Faculty Bibliography

The problem with media headlines on pharma is that they are rarely subtle or nuanced, instead they smear and cripple some of the best medications. The latest pronouncement involves some of the best anticonvulsant drugs, which have now raised alarms because they have significantly increased suicide risk. Patients have been led to believe by the media that either a drug will kill them or it will save them. The media is a powerful force for doctors to have to contend with

AIMS/OBJECTIVE:Myostatin inhibits myoblast differentiation/proliferation and may play a role in heart failure (HF) and reverse remodelling after left ventricular assist device (LVAD) support. This study sought to characterize myostatin expression and activation in advanced HF before and after LVAD support. METHODS AND RESULTS/RESULTS:Left ventricular tissue pairs were collected at LVAD implantation (core) and at cardiac transplantation/LVAD explantation in patients with advanced ischaemic (ICM-ischaemic cardiomyopathy) and non-ischaemic (DCM-dilated cardiomyopathy) HF. Normal cardiac tissue (control) was obtained from hearts not placed for transplantation. Serum was collected independently from patients with stable DCM HF and from healthy controls. Full-length and cleaved propeptide myostatin levels were quantified by western blot analysis. Dilated cardiomyopathy propeptide levels at core were significantly higher than control and significantly increased after LVAD support. Ischaemic cardiomyopathy propeptide levels were higher than control, but did not change after LVAD support. No changes in full-length levels were seen. Serum myostatin levels were significantly higher in DCM HF patients than in healthy controls. CONCLUSION/CONCLUSIONS:This is the first clinical evidence that myostatin activation is increased in HF. Myostatin may affect cardiac hypertrophy and may mediate regression of cellular hypertrophy after mechanical unloading.

OBJECTIVE:To test whether glucocorticoids act as the endogenous agonist of cardiac mineralocorticoid receptors, we evaluated the cardiac effects of aldosterone and corticosterone and cardiac steroidogenesis vs. steroid uptake from plasma. METHODS AND RESULTS/RESULTS:Both corticosterone and aldosterone increased left ventricular pressure in the rat heart. Aldosterone decreased coronary flow, whereas corticosterone increased it. All corticosterone effects were blocked by the glucocorticoid receptor antagonist, RU486, and unaltered by the mineralocorticoid receptor antagonist, canrenoate, or the 11beta-hydroxysteroid dehydrogenase (HSD11B)2 inhibitor, carbenoxolone. Unlike mineralocorticoid receptor blockade, RU486 did not ameliorate postischemia infarct size and arrhythmias. Corticosterone, when added to the perfusion buffer, rapidly accumulated at cardiac tissue sites, reaching steady-state levels that were identical to those in coronary effluent, independently of the presence of aldosterone, RU486 or canrenoate. After stopping the perfusion, cardiac corticosterone fully washed away with a half-life of less than 1 min. Measurements of steroid-synthesizing enzyme gene expression levels in human ventricular and atrial tissue pieces from heart-beating organ donors, patients with end-stage heart failure and hypertrophic cardiomyopathy patients revealed that under no condition, the human heart was capable of synthesizing aldosterone or cortisol de novo. Yet, expression of HSD11B1, HSD11B2, mineralocorticoid receptors and glucocorticoid receptors was found, and HSD11B2 and mineralocorticoid receptors were upregulated in pathological conditions. Moreover, aldosterone reduced cardiac inotropy in a Na/K/2Cl cotransporter-dependent manner. CONCLUSION/CONCLUSIONS:Both cortisol/corticosterone and aldosterone accumulate in the cardiac interstitium. The presence of HSD11B2 and mineralocorticoid receptors/glucocorticoid receptors at cardiac tissue sites allows both steroids to exert their effects via separate mechanisms.

Heat stress cognate 70 (Hsc70) is a host protein associated with hepatitis B virus (HBV) replication. The goal of this study was to investigate whether Hsc70 could be an anti-HBV drug target. Our results showed that introducing Hsc70 increased HBV replication in HBV(+) human hepatocytes (HepG2.2.15 cells). The coiled-coil region on Hsc70 (nucleotides 1533 to 1608; amino acids 511 to 536) was the key sequence for HBV replication. Knockdown of Hsc70 expression by RNA interference (RNAi) largely inhibited HBV replication with no cytotoxicity to the host. Using an Hsc70 mRNA screening assay, the natural compound oxymatrine (OMTR) was found to be a selective inhibitor for Hsc70 expression. Then, OMTR was used to investigate the potential of Hsc70 as an anti-HBV drug target. OMTR inhibited Hsc70 mRNA expression by 80% and HBV DNA replication by over 60% without causing cytotoxicity. The anti-HBV effect of OMTR appeared to be mediated by destabilizing Hsc70 mRNA. The half-life (T(1/2)) of Hsc70 mRNA decreased by 50% in OMTR-treated hepatocytes. The Hsc70 mRNA 3'-untranslated-region (UTR) sequence was the element responsible for OMTR's destabilization activity. OMTR suppressed HBV de novo synthesis at the reverse transcription stage from pregenomic RNA (pgRNA) to DNA and was active against either wild-type HBV or strains resistant to lamivudine, adefovir, and entecavir. Therefore, host Hsc70 could be a novel drug target against HBV, and OMTR appears to inhibit HBV replication by destabilizing Hsc70 mRNA. As the target is not a viral protein, OMTR is active for either wild-type HBV or strains resistant to reverse transcriptase (RT) inhibitors

BACKGROUND:Educating medical students about health disparities may be one step in diminishing the disparities in health among different populations. According to adult learning theory, learners' opinions are vital to the development of future curricula. DESIGN/METHODS:Qualitative research using focus group methodology. OBJECTIVES/OBJECTIVE:Our objectives were to explore the content that learners value in a health disparities curriculum and how they would want such a curriculum to be taught. PARTICIPANTS/METHODS:Study participants were first year medical students with an interest in health disparities (n = 17). APPROACH/METHODS:Semi-structured interviews consisting of 12 predetermined questions, with follow-up and clarifying questions arising from the discussion. Using grounded theory, codes were initially developed by the team of investigators, applied, and validated through an iterative process. MAIN RESULTS/RESULTS:The students perceived negative attitudes towards health disparities education as a potential barrier towards the development of a health disparities curriculum and proposed possible solutions. These solutions centered around the learning environment and skill building to combat health disparities. CONCLUSIONS:While many of the students' opinions were corroborated in the literature, the most striking differences were their opinions on how to develop good attitudes among the student body. Given the impact of the provider on health disparities, how to develop such attitudes is an important area for further research.

The use of isobaric tags such as iTRAQ allows the relative and absolute quantification of hundreds of proteins in a single experiment for up to eight different samples. More classical techniques such as 2-DE can offer a complimentary approach for the analysis of complex protein samples. In this study, the proteomes of secreted and cytosolic proteins of genetically closely related strains of Mycobacterium tuberculosis were analyzed. Analysis of 2-D gels afforded 28 spots with variations in protein abundance between strains. These were identified by MS/MS. Meanwhile, a rigorous statistical analysis of iTRAQ data allowed the identification and quantification of 101 and 137 proteins in the secreted and cytosolic fractions, respectively. Interestingly, several differences in protein levels were observed between the closely related strains BE, C28 and H6. Seven proteins related to cell wall and cell processes were more abundant in BE, while enzymes related to metabolic pathways (GltA2, SucC, Gnd1, Eno) presented lower levels in the BE strain. Proteins involved in iron and sulfur acquisition (BfrB, ViuB, TB15.3 and SseC2) were more abundant in C28 and H6. In general, iTRAQ afforded rapid identification of fine differences between protein levels such as those presented between closely related strains. This provides a platform from which the relevance of these differences can be assessed further using complimentary proteomic and biological modeling methods

BACKGROUND: The range of protein intakes for optimizing bone health among premenopausal women is unclear. Protein is a major constituent of bone, but acidic amino acids may promote bone resorption. OBJECTIVE: The objective was to examine cross-sectional and longitudinal associations between baseline dietary protein and bone mineral density (BMD) among 560 females aged 14-40 y at baseline enrolled in a Pacific Northwest managed-care organization. The role of protein source (animal or vegetable) and participant characteristics were considered. DESIGN: Dietary protein intake was assessed by using a semiquantitative food-frequency questionnaire in participants enrolled in a study investigating associations between hormonal contraceptive use and bone health. Annual changes in hip, spine, and whole-body BMD were measured by using dual-energy X-ray absorptiometry. Cross-sectional and longitudinal associations between baseline protein intake (% of energy) and BMD were examined by using linear regression analysis and generalized estimating equations adjusted for confounders. RESULTS: The mean (+/-SD) protein intake at baseline was 15.5 +/- 3.2%. After multivariable adjustment, the mean BMD was similar across each tertile of protein intake. In cross-sectional analyses, low vegetable protein intake was associated with a lower BMD (P = 0.03 for hip, P = 0.10 for spine, and P = 0.04 for whole body). For every percentage increase in the percentage of energy from protein, no significant longitudinal changes in BMD were observed at any anatomic site over the follow-up period. CONCLUSIONS: Data from this longitudinal study suggest that a higher protein intake does not have an adverse effect on bone in premenopausal women. Cross-sectional analyses suggest that low vegetable protein intake is associated with lower BMD.

BACKGROUND: It is uncertain whether training improves physicians' obesity counseling. OBJECTIVE: To assess the impact of an obesity counseling curriculum for residents. DESIGN: A non-randomized, wait-list/control design. PARTICIPANTS: Twenty-three primary care internal medicine residents; 12 were assigned to the curriculum group, and 11 were assigned to the no-curriculum group. Over a 7-month period (1-8 months post-intervention) 163 of the residents' obese patients were interviewed after their medical visits. INTERVENTION: A 5-hour, multi-modal obesity counseling curriculum based on the 5As (Assess, Advise, Agree, Assist, Arrange) using didactics, role-playing, and standardized patients. MAIN MEASURES: Patient-report of physicians' use of the 5As was assessed using a structured interview survey. Main outcomes were whether obese patients were counseled about diet, exercise, or weight loss (rate of counseling) and the quality of counseling provided (percentage of 5As skills performed during the visit). Univariate statistics (t-tests) were used to compare the rate and quality of counseling in the two resident groups. Logistic and linear regression was used to isolate the impact of the curriculum after controlling for patient, physician, and visit characteristics. KEY RESULTS: A large percentage of patients seen by both groups of residents received counseling about their weight, diet, and/or exercise (over 70%), but the quality of counseling was low in both the curriculum and no curriculum groups (mean 36.6% vs. 31.2% of 19 possible 5As counseling strategies, p = 0.21). This difference was not significant. However, after controlling for patient, physician and visit characteristics, residents in the curriculum group appeared to provide significantly higher quality counseling than those in the control group (std beta = 0.18; R(2) change = 2.9%, P < 0.05). CONCLUSIONS: Residents who received an obesity counseling curriculum were not more likely to counsel obese patients than residents who did not. Training, however, is associated with higher quality of counseling when patient, physician, and visit characteristics are taken into account

Researchers lack the rich evidence base and benchmark patient outcomes needed to evaluate the effectiveness of medical education practice and guide policy. The authors offer a framework for medical education research that focuses on physician-influenced patient outcomes that are potentially sensitive to medical education. Adapting the concept of ambulatory care sensitive conditions, which provided traction to health services research by defining benchmark patient outcomes to measure health system performance, the authors introduce the concept and propose the adoption of educationally sensitive patient outcomes and suggest two measures: patient activation and clinical microsystem activation. They assert that the ultimate goal of medical education is to ensure that measurement of future physicians' competence and skills is based not only on biomedical knowledge and critical clinical skills but also on the ability to translate these competencies into effective patient- and systems-level outcomes. The authors consider methodological approaches and challenges to measuring such outcomes and argue for large, multiinstitutional, prospective cohort studies and the development of a national Database for Research in Education in Academic Medicine to provide the needed infrastructure. They advocate taking the next steps to establish an educational evidence base to guide the academic medical centers of the 21st century in aligning medical education practice with health care delivery that meets the needs of individuals and populations

The inflammatory nature of atherosclerosis is well established but the agent(s) that incite inflammation in the artery wall remain largely unknown. Germ-free animals are susceptible to atherosclerosis, suggesting that endogenous substances initiate the inflammation. Mature atherosclerotic lesions contain macroscopic deposits of cholesterol crystals in the necrotic core, but their appearance late in atherogenesis had been thought to disqualify them as primary inflammatory stimuli. However, using a new microscopic technique, we revealed that minute cholesterol crystals are present in early diet-induced atherosclerotic lesions and that their appearance in mice coincides with the first appearance of inflammatory cells. Other crystalline substances can induce inflammation by stimulating the caspase-1-activating NLRP3 (NALP3 or cryopyrin) inflammasome, which results in cleavage and secretion of interleukin (IL)-1 family cytokines. Here we show that cholesterol crystals activate the NLRP3 inflammasome in phagocytes in vitro in a process that involves phagolysosomal damage. Similarly, when injected intraperitoneally, cholesterol crystals induce acute inflammation, which is impaired in mice deficient in components of the NLRP3 inflammasome, cathepsin B, cathepsin L or IL-1 molecules. Moreover, when mice deficient in low-density lipoprotein receptor (LDLR) were bone-marrow transplanted with NLRP3-deficient, ASC (also known as PYCARD)-deficient or IL-1alpha/beta-deficient bone marrow and fed on a high-cholesterol diet, they had markedly decreased early atherosclerosis and inflammasome-dependent IL-18 levels. Minimally modified LDL can lead to cholesterol crystallization concomitant with NLRP3 inflammasome priming and activation in macrophages. Although there is the possibility that oxidized LDL activates the NLRP3 inflammasome in vivo, our results demonstrate that crystalline cholesterol acts as an endogenous danger signal and its deposition in arteries or elsewhere is an early cause rather than a late consequence of inflammation. These findings provide new insights into the pathogenesis of atherosclerosis and indicate new potential molecular targets for the therapy of this disease