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: 45 min 30 sec ago

The Impact of Grantsmanship Self-Efficacy on Early Stage Investigators of The National Research Mentoring Network Steps Toward Academic Research (NRMN STAR).

3 hours 45 min ago
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The Impact of Grantsmanship Self-Efficacy on Early Stage Investigators of The National Research Mentoring Network Steps Toward Academic Research (NRMN STAR).

Ethn Dis. 2020;30(1):75-82

Authors: Thorpe RJ, Vishwanatha JK, Harwood EM, Krug EL, Unold T, Boman KE, Jones HP

Abstract
The NRMN STAR program was created to address the persistent underrepresentation in grant submissions and receipt of National Institutes of Health (NIH) awards by racial/ethnic minority groups. In our current study, we assessed program impact on trainees' self-efficacy related to grant writing. The program was conducted with two cohorts: one in June 2014 and one in June 2015. We used a 19-item grant writing self-efficacy scale drawn from the 88-item Clinical Research Assessment Inventory of three domains (conceptualizing, designing, and funding a study) to predict whether self-efficacy influences researchers' grant submissions. Trainees were assessed prior to and following program completion with subsequent assessments at 6 and 12 months beyond participation. The majority of trainees were Black (62%), female (62%), and had obtained a PhD (90%). More than half (52%) were assistant professors and 57% had none or <1 year of research experience beyond postdoctoral training. However, 24% of trainees reported no postdoctoral research training. NRMN STAR trainees' self-efficacy significantly improved on all three domains exhibiting a 2.0-point mean change score on two domains (conceptualizing and design) and 3.7 point mean change score on the domain, funding a study. Findings suggest that NRMN's STAR provides impactful, confidence-building training for diverse, early stage investigators with little-to-no skills, experiences, or low self-efficacy in writing research grants.

PMID: 31969786 [PubMed - in process]

Knee osteoarthritis, potential mediators, and risk of all-cause mortality: data from the Osteoarthritis Initiative.

Wed, 01/22/2020 - 05:32

Knee osteoarthritis, potential mediators, and risk of all-cause mortality: data from the Osteoarthritis Initiative.

Arthritis Care Res (Hoboken). 2020 Jan 21;:

Authors: Wang Y, Nguyen UDT, Lane NE, Lu N, Wei J, Lei G, Zeng C, Zhang Y

Abstract
OBJECTIVE: To assess the relation of symptomatic knee osteoarthritis (OA), knee pain, and radiographic knee OA to all-cause mortality and identify mediators in the causal pathway.
METHODS: Participants from the Osteoarthritis Initiative were divided into four groups: (1) symptomatic knee OA (i.e., both radiographic knee OA [Kellgren and Lawrence grade ≥2] and knee pain); (2) knee pain only; (3) radiographic knee OA only; and (4) neither radiographic knee OA nor knee pain. We examined the relation of knee OA status to all-cause mortality using a multivariable Cox-proportional model and assessed the extent to which the association was mediated by disability, physical (PCS) and mental component summary scores (MCS) of quality of life (QoL), and oral pain-relief medications (i.e. nonsteroidal anti-inflammatory drugs and opioids) use.
RESULTS: Among 4,796 participants, 282 died over the 96-month follow-up period. Compared with those with neither radiographic knee OA nor knee pain, multivariable-adjusted hazard ratios (HRs) of mortality were 2.2 (95% confidence interval [CI]: 1.6-3.1) for symptomatic knee OA, 0.9 (95%CI: 0.6-1.4) for knee pain only, and 2.0 (95%CI: 1.4-2.9) for radiographic knee OA only, respectively. Indirect effects (HRs) of symptomatic knee OA on mortality via disability and PCS of QoL were 1.1 (95%CI: 1.0-1.4) and 1.2 (95%CI: 1.0-1.4), respectively. No apparent mediation effect was observed through either MCS of QoL or oral pain-relief medications use.
CONCLUSION: Participants with either symptomatic or radiographic knee OA were at an increased risk of all-cause mortality. Increased risk of mortality from symptomatic knee OA was partially mediated through its effect on disability and PCS of QoL.

PMID: 31961495 [PubMed - as supplied by publisher]

Identification of Binding Sites for Efflux Pump Inhibitors of the AcrAB-TolC Component AcrA.

Wed, 01/22/2020 - 05:32
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Identification of Binding Sites for Efflux Pump Inhibitors of the AcrAB-TolC Component AcrA.

Biophys J. 2019 02 19;116(4):648-658

Authors: Darzynkiewicz ZM, Green AT, Abdali N, Hazel A, Fulton RL, Kimball J, Gryczynski Z, Gumbart JC, Parks JM, Smith JC, Zgurskaya HI

Abstract
The overexpression of multidrug efflux pumps is an important mechanism of clinical resistance in Gram-negative bacteria. Recently, four small molecules were discovered that inhibit efflux in Escherichia coli and interact with the AcrAB-TolC efflux pump component AcrA. However, the binding site(s) for these molecules was not determined. Here, we combine ensemble docking and molecular dynamics simulations with tryptophan fluorescence spectroscopy, site-directed mutagenesis, and antibiotic susceptibility assays to probe binding sites and effects of binding of these molecules. We conclude that clorobiocin and SLU-258 likely bind at a site located between the lipoyl and β-barrel domains of AcrA.

PMID: 30691677 [PubMed - indexed for MEDLINE]

Copper-tolfenamic acid: evaluation of stability and anti-cancer activity.

Wed, 01/22/2020 - 05:32
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Copper-tolfenamic acid: evaluation of stability and anti-cancer activity.

Invest New Drugs. 2019 02;37(1):27-34

Authors: Hurtado M, Sankpal UT, Chhabra J, Brown DT, Maram R, Patel R, Gurung RK, Simecka J, Holder AA, Basha R

Abstract
The non-steroidal anti-inflammatory drug, Tolfenamic acid (TA) acts as an anti-cancer agent in several adult and pediatric cancer models. Copper (Cu) is an important element with multiple biological functions and has gained interest in medical applications. Recently, [Cu(TA)2(bpy)] (Cu-TA) has been synthesized in order to enhance therapeutic activity. In this study, we synthesized Cu-TA using an established method, characterized it by UV visible spectroscopy and Fourier-transform infrared spectroscopy (FTIR), and tested its anti-cancer activity using twelve cell lines representing various cancers, such as Ewing sarcoma, glioblastoma, medulloblastoma, neuroblastoma, pancreatic and prostate. The anti-proliferative activity of Cu-TA was determined at 48 h post-treatment and compared with the parental compound, TA. The IC50 values were calculated using GraphPad Prism software. The biological stability of Cu-TA was evaluated using twelve-month-old powder and six-month-old stock solution. Cardiomyocytes (H9C2) were used to test the cytotoxicity in non-malignant cells. Cu-TA showed higher anti-proliferative activity, and the IC50 values were 30 to 80% lower when compared with TA. H9C2 cells were non-responsive to Cu-TA, suggesting that it is selective towards malignant cells. Comparison of the twelve-month-old powder and six-month-old stock solution using the Panc1 cell line showed similar IC50 values (<5% variation), confirming the stability of Cu-TA either in powder or solution form. These findings demonstrate the potential of Cu-TA as an effective anti-cancer agent. Further studies to delineate the detailed mechanism of action of Cu-TA for specific cancer model are underway.

PMID: 29761244 [PubMed - indexed for MEDLINE]

Muscular architecture of the popliteus muscle and the basic science implications.

Mon, 01/20/2020 - 07:33
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Muscular architecture of the popliteus muscle and the basic science implications.

Knee. 2020 Jan 15;:

Authors: Wood A, Boren M, Dodgen T, Wagner R, Patterson RM

Abstract
BACKGROUND: The function of the popliteus muscle is largely treated as a static stabilizer and has a lack of basic muscular architectural data to enable study of its dynamic function. A large volume of literature supports its static function and the essential need for reconstruction in the posterolateral knee when injured to restore knee stability.
HYPOTHESIS/PURPOSE: We hypothesize that the popliteus muscle is more significant as a dynamic presence in the knee.
METHODS: A collection of popliteus architectural data was collected from 28 cadaver specimens (mean (SD) 76 years (11)). Physiological cross-sectional area of the popliteus and semimembranosus muscles were calculated from muscle volume and fiber length to power future muscle force prediction models. Posterior knee muscle trajectories were measured with respect to the longitudinal axis of the tibia. A 2-tailed T test was performed.
RESULTS: Significant differences between males and females were found for both the popliteus (p = 1.1E-05) and semimembranosus (p = 2.0E-05) muscle volumes. Significant differences between males and females were also found in PCSA for the popliteus (p = 0.005) and semimembranosus (p = 4.1E-05) muscles. There were no significant differences in fiber length, overall muscle length (with tendon removed), age, and orientation.
CONCLUSION: Further consideration should be given to include the popliteus muscle as a dynamic entity in the knee given its mechanical properties, trajectory, and prior biomechanical evidence showing when and how it is activated. The present study provides data that may shape future directions of research and treatment with regard to posterolateral corner injuries and ligamentous balancing of the knee.

PMID: 31954610 [PubMed - as supplied by publisher]

Intermittent Hypoxic Conditioning Alleviates Post-Traumatic Stress Disorder-Induced Damage and Dysfunction of Rat Visceral Organs and Brain.

Sat, 01/18/2020 - 06:17
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Intermittent Hypoxic Conditioning Alleviates Post-Traumatic Stress Disorder-Induced Damage and Dysfunction of Rat Visceral Organs and Brain.

Int J Mol Sci. 2020 Jan 05;21(1):

Authors: Manukhina EB, Tseilikman VE, Karpenko MN, Pestereva NS, Tseilikman OB, Komelkova MV, Kondashevskaya MV, Goryacheva AV, Lapshin MS, Platkovskii PO, Sarapultsev AP, Alliluev AV, Downey HF

Abstract
Posttraumatic stress disorder (PTSD) causes mental and somatic diseases. Intermittent hypoxic conditioning (IHC) has cardio-, vaso-, and neuroprotective effects and alleviates experimental PTSD. IHC's ability to alleviate harmful PTSD effects on rat heart, liver, and brain was examined. PTSD was induced by 10-day exposure to cat urine scent (PTSD rats). Some rats were then adapted to 14-day IHC (PTSD+IHC rats), while PTSD and untreated control rats were cage rested. PTSD rats had a higher anxiety index (AI, X-maze test), than control or PTSD+IHC rats. This higher AI was associated with reduced glycogen content and histological signs of metabolic and hypoxic damage and of impaired contractility. The livers of PTSD rats had reduced glycogen content. Liver and blood alanine and aspartate aminotransferase activities of PTSD rats were significantly increased. PTSD rats had increased norepinephrine concentration and decreased monoamine oxidase A activity in cerebral cortex. The PTSD-induced elevation of carbonylated proteins and lipid peroxidation products in these organs reflects oxidative stress, a known cause of organ pathology. IHC alleviated PTSD-induced metabolic and structural injury and reduced oxidative stress. Therefore, IHC is a promising preventive treatment for PTSD-related morphological and functional damage to organs, due, in part, to IHC's reduction of oxidative stress.

PMID: 31948051 [PubMed - in process]

Glycyrrhizin Protects γ-Irradiated Mice from Gut Bacteria-Associated Infectious Complications by Improving miR-222-Associated Gas5 RNA Reduction in Macrophages of the Bacterial Translocation Site.

Fri, 01/17/2020 - 06:02
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Glycyrrhizin Protects γ-Irradiated Mice from Gut Bacteria-Associated Infectious Complications by Improving miR-222-Associated Gas5 RNA Reduction in Macrophages of the Bacterial Translocation Site.

J Immunol. 2020 Jan 15;:

Authors: Ito I, Loucas BD, Suzuki S, Kobayashi M, Suzuki F

Abstract
Gut bacteria-associated sepsis is a serious concern in patients with gastrointestinal acute radiation syndrome (GIARS). In our previous studies, gut bacteria-associated sepsis caused high mortality rates in mice exposed to 6-9 Gy of γ-rays. IL-12+CD38+ iNOS+ Mϕ (M1Mϕ) located in the bacterial translocation site (mesenteric lymph nodes [MLNs]) of unirradiated mice were characterized as host defense antibacterial effector cells. However, cells isolated from the MLNs of GIARS mice were mostly CCL1+IL-10+LIGHT+miR-27a+ Mϕ (M2bMϕ, inhibitor cells for the M1Mϕ polarization). Reduced long noncoding RNA Gas5 and increased miR-222 expression in MLN-Mϕ influenced by the irradiation were shown to be associated with M2bMϕ polarization. In this study, the mortality of mice exposed to 7 Gy of γ-rays (7 Gy GIARS mice) was completely controlled after the administration of glycyrrhizin (GL), a major active ingredient in licorice root (Glycyrrhiza glabra). Bacterial translocation and subsequent sepsis were minimal in 7 Gy GIARS mice treated with GL. Increased Gas5 RNA level and decreased miR-222 expression were shown in MLN-Mϕ isolated from 7 Gy GIARS mice treated with GL, and these macrophages did not display any properties of M2bMϕ. These results indicate that gut bacteria-associated sepsis in 7 Gy GIARS mice was controlled by the GL through the inhibition of M2bMϕ polarization at the bacteria translocation site. Expression of Ccl1, a gene required for M2bMϕ survival, is silenced in the MLNs of 7 Gy GIARS mice because of Gas5 RNA, which is increased in these cells after the suppression of miR-222 (a Gas5 RNA expression inhibitor) by the GL.

PMID: 31941655 [PubMed - as supplied by publisher]

Kinematic Analysis of Combined Suture-Button and Suture Anchor Augment Constructs for Ankle Syndesmosis Injuries.

Fri, 01/17/2020 - 06:02
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Kinematic Analysis of Combined Suture-Button and Suture Anchor Augment Constructs for Ankle Syndesmosis Injuries.

Foot Ankle Int. 2020 Jan 15;:1071100719898181

Authors: Wood AR, Arshad SA, Kim H, Stewart D

Abstract
BACKGROUND: Syndesmosis injuries are common, with up to 25% of all ankle injuries being reported to involve an associated syndesmosis injury. These injuries are typically treated with cortical screw fixation or suture-button implants when indicated, but the addition of a suture anchor augment implant has yet to be evaluated. The purpose of this study was to evaluate the ability of a suture anchor augment to add sagittal plane translational and transverse plane rotational constraint to suture-button constructs with syndesmosis injuries. We hypothesized that the suture anchor augment oriented in parallel with the fibers of an injured anterior-inferior tibiofibular ligament (AITFL) in addition to a suture-button construct would achieve physiological motion and stability at the syndesmosis through increased rotational and translational constraint of the fibula.
METHODS: Eleven fresh-frozen cadaver ankles were stressed in external rotation using a custom-made ankle rig. Each ankle had simultaneous recording of ultrasound video, 6 degrees-of-freedom kinematics of the fibula and tibia, and torque as the ankle was stressed by an examiner. The ankles were tested in 6 different states: native uninjured; injured with interosseous ligament and AITFL sectioned; 1× suture button; 2× suture buttons, divergent; 1× suture anchor augment with 2× suture buttons, divergent; and 1× suture anchor augment with 1× suture buttons.
RESULTS: Only the suture anchor augment + 2× suture buttons and suture anchor augment + 1× suture-button constructs were found to be significantly different from the injured state (P = .0003, P = .002) with mean external rotation of the fibula.
CONCLUSION: Overall, the most important finding of this study was that the addition of a suture anchor augment to suture-button constructs provided a mechanism to increase external rotational constraint of the fibula.
CLINICAL RELEVANCE: This study provides a mechanistic understanding of how the combined suture-button and suture anchor augment construct provides an anatomically similar reconstruction of constraints found in the native ankle. However, none of the constructs examined in this study were able to fully restore physiologic motion.

PMID: 31941352 [PubMed - as supplied by publisher]

Electronic Nicotine Delivery Systems Marketing and Initiation Among Youth and Young Adults.

Fri, 01/17/2020 - 06:02
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Electronic Nicotine Delivery Systems Marketing and Initiation Among Youth and Young Adults.

Pediatrics. 2019 09;144(3):

Authors: Loukas A, Paddock EM, Li X, Harrell MB, Pasch KE, Perry CL

Abstract
BACKGROUND AND OBJECTIVES: Electronic nicotine delivery systems (ENDS) have become the most popular tobacco products among young people, yet ENDS marketing remains unregulated, and its effects on ENDS use behavior across age groups is poorly understood. In this study, using a longitudinal design, we examined how recall of ENDS marketing through 5 different channels predicted subsequent ENDS initiation up to 2.5 years later among youth (ages 12-17 years) and young adults (ages 18-29 years).
METHODS: Data were drawn from 2 large cohort studies in Texas. The analysis included school-going youth (n = 2288) and college-going young adults (n = 2423) who reported never having used ENDS at baseline in 2014. Logistic regression was used to assess the influence of recalled ENDS marketing exposure via television (TV), radio or Internet radio, billboards, retail stores, and the Internet on subsequent ENDS initiation, with adjustment for these channels, baseline sociodemographics, other past-30-day tobacco use, sensation seeking, and peer ENDS use.
RESULTS: Recall of retail store-based ENDS marketing at baseline was associated with significantly higher odds of subsequent ENDS initiation among youth (adjusted odds ratio [aOR] = 1.99; 95% confidence interval [CI]: 1.25-3.17) and young adults (aOR = 1.30; 95% CI: 1.05-1.61) up to 2.5 years later. Young adult initiation was also associated with recalled ENDS marketing on TV at baseline (aOR = 1.29; 95% CI: 1.03-1.63).
CONCLUSIONS: Marketing of ENDS at retail stores predicts youth and young adult ENDS initiation, and marketing on TV predicts young adult initiation. Future research and regulation should be used to address the most influential marketing channels.

PMID: 31451608 [PubMed - in process]

Development of zebrafish demyelination model for evaluation of remyelination compounds and RORγt inhibitors.

Fri, 01/17/2020 - 06:02
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Development of zebrafish demyelination model for evaluation of remyelination compounds and RORγt inhibitors.

J Pharmacol Toxicol Methods. 2019 Jul - Aug;98:106585

Authors: Zhu XY, Guo SY, Xia B, Li CQ, Wang L, Wang YH

Abstract
RAR-related orphan receptor-γt (RORγt) directs differentiation of proinflammatory T helper 17 cells and is a potential therapeutic target for chronic autoimmune and inflammatory diseases including multiple sclerosis. In this study, zebrafish at days post fertilization treated with ethidium bromide (EB) at a concentration of 75 μM for 72 h were determined as the optimum conditions for the demyelination model development. Zebrafish motility was recorded automatically using a video-track motion detector and quantitative myelin assay was measured by FluoroMyelin staining. A well-known remyelination agent thyroxine (T4) was tested to confirm whether EB-induced motility and myelin damage could be rescued. Two RORγt lead inhibitors GSK805 and SR1001 were assessed for their therapeutic effects on remyelination, axon regeneration, motor neuron promotion and anti-inflammation. T4 significantly improved EB-induced motility dysfunction and myelin damage and promoted myelin basic protein (MBP) regeneration in the demyelinated zebrafish. GSK805 and SR1001 enhanced remyelination in a dose-dependent manner and promoted MBP regeneration. Both GSK805 and SR1001 markedly recovered EB-induced axon and motor neuron damage, and exhibited significantly inhibitory effects of neutrophil infiltration and macrophage recruitment. These results indicate that EB treatment can induce zebrafish demyelination; and the zebrafish demyelination model in combination with quantitative motility and myelin assays is a predictive, reproducible and relatively high throughput screening for rapidly in vivo identification of remyelination compounds and RORγt inhibitors.

PMID: 31112751 [PubMed - in process]

Optimizing Patient Outcomes with PD-1/PD-L1 Immune Checkpoint Inhibitors for the First-Line Treatment of Advanced Non-Small Cell Lung Cancer.

Tue, 01/14/2020 - 05:15
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Optimizing Patient Outcomes with PD-1/PD-L1 Immune Checkpoint Inhibitors for the First-Line Treatment of Advanced Non-Small Cell Lung Cancer.

Pharmacotherapy. 2020 Jan 12;:

Authors: La-Beck NM, Nguyen DT, Le AD, Alzghari SK, Trinh ST

Abstract
The rapidly expanding repertoire of immune checkpoint inhibitors (ICIs) now includes two agents, pembrolizumab and atezolizumab, approved for first-line treatment of advanced non-small cell lung cancer (aNSCLC) as monotherapy or as part of combination chemo-immunotherapy. This review summarizes the clinical evidence supporting these indications, with a focus on strategies to optimize patient outcomes. These strategies include patient and tumor factors, adverse-effect profiles, pharmacokinetic and pharmacodynamic drug interactions, and quality of life and cost-effectiveness considerations. We performed a systematic literature search of the PubMed, Scopus, and Google Scholar databases, as well as a search of the conference proceedings of the American Society of Clinical Oncology, European Society for Medical Oncology, and American Association for Cancer Research (through August 31, 2019). The addition of ICIs to conventional chemotherapy as first-line treatment against aNSCLC is now part of the standard of care options. However, even though ICIs may be cost-effective in patients with aNSCLC, high drug and other associated costs can still be a barrier to treatment for patients. Moreover, the adverse-effect profiles of ICIs differ significantly from conventional chemotherapy, and some immune-related adverse effects may have a lasting impact on quality of life. Therefore, in adhering to a patient-centered model of care, clinicians should be mindful of patient- and treatment-specific factors when considering therapeutic options for patients with aNSCLC. Although the role of the immune system in cancer progression and regression has not been fully elucidated, it is likely that the full clinical potential of immunotherapeutics in the treatment of cancer remains to be unleashed.

PMID: 31930528 [PubMed - as supplied by publisher]

Children with Psychogenic Nonepileptic Seizures.

Tue, 01/14/2020 - 05:15
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Children with Psychogenic Nonepileptic Seizures.

Pediatr Neurol Briefs. 2019 Dec 31;33:4

Authors: Gillan A, Shareef S

Abstract
A large multicenter retrospective cohort study was conducted by researchers from the Pediatric Health Information System hospital network to determine differences in demographics, clinical characteristics, testing, treatment, and healthcare use between children aged 8-20 years with epilepsy (n = 13,241) and those with psychogenic nonepileptic seizures (PNES) secondary to conversion disorder (n = 399).

PMID: 31929715 [PubMed]

Racial discrimination and telomere shortening among African Americans: The Coronary Artery Risk Development in Young Adults (CARDIA) Study.

Tue, 01/14/2020 - 05:15
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Racial discrimination and telomere shortening among African Americans: The Coronary Artery Risk Development in Young Adults (CARDIA) Study.

Health Psychol. 2020 Jan 13;:

Authors: Chae DH, Wang Y, Martz CD, Slopen N, Yip T, Adler NE, Fuller-Rowell TE, Lin J, Matthews KA, Brody GH, Spears EC, Puterman E, Epel ES

Abstract
OBJECTIVE: Telomeres are protective sequences of DNA capping the ends of chromosomes that shorten over time. Leukocyte telomere length (LTL) is posited to reflect the replicative history of cells and general systemic aging of the organism. Chronic stress exposure leads to accelerated LTL shortening, which has been linked to increased susceptibility to and faster progression of aging-related diseases. This study examined longitudinal associations between LTL and experiences of racial discrimination, a qualitatively unique source of minority psychosocial stress, among African Americans.
METHOD: Data are from 391 African Americans in the Coronary Artery Risk Development in Young Adults (CARDIA) Telomere Ancillary Study. We examined the number of domains in which racial discrimination was experienced in relation to LTL collected in Years 15 and 25 (Y15: 2000/2001; Y25: 2010/2011). Multivariable linear regression examined if racial discrimination was associated with LTL. Latent change score analysis (LCS) examined changes in racial discrimination and LTL in relation to one another.
RESULTS: Controlling for racial discrimination at Y15, multivariable linear regression analyses indicated that racial discrimination at Y25 was significantly associated with LTL at Y25. This relationship remained robust after adjusting for LTL at Y15 (b = -.019, p = .015). Consistent with this finding, LCS revealed that increases in experiences of racial discrimination were associated with faster 10-year LTL shortening (b = -.019, p = .015).
CONCLUSIONS: This study adds to evidence that racial discrimination contributes to accelerated physiologic weathering and health declines among African Americans through its impact on biological systems, including via its effects on telomere attrition. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

PMID: 31928029 [PubMed - as supplied by publisher]

Nuclear factor-kappa beta signaling is required for transforming growth factor Beta-2 induced ocular hypertension.

Sat, 01/11/2020 - 07:31
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Nuclear factor-kappa beta signaling is required for transforming growth factor Beta-2 induced ocular hypertension.

Exp Eye Res. 2020 Jan 07;:107920

Authors: Hernandez H, Roberts AL, McDowell CM

Abstract
A major risk for the development of primary open-angle glaucoma (POAG) is elevated intraocular pressure (IOP). Elevated IOP is caused by increased outflow resistance due in part to excessive extracellular matrix (ECM) deposition in the trabecular meshwork (TM). The role of transforming growth factor beta 2 (TGFβ2) in inducing ECM production is well understood. Recent studies suggest that toll-like receptor 4 (TLR4) plays an important role in fibrogenesis. We have previously described a crosstalk between TGFβ2 and TLR4 in the development of ocular hypertension and glaucomatous TM damage. Nuclear factor-kappa beta (NF-κB) is critical for TLR4 signaling. To determine the transactivation of NF-κB, TM cells were stimulated with cellular fibronectin containing the EDA isoform (cFN-EDA), TGFβ2, or lipopolysaccharide (LPS) in combination with a selective TLR4 inhibitor. cFN-EDA, TGFβ2, and LPS all induced transactivation of NF-κB and inhibition of TLR4 blocked the effect of each treatment paradigm. To evaluate the role of NF-κB in IOP regulation, we utilized our inducible mouse model of ocular hypertension by injection of Ad5.TGFβ2 in mice harboring a mutation in NF-κB and wild-type controls. IOP was measured over time and eyes accessed by immunohistochemistry for the ECM protein FN and the specific FN-EDA isoform. Ad5.TGFβ2 induced ocular hypertension and expression of FN and FN-EDA in wild-type mice, but mutation in NF-κB blocked the effect. These data suggest that NF-κB is necessary for TGFβ2-induced ECM production and ocular hypertension and the transactivation of NF-κB is dependent on both TGFβ2 and TLR4.

PMID: 31923415 [PubMed - as supplied by publisher]

Two-stage Bayesian GWAS of 9576 individuals identifies SNP regions that are targeted by miRNAs inversely expressed in Alzheimer's and cancer.

Thu, 01/09/2020 - 06:56

Two-stage Bayesian GWAS of 9576 individuals identifies SNP regions that are targeted by miRNAs inversely expressed in Alzheimer's and cancer.

Alzheimers Dement. 2020 Jan;16(1):162-177

Authors: Pathak GA, Zhou Z, Silzer TK, Barber RC, Phillips NR, Alzheimer's Disease Neuroimaging Initiative, Breast and Prostate Cancer Cohort Consortium, and Alzheimer's Disease Genetics Consortium

Abstract
INTRODUCTION: We compared genetic variants between Alzheimer's disease (AD) and two age-related cancers-breast and prostate -to identify single-nucleotide polymorphisms (SNPs) that are associated with inverse comorbidity of AD and cancer.
METHODS: Bayesian multinomial regression was used to compare sex-stratified cases (AD and cancer) against controls in a two-stage study. A ±500 KB region around each replicated hit was imputed and analyzed after merging individuals from the two stages. The microRNAs (miRNAs) that target the genes involving these SNPs were analyzed for miRNA family enrichment.
RESULTS: We identified 137 variants with inverse odds ratios for AD and cancer located on chromosomes 19, 4, and 5. The mapped miRNAs within the network were enriched for miR-17 and miR-515 families.
DISCUSSION: The identified SNPs were rs4298154 (intergenic), within TOMM40/APOE/APOC1, MARK4, CLPTM1, and near the VDAC1/FSTL4 locus. The miRNAs identified in our network have been previously reported to have inverse expression in AD and cancer.

PMID: 31914222 [PubMed - in process]

Cell-free mitochondrial DNA increases in maternal circulation during healthy pregnancy: a prospective, longitudinal study.

Thu, 01/09/2020 - 06:56

Cell-free mitochondrial DNA increases in maternal circulation during healthy pregnancy: a prospective, longitudinal study.

Am J Physiol Regul Integr Comp Physiol. 2020 Jan 08;:

Authors: Cushen SC, Sprouse ML, Blessing A, Sun J, Jarvis SS, Okada Y, Fu Q, Romero SA, Phillips NR, Goulopoulou S

Abstract
Mitochondrial DNA (mtDNA) exposed to the extracellular space due to cell death has immunostimulatory properties. Case-control studies reported a positive association between odds of developing preeclampsia and circulating mtDNA. These findings are based on relative quantification protocols that do not allow determination of absolute concentrations of mtDNA and are highly sensitive to nuclear DNA contamination. Furthermore, circulating mtDNA concentrations in response to normal pregnancy, which is an inflammatory state characterized by continuous placental cell apoptosis, have not been established. The main objective of this study was to determine longitudinal changes in circulating mtDNA from preconception to 1st trimester, 3rd trimester, and postpartum in healthy pregnant women. Absolute real-time PCR quantification of mtDNA and nuclear DNA (nDNA) was performed on whole genomic extracts from serum using TaqMan® probes and chemistry. Serum cell-free mtDNA and nDNA concentrations were greater in late pregnancy as compared to early pregnancy and postpartum. Pregnant women carrying neonates at the upper quartile of birth length distribution had higher concentrations of mtDNA in late pregnancy compared to pregnancies carrying neonates at the lower quartile. The correlation between circulating mtDNA and nDNA concentrations varied by sex (i.e. pregnancies carrying female vs. male fetuses). This study is the first to establish temporal patterns of circulating cell-free mtDNA concentrations in normal human pregnancy using absolute DNA quantification techniques. Concentrations of circulating mtDNA in normal pregnancy may be used as reference values for the development of clinical prognostic or diagnostic tests in pregnant women with, or at risk, of developing gestational complications.

PMID: 31913687 [PubMed - as supplied by publisher]

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes-6.

Wed, 01/08/2020 - 06:45

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes-6.

Molecules. 2019 Dec 28;25(1):

Authors: Vanden Eynde JJ, Mangoni AA, Rautio J, Leprince J, Azuma YT, García-Sosa AT, Hulme C, Jampilek J, Karaman R, Li W, Gomes PAC, Hadjipavlou-Litina D, Capasso R, Geronikaki A, Cerchia L, Sabatier JM, Ragno R, Tuccinardi T, Trabocchi A, Winum JY, Luque FJ, Prokai-Tatrai K, Spetea M, Gütschow M, Kosalec I, Guillou C, Vasconcelos MH, Kokotos G, Rastelli G, de Sousa ME, Manera C, Gemma S, Mangani S, Siciliano C, Galdiero S, Liu H, Scott PJH, de Los Ríos C, Agrofoglio LA, Collina S, Guedes RC, Muñoz-Torrero D

Abstract
Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes is a series of Editorials that is published on a biannual basis by the Editorial Board of the Medicinal Chemistry section of the journal Molecules [...].

PMID: 31905602 [PubMed - in process]

Circumferential canal surgery: a brief history.

Tue, 01/07/2020 - 06:35

Circumferential canal surgery: a brief history.

Curr Opin Ophthalmol. 2020 Jan 03;:

Authors: Dickerson JE, Brown RH

Abstract
PURPOSE OF REVIEW: Most microinvasive glaucoma surgery (MIGS) procedures bypass outflow resistance residing proximally in the trabecular meshwork and inner wall of Schlemm's canal. A novel procedure combining trabeculotomy with viscodilation adds to this by also addressing distal resistance of the canal and collector channel ostia. This review examines the development and evidence for both trabeculotomy and canaloplasty separately and the combination in a single procedure.
RECENT FINDINGS: Recent aqueous angiography studies have confirmed the segmental nature of outflow through Schlemm's canal highlighting the need to address distal outflow pathway resistance. Combined trabeculotomy and viscodilation ab interno is a novel approach with a new purpose-designed device (OMNI Surgical System) becoming available to surgeons in early 2018. Recent results as both a standalone and combined with cataract procedure demonstrate significant intraocular pressure reductions with an average 41% reduction from baseline in the pseudophakic group.
SUMMARY: Targeting both distal as well as proximal points of outflow resistance in the conventional pathway may prove to be a highly efficacious MIGS modality. Additional large prospective studies are currently ongoing to confirm these preliminary results.

PMID: 31904595 [PubMed - as supplied by publisher]

Microglia exacerbate white matter injury via complement C3/C3aR pathway after hypoperfusion.

Tue, 01/07/2020 - 06:35

Microglia exacerbate white matter injury via complement C3/C3aR pathway after hypoperfusion.

Theranostics. 2020;10(1):74-90

Authors: Zhang LY, Pan J, Mamtilahun M, Zhu Y, Wang L, Venkatesh A, Shi R, Tu X, Jin K, Wang Y, Zhang Z, Yang GY

Abstract
Microglial activation participates in white matter injury after cerebral hypoperfusion. However, the underlying mechanism is unclear. Here, we explore whether activated microglia aggravate white matter injury via complement C3-C3aR pathway after chronic cerebral hypoperfusion. Methods: Adult male Sprague-Dawley rats (n = 80) underwent bilateral common carotid artery occlusion for 7, 14, and 28 days. Cerebral vessel density and blood flow were examined by synchrotron radiation angiography and three-dimensional arterial spin labeling. Neurobehavioral assessments, CLARITY imaging, and immunohistochemistry were performed to evaluate activation of microglia and C3-C3aR pathway. Furthermore, C3aR knockout mice were used to establish the causal relationship of C3-C3aR signaling on microglia activation and white matter injury after hypoperfusion. Results: Cerebral vessel density and blood flow were reduced after hypoperfusion (p<0.05). Spatial learning and memory deficits and white matter injury were shown (p<0.05). These impairments were correlated with aberrant microglia activation and an increase in the number of reactive microglia adhering to and phagocytosed myelin in the hypoperfusion group (p<0.05), which were accompanied by the up-regulation of complement C3 and its receptors C3aR (p<0.05). Genetic deletion of C3ar1 significantly inhibited aberrant microglial activation and reversed white matter injury after hypoperfusion (p<0.05). Furthermore, the C3aR antagonist SB290157 decreased the number of microglia adhering to myelin (p<0.05), attenuated white matter injury and cognitive deficits in chronic hypoperfusion rats (p<0.05). Conclusions: Our results demonstrated that aberrant activated microglia aggravate white matter injury via C3-C3aR pathway during chronic hypoperfusion. These findings indicate C3aR plays a critical role in mediating neuroinflammation and white matter injury through aberrant microglia activation, which provides a novel therapeutic target for the small vessel disease and vascular dementia.

PMID: 31903107 [PubMed - in process]

Intermittent Hypoxia Training for Treating Mild Cognitive Impairment: A Pilot Study.

Tue, 01/07/2020 - 06:35

Intermittent Hypoxia Training for Treating Mild Cognitive Impairment: A Pilot Study.

Am J Alzheimers Dis Other Demen. 2020 Jan-Dec;35:1533317519896725

Authors: Wang H, Shi X, Schenck H, Hall JR, Ross SE, Kline GP, Chen S, Mallet RT, Chen P

Abstract
Although intermittent hypoxia training (IHT) has proven effective against various clinical disorders, its impact on mild cognitive impairment (MCI) is unknown. This pilot study examined IHT's safety and therapeutic efficacy in elderly patients with amnestic MCI (aMCI). Seven patients with aMCI (age 69 ± 3 years) alternately breathed 10% O2 and room-air, each 5 minutes, for 8 cycles/session, 3 sessions/wk for 8 weeks. The patients' resting arterial pressures fell by 5 to 7 mm Hg (P < .05) and cerebral tissue oxygenation increased (P < .05) following IHT. Intermittent hypoxia training enhanced hypoxemia-induced cerebral vasodilation (P < .05) and improved mini-mental state examination and digit span scores from 25.7 ± 0.4 to 27.7 ± 0.6 (P = .038) and from 24.7 ± 1.2 to 26.1 ± 1.3 (P = .047), respectively. California verbal learning test score tended to increase (P = .102), but trail making test-B and controlled oral word association test scores were unchanged. Adaptation to moderate IHT may enhance cerebral oxygenation and hypoxia-induced cerebrovasodilation while improving short-term memory and attention in elderly patients with aMCI.

PMID: 31902230 [PubMed - in process]

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