Sandwich-Cultured Hepatocytes as a Tool to Study Drug Disposition and Drug-Induced Liver Injury.

Sandwich-cultured hepatocytes (SCH) are metabolically competent and have proper localization of basolateral and canalicular transporters with functional bile networks. Therefore, this cellular model is a unique tool that can be used to estimate biliary excretion of compounds. SCH have been used widely to assess hepatobiliary disposition of endogenous and exogenous compounds and metabolites.

Elucidating Differences in the Hepatotoxic Potential of Tolcapone and Entacapone With DILIsym(®), a Mechanistic Model of Drug-Induced Liver Injury.

Tolcapone and entacapone are catechol-O-methyltransferase (COMT) inhibitors developed as adjunct therapies for treating Parkinson's disease. While both drugs have been shown to cause mitochondrial dysfunction and inhibition of the bile salt export protein (BSEP), liver injury has only been associated with the use of tolcapone. Here we used a multiscale, mechanistic model (DILIsym(®)) to simulate the response to tolcapone and entacapone.

Endothelin-1 in the tumor microenvironment correlates with melanoma invasion.

Endothelin-1 (ET-1) is a vasoactive peptide that also plays a role in the tanning response of the skin. Animal and cell culture studies have also implicated ET-1 in melanoma progression, but no association studies have been performed to link ET-1 expression and melanoma in humans. Here, we present the first in-vivo study of ET-1 expression in pigmented lesions in humans: an ET-1 immunohistochemical screen of melanocytic nevi, melanoma in situ lesions, invasive melanomas, metastatic melanomas, and blue nevi was performed.

Differential Receptor for Advanced Glycation End Products Expression in Preeclamptic, Intrauterine Growth Restricted, and Gestational Diabetic Placentas.

Problem: Receptor for advanced glycation end products (RAGE) is a receptor implicated in the modulation of inflammation. Inflammation has been associated with pregnancy pathologies including preeclampsia (PE), intrauterine growth restriction (IUGR), and gestational diabetes mellitus (GDM). Our objective was to examine placental RAGE expression in PE, IUGR, and GDM complications.

Concordance between Self-Reports and Medicare Claims among Participants in a National Study of Chronic Disease Self-Management Program.

Objectives: To evaluate the concordance between self-reported data and variables obtained from Medicare administrative data in terms of chronic conditions and health care utilization.

Design: Retrospective observational study.

Participants: We analyzed data from a sample of Medicare beneficiaries who were part of the National Study of Chronic Disease Self-Management Program (CDSMP) and were eligible for the Centers for Medicare and Medicaid Services (CMS) pilot evaluation of CDSMP (n = 119).

Effects of a Community-Based Fall Management Program on Medicare Cost Savings.

Introduction: Fall-related injuries and health risks associated with reduced mobility or physical inactivity account for significant costs to the U.S. healthcare system.

Effects of frequency-dependent membrane capacitance on neural excitability.

Objective: Models of excitable cells consider the membrane specific capacitance as a ubiquitous and constant parameter. However, experimental measurements show that the membrane capacitance declines with increasing frequency, i.e.

Social buffering of stress responses in nonhuman primates: Maternal regulation of the development of emotional regulatory brain circuits.

Social buffering, the phenomenon by which the presence of a familiar individual reduces or even eliminates stress- and fear-induced responses, exists in different animal species and has been examined in the context of the mother-infant relationship, in addition to adults. Although it is a well-known effect, the biological mechanisms that underlie it as well as its developmental impact are not well understood. Here, we provide a review of evidence of social and maternal buffering of stress reactivity in nonhuman primates, and some data from our group suggesting that when the mother-infant relationship is disrupted, maternal buffering is impaired.

The Roles of Cost and Quality Information in Medicare Advantage Plan Enrollment Decisions: an Observational Study.

Background: To facilitate informed decision-making in the Medicare Advantage marketplace, the Centers for Medicare & Medicaid Services publishes plan information on the Medicare Plan Finder website, including costs, benefits, and star ratings reflecting quality. Little is known about how beneficiaries weigh costs versus quality in enrollment decisions.

Objective: We aimed to assess associations between publicly reported Medicare Advantage plan attributes (i.

Conditional pulmonary over-expression of Claudin 6 during embryogenesis delays lung morphogenesis.

Claudin 6 (Cldn6) is a tetraspanin protein expressed by barrier epithelial cells. In order to assess the effects of persistent tight junctions involving Cldn6 during lung development, a doxycycline (dox)-inducible conditional transgenic mouse was generated that up-regulates Cldn6 in the distal lung. Pups had unlimited access to dox from conception until sacrifice date at embryonic day (E) 18.

Design and in vivo evaluation of more efficient and selective deep brain stimulation electrodes.

Objective: Deep brain stimulation (DBS) is an effective treatment for movement disorders and a promising therapy for treating epilepsy and psychiatric disorders. Despite its clinical success, the efficiency and selectivity of DBS can be improved. Our objective was to design electrode geometries that increased the efficiency and selectivity of DBS.

What Motivates Older Adults to Improve Diet and Exercise Patterns?

Dietary intake and physical activity are lifestyle behaviors that are learned, developed, and practiced throughout an individual's lifetime. These lifestyle behaviors have a profound role on health and quality of life--with late-life changes still resulting in notable improvements. Despite well documented benefits of behavior change, such changes are extremely challenging.

Prevalence and factors associated with smoking tobacco among men recently released from prison in California: A cross-sectional study.

Background: Over 1.5 million people are incarcerated in state and federal correctional facilities in the United States. Formerly incarcerated men have significantly higher rates of mortality and morbidity than the general population, disparities that have been partially attributed to higher rates of tobacco smoking-related illnesses such as cardiovascular disease, pulmonary disease and cancer.

Towards biomarker-based tests that can facilitate decisions about prevention and management of preeclampsia in low-resource settings.

In recent years, an increasing amount of literature is emerging on candidate urine and blood-based biomarkers associated with incidence and severity of preeclampsia (PE) in pregnant women. While enthusiasm on the usefulness of several of these markers in predicting PE is evolving, essentially all work so far has focused on the needs of high-resource settings and high-income countries, resulting primarily in multi-parameter laboratory assays based on proteomic and metabolomics analysis techniques. These highly complex methods, however, require laboratory capabilities that are rarely available or affordable in low-resource settings (LRS).

Genetic Disruption of Protein Kinase STK25 Ameliorates Metabolic Defects in a Diet-Induced Type 2 Diabetes Model.

Understanding the molecular networks controlling ectopic lipid deposition, glucose tolerance, and insulin sensitivity is essential to identifying new pharmacological approaches to treat type 2 diabetes. We recently identified serine/threonine protein kinase 25 (STK25) as a negative regulator of glucose and insulin homeostasis based on observations in myoblasts with acute depletion of STK25 and in STK25-overexpressing transgenic mice. Here, we challenged Stk25 knockout mice and wild-type littermates with a high-fat diet and showed that STK25 deficiency suppressed development of hyperglycemia and hyperinsulinemia, improved systemic glucose tolerance, reduced hepatic gluconeogenesis, and increased insulin sensitivity.

Improving the performance of an EEG-based motor imagery brain computer interface using task evoked changes in pupil diameter.

For individuals with high degrees of motor disability or locked-in syndrome, it is impractical or impossible to use mechanical switches to interact with electronic devices. Brain computer interfaces (BCIs) can use motor imagery to detect interaction intention from users but lack the accuracy of mechanical switches. Hence, there exists a strong need to improve the accuracy of EEG-based motor imagery BCIs attempting to implement an on/off switch.

Older Patients' Recall of Lifestyle Discussions in Primary Care.

Despite the known benefits of engaging in healthy diet and physical activity across the life span, suboptimal diet and physical inactivity are pervasive among older adults. While health care providers can promote patients' engagement in health behaviors, patient recall of recommendations tends to be imperfect. This study sought to better understand older adults' recall of dietary and physical activity discussions in primary care.

Toscana virus encephalitis in a traveler returning to the United States.

In Italy, Toscana virus is the most common cause of meningitis from May to October. Though only a few cases have been reported in U.S.

Use of Medicare's Diabetes Self-Management Training Benefit.

Medicare began reimbursing for outpatient diabetes self-management training (DSMT) in 2000; however, little is known about program utilization. Individuals diagnosed with diabetes in 2010 were identified from a 20% random selection of the Medicare fee-for-service population (N = 110,064). Medicare administrative and claims files were used to determine DSMT utilization.

Acceptability and Feasibility of Physical Activity Assessment Methods for an Appalachian Population.

Nowhere is improving understanding and accurate assessment of physical activity more important for disease prevention and health promotion than among health disparities populations such as those residing in rural and Appalachian regions. To enhance accurate assessment of physical activity and potentially improve intervention capacity, we conducted a mixed-methods study examining the acceptability and feasibility of self-report physical activity questionnaires, pedometers, and accelerometers among rural Appalachian children, adolescents, and adults. Most participants reported positive experiences with all three physical activity assessment tools.

Evaluation of intradural stimulation efficiency and selectivity in a computational model of spinal cord stimulation.

Spinal cord stimulation (SCS) is an alternative or adjunct therapy to treat chronic pain, a prevalent and clinically challenging condition. Although SCS has substantial clinical success, the therapy is still prone to failures, including lead breakage, lead migration, and poor pain relief. The goal of this study was to develop a computational model of SCS and use the model to compare activation of neural elements during intradural and extradural electrode placement.

MITOsym®: A Mechanistic, Mathematical Model of Hepatocellular Respiration and Bioenergetics.

Purpose: MITOsym, a new mathematical model of hepatocellular respiration and bioenergetics, has been developed in partnership with the DILIsym® model with the purpose of translating in vitro compound screening data into predictions of drug induced liver injury (DILI) risk for patients. The combined efforts of these two models should increase the efficiency of evaluating compounds in drug development in addition to enhancing patient care.

Methods: MITOsym includes the basic, essential biochemical pathways associated with hepatocellular respiration and bioenergetics, including mitochondrial oxidative phosphorylation, electron transport chain activity, mitochondrial membrane potential, and glycolysis; also included are dynamic feedback signals based on perturbation of these pathways.

Exploring BSEP inhibition-mediated toxicity with a mechanistic model of drug-induced liver injury.

Inhibition of the bile salt export pump (BSEP) has been linked to incidence of drug-induced liver injury (DILI), presumably by the accumulation of toxic bile acids in the liver. We have previously constructed and validated a model of bile acid disposition within DILIsym®, a mechanistic model of DILI. In this paper, we use DILIsym® to simulate the DILI response of the hepatotoxic BSEP inhibitors bosentan and CP-724,714 and the non-hepatotoxic BSEP inhibitor telmisartan in humans in order to explore whether we can predict that hepatotoxic BSEP inhibitors can cause bile acid accumulation to reach toxic levels.

"It's just a way of fitting in:" Tobacco use and the lived experience of lesbian, gay, and bisexual appalachians.

Unlabelled: Lesbian, gay, and bisexual (LGB) people are affected by multiple health disparities and risk factors, including tobacco use. Few studies to date have examined tobacco use specifically in rural LGB populations, and none has investigated the intersections of identity, rural LGB culture, and tobacco. The purpose of this study was to explore the perspective of Appalachian LGB people regarding tobacco use.