Recent Research Articles from UNTHSC

Recent research articles indexed in PubMed from authors affiliated with the UNT Health Science Center.

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Fixed-dose gabapentin augmentation in the treatment of alcohol withdrawal syndrome: a retrospective, open-label study.

Sat, 09/07/2019 - 06:50
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Fixed-dose gabapentin augmentation in the treatment of alcohol withdrawal syndrome: a retrospective, open-label study.

Am J Drug Alcohol Abuse. 2019 Sep 06;:1-9

Authors: Andaluz A, DeMoss D, Claassen C, Blair S, Hsu J, Bakre S, Khan M, Atem F, Rush AJ

Abstract
Background: Lorazepam use in the treatment of alcohol withdrawal syndrome (AWS) is not without risk. Objective: This study compares AWS outcomes using a standard, symptom-triggered lorazepam dosing protocol (control group) and symptom-triggered lorazepam dosing augmented with a gabapentin loading dose and taper (GABA group). Methods: Consecutive, non-randomized adults (n = 982; 64.0% male) undergoing treatment for AWS were included in this retrospective, open-label study. Symptom-triggered lorazepam dosing was informed by scores on the Clinical Institute Withdrawal Assessment-Alcohol, revised (CIWA-Ar). Gabapentin augmentation utilized an initial loading dose (900 mg) and a three-day taper. Outcomes included average symptom severity per treatment hour and average lorazepam dose per treatment hour. Average time in the protocol by group, stratified by highest CIWA-Ar score, was examined as a secondary outcome. A priori group differences were controlled statistically. Results: GABA patients were older and exhibited somewhat more severe withdrawal symptoms than controls. After controlling for confounders, gabapentin augmentation did not significantly lower average lorazepam dosing per treatment hour or withdrawal symptom severity per treatment hour. Compared to controls, overall withdrawal symptoms diminished somewhat more rapidly for GABA patients experiencing low or moderate-level withdrawal symptoms; however, severe withdrawal symptoms remitted more slowly in the GABA group. Results should be interpreted in light of the uncontrolled nature of group assignment and other confounders. Conclusions: Compared to symptom-triggered lorazepam dosing alone, gabapentin augmentation did not produce better outcomes during treatment of acute AWS. These results do not support the use of scheduled gabapentin as an augmentation to benzodiazepines during inpatient treatment of AWS.

PMID: 31490712 [PubMed - as supplied by publisher]

Are Health Care Professionals Prepared to Implement Human Papillomavirus Testing? A Review of Psychosocial Determinants of Human Papillomavirus Test Acceptability in Primary Cervical Cancer Screening.

Wed, 09/04/2019 - 06:31

Are Health Care Professionals Prepared to Implement Human Papillomavirus Testing? A Review of Psychosocial Determinants of Human Papillomavirus Test Acceptability in Primary Cervical Cancer Screening.

J Womens Health (Larchmt). 2019 Sep 03;:

Authors: Tatar O, Wade K, McBride E, Thompson E, Head KJ, Perez S, Shapiro GK, Waller J, Zimet G, Rosberger Z

Abstract
Background: Guidelines for cervical cancer screening have been updated to include human papillomavirus (HPV) testing, which is more sensitive compared to cytology in detecting cervical intraepithelial neoplasia. Because of its increased sensitivity, a negative HPV test is more reassuring for a woman that she is at low risk for precancerous cervical lesions than a negative Pap test. Prompted by the inadequate translation of HPV test-based screening guidelines into practice, we aimed to synthesize the literature regarding health care providers (HCPs) knowledge, attitudes, and practices related to HPV testing and the influence of psychosocial factors on HCPs acceptability of HPV testing in primary cervical cancer screening. Materials and Methods: We searched MEDLINE, Embase, PsycINFO, CINAHL, Global Health, and Web of Science for journal articles from January 1, 1980 to July 25, 2018. A narrative synthesis of HCPs knowledge, attitudes, and practices related to HPV testing is provided. Informed by the Patient Pathway framework, we used deductive thematic analysis to synthesize the influence of psychosocial factors on HCPs acceptability of HPV testing. Results: The most important HCP knowledge gaps are related to the superior sensitivity of the HPV test and age-specific guideline recommendations for HPV testing. Thirty to fifty percent of HCPs are not compliant with guideline recommendations for HPV testing, for example, screening at shorter intervals than recommended. Barriers, facilitators, and contradictory evidence of HCPs' acceptability of the HPV test are grouped by category: (1) factors related to the HCP; (2) patient intrinsic factors; (3) factors corresponding to HCP's practice environment; and (4) health care system factors. Conclusions: HCP's adherence to guidelines for HPV testing in cervical cancer screening is suboptimal and could be improved by specialty organizations ensuring consistency across guidelines. Targeted educational interventions to address barriers of HPV test acceptability identified in this review may facilitate the translation of HPV testing recommendations into practice.

PMID: 31479381 [PubMed - as supplied by publisher]

CONNECT: Implementation of a School-Based Alcohol Screening and Brief Intervention for Youth in the Cherokee Nation.

Wed, 09/04/2019 - 06:31
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CONNECT: Implementation of a School-Based Alcohol Screening and Brief Intervention for Youth in the Cherokee Nation.

J Sch Health. 2019 Sep 02;:

Authors: Garrett BA, Komro KA, Merlo LJ, Livingston BJ, Rentmeester S, Tobler A, Livingston MD, Kominsky TK

Abstract
BACKGROUND: There is growing optimism regarding the use of screening and brief intervention (SBI) to identify and reduce risk behaviors during adolescence. However, understanding successful SBI implementation remains unclear. We previously reported the effects of CONNECT, a school-based SBI, on reducing the primary outcome, the rate of monthly alcohol use among primarily American Indian (AI) and White high school students in the Cherokee Nation. In this paper, we describe the design and implementation process for CONNECT.
METHOD: CONNECT was designed to reduce alcohol use with 2 key strategies: (1) SBI with motivational interviewing (MI), implemented by a school-based CONNECT coach, and (2) a media campaign.
RESULTS: Implementation results indicate that during each semester of the 2-1/2 years, between 73% and 100% of eligible students had at least one 15-minute meeting with a CONNECT coach. Postcards and posters with positive communication tips for parents were displayed in CONNECT communities. No statistically significant differences occurred between the CONNECT and control groups on the hypothesized intermediate outcomes.
CONCLUSIONS: We describe implementation of a universal, school-based, culturally adapted SBI that was effective in reducing alcohol use among youth living in the Cherokee Nation. Schools provide an important context for universal delivery of SBI interventions, such as CONNECT, for diverse adolescent populations, including AI youth.

PMID: 31478206 [PubMed - as supplied by publisher]

Angiotensin receptor and tumor necrosis factor-α activation contributes to glucose intolerance independent of systolic blood pressure in obese rats.

Wed, 09/04/2019 - 06:31
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Angiotensin receptor and tumor necrosis factor-α activation contributes to glucose intolerance independent of systolic blood pressure in obese rats.

Am J Physiol Renal Physiol. 2018 10 01;315(4):F1081-F1090

Authors: Rodriguez R, Lee A, Mathis KW, Broome HJ, Thorwald M, Martinez B, Nakano D, Nishiyama A, Ryan MJ, Ortiz RM

Abstract
Pathological activation of the renin-angiotensin system and inflammation are associated with hypertension and the development of metabolic syndrome (MetS). The contributions of angiotensin receptor type 1 (AT1) activation, independent of blood pressure, and inflammation to glucose intolerance and renal damage are not well defined. Using a rat model of MetS, we hypothesized that the onset of glucose intolerance is primarily mediated by AT1 activation and inflammation independent of elevated systolic blood pressure (SBP). To address this hypothesis, we measured changes in SBP, adiposity, plasma glucose and triglyceride levels, and glucose tolerance in six groups of rats: 1) lean, strain control Long-Evans Tokushima Otsuka (LETO; n = 5), 2) obese Otsuka Long-Evans Tokushima Fatty (OLETF; n = 8), 3) OLETF + angiotensin receptor blocker (ARB; 10 mg olmesartan/kg; n = 8), 4) OLETF + tumor necrosis factor-α (TNF-α) inhibitor (ETAN; 1.25 mg etanercept/kg; n = 6), 5) OLETF + TNF-α inhibitor + angiotensin receptor blocker (ETAN+ARB; 1.25 mg etanercept/kg + 10 mg olmesartan/kg; n = 6), and 6) OLETF + calcium channel blocker (CCB; 5 mg amlodipine/kg; n = 7). ARB and ETAN+ARB were most effective at decreasing SBP in OLETF, and ETAN did not offer any additional reduction. Glucose tolerance improved in ARB, ETAN, and ETAN+ARB compared with OLETF, whereas CCB had no detectable effect. Furthermore, all treatments reduced adiposity, whereas ETAN alone normalized urinary albumin excretion. These results suggest that AT1 activation and inflammation are primary factors in the development of glucose intolerance in a setting of MetS and that the associated increase in SBP is primarily mediated by AT1 activation.

PMID: 29993275 [PubMed - indexed for MEDLINE]

Short-term high-glucose treatment decreased abundance of Orai1 protein through posttranslational mechanisms in rat mesangial cells.

Wed, 09/04/2019 - 06:31
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Short-term high-glucose treatment decreased abundance of Orai1 protein through posttranslational mechanisms in rat mesangial cells.

Am J Physiol Renal Physiol. 2018 05 01;314(5):F855-F863

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 h, and the abundance of Orai1 protein was significantly decreased at the time points of 8 and 16 h. Consistently, HG treatment for 8 h 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 posttranslational mechanism was involved. However, the HG effect on Orai1 protein was significantly attenuated by MG132 (a ubiquitin-proteasome inhibitor) and NH4Cl (a lysosomal pathway inhibitor). Furthermore, HG treatment for 8 h stimulated ubiquitination of Orai1 protein. We further found that polyethylene glycol-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. Taken 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-proteasome and -lysosome mechanisms. This HG-stimulated posttranslational mechanism was mediated by H2O2.

PMID: 29363325 [PubMed - indexed for MEDLINE]

Pharmacological potentiation of the efferent vagus nerve attenuates blood pressure and renal injury in a murine model of systemic lupus erythematosus.

Fri, 08/30/2019 - 05:38
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Pharmacological potentiation of the efferent vagus nerve attenuates blood pressure and renal injury in a murine model of systemic lupus erythematosus.

Am J Physiol Regul Integr Comp Physiol. 2018 12 01;315(6):R1261-R1271

Authors: Pham GS, Wang LA, Mathis KW

Abstract
Recent evidence suggests hypertension may be secondary to chronic inflammation that results from hypoactive neuro-immune regulatory mechanisms. To further understand this association, we used systemic lupus erythematosus (SLE) as a model of inflammation-induced hypertension. In addition to prevalent inflammatory kidney disease and hypertension, SLE patients suffer from dysautonomia in the form of decreased efferent vagal tone. Based on this, the cholinergic anti-inflammatory pathway, an endogenous vagus-to-spleen mechanism that, when activated results in decreases in systemic inflammation, may be compromised in SLE. We hypothesized that stimulation of the cholinergic anti-inflammatory pathway via pharmacological potentiation of the efferent vagus nerve would reduce inflammation and halt the development of hypertension and renal injury in SLE. Female NZBWF1 mice, an established model of murine SLE, and female control mice were treated with galantamine (4 mg/kg daily ip), an acetylcholinesterase inhibitor, or saline for 14 days. At the end of therapy, carotid catheters were surgically implanted and were used to measure mean arterial pressure before the animals were euthanized. Chronic galantamine administration attenuated both splenic and renal cortical inflammation, which likely explains why the hypertension and renal injury (i.e., glomerulosclerosis and fibrosis) typically observed in murine SLE was attenuated following therapy. Based on this, the anti-inflammatory, antihypertensive, and renoprotective effects of galantamine may be mediated through activation of the cholinergic anti-inflammatory pathway. It is possible that dysfunction of the cholinergic anti-inflammatory pathway exists in SLE at the level of the efferent vagus nerve and promoting restoration of its activity through central cholinergic receptor activation may be beneficial.

PMID: 30332305 [PubMed - indexed for MEDLINE]

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

Fri, 08/30/2019 - 05:38
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Blood-based biomarkers for Alzheimer disease: mapping the road to the clinic.

Nat Rev Neurol. 2018 11;14(11):639-652

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 - indexed for MEDLINE]

Vasodilator function is impaired in burn injury survivors.

Fri, 08/30/2019 - 05:38
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Vasodilator function is impaired in burn injury survivors.

Am J Physiol Regul Integr Comp Physiol. 2018 11 01;315(5):R1054-R1060

Authors: Romero SA, Moralez G, Jaffery MF, Huang M, Crandall CG

Abstract
The effect of severe burn injury on vascular health is unknown. We tested the hypothesis that, compared with nonburn control subjects, vasodilator function would be reduced and that pulse-wave velocity (a measure of arterial stiffness) would be increased in individuals with prior burn injuries, the extent of which would be associated with the magnitude of body surface area having sustained a severe burn. Pulse-wave velocity and macrovascular (flow-mediated dilation) and microvascular (reactive hyperemia) dilator functions were assessed in 14 nonburned control subjects and 32 age-matched subjects with well-healed burn injuries. Fifteen subjects with burn injuries covering 17-40% of body surface area were assigned to a moderate burn injury group, and 17 subjects with burn injuries covering >40% of body surface area were assigned to a high burn injury group. Pulse-wave velocity [ P = 0.3 (central) and P = 0.3 (peripheral)] did not differ between the three groups. Macrovascular dilator function was reduced in the moderate ( P = 0.07) and high ( P < 0.05) burn injury groups compared with the control group. Likewise, peak vascular conductance during postocclusive reactive hyperemia differed from the moderate burn injury group ( P = 0.08 vs. control) and the high burn injury group ( P < 0.05 vs. control). These data suggest that vasodilator function is impaired in well-healed burn injury survivors, with the extent of impairment not dependent on the magnitude of body surface area having sustained a severe burn injury.

PMID: 30256680 [PubMed - indexed for MEDLINE]

Improved glucose homeostasis in male obese Zucker rats coincides with enhanced baroreflexes and activation of the nucleus tractus solitarius.

Fri, 08/30/2019 - 05:38
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Improved glucose homeostasis in male obese Zucker rats coincides with enhanced baroreflexes and activation of the nucleus tractus solitarius.

Am J Physiol Regul Integr Comp Physiol. 2018 12 01;315(6):R1195-R1209

Authors: Chaudhary P, Schreihofer AM

Abstract
Young adult male obese Zucker rats (OZR) develop insulin resistance and hypertension with impaired baroreflex-mediated bradycardia and activation of nucleus tractus solitarius (NTS). Because type 1 diabetic rats also develop impaired baroreflex-mediated NTS activation, we hypothesized that improving glycemic control in OZR would enhance compromised baroreflexes and NTS activation. Fasting blood glucose measured by telemetry was comparable in OZR and lean Zucker rats (LZR) at 12-17 wk. However, with access to food, OZR were chronically hyperglycemic throughout this age range. By 15-17 wk of age, tail samples yielded higher glucose values than those measured by telemetry in OZR but not LZR, consistent with reports of exaggerated stress responses in OZR. Injection of glucose (1g/kg ip) produced larger rises in glucose and areas under the curve in OZR than LZR. Treatment with metformin (300 mg·kg-1·day-1) or pioglitazone (5 mg·kg-1·day-1) in drinking water for 2-3 wk normalized fed glucose levels in OZR with no effect in LZR. After metformin treatment, area under the curve for blood glucose after glucose injection was reduced in OZR and comparable to LZR. Hyperinsulinemia was slightly reduced by each treatment in OZR, but insulin was still greatly elevated compared with LZR. Neither treatment reduced hypertension in OZR, but both treatments significantly improved the blunted phenylephrine-induced bradycardia and NTS c-Fos expression in OZR with no effect in LZR. These data suggest that restoring glycemic control in OZR enhances baroreflex control of heart rate by improving the response of the NTS to raising arterial pressure, even in the presence of hyperinsulinemia and hypertension.

PMID: 30256679 [PubMed - indexed for MEDLINE]

AT1a influences GABAA-mediated inhibition through regulation of KCC2 expression.

Fri, 08/30/2019 - 05:38
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AT1a influences GABAA-mediated inhibition through regulation of KCC2 expression.

Am J Physiol Regul Integr Comp Physiol. 2018 11 01;315(5):R972-R982

Authors: Farmer GE, Balapattabi K, Bachelor ME, Little JT, Cunningham JT

Abstract
The median preoptic nucleus (MnPO) is an integrative site involved in body fluid homeostasis, cardiovascular control, thermoregulation, and sleep homeostasis. Angiotensin II (ANG II), a neuropeptide shown to have excitatory effects on MnPO neurons, is of particular interest with regard to its role in body fluid homeostasis and cardiovascular control. The present study investigated the role of angiotensin type 1a (AT1a) receptor activation on neuronal excitability in the MnPO. Male Sprague-Dawley rats were infused with an adeno-associated virus with an shRNA against the AT1a receptor or a scrambled control. In vitro loose-patch voltage-clamp recordings of spontaneous action potential activity were made from labeled MnPO neurons in response to brief focal application of ANG II or the GABAA receptor agonist muscimol. Additionally, tissue punches from MnPO were taken to asses mRNA and protein expression. AT1a receptor knockdown neurons were insensitive to ANG II and showed a marked reduction in GABAA-mediated inhibition. The reduction in GABAA-mediated inhibition was not associated with reductions in mRNA or protein expression of GABAA β-subunits. Knockdown of the AT1a receptor was associated with a reduction in the potassium-chloride cotransporter KCC2 mRNA as well as a reduction in pS940 KCC2 protein. The impaired GABAA-mediated inhibition in AT1a knockdown neurons was recovered by bath application of phospholipase C and protein kinase C activators. The following study indicates that AT1a receptor activation mediates the excitability of MnPO neurons, in part, through the regulation of KCC2. The regulation of KCC2 influences the intracellular [Cl-] and the subsequent efficacy of GABAA-mediated currents.

PMID: 30156863 [PubMed - indexed for MEDLINE]

Case study: Scoliosis in a Bonobo (Pan paniscus).

Fri, 08/30/2019 - 05:38
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Case study: Scoliosis in a Bonobo (Pan paniscus).

J Med Primatol. 2018 04;47(2):114-116

Authors: Lloyd HMS, Kirchhoff CA

Abstract
Differential diagnosis of observed morphological features on an adult male bonobo skeleton was consistent with idiopathic scoliosis. Directional asymmetry was an order of magnitude higher compared with asymptomatic skeletons. This possible case of idiopathic scoliosis contributes to data that suggest a weaker tie between bipedalism and scoliosis than previously hypothesized.

PMID: 29193149 [PubMed - indexed for MEDLINE]

Vaping Expectancies: A Qualitative Study among Young Adult Nonusers, Smokers, Vapers, and Dual Users.

Thu, 08/29/2019 - 05:29

Vaping Expectancies: A Qualitative Study among Young Adult Nonusers, Smokers, Vapers, and Dual Users.

Subst Abuse. 2019;13:1178221819866210

Authors: Harrell PT, Brandon TH, England KJ, Barnett TE, Brockenberry LO, Simmons VN, Quinn GP

Abstract
Background: "Expectancies," or beliefs about outcomes, robustly correlate with and predict several behaviors including electronic nicotine delivery system ("e-cigarette") use. However, there is limited qualitative research available regarding relevant e-cigarette vaping expectancies.
Objectives: The present study used a qualitative approach to derive and refine e-cigarette expectancy themes among young adults.
Methods: We conducted 12 focus groups and two individual interviews with young adult nonusers, e-cigarette vapers, cigarette smokers, and dual users to assess beliefs about the effects of e-cigarettes. After a series of open-ended questions, follow-up questions assessed reactions to domains previously examined in expectancy measures for cigarette smoking and e-cigarette vaping. The constant comparative method was used to derive themes from transcripts.
Results: Four main themes (Positive Reinforcement, Social Benefits, Negative Affect Reduction, Negative Consequences) emerged from the results. Each theme contained three associated subthemes (Positive Reinforcement: Sensorimotor Experiences, Taste, Stimulation; Social Benefits: Social Facilitation, Influence on Others, Convenience; Negative Affect Reduction: Stress Reduction, Appetite Reduction, Boredom Reduction; and Negative Consequences: Health Risks, Addiction, Secondhand Effects).
Conclusions/importance: Previously identified smoking expectancies appear relevant for young adult vaping, with some notable refinements. Positive reinforcement aspects encompassed aerosol clouds, vaping tricks, and unique flavors. Social benefits included influencing others via social media and competitive activity, as well as the convenience of use in a variety of places. Negative affect reduction was controversial among user groups, but vaping was seen as more interesting than smoking and thus more effective at boredom reduction. Young adults were uncertain regarding negative consequences, but appreciated a potential for secondhand effects. Measure refinement via qualitative research and future field testing can enhance our understanding of this relatively new behavior, supporting tobacco control surveillance, marketing/labeling regulations, and counter-advertising development/evaluation.

PMID: 31456638 [PubMed]

Influence of neurovascular mechanisms on response to tDCS: an exploratory study.

Thu, 08/29/2019 - 05:29
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Influence of neurovascular mechanisms on response to tDCS: an exploratory study.

Exp Brain Res. 2019 Aug 27;:

Authors: Iyer PC, Rosenberg A, Baynard T, Madhavan S

Abstract
The beneficial effects of transcranial direct current stimulation (tDCS) for stroke rehabilitation are limited by the variability in changes in corticomotor excitability (CME) after tDCS. Neuronal activity is closely related to cerebral blood flow; however, the cerebral hemodynamics of neuromodulation in relation to neural effects have been less explored. In this study, we examined the effects of tDCS on cerebral blood velocity (CBv) in chronic stroke survivors using transcranial Doppler (TCD) ultrasound in relation to changes in CME and described the neurovascular characteristics of tDCS responders. Middle cerebral artery (MCA) CBv, cerebrovascular resistance (CVRi) and other cerebral hemodynamics-related variables were continuously measured before and after 15 min of 1 mA anodal tDCS to the lesioned lower limb M1. tDCS did not modulate CBv in the whole group and upon TMS-based stratification of responders and non-responders. However, at baseline, responders demonstrated lower CME levels, lower CBv and higher CVRi as compared to non-responders. These results indicate a possible difference in baseline CME and CBv in tDCS responders that may influence their response to neuromodulation. Future trials with a large sample size and repeated baseline measurements may help validate these findings and establish a relationship between neuromodulation and neurovascular mechanisms in stroke.

PMID: 31455998 [PubMed - as supplied by publisher]

Immunological Responses to the Relapsing Fever Spirochete Borrelia turicatae in Infected Rhesus Macaques: Implications for Pathogenesis and Diagnosis.

Thu, 08/29/2019 - 05:29
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Immunological Responses to the Relapsing Fever Spirochete Borrelia turicatae in Infected Rhesus Macaques: Implications for Pathogenesis and Diagnosis.

Infect Immun. 2019 04;87(4):

Authors: Embers ME, Krishnavajhala A, Armstrong BA, Curtis MW, Pahar B, Wilder HK, Allen MS, Beare PA, Hasenkampf NR, Lopez JE

Abstract
The global public health impact of relapsing fever (RF) spirochetosis is significant, since the pathogens exist on five of seven continents. The hallmark sign of infection is episodic fever and the greatest threat is to the unborn. With the goal of better understanding the specificity of B-cell responses and the role of immune responses in pathogenicity, we infected rhesus macaques with Borrelia turicatae (a new world RF spirochete species) by tick bite and monitored the immune responses generated in response to the pathogen. Specifically, we evaluated inflammatory mediator induction by the pathogen, host antibody responses to specific antigens, and peripheral lymphocyte population dynamics. Our results indicate that B. turicatae elicits from peripheral blood cells key inflammatory response mediators (interleukin-1β and tumor necrosis factor alpha), which are associated with preterm abortion. Moreover, a global decline in peripheral B-cell populations was observed in all animals at 14 days postinfection. Serological responses were also evaluated to assess the antigenicity of three surface proteins: BipA, BrpA, and Bta112. Interestingly, a distinction was observed between antibodies generated in nonhuman primates and mice. Our results provide support for the nonhuman primate model not only in studies of prenatal pathogenesis but also for diagnostic and vaccine antigen identification and testing.

PMID: 30642902 [PubMed - indexed for MEDLINE]

Stress and interferon signalling-mediated apoptosis contributes to pleiotropic anticancer responses induced by targeting NGLY1.

Thu, 08/29/2019 - 05:29
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Stress and interferon signalling-mediated apoptosis contributes to pleiotropic anticancer responses induced by targeting NGLY1.

Br J Cancer. 2018 12;119(12):1538-1551

Authors: Zolekar A, Lin VJT, Mishra NM, Ho YY, Hayatshahi HS, Parab A, Sampat R, Liao X, Hoffmann P, Liu J, Emmitte KA, Wang YC

Abstract
BACKGROUND: Although NGLY1 is known as a pivotal enzyme that catalyses the deglycosylation of denatured glycoproteins, information regarding the responses of human cancer and normal cells to NGLY1 suppression is limited.
METHODS: We examined how NGLY1 expression affects viability, tumour growth, and responses to therapeutic agents in melanoma cells and an animal model. Molecular mechanisms contributing to NGLY1 suppression-induced anticancer responses were revealed by systems biology and chemical biology studies. Using computational and medicinal chemistry-assisted approaches, we established novel NGLY1-inhibitory small molecules.
RESULTS: Compared with normal cells, NGLY1 was upregulated in melanoma cell lines and patient tumours. NGLY1 knockdown caused melanoma cell death and tumour growth retardation. Targeting NGLY1 induced pleiotropic responses, predominantly stress signalling-associated apoptosis and cytokine surges, which synergise with the anti-melanoma activity of chemotherapy and targeted therapy agents. Pharmacological and molecular biology tools that inactivate NGLY1 elicited highly similar responses in melanoma cells. Unlike normal cells, melanoma cells presented distinct responses and high vulnerability to NGLY1 suppression.
CONCLUSION: Our work demonstrated the significance of NGLY1 in melanoma cells, provided mechanistic insights into how NGLY1 inactivation leads to eradication of melanoma with limited impact on normal cells, and suggested that targeting NGLY1 represents a novel anti-melanoma strategy.

PMID: 30385822 [PubMed - indexed for MEDLINE]

Lifetime exposure to ambient air pollution and methylation of tumor suppressor genes in breast tumors.

Thu, 08/29/2019 - 05:29
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Lifetime exposure to ambient air pollution and methylation of tumor suppressor genes in breast tumors.

Environ Res. 2018 02;161:418-424

Authors: Callahan CL, Bonner MR, Nie J, Han D, Wang Y, Tao MH, Shields PG, Marian C, Eng KH, Trevisan M, Beyea J, Freudenheim JL

Abstract
BACKGROUND: We previously reported increased risk of breast cancer associated with early life exposure to two measures of air pollution exposure, total suspended particulates (TSP) and traffic emissions (TE), possible proxies for exposure to polycyclic aromatic hydrocarbons (PAHs). Exposure to PAHs has been shown to be associated with aberrant patterns of DNA methylation in peripheral blood of healthy individuals. Exposure to PAHs and methylation in breast tumor tissue has received little attention. We examined the association of early life exposure to TSP and TE with patterns of DNA methylation in breast tumors.
METHODS: We conducted a study of women enrolled in the Western New York Exposures and Breast Cancer (WEB) Study. Methylation of nine genes (SFN, SCGB3A1, RARB, GSTP1, CDKN2A CCND2, BRCA1, FHIT, and SYK) was assessed using bisulfite-based pyrosequencing. TSP exposure at each woman's home address at birth, menarche, and when she had her first child was estimated. TE exposure was modeled for each woman's residence at menarche, her first birth, and twenty and ten years prior to diagnosis. Unconditional logistic regression was employed to estimate odds ratios (OR) of having methylation greater than the median value, adjusting for age, secondhand smoke exposure before age 20, current smoking status, and estrogen receptor status.
RESULTS: Exposure to higher TSP at a woman's first birth was associated with lower methylation of SCGB3A1 (OR = 0.48, 95% CI: 0.23-0.99) and higher methylation of SYK (OR = 1.86, 95% CI: 1.03-3.35). TE at menarche was associated with increased methylation of SYK (OR = 2.37, 95% CI: 1.05-5.33). TE at first birth and ten years prior to diagnosis was associated with decreased methylation of CCND2 (OR ten years prior to diagnosis=0.48, 95% CI: 0.26-0.89). Although these associations were nominally significant, none were significant after adjustment for multiple comparisons (p < 0.01).
CONCLUSIONS: We observed suggestive evidence that exposure to ambient air pollution throughout life, measured as TSP and TE, may be associated with DNA methylation of some tumor suppressor genes in breast tumor tissue. Future studies with a larger sample size that assess methylation of more sites are warranted.

PMID: 29197760 [PubMed - indexed for MEDLINE]

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

Wed, 08/28/2019 - 14:26
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Electronic Nicotine Delivery Systems Marketing and Initiation Among Youth and Young Adults.

Pediatrics. 2019 Aug 26;:

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 - as supplied by publisher]

Ischaemic and hypoxic conditioning: potential for protection of vital organs.

Tue, 08/27/2019 - 05:19
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Ischaemic and hypoxic conditioning: potential for protection of vital organs.

Exp Physiol. 2019 03;104(3):278-294

Authors: Sprick JD, Mallet RT, Przyklenk K, Rickards CA

Abstract
NEW FINDINGS: What is the topic of this review? Remote ischaemic preconditioning (RIPC) and hypoxic preconditioning as novel therapeutic approaches for cardiac and neuroprotection. What advances does it highlight? There is improved understanding of mechanisms and signalling pathways associated with ischaemic and hypoxic preconditioning, and potential pitfalls with application of these therapies to clinical trials have been identified. Novel adaptations of preconditioning paradigms have also been developed, including intermittent hypoxia training, RIPC training and RIPC-exercise, extending their utility to chronic settings.
ABSTRACT: Myocardial infarction and stroke remain leading causes of death worldwide, despite extensive resources directed towards developing effective treatments. In this Symposium Report we highlight the potential applications of intermittent ischaemic and hypoxic conditioning protocols to combat the deleterious consequences of heart and brain ischaemia. Insights into mechanisms underlying the protective effects of intermittent hypoxia training are discussed, including the activation of hypoxia-inducible factor-1 and Nrf2 transcription factors, synthesis of antioxidant and ATP-generating enzymes, and a shift in microglia from pro- to anti-inflammatory phenotypes. Although there is little argument regarding the efficacy of remote ischaemic preconditioning (RIPC) in pre-clinical models, this strategy has not consistently translated into the clinical arena. This lack of translation may be related to the patient populations targeted thus far, and the anaesthetic regimen used in two of the major RIPC clinical trials. Additionally, we do not fully understand the mechanism through which RIPC protects the vital organs, and co-morbidities (e.g. hypercholesterolemia, diabetes) may interfere with its efficacy. Finally, novel adaptations have been made to extend RIPC to more chronic settings. One adaptation is RIPC-exercise (RIPC-X), an innovative paradigm that applies cyclical RIPC to blood flow restriction exercise (BFRE). Recent findings suggest that this novel exercise modality attenuates the exaggerated haemodynamic responses that may limit the use of conventional BFRE in some clinical settings. Collectively, intermittent ischaemic and hypoxic conditioning paradigms remain an exciting frontier for the protection against ischaemic injuries.

PMID: 30597638 [PubMed - indexed for MEDLINE]

Perceived vulnerability moderates the relations between the use of protective behavioral strategies and alcohol use and consequences among high-risk young adults.

Tue, 08/27/2019 - 05:19
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Perceived vulnerability moderates the relations between the use of protective behavioral strategies and alcohol use and consequences among high-risk young adults.

Addict Behav. 2018 06;81:150-156

Authors: Garcia TA, Fairlie AM, Litt DM, Waldron KA, Lewis MA

Abstract
Drinking protective behavioral strategies (PBS) have been associated with reductions in alcohol use and alcohol-related consequences in young adults. PBS subscales, Limiting/Stopping (LS), Manner of Drinking (MOD), and Serious Harm Reduction (SHR), have been examined in the literature; LS, MOD, and SHR have mixed support as protective factors. Understanding moderators between PBS and alcohol use and related consequences is an important development in PBS research in order to delineate when and for whom PBS use is effective in reducing harm from alcohol use. Perceptions of vulnerability to negative consequences, included in health-risk models, may be one such moderator. The current study examined whether two types of perceived vulnerability (perceived vulnerability when drinking; perceived vulnerability in uncomfortable/unfamiliar situations) moderated the relations between LS, MOD, SHR strategies and alcohol use and related negative consequences. High-risk young adults (N = 400; 53.75% female) recruited nationally completed measures of PBS, alcohol use and related consequences, and measures of perceived vulnerability. Findings demonstrated that perceived vulnerability when drinking moderated the relations between MOD strategies and alcohol use. The interactions between perceived vulnerability when drinking and PBS did not predict alcohol-related consequences. Perceived vulnerability in unfamiliar/uncomfortable social situations moderated relations between MOD strategies and both alcohol use and related negative consequences; no other significant interactions emerged. Across both perceived vulnerability types and MOD strategies, those with the highest levels of perceived vulnerability and who used MOD strategies the most had the greatest decrements in alcohol use and related negative consequences. Prevention and intervention implications are discussed.

PMID: 29459200 [PubMed - indexed for MEDLINE]

A novel phylogenetic approach for de novo discovery of putative nuclear mitochondrial (pNumt) haplotypes.

Mon, 08/26/2019 - 05:10
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A novel phylogenetic approach for de novo discovery of putative nuclear mitochondrial (pNumt) haplotypes.

Forensic Sci Int Genet. 2019 Aug 14;43:102146

Authors: Smart U, Budowle B, Ambers A, Soares Moura-Neto R, Silva R, Woerner AE

Abstract
Current approaches for parsing true variation (i.e. signal) from noise, broadly involve estimating a baseline value of the latter, below which all sequence data are ignored. In an effort to deliver a more objective criterion for setting such thresholds, a novel approach based on phylogenetic principles is presented here., Our method deconstructs a special category of noise from true mitochondrial genome data, namely nuclear insertions of mitochondrial DNA (Numts). This bioinformatic approach leverages the relationship of massively parallel sequence reads and is capable of discovering putative Numts (pNumts) in absence of a reference genome. The new method was tested on a whole mitochondrial genome dataset (n = 41 individuals from an admixed population sample from Rio de Janeiro) and led to the discovery of 451 pNumt variants. Comparison of these pNumts haplotypes against an existing Numt database revealed 147 exact matches to previously discovered Numts, while 122 haplotypes differed only by a single base pair and none matched exclusively to the mitochondrial genome. In general, these sequences were considerably more divergent from the mitochondrial genome than from those of the Numt database, supporting that the novel pNumts were probably hitherto uncatalogued variants. Unlike previous techniques, our method appears to be able to detect both polymorphic and fixed Numt sequences. It was also found that the region containing the D-Loop and associated Promoters (DLP) in the human mitochondrial genome, which harbors markers of forensic genetics importance, is the origin of several Numts. Though currently designed for the mitochondrial genome, our novel approach has the potential to be expanded to other scenarios that might require construing signal from noise, including the deconvolution of mixtures, thus significantly improving how analytical thresholds may be established.

PMID: 31446343 [PubMed - as supplied by publisher]

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