Lichtman DM, Pientka WF, Bain GI

Abstract
Over the past decade, a plethora of new information has been reported regarding etiology, natural history, classification, and treatment options for lunate osteonecrosis. New disease classifications have been described based on advanced imaging determination of lunate viability as well as a cartilage-based arthroscopic classification. Here we review the newest literature regarding Kienböck disease and present a new treatment algorithm that incorporates the traditional osseous classification system with a perfusion/viability classification and an articular cartilage-based classification.

PMID: 27055625 [PubMed - indexed for MEDLINE]

The health action process approach applied to African American breast cancer survivors.

Sat, 03/11/2017 - 07:34
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The health action process approach applied to African American breast cancer survivors.

Psychooncology. 2016 06;25(6):648-55

Authors: Paxton RJ

Abstract
BACKGROUND: The health action process approach (HAPA) is a relevant model for understanding physical activity (PA), yet it has not been examined in cancer survivors or minorities. In this study, we assessed the HAPA in African American breast cancer survivors using covariance modeling.
METHODS: A total of 304 African American breast cancer survivors (mean age = 54 years) participated in a Web-based survey assessing demographic and medical characteristics as well as constructs of the HAPA. A two-step covariance modeling approach was used to assess the structural relationships among the constructs.
RESULTS: The hypothesized measurement model fit the data; however, general severity was not significantly associated with the remaining constructs. General severity was removed, and the fit did not change significantly. The final adjusted model provided a reasonable fit to the data and accounted for significant variance in intentions (49%) and PA (42%). Action (β = 0.1, p < 0.01) and coping (β = 0.3, p < 0.01) planning mediated the relationship between intentions and behavior.
CONCLUSIONS: The HAPA appears to be a relevant model for understanding PA in African American breast cancer survivors. However, more work is needed to determine whether these relationships can be replicated in other breast cancer survivors. Copyright © 2015 John Wiley & Sons, Ltd.

PMID: 26058382 [PubMed - indexed for MEDLINE]

The factor of 10 in forensic DNA match probabilities.

Thu, 03/09/2017 - 07:34

The factor of 10 in forensic DNA match probabilities.

Forensic Sci Int Genet. 2017 Feb 16;28:178-187

Authors: Gittelson S, Moretti TR, Onorato AJ, Budowle B, Weir BS, Buckleton J

Abstract
An update was performed of the classic experiments that led to the view that profile probability assignments are usually within a factor of 10 of each other. The data used in this study consist of 15 Identifiler loci collected from a wide range of forensic populations. Following Budowle et al. [1], the terms cognate and non-cognate are used. The cognate database is the database from which the profiles are simulated. The profile probability assignment was usually larger in the cognate database. In 44%-65% of the cases, the profile probability for 15 loci in the non-cognate database was within a factor of 10 of the profile probability in the cognate database. This proportion was between 60% and 80% when the FBI and NIST data were used as the non-cognate databases. A second experiment compared the match probability assignment using a generalised database and recommendation 4.2 from NRC II (the 4.2 assignment) with a proxy for the matching proportion developed using subpopulation allele frequencies and the product rule. The findings support that the 4.2 assignment has a large conservative bias. These results are in agreement with previous research results.

PMID: 28273509 [PubMed - as supplied by publisher]

Flanking region variation of ForenSeq™ DNA Signature Prep Kit STR and SNP loci in Yavapai Native Americans.

Thu, 03/09/2017 - 07:34

Flanking region variation of ForenSeq™ DNA Signature Prep Kit STR and SNP loci in Yavapai Native Americans.

Forensic Sci Int Genet. 2017 Feb 27;28:146-154

Authors: Wendt FR, King JL, Novroski NM, Churchill JD, Ng J, Oldt RF, McCulloh KL, Weise JA, Smith DG, Kanthaswamy S, Budowle B

Abstract
Massively parallel sequencing (MPS) offers advantages over current capillary electrophoresis-based analysis of short tandem repeat (STR) loci for human identification testing. In particular STR repeat motif sequence information can be obtained, thereby increasing the discrimination power of some loci. While sequence variation within the repeat region is observed relatively frequently in some of the commonly used STRs, there is an additional degree of variation found in the flanking regions adjacent to the repeat motif. Repeat motif and flanking region sequence variation have been described for major population groups, however, not for more isolated populations. Flanking region sequence variation in STR and single nucleotide polymorphism (SNP) loci in the Yavapai population was analyzed using the ForenSeq™ DNA Signature Prep Kit and STRait Razor v2s. Seven and 14 autosomal STRs and identity-informative single nucleotide polymorphisms (iiSNPs), respectively, had some degree of flanking region variation. Three and four of these identity-informative loci, respectively, showed ≥5% increase in expected heterozygosity. The combined length- and sequence-based random match probabilities (RMPs) for 27 autosomal STRs were 6.11×10(-26) and 2.79×10(-29), respectively. When combined with 94 iiSNPs (a subset of which became microhaplotypes) the combined RMP was 5.49×10(-63). Analysis of length-based and sequence-based autosomal STRs in STRUCTURE indicated that the Yavapai are most similar to the Hispanic population. While producing minimal increase in X- and Y-STR discrimination potential, access to flanking region data enabled identification of one novel X-STR and three Y-STR alleles relative to previous reports. Five ancestry-informative SNPs (aiSNPs) and two phenotype-informative SNPs (piSNPs) exhibited notable flanking region variation.

PMID: 28273507 [PubMed - as supplied by publisher]

Enzymatic Debridement of Chronic Nonischemic Diabetic Foot Ulcers: Results of a Randomized, Controlled Trial.

Wed, 03/08/2017 - 07:35
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Enzymatic Debridement of Chronic Nonischemic Diabetic Foot Ulcers: Results of a Randomized, Controlled Trial.

Wounds. 2017 Feb 27;:

Authors: Jimenez JC, Agnew PS, Mayer P, Clements JR, Caporusso JM, Lange DL, Dickerson JE, Slade HB

Abstract
OBJECTIVE: The aim of this randomized, controlled multicenter trial was to evaluate the clinical outcomes associated with the use of clostridial collagenase ointment (CCO) for up to 12 weeks in 215 patients with type 1 or type 2 diabetes mellitus and a neuropathic, nonischemic diabetic foot ulcer (DFU).
MATERIALS AND METHODS: Patients were randomized into either a group receiving CCO applied once daily at a thickness of ~2 mm or a group receiving standard care (SC) consisting of a daily application of a hydrogel as needed to maintain a moist ulcer environment. All ulcers were covered with a nonadherent foam dressing that was changed once daily, and sharp debridement was allowed when the investigators deemed it medically warranted. Outcome measures included the percent change in ulcer area and the effect of baseline wound microbiota on subsequent healing. Patients with ulcers that showed no decrease in size after 4 weeks were crossed over to the other treatment group.
RESULTS: The wound area decreased relative to baseline for both the CCO group (-60%, P < .0001; -65%, P < .0001) and the control group (-50%, P = .0001; -51%, P = .0001) after 6 and 12 weeks, respectively. While the intergroup differences at 6 and 12 weeks did not reach statistical significance (P = .3801; P = .3606), mean percent reductions for the CCO group were greater than the control at all 12 time points (averages: -55%; -41%, respectively). Overall closure rate was 21% and 41% (weeks 6 and 12, P = .3705; P = .2358) with no significant differences between groups. However, the DFUs that showed no improvement at 4 weeks (N = 24, 12/group) were crossed over to the other treatment group. A numerically greater proportion of subjects who switched to CCO achieved closure (33%) than for those who switched to SC (8%). Baseline biopsy showed that despite the absence of clinical signs of infection, all ulcers were heavily colonized by 1 to 5 species of bacteria. No adverse events were assessed by the investigators as related to either treatment.
CONCLUSION: These results confirm observations from previous studies demonstrating positive outcomes associated with enzymatic debridement with CCO following 6 weeks of treatment.

PMID: 28267678 [PubMed - as supplied by publisher]

Superparamagnetic reconstituted high-density lipoprotein nanocarriers for magnetically guided drug delivery.

Tue, 03/07/2017 - 07:36
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Superparamagnetic reconstituted high-density lipoprotein nanocarriers for magnetically guided drug delivery.

Int J Nanomedicine. 2017;12:1453-1464

Authors: Sabnis S, Sabnis NA, Raut S, Lacko AG

Abstract
Current cancer chemotherapy is frequently associated with short- and long-term side effects, affecting the quality of life of cancer survivors. Because malignant cells are known to overexpress specific surface antigens, including receptors, targeted drug delivery is often utilized to reduce or overcome side effects. The current study involves a novel targeting approach using specifically designed nanoparticles, including encapsulation of the anti-cancer drug valrubicin into superparamagnetic iron oxide nanoparticle (SPION) containing reconstituted high-density lipoprotein (rHDL) nanoparticles. Specifically, rHDL-SPION-valrubicin hybrid nanoparticles were assembled and characterized with respect to their physical and chemical properties, drug entrapment efficiency and receptor-mediated release of the drug valrubicin from the nanoparticles to prostate cancer (PC-3) cells. Prussian blue staining was used to assess nanoparticle movement in a magnetic field. Measurements of cytotoxicity toward PC-3 cells showed that rHDL-SPION-valrubicin nanoparticles were up to 4.6 and 31 times more effective at the respective valrubicin concentrations of 42.4 µg/mL and 85 µg/mL than the drug valrubicin alone. These studies showed, for the first time, that lipoprotein drug delivery enhanced via magnetic targeting could be an effective chemotherapeutic strategy for prostate cancer.

PMID: 28260891 [PubMed - in process]

Glucocorticoid therapy and ocular hypertension.

Tue, 03/07/2017 - 07:36
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Glucocorticoid therapy and ocular hypertension.

Eur J Pharmacol. 2016 Sep 15;787:57-71

Authors: Dibas A, Yorio T

Abstract
The projected number of people who will develop age-related macular degeneration in estimated at 2020 is 196 million and is expected to reach 288 million in 2040. Also, the number of people with Diabetic retinopathy will grow from 126.6 million in 2010 to 191.0 million by 2030. In addition, it is estimated that there are 2.3 million people suffering from uveitis worldwide. Because of the anti-inflammatory properties of glucocorticoids (GCs), they are often used topically and/or intravitreally to treat ocular inflammation conditions or edema associated with macular degeneration and diabetic retinopathy. Unfortunately, ocular GC therapy can lead to severe side effects. Serious and sometimes irreversible eye damage can occur as a result of the development of GC-induced ocular hypertension causing secondary open-angle glaucoma. According to the world health organization, glaucoma is the second leading cause of blindness in the world and it is estimated that 80 million will suffer from glaucoma by 2020. In the current review, mechanisms of GC-induced damage in ocular tissue, GC-resistance, and enhancing GC therapy will be discussed.

PMID: 27388141 [PubMed - indexed for MEDLINE]

4-Chlorophenylguanidine is an ASIC3 agonist and positive allosteric modulator.

Mon, 03/06/2017 - 07:35

4-Chlorophenylguanidine is an ASIC3 agonist and positive allosteric modulator.

J Pharmacol Sci. 2017 Feb 17;:

Authors: Agharkar AS, Gonzales EB

Abstract
Acid-sensing ion channels (ASICs) are proton-sensitive sodium channels that open in response to lowered extracellular pH and are expressed in the central and peripheral nervous systems. The ASIC3 subtype is found primarily in the periphery where the channel mediates pain signals caused by ischemia and inflammation. Here, we provide identify 4-chlorophenylguanidine (4-CPG) as an ASIC3 positive allosteric modulator and newest member of the growing group of guanidine modulators of ASICs. Furthermore, the 4-CPG reversed the effects of ASIC3 desensitization. The molecule 4-CPG offers a novel chemical backbone for the design of new ASIC3 ligands to study ASIC3 in vivo.

PMID: 28259560 [PubMed - as supplied by publisher]

Stroke Cytoprotection: Can Repeating History with New Expectations Really Be the Path to Success in Stroke Research?

Fri, 03/03/2017 - 07:31
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Stroke Cytoprotection: Can Repeating History with New Expectations Really Be the Path to Success in Stroke Research?

Transl Stroke Res. 2017 Mar 01;:

Authors: Lapchak PA, Uteshev VV

PMID: 28251583 [PubMed - as supplied by publisher]

Fluorocycline TP-271 Is Potent against Complicated Community-Acquired Bacterial Pneumonia Pathogens.

Fri, 03/03/2017 - 07:31
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Fluorocycline TP-271 Is Potent against Complicated Community-Acquired Bacterial Pneumonia Pathogens.

mSphere. 2017 Jan-Feb;2(1):

Authors: Grossman TH, Fyfe C, O'Brien W, Hackel M, Minyard MB, Waites KB, Dubois J, Murphy TM, Slee AM, Weiss WJ, Sutcliffe JA

Abstract
TP-271 is a novel, fully synthetic fluorocycline antibiotic in clinical development for the treatment of respiratory infections caused by susceptible and multidrug-resistant pathogens. TP-271 was active in MIC assays against key community respiratory Gram-positive and Gram-negative pathogens, including Streptococcus pneumoniae (MIC90 = 0.03 µg/ml), methicillin-sensitive Staphylococcus aureus (MSSA; MIC90 = 0.25 µg/ml), methicillin-resistant S. aureus (MRSA; MIC90 = 0.12 µg/ml), Streptococcus pyogenes (MIC90 = 0.03 µg/ml), Haemophilus influenzae (MIC90 = 0.12 µg/ml), and Moraxella catarrhalis (MIC90 ≤0.016 µg/ml). TP-271 showed activity (MIC90 = 0.12 µg/ml) against community-acquired MRSA expressing Panton-Valentine leukocidin (PVL). MIC90 values against Mycoplasma pneumoniae, Legionella pneumophila, and Chlamydia pneumoniae were 0.004, 1, and 4 µg/ml, respectively. TP-271 was efficacious in neutropenic and immunocompetent animal pneumonia models, generally showing, compared to the burden at the start of dosing, ~2 to 5 log10 CFU reductions against MRSA, S. pneumoniae, and H. influenzae infections when given intravenously (i.v.) and ~1 to 4 log10 CFU reductions when given orally (p.o.). TP-271 was potent against key community-acquired bacterial pneumonia (CABP) pathogens and was minimally affected, or unaffected, by tetracycline-specific resistance mechanisms and fluoroquinolone or macrolide drug resistance phenotypes. IMPORTANCE Rising resistance rates for macrolides, fluoroquinolones, and β-lactams in the most common pathogens associated with community-acquired bacterial pneumonia (CABP) are of concern, especially for cases of moderate to severe infections in vulnerable populations such as the very young and the elderly. New antibiotics that are active against multidrug-resistant Streptococcus pneumoniae and Staphylococcus aureus are needed for use in the empirical treatment of the most severe forms of this disease. TP-271 is a promising new fluorocycline antibiotic demonstrating in vitro potency and nonclinical efficacy by intravenous and oral administration against the major pathogens associated with moderate to severe CABP.

PMID: 28251179 [PubMed - in process]

Upregulation of the endothelin A (ETA) receptor and its association with neurodegeneration in a rodent model of glaucoma.

Fri, 03/03/2017 - 07:31
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Upregulation of the endothelin A (ETA) receptor and its association with neurodegeneration in a rodent model of glaucoma.

BMC Neurosci. 2017 Mar 01;18(1):27

Authors: McGrady NR, Minton AZ, Stankowska DL, He S, Jefferies HB, Krishnamoorthy RR

Abstract
BACKGROUND: Primary open angle glaucoma is a heterogeneous group of optic neuropathies that results in optic nerve degeneration and a loss of retinal ganglion cells (RGCs) ultimately causing blindness if allowed to progress. Elevation of intraocular pressure (IOP) is the most attributable risk factor for developing glaucoma and lowering of IOP is currently the only available therapy. However, despite lowering IOP, neurodegenerative effects persist in some patients. Hence, it would be beneficial to develop approaches to promote neuroprotection of RGCs in addition to IOP lowering therapies. The endothelin system is a key target for intervention against glaucomatous neurodegeneration. The endothelin family of peptides and receptors, particularly endothelin-1 (ET-1) and endothelin B (ETB) receptor, has been shown to have neurodegenerative roles in glaucoma. The purpose of this study was to examine changes in endothelin A (ETA) receptor protein expression in the retinas of adult male Brown Norway rats following IOP elevation by the Morrison's model of ocular hypertension and the impact of ETA receptor overexpression on RGC viability in vitro.
RESULTS: IOP elevation was carried out in one eye of Brown Norway rats by injection of hypertonic saline through episcleral veins. After 2 weeks of IOP elevation, immunohistochemical analysis of retinal sections from rat eyes showed an increasing trend in immunostaining for ETA receptors in multiple retinal layers including the inner plexiform layer, ganglion cell layer and outer plexiform layer. Following 4 weeks of IOP elevation, a significant increase in immunostaining for ETA receptor expression was found in the retina, primarily in the inner plexiform layer and ganglion cells. A modest increase in staining for ETA receptors was also found in the outer plexiform layer in the retina of rats with IOP elevation. Cell culture studies showed that overexpression of ETA receptors in 661W cells as well as primary RGCs decreases cell viability, compared to empty vector transfected cells. Adeno-associated virus mediated overexpression of the ETA receptor produced an increase in the ETB receptor in primary RGCs.
CONCLUSIONS: Elevated IOP results in an appreciable change in ETA receptor expression in the retina. Overexpression of the ETA receptor results in an overall decrease in cell viability, accompanied by an increase in ETB receptor levels, suggesting the involvement of both ETA and ETB receptors in mediating cell death. These findings raise possibilities for the development of ETA/ETB dual receptor antagonists as neuroprotective treatments for glaucomatous neuropathy.

PMID: 28249604 [PubMed - in process]

Glutamate Impairs Mitochondria Aerobic Respiration Capacity and Enhances Glycolysis in Cultured Rat Astrocytes.

Thu, 03/02/2017 - 07:33
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Glutamate Impairs Mitochondria Aerobic Respiration Capacity and Enhances Glycolysis in Cultured Rat Astrocytes.

Biomed Environ Sci. 2017 Jan;30(1):44-51

Authors: Yan X, Shi ZF, Xu LX, Li JX, Wu M, Wang XX, Jia M, Dong LP, Yang SH, Yuan F

Abstract
OBJECTIVE: To study the effect of glutamate on metabolism, shifts in glycolysis and lactate release in rat astrocytes.
METHODS: After 10 days, secondary cultured astrocytes were treated with 1 mmol/L glutamate for 1 h, and the oxygen consumption rates (OCR) and extra cellular acidification rate (ECAR) was analyzed using a Seahorse XF 24 Extracellular Flux Analyzer. Cell viability was then evaluated by MTT assay. Moreover, changes in extracellular lactate concentration induced by glutamate were tested with a lactate detection kit.
RESULTS: Compared with the control group, treatment with 1 mmol/L glutamate decreased the astrocytes' maximal respiration and spare respiratory capacity but increased their glycolytic capacity and glycolytic reserve. Further analysis found that 1-h treatment with different concentrations of glutamate (0.1-1 mmol/L) increased lactate release from astrocytes, however the cell viability was not affected by the glutamate treatment.
CONCLUSION: The current study provided direct evidence that exogenous glutamate treatment impaired the mitochondrial respiration capacity of astrocytes and enhanced aerobic glycolysis, which could be involved in glutamate injury or protection mechanisms in response to neurological disorders.

PMID: 28245898 [PubMed - in process]

Association of Sp1 and survivin in epithelial ovarian cancer: Sp1 inhibitor and cisplatin, a novel combination for inhibiting epithelial ovarian cancer cell proliferation.

Wed, 03/01/2017 - 07:32
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Association of Sp1 and survivin in epithelial ovarian cancer: Sp1 inhibitor and cisplatin, a novel combination for inhibiting epithelial ovarian cancer cell proliferation.

Tumour Biol. 2016 Oct;37(10):14259-14269

Authors: Sankpal UT, Ingersoll SB, Ahmad S, Holloway RW, Bhat VB, Simecka JW, Daniel L, Kariali E, Vishwanatha JK, Basha R

Abstract
The expression of specificity protein 1 (Sp1) and survivin was evaluated in clinical specimens of epithelial ovarian cancer (EOC) patients. When compared to normal tissue, EOC samples showed high expression of Sp1 and survivin using qPCR (Sp1: ∼2-fold; survivin: ∼5-fold) and Western blot (Sp1: >2.6-fold; survivin: >100-fold). The Sp1 inhibitor, and anti-cancer small molecule, tolfenamic acid (TA), was tested to enhance the response of Cisplatin (Cis) in EOC cell lines. Cell viability (CellTiter-Glo), combination index (CalcuSyn software), apoptosis (Annexin-V staining), cell cycle analyses (flow cytometry), and reactive oxygen species (flow cytometry) were determined. Cell migration and invasion was assessed using matrigel coated transwell chambers. Agilent Technologies proteomics analysis identified potential signaling pathways involved. The combination of TA (50 μM) and Cis (5 μM) synergistically increased the growth inhibition in ES2 (∼80 %, p < 0.001) and OVCAR-3 (60 %, p < 0.001) cells. TA or TA + Cis treatment in ES2 cells caused cell cycle arrest in G1 Phase (TA) or S-Phase (TA + Cis) and unregulated reactive oxygen species. Invasion and migration was decreased in ES2 cells. Global proteomic profiling showed modulation of proteins associated with oxidative phosphorylation, apoptosis, electron transport chain, DNA damage, and cell cycle proteins. These results demonstrate an association of Sp1 and survivin in EOC and confirm targeting these candidates with TA potentially sensitizes EOC cells to cisplatin.

PMID: 27581819 [PubMed - indexed for MEDLINE]

TGFβ2 Induces the Formation of Cross-Linked Actin Networks (CLANs) in Human Trabecular Meshwork Cells Through the Smad and Non-Smad Dependent Pathways.

Tue, 02/28/2017 - 07:33

TGFβ2 Induces the Formation of Cross-Linked Actin Networks (CLANs) in Human Trabecular Meshwork Cells Through the Smad and Non-Smad Dependent Pathways.

Invest Ophthalmol Vis Sci. 2017 Feb 01;58(2):1288-1295

Authors: Montecchi-Palmer M, Bermudez JY, Webber HC, Patel GC, Clark AF, Mao W

Abstract
Purpose: Increased intraocular pressure results from increased aqueous humor (AH) outflow resistance at the trabecular meshwork (TM) due to pathologic changes including the formation of cross-linked actin networks (CLANs). Transforming growth factor β2 (TGFβ2) is elevated in the AH and TM of primary open angle glaucoma (POAG) patients and induces POAG-associated TM changes, including CLANs. We determined the role of individual TGFβ2 signaling pathways in CLAN formation.
Methods: Cultured nonglaucomatous human TM (NTM) cells were treated with control or TGFβ2, with or without the inhibitors of TGFβ receptor, Smad3, c-Jun N-terminal kinases (JNK), extracellular signal regulated kinase (ERK), P38, or Rho-associated protein kinase (ROCK). NTM cells were cotreated with TGFβ2 plus inhibitors for 10 days or pretreated with TGFβ2 for 10 days followed by 1-hour inhibitor treatment. NTM cells were immunostained with phalloidin-Alexa-488 and 4',6-diamidino-2-phenylindole (DAPI). Data were analyzed using 1-way ANOVA and Dunnett's post hoc test.
Results: TGFβ2 significantly induced CLAN formation (n = 6 to 12, P < 0.05), which was completely inhibited by TGFβ receptor, Smad3, and ERK inhibitors, as well as completely or partially inhibited by JNK, P38, and ROCK inhibitors, depending on cell strains. One-hour exposure to ROCK inhibitor completely resolved formed CLANs (P < 0.05), whereas TGFβ receptor, Smad3 inhibitor, and ERK inhibitors resulted in partial or complete resolution. The JNK and P38 inhibitors showed partial or no resolution. Among these inhibitors, the ROCK inhibitor was the most disruptive to the actin stress fibers, whereas ERK inhibition showed the least disruption.
Conclusions: TGFβ2-induced CLANs in NTM cells were prevented and resolved using various pathway inhibitors. Apart from CLAN inhibition, some of these inhibitors also had different effects on actin stress fibers.

PMID: 28241317 [PubMed - in process]

Non-Feminizing Estrogens Do Not Exhibit Antidepressant-like Activity.

Tue, 02/28/2017 - 07:33
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Non-Feminizing Estrogens Do Not Exhibit Antidepressant-like Activity.

J Pharm Drug Res. 2016;1(1):1-6

Authors: Prokai-Tatrai K, Nguyen V, Prokai L

Abstract
In this exploratory study, we performed an evaluation of non-feminizing estrogens as lead compounds for the safe treatment of menopausal symptoms. Despite confirming an enhancement of antioxidant potency as a consequence of increased lipophilicity of the prototype structures, our analyses have revealed serious shortcomings regarding pharmaceutically important properties and drug-likeness. In addition, our assessment in an animal model of estrogen deprivation has confirmed that genomic mechanisms are required for the alleviation of menopause-associated depression. Therefore, non-feminizing estrogens are not suitable to fulfill their implicated premise to address unmet needs to treat neurological and psychiatric conditions associated with estrogen deprivation of the brain.

PMID: 28239683 [PubMed - in process]

Cross-linked actin networks (CLANs) in glaucoma.

Tue, 02/28/2017 - 07:33
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Cross-linked actin networks (CLANs) in glaucoma.

Exp Eye Res. 2017 Feb 23;:

Authors: Bermudez JY, Montecchi-Palmer M, Mao W, Clark AF

Abstract
One of the major causes of decreased vision, irreversible vision loss and blindness worldwide is glaucoma. Increased intraocular pressure (IOP) is a major risk factor associated with glaucoma and its molecular mechanisms are not fully understood. The trabecular meshwork (TM) is the primary site of injury in glaucoma, and its dysfunction results in elevated IOP. The glaucomatous TM has increased extracellular matrix deposition as well as cytoskeletal rearrangements referred to as cross-linked actin networks (CLANs) that consist of dome like structures consisting of hubs and spokes. CLANs are thought to play a role in increased aqueous humor outflow resistance and increased IOP by creating stiffer TM cells and tissue. CLANs are inducible by glucocorticoids (GCs) and TGFβ2 in confluent TM cells and TM tissues. The signaling pathways of these induction agents give insight into the possible mechanisms of CLAN formation, but to date, the mechanism of CLANs regulation by these pathways has yet to be determined. Understanding the role CLANs play in IOP elevation and their mechanisms of induction and regulation may lead to novel treatment options to help prevent or intervene in glaucomatous damage to the trabecular meshwork.

PMID: 28238754 [PubMed - as supplied by publisher]

Intervention Mediators in a Randomized Controlled Trial to Increase Colonoscopy Uptake Among Individuals at Increased Risk of Familial Colorectal Cancer.

Mon, 02/27/2017 - 07:32
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Intervention Mediators in a Randomized Controlled Trial to Increase Colonoscopy Uptake Among Individuals at Increased Risk of Familial Colorectal Cancer.

Ann Behav Med. 2017 Feb 24;:

Authors: Brumbach BH, Birmingham WC, Boonyasiriwat W, Walters S, Kinney AY

Abstract
BACKGROUND: Understanding the pathways by which interventions achieve behavioral change is important for optimizing intervention strategies.
PURPOSE: We examined mediators of behavior change in a tailored-risk communication intervention that increased guideline-based colorectal cancer screening among individuals at increased familial risk.
METHODS: Participants at increased familial risk for colorectal cancer (N = 481) were randomized to one of two arms: (1) a remote, tailored-risk communication intervention (Tele-Cancer Risk Assessment and Evaluation (TeleCARE)) or (2) a mailed educational brochure intervention.
RESULTS: Structural equation modeling showed that participants in TeleCARE were more likely to get a colonoscopy. The effect was partially mediated through perceived threat (β = 0.12, p < 0.05), efficacy beliefs (β = 0.12, p < 0.05), emotions (β = 0.22, p < 0.001), and behavioral intentions (β = 0.24, p < 0.001). Model fit was very good: comparative fit index = 0.95, root-mean-square error of approximation = 0.05, and standardized root-mean-square residual = 0.08.
CONCLUSION: Evaluating mediating variables between an intervention (TeleCARE) and a primary outcome (colonoscopy) contributes to our understanding of underlying mechanisms that lead to health behavior change, thus leading to better informed and designed future interventions.
TRIAL REGISTRATION NUMBER: ClinicalTrials.gov , NCT01274143.

PMID: 28236077 [PubMed - as supplied by publisher]

Genetic redundancy of GATA factors in extraembryonic trophoblast lineage ensures progression of both pre and postimplantation mammalian development.

Sun, 02/26/2017 - 17:16
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Genetic redundancy of GATA factors in extraembryonic trophoblast lineage ensures progression of both pre and postimplantation mammalian development.

Development. 2017 Feb 23;:

Authors: Home P, Kumar RP, Ganguly A, Saha B, Milano-Foster J, Bhattacharya B, Ray S, Gunewardena S, Paul A, Camper SA, Fields PE, Paul S

Abstract
GATA transcription factors are implicated in establishing cell fate during mammalian development. In early mammalian embryos, GATA3 is selectively expressed in the extraembryonic trophoblast lineage and regulates gene expression to promote trophoblast fate. However, trophoblast-specific GATA3 function is dispensable for early mammalian development. Here, using dual conditional knockout mice, we show that genetic redundancy of GATA3 with paralog GATA2 in trophoblast progenitors ensures the successful progression of both pre and postimplantation mammalian development. Stage-specific gene deletion in trophoblasts reveals that loss of both GATA genes, but not either one alone, leads to embryonic lethality prior to the onset of their expression within the embryo proper. Using ChIP-seq and RNA-seq analyses, we define the global targets of GATA2/GATA3 and show that they directly regulate a large number of common genes to orchestrate stem vs. differentiated trophoblast fate. Also, in trophoblast progenitors GATA factors directly regulate BMP4, Nodal and Wnt signaling components that promote embryonic-extraembryonic signaling cross-talk, essential for the development of the embryo proper. Our study provides genetic evidence that impairment of trophoblast-specific GATA2/GATA3 function could lead to early pregnancy failure.

PMID: 28232602 [PubMed - as supplied by publisher]

Evaluation of Xpert MTB/RIF Versus AFB Smear and Culture to Identify Pulmonary Tuberculosis in Patients With Suspected Tuberculosis From Low and Higher Prevalence Settings.

Fri, 02/24/2017 - 07:33
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Evaluation of Xpert MTB/RIF Versus AFB Smear and Culture to Identify Pulmonary Tuberculosis in Patients With Suspected Tuberculosis From Low and Higher Prevalence Settings.

Clin Infect Dis. 2016 May 01;62(9):1081-8

Authors: Luetkemeyer AF, Firnhaber C, Kendall MA, Wu X, Mazurek GH, Benator DA, Arduino R, Fernandez M, Guy E, Johnson P, Metchock B, Sattler F, Telzak E, Wang YF, Weiner M, Swindells S, Sanne IM, Havlir DV, Grinsztejn B, Alland D, AIDS Clinical Trials Group A5295 and Tuberculosis Trials Consortium Study 34 Teams

Abstract
BACKGROUND: The Xpert MTB/RIF (Xpert) assay is a rapid nucleic acid amplification test widely used in settings of high tuberculosis prevalence to detect tuberculosis as well asrpoBmutations associated with rifampin resistance. Data are needed on the diagnostic performance of Xpert in lower-prevalence settings to inform appropriate use for both tuberculosis detection and the need for respiratory isolation.
METHODS: Xpert was compared to 2 sputum samples, each evaluated with acid-fast bacilli (AFB) smear and mycobacterial culture using liquid and solid culture media, from participants with suspected pulmonary tuberculosis from the United States, Brazil, and South Africa.
RESULTS: Of 992 participants enrolled with evaluable results, 22% had culture-confirmed tuberculosis. In 638 (64%) US participants, 1 Xpert result demonstrated sensitivity of 85.2% (96.7% in participants with AFB smear-positive [AFB(+)] sputum, 59.3% with AFB smear-negative [AFB(-)] sputum), specificity of 99.2%, negative predictive value (NPV) of 97.6%, and positive predictive value of 94.9%. Results did not differ between higher- and low-prevalence settings. A second Xpert assay increased overall sensitivity to 91.1% (100% if AFB(+), 71.4% if AFB(-)), with specificity of 98.9%. In US participants, a single negative Xpert result predicted the absence of AFB(+)/culture-positive tuberculosis with an NPV of 99.7%; NPV of 2 Xpert assays was 100%, suggesting a role in removing patients from airborne infection isolation. Xpert detected tuberculosis DNA and mutations associated with rifampin resistance in 5 of 7 participants with rifampin-resistant, culture-positive tuberculosis. Specificity for rifampin resistance was 99.5% and NPV was 98.9%.
CONCLUSIONS: In the United States, Xpert testing performed comparably to 2 higher-tuberculosis-prevalence settings. These data support the use of Xpert in the initial evaluation of tuberculosis suspects and in algorithms assessing need for respiratory isolation.

PMID: 26839383 [PubMed - indexed for MEDLINE]

Plasma Cystatin C and High-Density Lipoprotein Are Important Biomarkers of Alzheimer's Disease and Vascular Dementia: A Cross-Sectional Study.

Thu, 02/23/2017 - 07:32
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Plasma Cystatin C and High-Density Lipoprotein Are Important Biomarkers of Alzheimer's Disease and Vascular Dementia: A Cross-Sectional Study.

Front Aging Neurosci. 2017;9:26

Authors: Wang R, Chen Z, Fu Y, Wei X, Liao J, Liu X, He B, Xu Y, Zou J, Yang X, Weng R, Tan S, McElroy C, Jin K, Wang Q

Abstract
Objectives: Cystatin C (Cys C) and high-density lipoprotein (HDL) play critical roles in neurodegenerative diseases, such as dementia, Alzheimer's disease (AD) and vascular dementia (VaD). However, whether they can be used as reliable biomarkers to distinguish patients with dementia from healthy subjects and to determine disease severity remain largely unknown. Methods: We conducted a cross-sectional study to determine plasma Cys C and HDL levels of 88 patients with dementia (43 AD patients, 45 VaD patients) and 45 healthy age-matched controls. The severity of dementia was determined based on the Schwab and England Activities of Daily Living (ADL) Scale, the Mini-mental State Examination (MMSE), the Global Deterioration Scale (GDS), the Lawton Instrumental ADL (IADL) Scale, and the Hachinski Ischemia Scale (Hachinski). Receiver operating characteristic (ROC) curves were calculated to determine the diagnostic accuracy of Cys C and HDL levels in distinguishing patients with dementia from healthy subjects. Results: We found that plasma Cys C levels were higher, but HDL levels were lower in AD and VaD patients respectively, compared to healthy control subjects. Yet, Cys C levels were highest among patients with VaD. Interestingly, plasma Cys C levels were significantly correlated with IADL Scale scores. In addition, the ROC curves for Cys C (area under the curve, AUC 0.816 for AD, AUC 0.841 for VaD) and HDL (AUC 0.800 for AD, AUC 0.731 for VaD) exhibited potential diagnostic value in distinguishing AD/VaD patients from healthy subjects. While the ROC curve for the combination of Cys C and HDL (AUC 0.873 for AD, AUC 0.897 for VaD) showed higher diagnostic accuracy in distinguishing AD/VaD patients from healthy subjects than the separate curves for each parameter. Conclusions: Our findings suggest that the inflammatory mediators Cys C and HDL may play important roles in the pathogenesis of dementia, and plasma Cys C and HDL levels may be useful screening tools for differentiating AD/VaD patients from healthy subjects.
HIGHLIGHTS: Plasma Cys C levels were higher in patients with AD/VaD than in healthy subjects.Plasma HDL levels were lower in patients with AD/VaD than in healthy subjects.Plasma Cys C levels were significantly correlated with dementia.The ROC curve for the combination of Cys C and HDL showed potential diagnostic value in distinguishing AD/VaD from healthy subjects.

PMID: 28223934 [PubMed - in process]

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