Circulating Markers Reflect Both Anti- and Pro-Atherogenic Drug Effects in ApoE-Deficient Mice

Background: Current drug therapy of atherosclerosis is focused on treatment of major risk factors, e.g. hypercholesterolemia while in the future direct disease modification might provide additional benefits. However, development of medicines targeting vascular wall disease is complicated by the lack of reliable biomarkers. In this study, we took a novel approach to identify circulating biomarkers indicative of drug efficacy by reducing the complexity of the in vivo system to the level where neither disease progression nor drug treatment was associated with the changes in plasma cholesterol.Results: ApoE-/- mice were treated with an ACE inhibitor ramipril and HMG-CoA reductase inhibitor simvastatin. Ramipril significantly reduced the size of atherosclerotic plaques in brachiocephalic arteries, however simvastatin paradoxically stimulated atherogenesis. Both effects occurred without changes in plasma cholesterol. Blood and vascular samples were obtained from the same animals. In the whole blood RNA samples, expression of MMP9, CD14 and IL-1RN reflected pro and anti-atherogenic drug effects. In the plasma, several proteins, e.g. IL-1β, IL-18 and MMP9 followed similar trends while protein readout was less sensitive than RNA analysis.Conclusion: In this study, we have identified inflammation-related whole blood RNA and plasma protein markers reflecting anti-atherogenic effects of ramipril and pro-atherogenic effects of simwastatin in a mouse model of atherosclerosis. This opens an opportunity for early, non-invasive detection of direct drug effects on atherosclerotic plaques in complex in vivo systems

Doctors' personal health care choices: A cross-sectional survey in a mixed public/private setting

<p>Abstract</p> <p>Background</p> <p>Among Western countries, it has been found that physicians tend to manage their own illnesses and tend not have their own independent family physicians. This is recognized as a significant issue for both physicians and, by extension, the patients under their care, resulting in initiatives seeking to address this. Physicians' personal health care practices in Asia have yet to be documented.</p> <p>Methods</p> <p>An anonymous cross-sectional postal questionnaire survey was conducted in Hong Kong, China. All 9570 medical practitioners in Hong Kong registered with the Hong Kong Medical Council in 2003 were surveyed. Chi-square tests and logistic regression models were applied.</p> <p>Results</p> <p>There were 4198 respondents to the survey; a response rate of 44%. Two-thirds of respondents took care of themselves when they were last ill, with 62% of these self-medicating with prescription medication. Physicians who were graduates of Hong Kong medical schools, those working in general practice and non-members of the Hong Kong College of Family Physicians were more likely to do so. Physician specialty was found to be the most influential reason in the choice of caregiver by those who had ever consulted another medical practitioner. Only 14% chose consultation with a FM/GP with younger physians and non-Hong Kong medical graduates having a higher likelihood of doing so. Seventy percent of all respondents believed that having their own personal physician was unnecessary.</p> <p>Conclusion</p> <p>Similar to the practice of colleagues in other countries, a large proportion of Hong Kong physicians self-manage their illnesses, take self-obtained prescription drugs and believe they do not need a personal physician. Future strategies to benefit the medical care of Hong Kong physicians will have to take these practices and beliefs into consideration.</p

A call for transparent reporting to optimize the predictive value of preclinical research

The US National Institute of Neurological Disorders and Stroke convened major stakeholders in June 2012 to discuss how to improve the methodological reporting of animal studies in grant applications and publications. The main workshop recommendation is that at a minimum studies should report on sample-size estimation, whether and how animals were randomized, whether investigators were blind to the treatment, and the handling of data. We recognize that achieving a meaningful improvement in the quality of reporting will require a concerted effort by investigators, reviewers, funding agencies and journal editors. Requiring better reporting of animal studies will raise awareness of the importance of rigorous study design to accelerate scientific progress

A naturalistic study of the measurement of seizure adequacy in electroconvulsive therapy

The aim of this study was to assess an electroconvulsive therapy (ECT) rating scale by studying the intraictal electroencephalograph parameters induced by the seizure, and determine the clinical utility of such a scale in terms of time, application and ease of use.This naturalistic study of 55 depressed patients over a 2-year period examined specific parameters of the intraictal electroencephalograph seizure morphology and computer printout, and their association with overall clinical outcome. The rating scale was developed and evaluated in terms of clinical reliability and ease of use.Overall, 1076 individual ECT treatments were given. Using multiple regression analysis, overall seizure adequacy correlated most closely with abrupt seizure endpoint, a high amplitude rhythmic spike and wave phase of >13 s, a seizure energy index of >1000 u, and an electroencephalograph seizure length of > 24 s. "Adequate" overall ratings as determined by the rating scale were shown to correlate significantly with overall clinical improvement. The rating scale had extremely high interrater and test-retest reliability; and was relatively easy to use and time efficient.The use of the rating scale has the potential to help clinicians optimize ECT. While not perfect in any sense, it still gives clinicians good predictive qualities when used as a clinical guide. It is important that larger studies look at all the potential variables that may interact with seizure adequacy and clinical outcome.Edwards, Mark; Koopowitz, Leslie F.; Harvey, Eileen J

Evaluation of UV-C decontamination of clinical tissue sections for spatially resolved analysis by mass spectrometry imaging (MSI)

Clinical tissue specimens are often unscreened, and preparation of tissue sections for analysis by mass spectrometry imaging (MSI) can cause aerosolization of particles potentially carrying an infectious load. We here present a decontamination approach based on ultraviolet-C (UV-C) light to inactivate clinically relevant pathogens such as herpesviridae, papovaviridae human immunodeficiency virus, or SARS-CoV-2, which may be present in human tissue samples while preserving the biodistributions of analytes within the tissue. High doses of UV-C required for high-level disinfection were found to cause oxidation and photodegradation of endogenous species. Lower UV-C doses maintaining inactivation of clinically relevant pathogens to a level of increased operator safety were found to be less destructive to the tissue metabolome and xenobiotics. These doses caused less alterations of the tissue metabolome and allowed elucidation of the biodistribution of the endogenous metabolites. Additionally, we were able to determine the spatially integrated abundances of the ATR inhibitor ceralasertib from decontaminated human biopsies using desorption electrospray ionization-MSI (DESI-MSI)

Role of B cell-activating factor in chronic obstructive pulmonary disease

Rationale: B cell-activating factor (BAFF) plays a major role in activation of B cells and in adaptive humoral immune responses. In chronic obstructive pulmonary disease (COPD), lymphoid follicles have been associated with disease severity, and overexpression of BAFF has been demonstrated within lymphoid follicles of patients with severe COPD. Objectives: To investigate expression and localization of BAFF in the lungs of patients with COPD and to study the role of BAFF in COPD by antagonizing BAFF in a mouse model of chronic cigarette smoke (CS) exposure. Methods: We quantified and localized BAFF expression in lungs of never-smokers, smokers without COPD, and patients with COPD and in lungs of air- or CS-exposed mice by reverse-transcriptase polymerase chain reaction, ELISA, immunohistochemistry, and confocal imaging. Next, to investigate the role of BAFF in COPD, we antagonized BAFF by prophylactic or therapeutic administration of a soluble fusion protein of the BAFF-receptor, BAFFR-Fc, in mice exposed to air or CS for 24 weeks and evaluated several hallmarks of COPD and polarization of lung macrophages. Measurements and Main Results: BAFF expression was significantly increased in lungs of patients with COPD and CS-exposed mice. BAFF staining in lymphoid follicles was observed around B cells, CD4(+) cells, dendritic cells, follicular dendritic cells, and fibroblastic reticular cells. Prophylactic and therapeutic administration of BAFFR-Fc in mice reduced pulmonary B-cell numbers and prevented CS-induced formation of lymphoid follicles and increases in immunoglobulin levels. Interestingly, prophylactic BAFFR-Fc administration significantly attenuated pulmonary inflarnmation and destruction of alveolar walls. Moreover, antagonizing BAFF altered the phenotype of alveolar and interstitial macrophages. Conclusions: BAFF is significantly increased in lungs of patients with COPD and is present around both immune and stromal cells within lymphoid follicles. Antagonizing BAFF in CS-exposed mice attenuates pulmonary inflammation and alveolar destruction