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 16 min ago

Special Issue: "Perinatal therapeutics: Novel approaches to target adverse pregnancy outcomes and shape maternal and offspring health".

Tue, 10/16/2018 - 07:15
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Special Issue: "Perinatal therapeutics: Novel approaches to target adverse pregnancy outcomes and shape maternal and offspring health".

Pharmacol Res. 2018 Oct 12;:

Authors: Bourque SL, Goulopoulou S

PMID: 30321598 [PubMed - as supplied by publisher]

Stability of Locking Plate and Compression Screws for Lapidus Arthrodesis: A Biomechanical Comparison of Plate Position.

Tue, 10/16/2018 - 07:15
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Stability of Locking Plate and Compression Screws for Lapidus Arthrodesis: A Biomechanical Comparison of Plate Position.

J Foot Ankle Surg. 2018 May - Jun;57(3):466-470

Authors: Drummond D, Motley T, Kosmopoulos V, Ernst J

Abstract
Lapidus (first tarsometatarsal joint) arthrodesis is an established and widely used procedure for the management of moderate to severe hallux valgus, especially in cases involving hypermobility of the first tarsometatarsal joint. Multiple fixation methods are available, and several previous investigations have studied the relative strengths of these methods, including dorsomedial and plantar plating comparisons. However, these studies compared plates of varying designs and mechanical properties and used varying modes of compression and interfragmentary screw techniques. The present study mechanically investigated the resulting motion, stiffness, and strength of identical locking plate constructs fixed at various anatomic positions around the first tarsometatarsal joint. In a bench-top study, fourth-generation composite bones were divided into 3 fixation groups, each having identical interfragmentary screw applications, and randomized to 1 of 3 plate positions: dorsal, medial, or plantar. The plates applied in each case were identical locking plates, precontoured to fit the anatomy. Each construct was experimentally tested using a cantilever bending approach. The outcomes obtained were stiffness, yield force, displacement at yield, ultimate force, and displacement at ultimate force. The plantar plate position showed superior initial stiffness and force to ultimate failure. The plantar and medial plate positions exhibited superior force to yield. The medial plate position was superior regarding displacement tolerated before the yield point and catastrophic failure. The dorsal plate position was not superior for any outcome measured. Plantar and medial plating each offered biomechanical benefits. Clinical studies using similarly matched constructs are required to show whether these findings translate into improved clinical outcomes.

PMID: 29472168 [PubMed - indexed for MEDLINE]

What's the influence of social interactions on substance use and treatment initiation? A prospective analysis among substance-using probationers.

Sun, 10/14/2018 - 07:07
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What's the influence of social interactions on substance use and treatment initiation? A prospective analysis among substance-using probationers.

Addict Behav. 2018 Oct 01;89:143-150

Authors: Spohr SA, Livingston MD, Taxman FS, Walters ST

Abstract
INTRODUCTION: A person's social environment greatly affects the likelihood of substance use, which in turn affects risk for criminal behavior. This study examined how people's social environment early in probation contributed to later substance use and treatment outcome, both of which predict probation success.
METHODS: Data were analyzed from a randomized controlled trial of substance-using probationers (N = 316). Moderation analyses assessed the relationship between social support near the start of probation and substance use and treatment initiation after 2 and 6 months.
RESULTS: Abstinence at 2-months was associated with better baseline measures of support quality (more positive support, fewer negative interactions, and reduced conflict). Similar associations were identified for 6-month abstinence including better baseline quality, more positive support, and less family and peer conflict. There were no significant associations between the baseline social support and treatment initiation at 2-months. However, poorer baseline quality support and more negative interactions predicted increased treatment initiation at 6-months.
CONCLUSIONS: Social support and the quality of an offender's social network have important implications for substance use and treatment compliance. The criminal justice system emphasizes ways to minimize negative social influences among offenders (i.e., probation conditions that limit contact with other offenders). However, this study suggests that behavior change is a function of not only reducing negative influences but also increasing positive or good quality supports.

PMID: 30316139 [PubMed - as supplied by publisher]

Dopamine D3 receptor partial agonist LS-3-134 attenuates cocaine-motivated behaviors.

Fri, 10/12/2018 - 07:00
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Dopamine D3 receptor partial agonist LS-3-134 attenuates cocaine-motivated behaviors.

Pharmacol Biochem Behav. 2018 Oct 08;:

Authors: Powell GL, Bonadonna JP, Vannan A, Mach RH, Luedtke RR, Neisewander JL

Abstract
AIMS: The dopamine D3 receptor (D3R) is a pharmacotherapeutic target for drug dependence. We have successfully imaged human D3Rs using radiolabeled LS-3-134, an arylamide phenylpiperazine with moderate selectivity for the D3R over D2R and low efficacy at the D2 and D3R. In this study, we screened for effects of LS-3-134 as a potential anti-cocaine therapeutic.
METHODS: Male rats were pretreated with LS-3-134 (0, 1.0, 3.2, or 5.6 mg/kg, IP) 15 min prior to tests for its effects on spontaneous and cocaine-induced locomotion. We next investigated the effects of LS-3-134 (0, 1.0, 3.2, 5.6, or 10.0 mg/kg, IP) on operant responding on a multiple variable-interval (VI) 60-second schedule with alternating cocaine (0.375 mg/kg, IV) and sucrose (45 mg) reinforcer components. Additionally, we tested LS-3-134 (5.6 mg/kg, IP) effects on a progressive ratio (PR) schedule of cocaine reinforcement, on extinction of cocaine-seeking behavior, and on reinstatement of extinguished cocaine-seeking behavior by cocaine-associated light/tone cues.
RESULTS: LS-3-134 did not alter spontaneous locomotion, but reduced cocaine-induced locomotion, break points on the high-effort progressive ratio schedule of reinforcement, and responding during extinction and cue reinstatement. In contrast, LS-3-134 did not alter cocaine or sucrose reinforcement on the low-effort multiple VI 60-second schedule.
CONCLUSIONS: The effects of LS-3-134 are similar to other dopamine D3 low efficacy partial agonists and antagonists in attenuating cocaine intake under high effort schedules of reinforcement and in attenuating cocaine-seeking behavior elicited by cocaine-associated cues. These findings are consistent with the anti-craving profile of other dopamine D3 drugs.

PMID: 30308214 [PubMed - as supplied by publisher]

Recent Progress in European Advanced Therapy Medicinal Products and Beyond.

Wed, 10/10/2018 - 07:55
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Recent Progress in European Advanced Therapy Medicinal Products and Beyond.

Front Bioeng Biotechnol. 2018;6:130

Authors: Yu TTL, Gupta P, Ronfard V, Vertès AA, Bayon Y

Abstract
Cell- and gene-based therapies form one of the pillars of regenerative medicine. They have the potential to transform quality of life and improve the health status of patients with genetic and cellular defects, including genetic diseases, neurodegenerative diseases and tissue malignancies, amongst others. Despite numerous challenges, in the last decade, tremendous unified efforts by research and clinical scientists in academic, translational and industry settings have resulted in tangible outcomes in the form of many marketing authorizations and approved commercial firsts, such as Glybera®, Kymriah®, YESCARTA®, Holoclar®, and Luxturna™. This report presents a succinct analysis of developments in the regenerative medicine landscape, including immuno-oncology, with a focus on the European Union and examples of clinical and commercial successes and failures. The factors that led to these exciting developments in immune-oncology are also considered. Concurrently, several key issues, spanning from the identification of unmet clinical need, associated challenges, economic evaluation to policy improvements are emphasized. Furthermore, industry insights encompassing the five-dimensional research and development framework for the focused development of medicine, pricing and reimbursement issues, technology adoption and permeation of innovative advanced therapy medicinal products in the clinical set up are reflected upon, following elaborate discussions that transpired in different thematic tracks of Tissue Engineering & Regenerative Medicine International Society European Chapter 2017 Industry Symposium.

PMID: 30298129 [PubMed]

Blood-based biomarkers for Alzheimer disease: mapping the road to the clinic.

Wed, 10/10/2018 - 07:55
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Blood-based biomarkers for Alzheimer disease: mapping the road to the clinic.

Nat Rev Neurol. 2018 Oct 08;:

Authors: Hampel H, O'Bryant SE, Molinuevo JL, Zetterberg H, Masters CL, Lista S, Kiddle SJ, Batrla R, Blennow K

Abstract
Biomarker discovery and development for clinical research, diagnostics and therapy monitoring in clinical trials have advanced rapidly in key areas of medicine - most notably, oncology and cardiovascular diseases - allowing rapid early detection and supporting the evolution of biomarker-guided, precision-medicine-based targeted therapies. In Alzheimer disease (AD), breakthroughs in biomarker identification and validation include cerebrospinal fluid and PET markers of amyloid-β and tau proteins, which are highly accurate in detecting the presence of AD-associated pathophysiological and neuropathological changes. However, the high cost, insufficient accessibility and/or invasiveness of these assays limit their use as viable first-line tools for detecting patterns of pathophysiology. Therefore, a multistage, tiered approach is needed, prioritizing development of an initial screen to exclude from these tests the high numbers of people with cognitive deficits who do not demonstrate evidence of underlying AD pathophysiology. This Review summarizes the efforts of an international working group that aimed to survey the current landscape of blood-based AD biomarkers and outlines operational steps for an effective academic-industry co-development pathway from identification and assay development to validation for clinical use.

PMID: 30297701 [PubMed - as supplied by publisher]

The effect of age, sex and strains on the performance and outcome in animal models of stroke.

Sun, 10/07/2018 - 07:29
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The effect of age, sex and strains on the performance and outcome in animal models of stroke.

Neurochem Int. 2018 Oct 03;:

Authors: Zhang H, Lin S, Chen X, Gu L, Zhu X, Zhang Y, Reyes K, Wang B, Jin K

Abstract
Stroke is one of the leading causes of death worldwide, and the majority of cerebral stroke is caused by occlusion of cerebral circulation, which eventually leads to brain infarction. Although stroke occurs mainly in the aged population, most animal models for experimental stroke in vivo almost universally rely on young-adult rodents for the evaluation of neuropathological, neurological, or behavioral outcomes after stroke due to their greater availability, lower cost, and fewer health problems. However, it is well established that aged animals differ from young animals in physiology, neurochemistry, and behavior. Stroke-induced changes are more pronounced with advancing age. Therefore, the overlooked role of age in animal models of stroke could impact on data quality and hinder the translation of rodent models to humans. In addition to aging, other factors also influence the performance after ischemic stroke. In this article, we summarize the differences between young and aged animals, the impact of age, sex and animal strains on performance and outcome in the animal models of stroke and emphasize age as a key factor in preclinical stroke studies in animal models of stroke.

PMID: 30291954 [PubMed - as supplied by publisher]

A systematic evaluation of effect of adherence patterns on the sample size and power of a clinical study.

Sun, 10/07/2018 - 07:29
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A systematic evaluation of effect of adherence patterns on the sample size and power of a clinical study.

CPT Pharmacometrics Syst Pharmacol. 2018 Oct 05;:

Authors: Mallayasamy S, Chaturvedula A, Blaschke T, Fossler MJ

Abstract
The objective of our study was to evaluate the effect of adherence patterns on the sample size and power of a clinical trial. Simulations from a population pharmacokinetic (PK)-pharmacodynamic (PD) model linked to an adherence model were used. Four types of drug characteristics such as long (~35 hr) and short (~12 hr) half-life in combination with earlier or delayed time to reach steady-state PD endpoints were studied. Adherence patterns were simulated using Markov chains. Our results clearly demonstrate the significant impact of varying levels and patterns of non-adherence on the sample size and power of a study. For drugs with short-half-lives the evidence to support efficacy could be diluted by various patterns of non-adherence that would make its efficacy indistinguishable from the response to placebo. Prospectively utilizing clinical trial simulations with thorough incorporation of various adherence patterns would provide valuable information when designing a trial.

PMID: 30291680 [PubMed - as supplied by publisher]

Lipopolysaccharide Challenge Reveals Hypothalamic-Pituitary-Adrenal Axis Dysfunction in Murine Systemic Lupus Erythematosus.

Sat, 10/06/2018 - 07:29
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Lipopolysaccharide Challenge Reveals Hypothalamic-Pituitary-Adrenal Axis Dysfunction in Murine Systemic Lupus Erythematosus.

Brain Sci. 2018 Oct 04;8(10):

Authors: Pham GS, Mathis KW

Abstract
Crosstalk between the brain and innate immune system may be dysregulated in systemic lupus erythematosus (SLE), a chronic autoimmune disease that presents with dysautonomia and aberrant inflammation. The hypothalamic-pituitary-adrenal (HPA) axis is an endogenous neuro-endocrine-immune pathway that can regulate inflammation following activation of vagal afferents. We hypothesized that chronic inflammatory processes in SLE are in part due to HPA axis dysfunction, at the level of either the afferent vagal-paraventricular nuclei (PVN) interface, the anterior pituitary, and/or at the adrenal glands. To study this, we challenged female control and SLE mice with lipopolysaccharide (LPS) and measured c-Fos expression as an index of neuronal activation, plasma adrenocorticotrophic hormone (ACTH) as an index of anterior pituitary function, and plasma corticosterone as an index of adrenal function. We found that c-Fos expression in the PVN, and plasma ACTH and corticosterone were comparable between unchallenged SLE and control mice. PVN c-Fos was increased similarly in control and SLE mice three hours after LPS challenge; however, there were no changes in plasma ACTH amongst any experimental groups post inflammatory challenge. Plasma corticosterone was markedly increased in LPS-challenged SLE mice compared to their vehicle-treated counterparts, but not in controls. Paradoxically, following LPS challenge, brain and spleen TNF-α were elevated in LPS-challenged SLE mice despite heightened plasma corticosterone. This suggests that, despite normal c-Fos expression in the PVN and activation of the HPA axis following LPS challenge, this cumulative response may not adequately defend SLE mice against inflammatory stimuli, leading to abnormally heightened innate immune responses and peripheral inflammation.

PMID: 30287776 [PubMed]

Quality and the Health System: Becoming a High Reliability Organization.

Sat, 10/06/2018 - 07:29
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Quality and the Health System: Becoming a High Reliability Organization.

Anesthesiol Clin. 2018 Jun;36(2):217-226

Authors: Gaw M, Rosinia F, Diller T

Abstract
Since the publication of "To Err is Human" in 1999, substantial efforts have been made within the health care industry to improve quality and patient safety. Although improvements have been made, recent estimates continue to indicate the need for a marked change in approach. In this article, the authors discuss the concepts and characteristics of high reliability organizations, safety culture, and clinical microsystems. The health care delivery system must move beyond current quality and patient safety approaches and fully engage in these new concepts to transform health care system performance.

PMID: 29759284 [PubMed - indexed for MEDLINE]

Microbial enrichment and gene functional categories revealed on the walls of a spent fuel pool of a nuclear power plant.

Fri, 10/05/2018 - 07:28
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Microbial enrichment and gene functional categories revealed on the walls of a spent fuel pool of a nuclear power plant.

PLoS One. 2018;13(10):e0205228

Authors: Silva R, Almeida DM, Cabral BCA, Dias VHG, Mello ICTE, Ürményi TP, Woerner AE, Neto RSM, Budowle B, Nassar CAG

Abstract
Microorganisms developing in the liner of the spent fuel pool (SFP) and the fuel transfer channel (FTC) of a Nuclear Power Plant (NPP) can form high radiation resistant biofilms and cause corrosion. Due to difficulties and limitations to obtain large samples from SFP and FTC, cotton swabs were used to collect the biofilm from the wall of these installations. Molecular characterization was performed using massively parallel sequencing to obtain a taxonomic and functional gene classification. Also, samples from the drainage system were evaluated because microorganisms may travel over the 12-meter column of the pool water of the Brazilian Nuclear Power Plant (Angra1), which has been functioning since 1985. Regardless of the treatment of the pool water, our data reveal the unexpected presence of Fungi (Basidiomycota and Ascomycota) as the main contaminators of the SFP and FTC. Ustilaginomycetes (Basidiomycota) was the major class contributor (70%) in the SFP and FTC reflecting the little diversity in these sites; nevertheless, Proteobacteria, Actinobacteria, Firmicutes (Bacilli) were present in small proportions. Mapping total reads against six fungal reference genomes indicate that there is, in fact, a high abundance of fungal sequences in samples collected from SFP and FTC. Analysis of the ribosomal internal transcribed spacer (ITS) 1 and 2 regions and the protein found in the mitochondria of eukaryotic cells, cytochrome b (cytb) grouped our sample fungi in the clade 7 as Ustilago and Pseudozyma. In contrast, in the drainage system, Alphaproteobacteria were present in high abundances (55%). The presence of Sphingopyxis, Mesorhizobium, Erythrobacter, Sphingomonas, Novosphingobium, Sphingobium, Chelativorans, Oceanicaulis, Acidovorax, and Cyanobacteria was observed. Based on genomic annotation data, the assessment of the biological function found a higher proportion of protein-coding sequences related to respiration and protein metabolism in SFP and FTC samples. The knowledge of this biological inventory present in the system may contribute to further studies of potential microorganisms that might be useful for bioremediation of nuclear waste.

PMID: 30286173 [PubMed - in process]

CRISPR deletion of MIEN1 in breast cancer cells.

Fri, 10/05/2018 - 07:28
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CRISPR deletion of MIEN1 in breast cancer cells.

PLoS One. 2018;13(10):e0204976

Authors: Van Treuren T, Vishwanatha JK

Abstract
Migration and Invasion Enhancer (MIEN1) is an oncogene which is involved in facilitating motility of cancer cells through actin dynamics and gene expression. Increased MIEN1 expression in many types of tumors leads to disease progression and metastatic propensity. It is unclear precisely how MIEN1 is involved in this process and more studies are required to tease out the mechanisms. Here we show that Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR) genome editing effectively produced specific genomic deletions in the MIEN1 gene which led to the abrogation of its expression in breast cancer cells. The single guide RNAs (sgRNAs) mediated targeting of MIEN1 was specific and none of the clones screened for off-target cleavage revealed any insertions or deletions (indels). Additionally, disruption of the MIEN1 gene did not alter the cell morphology, growth, proliferation or survival. Knocking out MIEN1 in these breast cancer cells will allow future studies to determine the exact role MIEN1 plays in breast tumor metastasis, which might lead to production of novel therapeutics to treat this and other cancers.

PMID: 30286132 [PubMed - in process]

Recurrent Granuloma Gluteale Infantum Secondary to Fecal Overflow Incontinence.

Fri, 10/05/2018 - 07:28
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Recurrent Granuloma Gluteale Infantum Secondary to Fecal Overflow Incontinence.

Case Rep Dermatol. 2018 May-Aug;10(2):203-207

Authors: Ingersoll Z, Garza-Chapa JI, Pham R, Malouf P, Susa J, Weis S

Abstract
Granuloma gluteale infantum is a rare pediatric dermatological disorder of uncertain etiology. Suggested causes include fluorinated corticosteroids, Candida albicans, and irritant contact dermatitis. We present the case of a 3-year-old boy with recurrent episodes of granuloma gluteale infantum which resolved with treatment of his fecal overflow incontinence. As each recurrence correlated with a relapse of overflow incontinence, in this case the cause was irritant contact dermatitis from the liquid stool. This is the first reported case of recurrent granuloma gluteale infantum.

PMID: 30283312 [PubMed]

FRET study in oligopeptide-linked donor-acceptor system in PVA matrix.

Fri, 10/05/2018 - 07:28
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FRET study in oligopeptide-linked donor-acceptor system in PVA matrix.

Methods Appl Fluoresc. 2016 12 13;4(4):047002

Authors: Shah S, Mandecki W, Li J, Gryczynski Z, Borejdo J, Gryczynski I, Fudala R

Abstract
An oligopeptide: Lys-Gly-Pro-Arg-Ser-Leu-Ser-Gly-Lys-NH2, cleaved specifically by a matrix metalloproteinase 9 (MMP-9) at the Ser-Leu bond, was labeled on the ε-NH2 groups of lysine with donor (5, 6 TAMRA) and acceptor (HiLyte647) dye. The donor control was a peptide labeled with 5, 6 TAMRA only on the C-terminal lysine, and the acceptor control was free HiLyte647. Following three products were studied by dissolving in 10% (w/w) poly(vinyl alcohol) and dried on glass slides forming 200 micron films. Absorption spectra of the films show full additivity of donor and acceptor absorptions. A strong Fluorescence Resonance Energy Transfer (FRET) with an efficiency of about 85% was observed in the fluorescence emission and excitation spectra. The lifetime of the donor was shorter and heterogeneous compared with the donor control.

PMID: 28192309 [PubMed - indexed for MEDLINE]

Fluorescence lifetime imaging with time-gated detection of hyaluronidase using a long lifetime azadioxatriangulenium (ADOTA) fluorophore.

Fri, 10/05/2018 - 07:28
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Fluorescence lifetime imaging with time-gated detection of hyaluronidase using a long lifetime azadioxatriangulenium (ADOTA) fluorophore.

Methods Appl Fluoresc. 2016 11 17;4(4):047001

Authors: Chib R, Requena S, Mummert M, Strzhemechny YM, Gryczynski I, Borejdo J, Gryczynski Z, Fudala R

Abstract
A fluorescence lifetime imaging probe with a long lifetime was used in combination with time-gating for the detection of hyaluronidase using hyaluronic acid as the probe template. This probe was developed by heavily labeling hyaluronic acid with long lifetime azadioxatriangulenium fluorophores (ADOTA). We used this probe to image hyaluronidase produced by DU-145 prostate cancer cells.

PMID: 28192308 [PubMed - indexed for MEDLINE]

Contraceptive Use Effectiveness and Pregnancy Prevention Information Preferences Among Heterosexual and Sexual Minority College Women.

Thu, 10/04/2018 - 07:28
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Contraceptive Use Effectiveness and Pregnancy Prevention Information Preferences Among Heterosexual and Sexual Minority College Women.

Womens Health Issues. 2018 Jul - Aug;28(4):342-349

Authors: Blunt-Vinti HD, Thompson EL, Griner SB

Abstract
BACKGROUND: Previous research shows that sexual minority women have higher rates of unintended pregnancy than heterosexual women, but has not considered the wide range of contraceptive method effectiveness when exploring this disparity. We examine contraceptive use effectiveness and desire for pregnancy prevention information among college women across sexual orientation identity as a risk factor for unintended pregnancy.
METHODS: Using the National College Health Assessment Fall 2015 dataset, restricted to women who reported engaging in vaginal sex and not wanting to be pregnant (N = 6,486), logistic regression models estimated the odds of contraceptive method effectiveness and desire for pregnancy prevention information by sexual orientation.
RESULTS: Most women (57%) reported using a moderately effective contraceptive method (e.g., pill, patch, ring, shot) at last vaginal sex. Compared with heterosexual women, bisexual (adjusted odds ratio [aOR], 0.48; 95% confidence interval [CI], 0.37-0.62), lesbian (aOR, 0.03; 95% CI, 0.02-0.06), pansexual/queer (aOR, 0.38; 95% CI, 0.25-.56), and other (aOR, 0.50; 95% CI, 0.30-0.81) women were significantly less likely to have used a moderately effective method compared with no method. Only 9% of the sample used a highly effective method; asexual (aOR, 0.58; 95% CI, 0.37-0.92) and lesbian (aOR, 0.07; 95% CI, 0.03-0.20) women were significantly less likely than heterosexual women to have used these methods. Pansexual/queer and bisexual women were more likely than heterosexual women to desire pregnancy prevention information.
CONCLUSIONS: Several groups of sexual minority women were less likely than heterosexual women to use highly or moderately effective contraceptive methods, putting them at increased risk for unintended pregnancy, but desired pregnancy prevention information. These findings bring attention to the importance of patient-centered sexual and reproductive care to reduce unintended pregnancy.

PMID: 29666034 [PubMed - indexed for MEDLINE]

Vascular endothelium: a potential source of podocalyxin in serum from pregnancies with preeclampsia.

Thu, 10/04/2018 - 07:28
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Vascular endothelium: a potential source of podocalyxin in serum from pregnancies with preeclampsia.

J Hypertens. 2017 11;35(11):2176-2177

Authors: Goulopoulou S

PMID: 28953590 [PubMed - indexed for MEDLINE]

Humanin Attenuates NMDA-Induced Excitotoxicity by Inhibiting ROS-dependent JNK/p38 MAPK Pathway.

Wed, 10/03/2018 - 07:29
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Humanin Attenuates NMDA-Induced Excitotoxicity by Inhibiting ROS-dependent JNK/p38 MAPK Pathway.

Int J Mol Sci. 2018 Sep 29;19(10):

Authors: Yang X, Zhang H, Wu J, Yin L, Yan LJ, Zhang C

Abstract
Humanin (HN) is a novel 24-amino acid peptide that protects neurons against N-methyl-d-aspartate (NMDA)-induced toxicity. However, the contribution of the different mitogen-activated protein kinases (MAPKs) signals to HN neuroprotection against NMDA neurotoxicity remains unclear. The present study was therefore aimed to investigate neuroprotective mechanisms of HN. We analyzed intracellular Ca2+ levels, reactive oxygen species (ROS) production, and the MAPKs signal transduction cascade using an in vitro NMDA-mediated excitotoxicity of cortical neurons model. Results showed that: (1) HN attenuated NMDA-induced neuronal insults by increasing cell viability, decreasing lactate dehydrogenase (LDH) release, and increasing cell survival; (2) HN reversed NMDA-induced increase in intracellular calcium; (3) pretreatment by HN or 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA-AM), an intracellular calcium chelator, decreased ROS generation after NMDA exposure; (4) administration of HN or N-Acetyl-l-cysteine (NAC), a ROS scavenger, inhibited NMDA-induced JNK and p38 MAPK activation. These results indicated that HN reduced intracellular elevation of Ca2+ levels, which, in turn, inhibited ROS generation and subsequent JNK and p38 MAPK activation that are involved in promoting cell survival in NMDA-induced excitotoxicity. Therefore, the present study suggests that inhibition of ROS-dependent JNK/p38 MAPK signaling pathway serves an effective strategy for HN neuroprotection against certain neurological diseases.

PMID: 30274308 [PubMed - in process]

Limb Ischemic Conditioning Improved Cognitive Deficits via eNOS-Dependent Augmentation of Angiogenesis after Chronic Cerebral Hypoperfusion in Rats.

Tue, 10/02/2018 - 16:31

Limb Ischemic Conditioning Improved Cognitive Deficits via eNOS-Dependent Augmentation of Angiogenesis after Chronic Cerebral Hypoperfusion in Rats.

Aging Dis. 2018 Oct;9(5):869-879

Authors: Ren C, Li N, Li S, Han R, Huang Q, Hu J, Jin K, Ji X

Abstract
Intracranial and extracranial arterial stenosis, the primary cause of chronic cerebral hypoperfusion (CCH), is a critical reason for the pathogenesis of vascular dementia and Alzheimer's disease characterized by cognitive impairments. Our previous study demonstrated that limb remote ischemic conditioning (LRIC) improved cerebral perfusion in intracranial arterial stenosis patients. The current study aimed to test whether LRIC promotes angiogenesis and increases phosphorylated endothelial nitric oxide synthase (p-eNOS) activity in CCH rat model. Adult male Sprague-Dawley rats were randomly assigned to three different groups: sham group, bilateral carotid artery occlusion (2VO) group and 2VO+LRIC group. Cerebral Blood Flow (CBF) was measured with laser speckle contrast imager at 4 weeks. Cognitive testing was performed at four and six weeks after 2VO surgery. We demonstrated that LRIC treatment increased cerebral perfusion and improved the CCH induced spatial learning and memory impairment. Immunohistochemistry confirmed that LRIC prevented cell death in the CA1 region, and increased the number of vessels and angiogenesis in the hippocampus after 2VO. Western blot analysis shows that LRIC therapy significantly increased p-eNOS expression in the hippocampus when compared with 2VO rats. Moreover, eNOS inhibitor reduced the effect of LRIC on angiogenesis in the hippocampus and spatial learning and memory function. Our data suggested that LRIC promoted angiogenesis, which is mediated, in part, by eNOS/NO.

PMID: 30271664 [PubMed]

Androgens modulate chronic intermittent hypoxia effects on brain and behavior.

Mon, 10/01/2018 - 07:28
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Androgens modulate chronic intermittent hypoxia effects on brain and behavior.

Horm Behav. 2018 Sep 27;:

Authors: Snyder B, Duong P, Trieu J, Cunningham RL

Abstract
Sleep apnea is associated with testosterone dysregulation as well as increased risk of developing neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). A rodent model of the hypoxic events of sleep apnea, chronic intermittent hypoxia (CIH), has been previously documented to impair cognitive function and elevate oxidative stress in male rats, while simultaneously decreasing testosterone. Therefore, androgens may modulate neuronal function under CIH. To investigate the role of androgens during CIH, male rats were assigned to one of four hormone groups: 1) gonadally intact, 2) gonadectomized (GDX), 3) GDX + testosterone (T) supplemented, or 4) GDX + dihydrotestosterone (DHT) supplemented. Each group was exposed to either normal room air or CIH exposure for one week, followed by memory and motor task assessments. Brain regions associated with AD and PD (entorhinal cortex, dorsal hippocampus, and substantia nigra) were examined for oxidative stress and inflammatory markers, key characteristics of AD and PD. Gonadally intact rats exhibited elevated oxidative stress due to CIH, but no significant memory and motor impairments. GDX increased memory impairments, regardless of CIH exposure. T preserved memory function and prevented detrimental CIH-induced changes. In contrast, DHT was not protective, as evidenced by exacerbated oxidative stress under CIH. Further, CIH induced significant spatial memory impairment in rats administered DHT. These results indicate androgens can have both neuroprotective and detrimental effects under CIH, which may have clinical relevance for men with untreated sleep apnea.

PMID: 30268884 [PubMed - as supplied by publisher]

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