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: 18 min 51 sec ago

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

Tue, 02/06/2018 - 07:40
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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 Oct;51(5):694-706

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 - indexed for MEDLINE]

A Post-Hurricane Katrina Examination of Substance Abuse Treatment Discharges With Co-Occurring Psychiatric and Substance Use Disorders.

Tue, 02/06/2018 - 07:40
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A Post-Hurricane Katrina Examination of Substance Abuse Treatment Discharges With Co-Occurring Psychiatric and Substance Use Disorders.

J Dual Diagn. 2017 Apr-Jun;13(2):144-156

Authors: Shuler M, Suzuki S, Podesta A, Qualls-Hampton R, Wallington SF

Abstract
OBJECTIVES: There is increasing literature supporting the adverse effects of disasters on substance use and psychiatric disorders. The co-occurrence of psychiatric disorders with substance use intensifies the challenge of treatment delivery. Thus the aim of this study was to examine the prevalence of substance use, treatment characteristics, and demographics of discharges from substance abuse treatment in New Orleans, post-Hurricane Katrina. Trends associated with discharges that have a co-occurring psychiatric and substance use disorder (COD) were also assessed. The secondary aim of this study was to examine the association of successful substance abuse treatment completion among those with a COD post-Hurricane Katrina.
METHODS: Substance abuse treatment discharge data (N = 16,507) from New Orleans, Louisiana, for years 2006 through 2011 were obtained from the Treatment Episode Data Set-Discharge. Multiple logistic regression analysis was employed to examine the association of discharges with a COD and completion of substance abuse treatment. Demographic, psychiatric, and treatment characteristics of discharges in 2006 were compared to characteristics in 2011. Trends of characteristics were also assessed through the study period.
RESULTS: Roughly a third (35.2%) of all discharges in New Orleans from 2006 to 2011 had a COD. After controlling for race, employment, treatment service setting at discharge, primary substance problem, and the discharge's principal source of referral, discharges with a COD were 29% less likely to complete treatment as compared to those with no COD (AOR = 0.71, 95% CI [0.56, 0.90], p = .004). Treatment completion among discharges with a COD has significantly declined from 36.8% in 2006 to 18.7% in 2011 (p < .0001). Notable significant trends in homelessness, criminality, and heroin use were identified among discharges with a COD.
CONCLUSIONS: Substance abuse treatment undergoes various changes in the event of a natural disaster. These changes may increase challenges for successful treatment completion for vulnerable populations such as those with a COD. Results of this study demonstrate that discharges with a COD are less likely to complete treatment as compared to those with no COD disorder. Unmet treatment needs may also increase odds of criminalization and homelessness.

PMID: 28045601 [PubMed - indexed for MEDLINE]

Increased Substrate Stiffness Elicits a Myofibroblastic Phenotype in Human Lamina Cribrosa Cells.

Sat, 02/03/2018 - 05:55

Increased Substrate Stiffness Elicits a Myofibroblastic Phenotype in Human Lamina Cribrosa Cells.

Invest Ophthalmol Vis Sci. 2018 Feb 01;59(2):803-814

Authors: Liu B, Kilpatrick JI, Lukasz B, Jarvis SP, McDonnell F, Wallace DM, Clark AF, O'Brien CJ

Abstract
Purpose: Alteration in the extracellular matrix (ECM) of the optic nerve head (ONH) causes lamina cribrosa (LC) fibrosis and affects the mechanical integrity of the ONH. Increased ECM tissue stiffness drives myofibroblast activation leading to tissue fibrosis throughout the body. Here using primary human LC cells, we investigate the effect of substrate stiffness on profibrotic changes, which might be a key molecular mechanism driving ECM remodeling of the LC in primary open-angle glaucoma (POAG) glaucoma.
Methods: Primary human LC cells from normal and age-matched POAG glaucoma donors were cultured on substrates with defined mechanical properties of 5 and 100 kPa to replicate the range of mechanical microenvironments that cells may experience in vivo. Cell morphology, spread area, actin stress fibers, vinculin-focal adhesion formation, and α-smooth muscle actin (α-SMA) signal were examined using immunofluorescence staining. The elastic modulus of cells was measured using atomic force microscopy (AFM).
Results: Significantly greater cell spread area along with increased actin filament development, and vinculin-focal adhesion formation (number and size) were found in both normal and glaucoma LC cells cultured on stiff substrates. These changes were positively associated with elevated cell stiffness measured by AFM. Changes in spreading and cytoskeleton organization of glaucoma LC cells were significantly more pronounced than those in normal cells. The transformation to a myofibroblast-like cell phenotype was identified in both LC cells exposed to stiffer substrates, as indicated by an increased α-SMA signal and its colocalization with the actin stress fibers.
Conclusions: These findings demonstrated that a stiffer cell microenvironment activates a myofibroblastic transformation in human LC cells, and therefore contributes to LC remodelling and fibrosis in glaucoma.

PMID: 29392327 [PubMed - in process]

Magnetic Resonance Imaging (MRI): Operative Findings Correlation in 229 Fistula-in-Ano Patients.

Sat, 02/03/2018 - 05:55
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Magnetic Resonance Imaging (MRI): Operative Findings Correlation in 229 Fistula-in-Ano Patients.

World J Surg. 2017 Jun;41(6):1618-1624

Authors: Garg P, Singh P, Kaur B

Abstract
BACKGROUND: To correlate the operative findings of patients with fistula-in-ano with preoperative MRI and quantify the information added with MRI.
METHODS: All consecutive fistula-in-ano patients operated between July 2013 and May 2015 were prospectively enrolled. Preoperative MRI was done in every patient. The details of tracts, internal opening and "complex parameters" (additional tract or additional internal opening, horseshoe tract, associated abscess and supralevator extension) found at surgery were compared to the findings determined by MRI.
RESULTS: A total of 229 patients (424 tracts) with mean age-49.0 ± 11.3 years were included. M/F 198/31. James hospital classification: Type I 58, II 20, III 49, IV 86 and V 16. The sensitivity and specificity of MRI in diagnosing fistula tracts were 98.8 and 99.7%, respectively, and in identifying internal opening were 97.7 and 98.6%, respectively. MRI added significant information in 46.7% (107/229) patients which was presence of additional tracts in 71 (66.3%), horseshoe tract in 63 (58.8%), supralevator extension in 16 (14.9%), unsuspected abscess in 11 (10.3%) and multiple internal openings in one patient (1%). The proportion of simple/complex fistula (based on history and clinical examination alone) was 32.8/67.2% which changed to 21.4/78.6% after the MRI scan. MRI added significant information about unsuspecting complex parameters which were missed on history and clinical examination in more than one-third (26/75: 34.6%) of simple fistulae and more than half (81/154: 52.5%) of already known complex fistulae.
CONCLUSIONS: MRI is highly accurate in diagnosing fistula-in-ano and added significant information about unsuspected complex parameters in over one-third (34.6%) of simple and in half (52.5%) of complex fistula-in-ano.

PMID: 28097414 [PubMed - indexed for MEDLINE]

Planktonic microbial profiling in water samples from a Brazilian Amazonian reservoir.

Wed, 01/31/2018 - 07:35

Planktonic microbial profiling in water samples from a Brazilian Amazonian reservoir.

Microbiologyopen. 2018 Jan 30;:

Authors: Cabral BCA, Hoffmann L, Budowle B, Ürményi TP, Moura-Neto RS, Azevedo SMFO, Silva R

Abstract
Our comprehension of the dynamics and diversity of freshwater planktonic bacterial communities is far from complete concerning the Brazilian Amazonian region. Therefore, reference studies are urgently needed. We mapped bacterial communities present in the planktonic communities of a freshwater artificial reservoir located in the western Amazonian basin. Two samples were obtained from rainy and dry seasons, the periods during which water quality and plankton diversity undergo the most significant changes. Hypervariable 16S rRNA and shotgun sequencing were performed to describe the first reference of a microbial community in an Amazonian lentic system. Microbial composition consisted mainly of Betaproteobacteria, Cyanobacteria, Alphaproteobacteria, and Actinobacteria in the dry period. The bacteria distribution in the rainy period was notably absent of Cyanobacteria. Microcystis was observed in the dry period in which the gene cluster for cyanotoxins was found. Iron acquisition gene group was higher in the sample from the rainy season. This work mapped the first inventory of the planktonic microbial community of a large water reservoir in the Amazon, providing a reference for future functional studies and determining other communities and how they interact.

PMID: 29380948 [PubMed - as supplied by publisher]

Perceptions of Zika Virus Prevention Among College Students in Florida.

Wed, 01/31/2018 - 07:35

Perceptions of Zika Virus Prevention Among College Students in Florida.

J Community Health. 2018 Jan 29;:

Authors: Thompson EL, Vamos CA, Jones J, Liggett LG, Griner SB, G Logan R, Daley EM

Abstract
Zika virus in Florida prompted a strong public health response, due to its causal association with birth defects. While primarily spread by mosquitos, Zika can be transmitted sexually. The spread of Zika may influence reproductive behaviors among sexually active persons in Florida. This study examined factors associated with willingness to change birth control method use in response to Zika virus among college women and men in Florida. Women and men ages 18-44 at a Florida university (N = 328) were surveyed about Zika knowledge, beliefs about Zika, use of contraceptives and condoms, and socio-demographics between November 2016-April 2017. The outcome variable was willingness to change birth control method were Zika in their area. Logistic regression models in SAS 9.4 were used. Most participants were women (80%), and 47% were 20-22 years old. Only 27% of participants said they would change their birth control method if Zika were in their area. Participants who knew that Zika was sexually transmitted were more likely to be willing to change their birth control method (aOR = 1.71, 95%CI 1.01-2.91). Participants who agreed or strongly agreed that they were fearful of being infected with Zika virus were more likely to be willing to change their birth control methods (aOR = 1.98, 95%CI 1.07-3.67). This study found that, among Florida college students, Zika beliefs and knowledge were associated with a willingness to change birth control method in response to Zika. Understanding the factors that motivate individuals to change reproductive behaviors during an emerging health issue can help tailor preventative messages.

PMID: 29380211 [PubMed - as supplied by publisher]

"Ecstasy" to addiction: Mechanisms and reinforcing effects of three synthetic cathinone analogs of MDMA.

Tue, 01/30/2018 - 07:38

"Ecstasy" to addiction: Mechanisms and reinforcing effects of three synthetic cathinone analogs of MDMA.

Neuropharmacology. 2018 Jan 26;:

Authors: Dolan SB, Chen Z, Huang R, Gatch MB

Abstract
This study aimed to address the mechanisms and reinforcing effects of three synthetic cathinone analogs of MDMA commonly reported in "Ecstasy" formulations: methylone, butylone, and pentylone. Whole-cell patch clamp techniques were used to assess the mechanism of each compound at the dopamine and serotonin transporters. Separate groups of rats were trained to discriminate methamphetamine, DOM, or MDMA from vehicle. Substitution studies were performed in each group and antagonism studies with SCH23390 were performed against each compound that produced substitution. Self-administration of each compound was evaluated under a progressive ratio schedule of reinforcement. Each compound produced an inward current at the serotonin transporter, but little or no current at the dopamine transporter. Each of the test compounds substituted fully for the discriminative stimulus effects of methamphetamine, methylone and butylone substituted partially for DOM and fully for MDMA, whereas pentylone failed to substitute for DOM and substituted only partially for MDMA. SCH23390 fully and dose-dependently attenuated methamphetamine-appropriate responding produced by each test compound, but was least potent against pentylone. MDMA-appropriate responding was minimally affected by SCH23390. Each test compound was robustly self-administered with pentylone producing the greatest self-administration at the doses tested. Given the prevalence of synthetic cathinones in "Ecstasy" formulations, these data indicate that adulterated "Ecstasy" formulations may drive more compulsive drug use than those containing only MDMA.

PMID: 29378213 [PubMed - as supplied by publisher]

Characteristics of Cognitively Normal Mexican-Americans with Cognitive Complaints.

Tue, 01/30/2018 - 07:38

Characteristics of Cognitively Normal Mexican-Americans with Cognitive Complaints.

J Alzheimers Dis. 2018;61(4):1485-1492

Authors: Hall JR, Wiechmann A, Johnson LA, Edwards M, O'Bryant SE

Abstract
BACKGROUND: Subjective cognitive complaints in cognitively normal adults have been linked to later cognitive decline and dementia. Research on the characteristics of this group has been conducted on a variety of clinical and community-based populations. The current study focuses on the rapidly expanding population of Mexican-American elders.
OBJECTIVE: The objective of the study is the determination of characteristics of cognitively normal Mexican-Americans with cognitive complaints.
METHODS: Data on 319 cognitively normal participants in a large-scale community-based study of elderly Mexican-Americans (HABLE) were analyzed comparing those with cognitive complaints with those without on clinical characteristics, affective status, neuropsychological functioning, and proteomic markers.
RESULTS: Those expressing concern about cognitive decline scored lower on the MMSE, were more likely to have significantly more affective symptoms, higher levels of diabetic markers, poorer performance on attention and executive functioning, and a different pattern of inflammatory markers.
CONCLUSION: Although longitudinal research is needed to determine the impact of these differences on later cognition, possible targets for early intervention with Mexican-Americans were identified.

PMID: 29376872 [PubMed - in process]

A new approach to mentoring for research careers: the National Research Mentoring Network.

Tue, 01/30/2018 - 07:38
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A new approach to mentoring for research careers: the National Research Mentoring Network.

BMC Proc. 2017;11(Suppl 12):22

Authors: Sorkness CA, Pfund C, Ofili EO, Okuyemi KS, Vishwanatha JK, NRMN team, Zavala ME, Pesavento T, Fernandez M, Tissera A, Deveci A, Javier D, Short A, Cooper P, Jones H, Manson S, Buchwald D, Eide K, Gouldy A, Kelly E, Langford N, McGee R, Steer C, Unold T, Weber-Main AM, Báez A, Stiles J, Pemu P, Thompson W, Gwathmey J, Lawson K, Johnson J, Hall M, Paulsen D, Fouad M, Smith A, Luna R, Wilson D, Adelsberger G, Simenson D, Cook A, Feliu-Mojer M, Harwood E, Jones A, Branchaw J, Thomas S, Butz A, Byars-Winston A, House S, McDaniels M, Quinn S, Rogers J, Spencer K, Utzerath E, Duplicate Of Weber-Main, Womack V

Abstract
Background and purpose: Effective mentorship is critical to the success of early stage investigators, and has been linked to enhanced mentee productivity, self-efficacy, and career satisfaction. The mission of the National Research Mentoring Network (NRMN) is to provide all trainees across the biomedical, behavioral, clinical, and social sciences with evidence-based mentorship and professional development programming that emphasizes the benefits and challenges of diversity, inclusivity, and culture within mentoring relationships, and more broadly the research workforce. The purpose of this paper is to describe the structure and activities of NRMN.
Key highlights: NRMN serves as a national training hub for mentors and mentees striving to improve their relationships by better aligning expectations, promoting professional development, maintaining effective communication, addressing equity and inclusion, assessing understanding, fostering independence, and cultivating ethical behavior. Training is offered in-person at institutions, regional training, or national meetings, as well as via synchronous and asynchronous platforms; the growing training demand is being met by a cadre of NRMN Master Facilitators. NRMN offers career stage-focused coaching models for grant writing, and other professional development programs. NRMN partners with diverse stakeholders from the NIH-sponsored Diversity Program Consortium (DPC), as well as organizations outside the DPC to work synergistically towards common diversity goals. NRMN offers a virtual portal to the Network and all NRMN program offerings for mentees and mentors across career development stages. NRMNet provides access to a wide array of mentoring experiences and resources including MyNRMN, Guided Virtual Mentorship Program, news, training calendar, videos, and workshops. National scale and sustainability are being addressed by NRMN "Coaches-in-Training" offerings for more senior researchers to implement coaching models across the nation. "Shark Tanks" provide intensive review and coaching for early career health disparities investigators, focusing on grant writing for graduate students, postdoctoral trainees, and junior faculty.
Implications: Partners from diverse perspectives are building the national capacity and sparking the institutional changes necessary to truly diversify and transform the biomedical research workforce. NRMN works to leverage resources towards the goals of sustainability, scalability, and expanded reach.

PMID: 29375663 [PubMed]

Enhancing research careers: an example of a US national diversity-focused, grant-writing training and coaching experiment.

Tue, 01/30/2018 - 07:38
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Enhancing research careers: an example of a US national diversity-focused, grant-writing training and coaching experiment.

BMC Proc. 2017;11(Suppl 12):16

Authors: Jones HP, McGee R, Weber-Main AM, Buchwald DS, Manson SM, Vishwanatha JK, Okuyemi KS

Abstract
Background and purpose: Preparing a successful research proposal is one of the most complex skills required of professional scientists, yet this skill is rarely if ever, taught. A major goal of the National Research Mentoring Network (NRMN) in the United States (U.S.) is to support the professional advancement of postdoctoral fellows and junior faculty from diverse populations by offering intensive coaching in the development of grant proposals early in their careers. This article highlights the National Institutes of Health's (NIH) NRMN initiative to prepare diverse constituencies of early-stage biomedicine scientists for research careers by implementation of an evidence-based nationwide program of comprehensive grant writing and professional development.
Program and key highlights: NRMN delivers four unique but complementary coaching models: the Proposal Preparation Program from the University of Minnesota (UMN); Grantwriters Coaching Groups from Northwestern University (NU); Grantwriting Uncovered: Maximizing Strategies, Help, Opportunities, Experiences from the University of Colorado Anschutz Medical Campus (UC) and Washington State University (WSU); and Steps Towards Academic Research from the University of North Texas Health Science Center (UNTHSC). Because these programs cater to scientists at different career stages, rather than employ a single approach, each is uniquely tailored to test its efficacy at the national level. The first two models prioritize scientists with reasonably well-developed research projects who are ready to write proposals for specific NIH research competitions. The other two models target postdoctoral fellows and early-career faculty who need more extensive guidance in proposal development plans. To achieve scalability, all programs also recruit faculty as Coaches-in-Training to learn approaches and acquire particular group facilitation skills required by each model.
Implications: These efforts exemplify NRMN's potential to enhance the career development of diverse trainees on a national scale, building research skills, competitiveness for obtaining faculty positions and capacities that will result in high quality research proposals from a diverse pool of applicants, thereby advancing innovations in science and diversifying the U.S. biomedical workforce.

PMID: 29375659 [PubMed]

A Depressive Endophenotype for Predicting Cognitive Decline among Mexican American Adults and Elders.

Tue, 01/30/2018 - 07:38
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A Depressive Endophenotype for Predicting Cognitive Decline among Mexican American Adults and Elders.

J Alzheimers Dis. 2016 Jul 25;54(1):201-6

Authors: Johnson LA, Gamboa A, Vintimilla R, Edwards M, Hall J, Weiser B, Yadav M, Dickensheets T, O'Bryant SE

Abstract
BACKGROUND: Late life depression is a prodromal feature and a risk factor for Alzheimer's disease (AD) and mild cognitive impairment (MCI). We identified five items in the Geriatric Depression scale (DepE) that are important as a risk for MCI and AD: memory problems, feeling blue, crying, feeling worthless, and trouble concentrating.
OBJECTIVE: Our goal was to examine the relationship between DepE and cognition in a cohort of Mexican Americans.
METHODS: Data from 317 Mexican Americans from the HABLE study were analyzed. DepE scores were dichotomized into two groups: endorsement of 1 item or less, and endorsement of 2 or more items. Cognition was assessed via neuropsychological tests, and diagnosis was based on consensus review. We utilized linear regression to examine the association between DepE and cognitive performance, and logistic regression to examine the utility of DepE in predicting MCI. To examine the impact of DepE on memory over 12 months, we performed ANOVA analysis.
RESULTS: Elevated DepE scores were associated with poorer performance on various measures of memory and cognition, but not executive or visual spatial skills. Over 12 months, we found a decline in immediate memory among women but not men. Those with high scores were 4 times more likely to have MCI. ANOVA of total scores revealed differences between groups on immediate memory (p < 0.05) in women, with no significant differences on delay recall in either gender.
CONCLUSION: DepE can be utilized in Mexican Americans to identify those at risk of memory related cognitive decline.

PMID: 27472872 [PubMed - indexed for MEDLINE]

Locomotor and discriminative stimulus effects of four novel hallucinogens in rodents.

Sat, 01/27/2018 - 07:41
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Locomotor and discriminative stimulus effects of four novel hallucinogens in rodents.

Behav Pharmacol. 2017 Aug;28(5):375-385

Authors: Gatch MB, Dolan SB, Forster MJ

Abstract
There has been increasing use of novel synthetic hallucinogenic compounds, 2-(4-bromo-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine hydrochloride (25B-NBOMe), 2-(4-chloro-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine hydrochloride (25C-NBOMe), 2-(4-iodo-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine hydrochloride (25I-NBOMe), and N,N-diallyl-5-methoxy tryptamine (5-MeO-DALT), which have been associated with severe toxicities. These four compounds were tested for discriminative stimulus effects similar to a prototypical hallucinogen (-)-2,5-dimethoxy-4-methylamphetamine (DOM) and the entactogen (±)-3,4-methylenedioxymethamphetamine (MDMA). Locomotor activity in mice was tested to obtain dose range and time-course information. 25B-NBOMe, 25C-NBOMe, and 25I-NBOMe decreased locomotor activity. 5-MeO-DALT dose dependently increased locomotor activity, with a peak at 10 mg/kg. A higher dose (25 mg/kg) suppressed activity. 25B-NBOMe fully substituted (≥80%) in both DOM-trained and MDMA-trained rats at 0.5 mg/kg. However, higher doses produced much lower levels of drug-appropriate responding in both DOM-trained and MDMA-trained rats. 25C-NBOMe fully substituted in DOM-trained rats, but produced only 67% drug-appropriate responding in MDMA-trained rats at doses that suppressed responding. 25I-NBOMe produced 74-78% drug-appropriate responding in DOM-trained and MDMA-trained rats at doses that suppressed responding. 5-MeO-DALT fully substituted for DOM, but produced few or no MDMA-like effects. All of the compounds, except 25I-NBOMe, fully substituted for DOM, whereas only 25B-NBOMe fully substituted for MDMA. However, the failure of 25I-NBOMe to fully substitute for either MDMA or DOM was more likely because of its substantial rate-depressant effects than weak discriminative stimulus effects. All of the compounds are likely to attract recreational users for their hallucinogenic properties, but probably of much less interest as substitutes for MDMA. Although no acute adverse effects were observed at the doses tested, the substantial toxicities reported in humans, coupled with the high likelihood for illicit use, suggests that these compounds have the same potential for abuse as other, currently scheduled compounds.

PMID: 28537942 [PubMed - indexed for MEDLINE]

Chloroquine Suppresses the Development of Hypertension in Spontaneously Hypertensive Rats.

Sat, 01/27/2018 - 07:41
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Chloroquine Suppresses the Development of Hypertension in Spontaneously Hypertensive Rats.

Am J Hypertens. 2017 Feb;30(2):173-181

Authors: McCarthy CG, Wenceslau CF, Goulopoulou S, Baban B, Matsumoto T, Webb RC

Abstract
BACKGROUND: Innate immune system responses to damage-associated molecular patterns (DAMPs) are involved in hypertension. However, the mechanisms of this contribution are not well understood. Circulating mitochondrial DNA is a DAMP that activates Toll-like receptor (TLR) 9 and is elevated in spontaneously hypertensive rats (SHR). Therefore, we hypothesized that lysosomotropic agent chloroquine (CQ) would impair TLR9 signaling, as well as prevent the development of hypertension and immune cell recruitment to the vasculature, in SHR.
METHODS: Initially, adult SHR and Wistar-Kyoto (WKY) rats (12 weeks old), as well as a group of young SHR (5 weeks old), were treated with CQ (40mg/kg/day) or vehicle (saline) via intraperitoneal injections for 21 days and then TLR9-myeloid differentiation primary response protein (MyD88) signaling proteins were assessed in mesenteric resistance arteries (MRA) via western blot. Subsequently, young SHR and WKY were treated from 5-8 weeks of age and then were allowed to mature without further treatment. Blood pressure was measured pretreatment, posttreatment, and after maturation, and immune cell recruitment to the vasculature was measured via flow cytometry after maturation.
RESULTS: In MRA from adult SHR, CQ increased the expression of MyD88-dependent proteins, whereas young SHR MRA exhibited a decrease. This inhibition was subsequently associated with suppression of blood pressure, as well as decreased counts of circulating T cells and vascular infiltrating leukocytes in SHR, when CQ was administered during the prehypertensive phase.
CONCLUSIONS: These data bring into question the participation of TLRs during the maintenance phase of hypertension and promote the exploration of innate immune system therapy during the critical developmental phase.

PMID: 27623761 [PubMed - indexed for MEDLINE]

Characterization of Alzheimer's Disease and Mild Cognitive Impairment in Older Adults in Panama.

Sat, 01/27/2018 - 07:41
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Characterization of Alzheimer's Disease and Mild Cognitive Impairment in Older Adults in Panama.

J Alzheimers Dis. 2016 Oct 04;54(3):897-901

Authors: Villarreal AE, Grajales S, O'Bryant SE, Edwards M, López L, Montalván A, Britton GB, Panama Aging Research Initiative (PARI)

Abstract
Research on age-related cognitive impairment is scarce in Central America. We report factors associated with cognitive impairment among a sample of older adults in Panama diagnosed with Alzheimer's disease (AD, n = 31), mild cognitive impairment (MCI, n = 43), or no cognitive impairment (controls, n = 185). Apolipoprotein E (ApoE) genotype was assessed in a subset of cases (n = 135). Age (OR = 2.53, 95% CI = 1.03-6.17) and ApoE ɛ4 (OR = 5.14, 95% CI = 2.11-12.52) were significantly related to cognitive impairment (AD/MCI combined). Results underscore the potential of genetic screening in Panama for identifying those at risk of dementia.

PMID: 27567849 [PubMed - indexed for MEDLINE]

The Role of Minimally Invasive Glaucoma Surgery Devices in the Management of Glaucoma.

Fri, 01/26/2018 - 07:39
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The Role of Minimally Invasive Glaucoma Surgery Devices in the Management of Glaucoma.

Optom Vis Sci. 2018 Jan 25;:

Authors: Fingeret M, Dickerson JE

Abstract
SIGNIFICANCE: Noncompliance is a problem affecting glaucoma patients. Approaches to improve adherence include the use of drug-delivery systems and safer forms of surgery. Minimally invasive glaucoma surgery (MIGS) has reduced complications, particularly in combination with cataract surgery, and with its good intraocular pressure (IOP) reduction may reduce or eliminate glaucoma medications.Glaucoma is a progressive disease and a leading cause of irreversible blindness. Elevated IOP is the most important risk factor, but effective medical management is dependent on patient adherence. This review summarizes the adherence problem in glaucoma and the efforts, including MIGS, to provide effective IOP control that is not dependent on patient compliance.The current understanding of patient adherence to pharmacological treatment of glaucoma is discussed including the challenges facing glaucoma patients. Historical approaches to providing IOP control in a sustained and reliable way are presented culminating in a review of the burgeoning use of MIGS devices.It is estimated that, in the United States, 27% of prescriptions written, across all medications, are not filled or are filled but not taken. For ocular hypotensive medications, even when filled, a large percentage (which varies widely by study) are not instilled as prescribed. To address this problem, methods for sustained drug delivery have been and continue to be developed, as well as surgical and laser approaches. Most recently, MIGS devices have gained popularity because of the ease of implantation during cataract surgery, favorable safety profile, and the possibility for effective and long-lasting IOP lowering, as well as the reduction or elimination of need for IOP-lowering medication.Poor adherence to treatment is relatively common among glaucoma patients and is associated with progression of disease. Recommending MIGS implantation during cataract surgery may offer optometrists a valuable treatment option in managing glaucoma patients, particularly where good adherence is in doubt.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

PMID: 29370021 [PubMed - as supplied by publisher]

Short Term High Glucose Treatment Decreased Abundance of Orai1 Protein through Posttranslational Mechanisms in Rat Mesangial Cells.

Thu, 01/25/2018 - 07:42

Short Term High Glucose Treatment Decreased Abundance of Orai1 Protein through Posttranslational Mechanisms in Rat Mesangial Cells.

Am J Physiol Renal Physiol. 2018 Jan 24;:

Authors: Jiang H, Zou S, Chaudhari S, Ma R

Abstract
The short-term effect of high glucose (HG) treatment on store-operated Ca2+ entry in mesangial cells (MCs) is not well known. The aim of the present study was to determine whether and how HG treatment for a short period altered protein abundance of Orai1, the channel mediating store-operated Ca2+ entry in MCs. Rat and human MCs were exposed to HG (25 mM) for 2, 4, 8, and 24 hours and the abundance of Orai1 protein was significantly decreased at the time point of 8 and 16 hours. Consistently, HG treatment for 8 hours significantly reduced store-operated Ca2+ entry in rat MCs. However, HG treatment for the same time periods did not alter the levels of Orai1 transcript. Cycloheximide, a protein synthesis inhibitor did not affect the HG-induced decrease of Orai1 protein, suggesting a post-translation mechanism involved. However, the HG effect on Oari1 protein was significantly attenuated by MG132 (a ubiquitin-proteasome inhibitor) and NH4Cl (a lysosomal pathway inhibitor). Furthermore, HG treatment for 8 hours stimulated ubiquitination of Orai1 protein. We further found that PEG-catalase, an antioxidant significantly blunted the HG-induced reduction of Orai1 protein. In support of involvement of reactive oxygen species in the HG effects, hydrogen peroxide (H2O2) itself significantly decreased abundance of Orai1 protein and increased the level of ubiquitinated Orai1. Taking together, these results suggest that a short-term HG treatment decreased abundance of Orai1 protein in MCs by promoting the protein degradation through the ubiquitination-proteosome and -lysosome mechanisms. This HG-stimulated posttranslational mechanism was mediated by H2O2.

PMID: 29363325 [PubMed - as supplied by publisher]

Exosome-associated release, uptake, and neurotoxicity of HIV-1 Tat protein.

Wed, 01/24/2018 - 07:39
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Exosome-associated release, uptake, and neurotoxicity of HIV-1 Tat protein.

J Neurovirol. 2016 Dec;22(6):774-788

Authors: Rahimian P, He JJ

Abstract
HIV-1 Tat is an indispensible transactivator for HIV gene transcription and replication. It has been shown to exit cells as a free protein and enter neighboring cells or interact with surface receptors of neighboring cells to regulate gene expression and cell function. In this study, we report, for the first time, exosome-associated Tat release and uptake. Using a HIV-1 LTR-driven luciferase reporter-based cell assay and Western blotting or in combination with exosome inhibitor, OptiPrep gradient fractionation, and exosome depletion, we demonstrated significant presence of HIV-1 Tat in exosomes derived from Tat-expressing primary astrocytes, Tat-transfected U373.MG and 293T, and HIV-infected MT4. We further showed that exosome-associated Tat from Tat-expressing astrocytes was capable of causing neurite shortening and neuron death, further supporting that this new form of extracellular Tat is biologically active. Lastly, we constructed a Tat mutant deleted of its basic domain and determined the role of the basic domain in Tat trafficking into exosomes. Basic domain-deleted Tat exhibited no apparent effects on Tat trafficking into exosomes, while maintained its dominant-negative function in Tat-mediated LTR transactivation. Taken together, these results show a significant fraction of Tat is secreted and present in the form of exosomes and may contribute to the stability of extracellular Tat and broaden the spectrum of its target cells.

PMID: 27173397 [PubMed - indexed for MEDLINE]

HIV-1-associated inflammation and antiretroviral therapy regulate astrocyte endoplasmic reticulum stress responses.

Tue, 01/23/2018 - 07:35

HIV-1-associated inflammation and antiretroviral therapy regulate astrocyte endoplasmic reticulum stress responses.

Cell Death Discov. 2017;3:17061

Authors: Nooka S, Ghorpade A

Abstract
Antiretroviral (ARV) therapy (ART) has effectively suppressed the incidence of human immunodeficiency virus (HIV)-associated dementia in HIV-1 positive individuals. However, the prevalence of more subtle forms of neurocognitive dysfunction continues to escalate. Recently, endoplasmic reticulum (ER) stress has been linked to many neurological diseases; yet, its role in HIV/neuroAIDS remains largely unexplored. Furthermore, upregulation of astrocyte elevated gene-1 (AEG-1), a novel HIV-1 inducible gene, along with ER stress markers in a Huntington's disease model, suggests a possible role in HIV-associated ER stress. The current study is focused on unfolded protein responses (UPRs) and AEG-1 regulation in primary human astrocytes exposed to HIV-associated neurocognitive disorders (HAND)-relevant stimuli (HIV-1 virions, inflammation and ARV drugs). Interleukin (IL)-1β and the nucleoside reverse transcriptase inhibitor abacavir upregulated expression of ER stress markers in human astrocytes, including binding immunoglobulin protein (BiP), C/EBP homologous protein (CHOP), and calnexin. In addition, IL-1β activated all three well-known UPR pathways: protein kinase RNA-like ER kinase (PERK); activating transcription factor 6 (ATF-6); and inositol-requiring enzyme 1α (IRE1α). AEG-1 upregulation correlated to ER stress and demonstrated astrocyte AEG-1 interaction with the calcium-binding chaperone, calnexin. IL-1β and abacavir enhanced intracellular calcium signaling in astrocytes in the absence of extracellular calcium, illustrating ER-associated calcium release. Alternatively, calcium evoked in response to HAND-relevant stimuli led to mitochondrial permeability transition pore (mPTP) opening in human astrocytes. Importantly, IL-1β- and abacavir-induced UPR and mPTP opening were inhibited by the intracellular calcium chelation, indicating the critical role of calcium signaling in HAND-relevant ER stress in astrocytes. In summary, our study highlights that ARV drugs and IL-1β induced UPR, AEG-1 expression, intracellular calcium, and mitochondrial depolarization in astrocytes. This study uncovers astrocyte ER stress as a novel therapeutic target in the management of HIV-1-associated neurotoxicity and possibly in the treatment of neuroAIDS.

PMID: 29354290 [PubMed]

B7-H4(B7x)-Mediated Cross-talk between Glioma-Initiating Cells and Macrophages via the IL6/JAK/STAT3 Pathway Lead to Poor Prognosis in Glioma Patients.

Tue, 01/23/2018 - 07:35
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B7-H4(B7x)-Mediated Cross-talk between Glioma-Initiating Cells and Macrophages via the IL6/JAK/STAT3 Pathway Lead to Poor Prognosis in Glioma Patients.

Clin Cancer Res. 2016 Jun 01;22(11):2778-2790

Authors: Yao Y, Ye H, Qi Z, Mo L, Yue Q, Baral A, Hoon DSB, Vera JC, Heiss JD, Chen CC, Zhang J, Jin K, Wang Y, Zang X, Mao Y, Zhou L

Abstract
PURPOSE: The objective of this study was to evaluate clinical significance and immunosuppressive mechanisms of B7-H4 (B7x/B7S1), a B7 family member, in glioma.
EXPERIMENTAL DESIGN: B7-H4 levels in glioma tissue/cerebral spinal fluid (CSF) were compared between different grades of glioma patients. Survival data were analyzed with Kaplan-Meier to determine the prognostic value of B7-H4. Cytokines from CD133(+) cells to stimulate the expression of B7-H4 on human macrophages (Mφs) were investigated by FACS, neutralizing antibodies, and Transwell chemotaxis assay. shRNA, reporter vector, and chromatin immunoprecipitation were used to determine the binding of STAT3 to the B7-H4 promoter. The function of B7-H4(+) Mφs in vitro was evaluated through phagocytosis, T-cell proliferation/apoptosis, and cytokine production as well as in the xenografted model for in vivo analysis.
RESULTS: We found that B7-H4 expression in tumors was associated with prognosis of human glioblastoma and correlated directly with malignant grades. Mechanistically, glioma initiating CD133(+) cells and Mφs/microglia cointeraction activated expression of B7-H4 via IL6 and IL10 in both tumor cells and microenvironment supporting cells. IL6-activated STAT3 bound to the promoter of B7-H4 gene and enhanced B7-H4 expression. Furthermore, CD133(+) cells mediated immunosuppression through B7-H4 expression on Mφs/microglia by silencing of B7-H4 expression on these cells, which led to increased microenvironment T-cell function and tumor regression in the xenograft glioma mouse model.
CONCLUSIONS: We have identified B7-H4 activation on Mφs/microglia in the microenvironment of gliomas as an important immunosuppressive event blocking effective T-cell immune responses. Clin Cancer Res; 22(11); 2778-90. ©2016 AACR.

PMID: 27001312 [PubMed - indexed for MEDLINE]

The effects of state rules on opioid prescribing in Indiana.

Sat, 01/20/2018 - 07:40

The effects of state rules on opioid prescribing in Indiana.

BMC Health Serv Res. 2018 Jan 18;18(1):29

Authors: Al Achkar M, Grannis S, Revere D, MacKie P, Howard M, Gupta S

Abstract
BACKGROUND: Prescription opioids have been linked to over half of the 28,000 opioid overdose deaths in 2014. High rates of prescription opioid non-medical use have continued despite nearly all states implementing large-scale prescription drug monitoring programs (PDMP), which points to the need to examine the impact of state PDMP's on curbing inappropriate opioid prescribing. In the short-term, PDMPs have been associated with short-term prescribing declines. Yet little is known about how such policies differentially impact patient subgroups or are interpreted by prescribing providers. Our objective was to compare volumes of prescribed opioids before and after Indiana implemented opioid prescribing emergency rules and stratify the changes in opioid prescribing by patient and provider subgroups.
METHODS: An interrupted time series analysis was conducted using data obtained from the Indiana PDMP. Prescription level data was merged with census data to characterize patient socioeconomic status. Analyses were stratified by patients' gender, age, opioid dosage, and payer. The primary outcome indicator was the total morphine equivalent dose (MED) of dispensed opioids per day in the state of Indiana. Also considered were number of unique patients, unique providers, and prescriptions; MED per transaction and per day; and number of days supplied.
RESULTS: After controlling for time trends, we found that total MED for opioids decreased after implementing the new emergency rules, differing by patient gender, age, and payer. The effect was larger for males than females and almost 10 times larger for 0-20 year olds as compared to the 60+ age range. Medicare and Medicaid patients experienced more decline in prescribing than patients with private insurance. Patients with prescriptions paid for by workers' comp experienced the most significant decline. The emergency rules were associated with decline in both the number of prescribers and the number of day supply.
CONCLUSIONS: Although the Indiana opioid prescribing emergency rules impacted statewide prescribing behavior across all individual patient and provider characteristics, the emergency rules' effect was not consistent across patient characteristics. Further studies are needed to assess how individual patient characteristics influence the interpretation and application of state policies on opioid prescribing.

PMID: 29347984 [PubMed - in process]

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