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: 1 hour 41 min ago

Isolation and characterization of human optic nerve head astrocytes and lamina cribrosa cells.

Fri, 06/12/2020 - 05:30
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Isolation and characterization of human optic nerve head astrocytes and lamina cribrosa cells.

Exp Eye Res. 2020 Jun 06;:108103

Authors: Lopez NN, Clark AF, Tovar-Vidales T

Abstract
The lamina cribrosa is the initial site of glaucomatous injury. Pathological changes to the lamina cribrosa include posterior displacement of the lamina cribrosa, loss of trophic support, and remodeling of the extracellular matrix. Optic nerve head (ONH) astrocytes and lamina cribrosa cells synthesize extracellular matrix proteins to support and maintain the lamina cribrosa under physiological conditions. During glaucoma, these cells respond to mechanical strain and other stimuli, which leads to pathological remodeling of the ONH. Although ONH astrocytes and lamina cribrosa cells have been previously cultured, there is no well-accepted, straightforward technique to isolate both cell types from a single dissected human ONH. To better understand the pathophysiology of glaucoma, we obtained and cultured lamina cribrosa explants from human donor eyes. Initially, cells that grew out from the explant were ONH astrocytes and lamina cribrosa cells. Using a specialized medium, we isolated pure populations of lamina cribrosa cells and ONH astrocytes. ONH astrocytes expressed glial fibrillary acidic protein (GFAP). Lamina cribrosa cells expressed alpha-smooth muscle actin (α-SMA), but were negative for GFAP. This method of ONH cell isolation and cell-culture will provide a technique to better understand the molecular and cell-specific changes in glaucomatous damage to the ONH.

PMID: 32522476 [PubMed - as supplied by publisher]

A pathway-driven predictive model of tramadol pharmacogenetics.

Fri, 06/12/2020 - 05:30
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A pathway-driven predictive model of tramadol pharmacogenetics.

Eur J Hum Genet. 2019 07;27(7):1143-1156

Authors: Wendt FR, Novroski NMM, Rahikainen AL, Sajantila A, Budowle B

Abstract
Predicting metabolizer phenotype (MP) is typically performed using data from a single gene. Cytochrome p450 family 2 subfamily D polypeptide 6 (CYP2D6) is considered the primary gene for predicting MP in reference to approximately 30% of marketed drugs and endogenous toxins. CYP2D6 predictions have proven clinically effective but also have well-documented inaccuracies due to relatively high genotype-phenotype discordance in certain populations. Herein, a pathway-driven predictive model employs genetic data from uridine diphosphate glucuronosyltransferase, family 1, polypeptide B7 (UGT2B7), adenosine triphosphate (ATP)-binding cassette, subfamily B, number 1 (ABCB1), opioid receptor mu 1 (OPRM1), and catechol-O-methyltransferase (COMT) to predict the tramadol to primary metabolite ratio (T:M1) and the resulting toxicologically inferred MP (t-MP). These data were then combined with CYP2D6 data to evaluate performance of a fully combinatorial model relative to CYP2D6 alone. These data identify UGT2B7 as a potentially significant explanatory marker for T:M1 variability in a population of tramadol-exposed individuals of Finnish ancestry. Supervised machine learning and feature selection were used to demonstrate that a set of 16 loci from 5 genes can predict t-MP with over 90% accuracy, depending on t-MP category and algorithm, which was significantly greater than predictions made by CYP2D6 alone.

PMID: 30824817 [PubMed - indexed for MEDLINE]

Glucagon-like peptide-1 receptor pathway inhibits extracellular matrix production by mesangial cells through store-operated Ca2+ channel.

Thu, 06/11/2020 - 05:19
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Glucagon-like peptide-1 receptor pathway inhibits extracellular matrix production by mesangial cells through store-operated Ca2+ channel.

Exp Biol Med (Maywood). 2019 10;244(14):1193-1201

Authors: Huang L, Ma R, Lin T, Chaudhari S, Shotorbani PY, Yang L, Wu P

PMID: 31510798 [PubMed - indexed for MEDLINE]

Diversity in the Era of Precision Medicine - From Bench to Bedside Implementation.

Thu, 06/11/2020 - 05:19
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Diversity in the Era of Precision Medicine - From Bench to Bedside Implementation.

Ethn Dis. 2019;29(3):517-524

Authors: Mamun A, Nsiah NY, Srinivasan M, Chaturvedula A, Basha R, Cross D, Jones HP, Nandy K, Vishwanatha JK

Abstract
Recent evidence shows how patients' unique genetic makeup can affect disease outcomes and the increasing availability of targeted treatments promises a future in health care, whereby treatments will be tailored to individual needs. This article reports on the topics discussed at the 13th Annual Texas Conference on Health Disparities, organized by the Texas Center for Health Disparities at the University of North Texas Health Science Center; the meeting focused on the theme, "Diversity in the Era of Precision Medicine" and was held during June 2018 in Fort Worth, Texas. The primary focus of this conference, which brought together clinical and basic scientists, was on the inclusion of diversity in precision medicine to bridge the gap in health disparities. Here, we present the highlights of the conference that include the potential application of precision medicine at the population level, the effects of precision medicine and direct-to-consumer testing on health disparities, genetic basis of health disparities, pharmacogenomics, and strategies to enhance participation of under-represented populations in precision medicine. Furthermore, we conclude with recommendations for future implementation, including how to mitigate disparities in genomics services and enhance participation of diverse groups in clinical trials.

PMID: 31367173 [PubMed - indexed for MEDLINE]

Identifying diverse concepts of discharge failure patients at emergency department in the USA: a large-scale retrospective observational study.

Tue, 06/09/2020 - 07:31
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Identifying diverse concepts of discharge failure patients at emergency department in the USA: a large-scale retrospective observational study.

BMJ Open. 2019 06 27;9(6):e028051

Authors: Schrader CD, Robinson RD, Blair S, Shaikh S, d'Etienne JP, Kirby JJ, Cheeti R, Zenarosa NR, Wang H

Abstract
OBJECTIVES: Identifying patients who are at high risk for discharge failure allows for implementation of interventions to improve their care. However, discharge failure is currently defined in literature with great variability, making targeted interventions more difficult. We aim to derive a screening tool based on the existing diverse discharge failure models.
DESIGN, SETTING AND PARTICIPANTS: This is a single-centre retrospective cohort study in the USA. Data from all patients discharged from the emergency department were collected from 1 January 2015 through 31 December 2017 and followed up within 30 days.
METHODS: Scoring systems were derived using modified Framingham methods. Sensitivity, specificity and area under the receiver operational characteristic (AUC) were calculated and compared using both the broad and restricted discharge failure models.
RESULTS: A total of 227 627 patients were included. The Screening for Healthcare fOllow-Up Tool (SHOUT) scoring system was derived based on the broad and restricted discharge failure models and applied back to the entire study cohort. A sensitivity of 80% and a specificity of 71% were found in SHOUT scores to identify patients with broad discharge failure with AUC of 0.83 (95% CI 0.83 to 0.84). When applied to a 3-day restricted discharge failure model, a sensitivity of 86% and a specificity of 60% were found to identify patients with AUC of 0.79 (95% CI 0.78 to 0.80).
CONCLUSION: The SHOUT scoring system was derived and used to screen and identify patients that would ultimately become discharge failures, especially when using broad definitions of discharge failure. The SHOUT tool was internally validated and can be used to identify patients across a wide spectrum of discharge failure definitions.

PMID: 31248927 [PubMed - indexed for MEDLINE]

Mechanisms of sympathetic restraint in human skeletal muscle during exercise: role of α-adrenergic and non-adrenergic mechanisms.

Sat, 06/06/2020 - 06:32

Mechanisms of sympathetic restraint in human skeletal muscle during exercise: role of α-adrenergic and non-adrenergic mechanisms.

Am J Physiol Heart Circ Physiol. 2020 Jun 05;:

Authors: Hansen AB, Moralez G, Romero SA, Gasho C, Tymko MM, Ainslie PN, Hofstätter F, Rainer SL, Lawley JS, Hearon CM

Abstract
Sympathetic vasoconstriction is mediated by α-adrenergic receptors under resting conditions. During exercise increased sympathetic nerve activity (SNA) is directed to inactive and active skeletal muscle; however, it is unclear what mechanism(s) are responsible for vasoconstriction during large muscle mass exercise in humans. The aim of this study was to determine the contribution of α-adrenergic receptors to sympathetic restraint of 1) inactive skeletal muscle, and 2) active skeletal muscle, during cycle exercise in healthy humans. In ten male participants (18-35yrs.) mean arterial pressure (intra-arterial catheter) and forearm vascular resistance (FVR) and conductance (FVC) were assessed during 1) cycle exercise (60% total peak workload) alone, and 2) during combined cycle exercise + handgrip exercise (HGE), before and after intra-arterial blockade of α- and β-adrenoreceptors via phentolamine and propranolol, respectively. Cycle exercise caused vasoconstriction in the inactive forearm that was attenuated ~80% with adrenoreceptor blockade (%ΔFVR: +81.7±84.6 vs. +9.7±30.7%; P=0.05). When HGE was performed during cycle exercise, the vasodilatory response to HGE was restrained by ~40% (ΔFVC HGE: +139.3±67.0 vs. cycle exercise: +81.9±66.3 ml min-1 100mmHg-1; P=0.03); however, the restraint of active skeletal muscle blood flow was not due to α-adrenergic signaling. These findings highlight that α-adrenergic receptors are the primary, but not the exclusive mechanism by which sympathetic vasoconstriction occurs in inactive and active skeletal muscle during exercise. Metabolic activity or higher sympathetic firing frequencies may alter the contribution of α-adrenergic receptors to sympathetic vasoconstriction. Finally, non-adrenergic vasoconstrictor mechanisms may be important for understanding the regulation of blood flow during exercise.

PMID: 32502375 [PubMed - as supplied by publisher]

Reduced cerebrovascular and cardioventilatory responses to intermittent hypoxia in elderly.

Sat, 06/06/2020 - 06:32
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Reduced cerebrovascular and cardioventilatory responses to intermittent hypoxia in elderly.

Respir Physiol Neurobiol. 2020 01;271:103306

Authors: Liu X, Chen X, Kline G, Ross SE, Hall JR, Ding Y, Mallet RT, Shi X

Abstract
BACKGROUND: The impact of aging on cerebrovascular function and tissue oxygenation during graded hypoxemia is incompletely known. This study compared the age effect on these variables during cyclic hypoxemia-reoxygenation.
METHODS: Hypoxia-induced changes in arterial (SaO2) and cerebral tissue (ScO2) O2 saturation, middle cerebral arterial flow velocity (VMCA), estimated cerebral vascular conductance (CVC), heart rate (HR) and ventilation were compared between 12 elderly (71 ± 2 yr, 7 women) and 13 young (24 ± 3 yr, 5 women) adults during the first and fifth 5-min exposures to 10% O2.
RESULTS: Although pre-hypoxia SaO2 did not differ between the groups, ScO2 was lower (P < 0.05) in the elderly (68.4 ± 1.2%) than young (73.8 ± 0.9%) adults, commensurate with a lower resting VMCA (P < 0.05). SaO2 fell less sharply (P < 0.05) in the elderly subjects during the first and fifth hypoxia exposures. Moreover, the responses of ScO2, VMCA, CVC, HR and breathing frequency to hypoxia were attenuated in the elderly subjects. Systolic and diastolic arterial pressures fell by 2-6 mmHg during hypoxia in both young and elderly. Thus, hypoxemia developed more gradually in elderly than young adults during normobaric hypoxia, concordant with a reduced metabolic demand in the elderly.
CONCLUSIONS: The elderly adults safely tolerated cyclic, moderate hypoxemia which lowered SaO2 by 20-25%, despite dampening of cerebrovascular and cardiac responses to hypoxemia.

PMID: 31557538 [PubMed - indexed for MEDLINE]

COVID-19 in India: Are Biological and Environmental Factors Helping to Stem the Incidence and Severity?

Thu, 06/04/2020 - 06:06
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COVID-19 in India: Are Biological and Environmental Factors Helping to Stem the Incidence and Severity?

Aging Dis. 2020 May;11(3):480-488

Authors: Chakrabarti SS, Kaur U, Banerjee A, Ganguly U, Banerjee T, Saha S, Parashar G, Prasad S, Chakrabarti S, Mittal A, Agrawal BK, Rawal RK, Zhao RC, Gambhir IS, Khanna R, Shetty AK, Jin K, Chakrabarti S

Abstract
The ongoing Corona virus (COVID-19) pandemic has witnessed global political responses of unimaginable proportions. Many nations have implemented lockdowns that involve mandating citizens not to leave their residences for non-essential work. The Indian government has taken appropriate and commendable steps to curtail the community spread of COVID-19. While this may be extremely beneficial, this perspective discusses the other reasons why COVID-19 may have a lesser impact on India. We analyze the current pattern of SARS-CoV-2 transmission, testing, and mortality in India with an emphasis on the importance of mortality as a marker of the clinical relevance of COVID-19 disease. We also analyze the environmental and biological factors which may lessen the impact of COVID-19 in India. The importance of cross-immunity, innate immune responses, ACE polymorphism, and viral genetic mutations are discussed.

PMID: 32489695 [PubMed]

Carisoprodol pharmacokinetics and distribution in the nucleus accumbens correlates with behavioral effects in rats independent from its metabolism to meprobamate.

Tue, 06/02/2020 - 05:33

Carisoprodol pharmacokinetics and distribution in the nucleus accumbens correlates with behavioral effects in rats independent from its metabolism to meprobamate.

Neuropharmacology. 2020 May 29;:108152

Authors: Carbonaro TM, Nguyen V, Forster MJ, Gatch MB, Prokai L

Abstract
Carisoprodol (Soma®) is a centrally-acting skeletal-muscle relaxant frequently prescribed for treatment of acute musculoskeletal conditions. Carisoprodol's mechanism of action is unclear and is often ascribed to that of its active metabolite, meprobamate. The purpose of this study was to ascertain whether carisoprodol directly produces behavioral effects, or whether metabolism into meprobamate via cytochrome P450 (CYP450) enzymatic reaction is necessary. Rats were trained to discriminate carisoprodol (100 mg/kg) to assess time course and whether a CYP450 inhibitor (cimetidine) administered for 4 days would alter the discriminative effects of carisoprodol. Additionally, pharmacokinetics of carisoprodol and meprobamate with and without co-administration of cimetidine were assessed via in-vivo microdialysis combined with liquid-chromatography-tandem mass spectrometry from blood and nucleus accumbens (NAc). The time course of the discriminative-stimulus effects of carisoprodol closely matched the time course of the levels of carisoprodol in blood and NAc, but did not match the time course of meprobamate. Administration of cimetidine increased levels of carisoprodol and decreased levels of meprobamate consistent with its interfering with metabolism of carisoprodol into meprobamate. However, cimetidine failed to alter the discriminative-stimulus effects of carisoprodol. Carisoprodol penetrated into brain tissue and directly produced behavioral effects without being metabolized into meprobamate. These findings indicate that understanding the mechanism of action of carisoprodol independently of meprobamate will be necessary to determine the validity of its clinical uses.

PMID: 32479814 [PubMed - as supplied by publisher]

An Epigenetics-Based, Lifestyle Medicine-Driven Approach to Stress Management for Primary Patient Care: Implications for Medical Education.

Tue, 06/02/2020 - 05:33
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An Epigenetics-Based, Lifestyle Medicine-Driven Approach to Stress Management for Primary Patient Care: Implications for Medical Education.

Am J Lifestyle Med. 2020 May-Jun;14(3):294-303

Authors: Lee J, Papa F, Jaini PA, Alpini S, Kenny T

Abstract
Over 75% of patients in the primary care setting present with stress-related complaints. Curiously, patients and health care providers all too often see stress as a relatively benign sequela of many common illnesses such as heart disease, cancer, lung disease, dementia, diabetes, and mental illness. Unfortunately, various day-to-day lifestyle choices and environmental factors, unrelated to the presence of any disease, can cause stress sufficient to contribute to the development of various diseases/disorders and suboptimal health. There is evidence suggesting that counseling in stress management-oriented therapeutic interventions (as offered by lifestyle medicine-oriented practitioners) may prevent or reduce the onset, severity, duration, and/or overall burden of stress-related illnesses. Such counseling often involves considerations such as the patient's nutrition, physical activity, interest in/capacity to meditate, drug abuse/cessation, and so on. Unfortunately, lifestyle medicine-oriented approaches to stress management are rarely offered in primary care-the patient care arena wherein such counseling would likely be best received by patients. Would health care outcomes improve if primary care providers offered counseling in both stress management and positive lifestyle choices? The purpose of this article is to provide both primary care practitioners and educators in health care training programs with an introductory overview of epigenetics. An emerging field of science offering insights into how factors such as stress and lifestyle choices interact with our genes in ways that can both positively and negatively impact the various micro (eg, cellular) through macro (eg, physiologic, pathophysiologic) processes that determine our tendencies toward illness or wellness. A deeper understanding of epigenetics, as provided herein, should enable primary care providers and medical educators to more confidently advocate for the primary benefits associated with counseling in both stress reduction and the pursuit of healthy lifestyle choices.

PMID: 32477032 [PubMed]

Novel Investigation of the Deep Band of the Lateral Plantar Aponeurosis and Its Relationship With the Lateral Plantar Nerve.

Tue, 06/02/2020 - 05:33
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Novel Investigation of the Deep Band of the Lateral Plantar Aponeurosis and Its Relationship With the Lateral Plantar Nerve.

Foot Ankle Int. 2019 Nov;40(11):1325-1330

Authors: Beck CM, Dickerson AR, Kadado KJ, Cohen ZA, Blair SE, Motley TA, Holcomb JC, Fisher CL

Abstract
BACKGROUND: We describe a thick fascial band arising from the medial aspect of the lateral plantar aponeurosis diving deep into the forefoot crossing over a branch of the lateral plantar nerve. Because a review of current literature resulted in limited and outdated sources, we sought to first determine the frequency of this fascial band and the location where it crosses the lateral plantar nerve and, second, discuss the clinical applications these anatomical findings could have.
METHODS: 50 pairs of cadaveric feet (n = 100) were dissected to investigate for presence of the fascial band and its interaction with the lateral plantar nerve. Images were taken of each foot with the fascial band. ImageJ was used to take 2 measurements assessing the relationship of the tuberosity of the base of the fifth metatarsal to where the nerve crossed deep to the fascial band.
RESULTS: Overall, 38% of the feet possessed the fascial band. It was found unilaterally in 10 pairs and bilaterally in 14 pairs. On average, the point at which the lateral plantar nerve passed deep to the fascial band was 2.0 cm medial and 1.7 cm anterior to the tuberosity of the base of the fifth metatarsal.
CONCLUSION: When present, the deep band of the lateral plantar aponeurosis (PA) was consistently found to be crossing the lateral plantar nerve. The discovery of the location where this most commonly occurs has not been previously reported and adds an interesting dimension that elevates an anatomical study to one that has clinical potential.
CLINICAL RELEVANCE: The established target zone gives a precise location for where the relationship between the deep band of the lateral PA and the lateral plantar nerve exists when evaluating the foot. The target zone provides a potential springboard for future investigations concerning said relationship clinically.

PMID: 31387386 [PubMed - indexed for MEDLINE]

Obstetrics and Gynecology and Family Medicine Residents' Training and Knowledge on Emergency Contraception.

Tue, 06/02/2020 - 05:33
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Obstetrics and Gynecology and Family Medicine Residents' Training and Knowledge on Emergency Contraception.

J Womens Health (Larchmt). 2019 06;28(6):794-801

Authors: Rapkin RB, Griner SB, Godcharles CL, Vamos CA, Neelamegam M, Thompson EL, Daley EM

Abstract
Background: Emergency contraception (EC) has the potential to play a vital role in preventing unintended pregnancies after unprotected sexual intercourse or contraceptive failure. Residency training can influence practice behaviors, however, the extent to which EC-related information is taught in training programs remains unknown. This study examined where residents obtain information about EC and whether knowledge differs by resident program characteristics. Materials and Methods: Program coordinators of Obstetrics and Gynecology (OB/GYN) and Family Medicine residency programs (n = 689) were emailed and requested to forward the survey link to residents. The survey included measures of EC education (hours, sources, including lectures, grand rounds), and EC-related knowledge. EC knowledge items assessed the three methods of EC (copper intrauterine device, ulipristal acetate, and oral levonorgestrel), effectiveness, mechanism of action, contraindications, and side effects. t-Tests and analysis of variances were used to compare mean knowledge scores (maximum = 20; higher scores indicating higher knowledge). Results: Among participants (n = 676), 61% were Family Medicine residents, 66% were white, and 72% were female. Overall, 34% received <1 hour of EC education, with OB/GYN residents receiving significantly more hours than Family Medicine residents. OB/GYN residents (mean = 14.40, standard deviation [SD] = 2.69) had a significantly higher mean knowledge score than Family Medicine residents (12.12, SD = 2.63; p < 0.000). Mean knowledge score differences were found by region of residency program, with residents in the Northeast reporting higher knowledge. Conclusions: Overall, residents received very little EC education, with OB/GYN residents receiving more training and having higher knowledge than their Family Medicine counterparts. Additional training is needed to ensure that residents are knowledgeable about this effective method to decrease unintended pregnancies.

PMID: 30939069 [PubMed - indexed for MEDLINE]

Social media engagement association with human papillomavirus and vaccine awareness and perceptions: Results from the 2017 US Health Information National Trends Survey.

Sun, 05/31/2020 - 05:02

Social media engagement association with human papillomavirus and vaccine awareness and perceptions: Results from the 2017 US Health Information National Trends Survey.

Prev Med. 2020 May 27;:106151

Authors: Rosen BL, Wheldon C, Thompson EL, Maness S, Massey PM

Abstract
Due to social media's ability to publicize misinformation about vaccines, there is a need to study associations between social media engagement (SME) with human papillomavirus (HPV) and vaccine-related awareness and beliefs. Therefore, the study objectives were to (1) describe the SME of a nationally representative sample of US adults, and (2) determine the associations between SME and HPV-related awareness, HPV-related knowledge, HPV vaccine-related awareness, and perceived HPV vaccine efficacy. In 2019, we completed a secondary analysis of the 2017 Health Information National Trends Survey (Cycle 5.1). We created the SME index from 5 social media items. For each outcome variable, 3 models using binary and multinomial logistic regression were estimated. SME in the sample (n = 3171) was low (M = 0.9; range: 0-2). Respondents with higher SME had higher odds of HPV awareness (AOR = 1.56; 95% CI = 1.23, 1.99). Higher SME was associated with awareness of the HPV vaccine (AOR = 1.46; 95% CI = 1.16, 1.85). Respondents with higher SME had higher odds of perceiving HPV vaccine to be "not at all successful" (AOR = 2.22; 95% CI = 1.16, 4.24), "a little successful" (AOR = 1.99; 95% CI = 1.35, 2.94), "pretty successful" (AOR = 1.40; 95% CI = 1.04, 1.89), and "very successful" (AOR = 1.40; 95% CI = 1.02, 1.92) compared to those who selected "don't know" after adjusting for demographics and internet use. Our study highlights novel findings using a comprehensive SME index with a national sample providing insight to leverage existing consumer behaviors to better connect and disseminate accurate HPV information in a more strategic manner.

PMID: 32473273 [PubMed - as supplied by publisher]

The lot-to-lot variability in the mitochondrial genome of controls.

Fri, 05/29/2020 - 07:20
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The lot-to-lot variability in the mitochondrial genome of controls.

Forensic Sci Int Genet. 2020 Apr 30;47:102298

Authors: Cihlar JC, Peters D, Strobl C, Parson W, Budowle B

Abstract
Current research in the biomedical field has illustrated how cell lines used as reference standards can change over time and, more importantly, can affect research and diagnostic results obtained from these cell lines. With the use of increasingly sensitive and highly resolving technologies (e.g., massively parallel sequencing), forensic scientists must be aware of and account for potential variability in the cell lines used as controls in their validation studies and day-to-day casework. In this study, multiple lot numbers from four commonly-used control cell line DNAs were sequenced with massively parallel sequencing on the Ion S5. The variability among these different lots was evaluated, and the effect on forensic laboratory work discussed.

PMID: 32464353 [PubMed - as supplied by publisher]

Mechanisms underlying selective coupling of endothelial Ca2+ signals with eNOS versus IK/SK channels in systemic and pulmonary arteries.

Fri, 05/29/2020 - 07:20
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Mechanisms underlying selective coupling of endothelial Ca2+ signals with eNOS versus IK/SK channels in systemic and pulmonary arteries.

J Physiol. 2020 May 28;:

Authors: Ottolini M, Daneva Z, Chen YL, Cope EL, Kasetti RB, Zode GS, Sonkusare SK

Abstract
KEY POINTS: Endothelial cell TRPV4 (TRPV4EC ) channels exert a dilatory effect on the resting diameter of resistance mesenteric and pulmonary arteries. Functional IK/SK channels and eNOS are present in the endothelium of mesenteric and pulmonary arteries. TRPV4EC sparklets preferentially couple with IK/SK channels in mesenteric arteries and with eNOS in pulmonary arteries. TRPV4EC channels co-localize with IK/SK channels in mesenteric arteries, but not in pulmonary arteries, which may explain TRPV4EC -IK/SK channel coupling in mesenteric arteries and its absence in pulmonary arteries. The presence of the nitric oxide-scavenging protein, hemoglobin α, limits TRPV4EC -eNOS signalling in mesenteric arteries. Spatial proximity of TRPV4EC channels with eNOS and the absence of hemoglobin α favor TRPV4EC -eNOS signalling in pulmonary arteries.
ABSTRACT: Spatially localized Ca2+ signals activate Ca2+ -sensitive intermediate- and small-conductance K+ (IK and SK) channels in some vascular beds and endothelial nitric oxide synthase (eNOS) in others. The goal of this study was to uncover the signalling organization that determines selective Ca2+ signal to vasodilatory target coupling in the endothelium. Resistance-sized mesenteric arteries (MAs) and pulmonary arteries (PAs) were used as prototypes for arteries with predominantly IK/SK channel- and eNOS-dependent vasodilation, respectively. Ca2+ influx signals through endothelial transient receptor potential vanilloid 4 (TRPV4EC ) channels played an important role in controlling the baseline diameter of both MAs and PAs. TRPV4EC channel activity was similar in MAs and PAs. However, the TRPV4 channel agonist GSK1016790A (10 nM) selectively activated IK/SK channels in MAs and eNOS in PAs, revealing preferential TRPV4EC -IK/SK channel coupling in MAs and TRPV4EC -eNOS coupling in PAs. IK/SK channels co-localized with TRPV4EC channels at myoendothelial projections (MEPs) in MAs, but lacked the spatial proximity necessary for their activation by TRPV4EC channels in PAs. Additionally, the presence of the NO scavenging protein hemoglobin α (Hbα) within nanometer proximity to eNOS limits TRPV4EC -eNOS signalling in MAs. In contrast, co-localization of TRPV4EC channels and eNOS at MEPs, and the absence of Hbα, favor TRPV4EC -eNOS coupling in PAs. Thus, our results reveal that differential spatial organization of signalling elements determines TRPV4EC -IK/SK versus TRPV4EC -eNOS coupling in resistance arteries. This article is protected by copyright. All rights reserved.

PMID: 32463112 [PubMed - as supplied by publisher]

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

Fri, 05/29/2020 - 07:20
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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 - indexed for MEDLINE]

Post-Traumatic Stress Disorder Chronification via Monoaminooxidase and Cortisol Metabolism.

Fri, 05/29/2020 - 07:20
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Post-Traumatic Stress Disorder Chronification via Monoaminooxidase and Cortisol Metabolism.

Horm Metab Res. 2019 Sep;51(9):618-622

Authors: Tseilikman V, Dremencov E, Maslennikova E, Ishmatova A, Manukhina E, Downey HF, Klebanov I, Tseilikman O, Komelkova M, Lapshin MS, Vasilyeva MV, Bornstein SR, Perry SW, Wong ML, Licinio J, Yehuda R, Ullmann E

PMID: 31505706 [PubMed - indexed for MEDLINE]

Medical virtual reality.

Wed, 05/27/2020 - 06:58
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Medical virtual reality.

J Hand Ther. 2020 May 22;:

Authors: Dennis OP, Patterson RM

PMID: 32451173 [PubMed - as supplied by publisher]

Hemorrhage simulated by lower body negative pressure provokes an oxidative stress response in healthy young adults.

Wed, 05/27/2020 - 06:58
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Hemorrhage simulated by lower body negative pressure provokes an oxidative stress response in healthy young adults.

Exp Biol Med (Maywood). 2019 03;244(3):272-278

Authors: Park FS, Kay VL, Sprick JD, Rosenberg AJ, Anderson GK, Mallet RT, Rickards CA

Abstract
IMPACT STATEMENT: We characterize the systemic oxidative stress response in young, healthy human subjects with exposure to simulated hemorrhage via application of lower body negative pressure (LBNP). Prior work has demonstrated that LBNP and actual blood loss evoke similar hemodynamic and immune responses (i.e. white blood cell count), but it is unknown whether LBNP elicits oxidative stress resembling that produced by blood loss. We show that LBNP induces a 29% increase in F2-isoprostanes, a systemic marker of oxidative stress. The findings of this investigation may have important implications for the study of hemorrhage using LBNP, including future assessments of targeted interventions that may reduce oxidative stress, such as novel fluid resuscitation approaches.

PMID: 30727766 [PubMed - indexed for MEDLINE]

Severe hypercholesterolemia in a 2-year-old.

Tue, 05/26/2020 - 06:30
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Severe hypercholesterolemia in a 2-year-old.

J Clin Lipidol. 2019 May - Jun;13(3):393-396

Authors: Horner S, Hamilton L, Hamby T, Wilson DP

Abstract
Routine and selective cholesterol screening of children is an effective tool to help identify those with familial hypercholesterolemia. In children found to have elevated levels of cholesterol, secondary causes should be excluded, including hypothyroidism. Thyroid hormone has multiple effects on the regulation of lipid synthesis, absorption, and metabolism. In this case report, we described a 2-year-old with a history of congenital hypothyroidism who was found to have severe hypercholesterolemia. A detailed medical history and appropriate screening tests are important in determining the underlying cause of elevated low-density lipoprotein cholesterol to help inform clinical decision-making.

PMID: 31088731 [PubMed - indexed for MEDLINE]

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