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Erbel R.,University of Duisburg - Essen | Budoff M.,Los Angeles Biomedical Research Institute
European Heart Journal

Deaths from diseases of the heart are decreasing. Cardiovascular diseases (CVD) will be the main cause of morbidity and mortality in 2015 according to a WHO report. The main problem is related to the long-time delay between the start of the development of atherosclerosis in young adults and the manifestation many decades later. Despite a recent decline in a CVD mortality rate in men and women, the main problem is related to the acute manifestation as the acute coronary syndrome, which leads 3050 of subjects to sudden and fatal outcomes. In addition, about 20 of first and recurrent acute myocardial infarctions are silent. The lifetime risk of coronary artery disease after 40 years is 49 for men and 32 for women. That means, we are confronted with a major health care problem. This is even more obvious, when the rate of coronary heart disease deaths out of the hospital are taken into account which amount to 70 in 2007. These data are confirmed for Europe despite a strong decline of hospital deaths. Another problem is related to the fact that the number of sudden cardiac death amounts to >300 000 in the general US population. It is about 10 times higher than in those patients who are defined as prone to sudden death due to low ejection fraction, ventricular arrhythmias, and acute myocardial infarction. For cardiologists, this general topic becomes even more obvious, because even well-known cardiologists experienced early (≤65 years) sudden cardiac deaths such as RW Campbell, JM Isner, PA Poole-Wilson, H Drexler, and recently the paediatric cardiologist from Hannover, A Wessels. These events underline again what has been emphasized 15 years ago by the MONICA study that two-thirds of patients die outside the hospital and that we have to concentrate on primary and secondary prevention, also in memory of these colleagues. This review will demonstrate the potential value of coronary artery calcification screening which can be used as a sign of subclinical coronary arteriosclerosis for improved risk prediction, the first step to prevention. Subclinical atherosclerosis represents the vessel memory of risk factor exposure. © 2011 The Author. Source

Sue D.Y.,University of California at Los Angeles | Sue D.Y.,Los Angeles Biomedical Research Institute
American Journal of Respiratory and Critical Care Medicine

Excess ventilation during exercise with accompanying dyspnea is characteristic of chronic heart failure (CHF), and these patients often exhibit increased V̇E relative to the V̇CO 2 compared with normal subjects. This can be measured in several ways, including using such variables as the slope of V̇E versus V̇CO 2, the lowest ratio of V̇E/V̇CO 2, and the ratio of V̇E/V̇CO 2 at the lactic acidosis threshold or peak exercise. There is now considerable evidence that the degree of excess ventilation during exercise in patients with CHF is a robust predictor of outcome and identifies higher-risk patients requiring aggressive treatment, including heart transplantation. The mechanism of excess ventilation in patients with CHF during exercise is not completely understood. It may be related to enhanced output of chemoreceptors or peripheralmuscleergoreceptors, increaseddead space/VT ratio due to increased contribution of high ventilation-perfusion lung regions or rapid shallow breathing caused by earlier onsetof lactic acidosis, or likely resultingfroma combinationof these causes. Source

Abdulla J.,Copenhagen University | Pedersen K.S.,Copenhagen University | Budoff M.,Los Angeles Biomedical Research Institute | Kofoed K.F.,Copenhagen University
International Journal of Cardiovascular Imaging

To determine via meta-analysis the diagnostic accuracy of 64-slice computed tomography coronary angiography (CTA) for assessment of significant obstructive coronary artery stenosis at different coronary artery calcium score (CACS) levels. Data of 12,053 versus 5,890 segments, 906 versus 758 arteries and 1,120 versus 514 patients in low versus high CACS subgroups from 19 eligible studies were compared. The per-patient prevalence of coronary artery disease was 48% versus 68%, respectively. Subgroups were stratified by different CACS thresholds ranging from 100 to 400. Meta-analyses of perpatient data comparing overall low versus high CACS subgroups resulted in a sensitivity of 97.5 (95.5-99)% versus 97 (94.5-98.5)%, specificity of 85 (82-88)% versus 66.5 (58-74.5)%, diagnostic odds ratio of 153 (81-290) versus 40 (20-83), positive predictive value of 85 (82-87)% versus 86 (84-88)%, negative predictive value of 97.5 (95-99)% versus 91 (88-94)% and overall accuracy of 91% versus 89% with 95% confidence interval, respectively. The drop in specificity was significant (P = 0.035), while the sensitivity and overall accuracy were insignificantly changed (P>0.05). Meta-analyses of independent subgroups at CACS levels ≤10 and ≤100 demonstrated high specificities of 90 (94-100)% and 88.5 (81-91.5)%, whereas at CACS levels ≥400 the specificity declined significantly to 42 (28-56)% but with consistently retained high sensitivity of 97.5 (94-99)%. The specificity of CTA decreases with increasing CACS, while the sensitivity remains high independent of that. The suggested CACS thresholds are arbitrary and do not necessarily warrant cancelling angiography. Diagnostic studies are needed to explore whether a specific CACS threshold may serve as a pre-angiographic gatekeeper to prevent likely equivocal angiographies. © Springer Science+Business Media, B.V. 2011. Source

Spellberg B.,University of California at Los Angeles | Spellberg B.,Los Angeles Biomedical Research Institute
Critical Care

Antibiotic resistance continues to spread even as society is experiencing a market failure of new antibiotic research and development (R&D). Scientific, economic, and regulatory barriers all contribute to the antibiotic market failure. Scientific solutions to rekindle R&D include finding new screening strategies to identify novel antibiotic scaffolds and transforming the way we think about treating infections, such that the goal is to disarm the pathogen without killing it or modulate the host response to the organism without targeting the organism for destruction. Future economic strategies are likely to focus on 'push' incentives offered by public-private partnerships as well as increasing pricing by focusing development on areas of high unmet need. Such strategies can also help protect new antibiotics from overuse after marketing. Regulatory reform is needed to re-establish feasible and meaningful traditional antibiotic pathways, to create novel limited-use pathways that focus on highly resistant infections, and to harmonize regulatory standards across nations. We need new antibiotics with which to treat our patients. But we also need to protect those new antibiotics from misuse when they become available. If we want to break the cycle of resistance and change the current landscape, disruptive approaches that challenge long-standing dogma will be needed. © 2014 Spellberg; licensee BioMed Central. Source

Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase I | Award Amount: 574.26K | Year: 2013

DESCRIPTION (provided by applicant): In the last decade, Acinetobacter baumannii has emerged as one of the most highly antibiotic-resistant pathogens in the United States (US) and throughout the world. These infections are increasingly prevalent and highlylethal, killing 50-60% of those infected. Worse, strains of A. baumannii that no known antibiotic will kill have now emerged, and will continue to increase in frequency given the lack of antibiotics in development to treat A. baumannii. Given the tremendous scientific barriers to developing new antibiotics to treat A. baumannii and the economic market failure of antibiotics, new treatments are critically needed for this bacteria. We propose to develop a passive vaccine targeting A. baumannii (i.e., an antibody that can be administered to patients with A. baumannii infection). Our data indicate that antibody-based therapy is a promising strategy to treat A. baumannii infections. We first identified a protein that the bacteria expresses on its surface calledOmpA (Outer membrane protein A) that appeared to be a suitable target for a vaccine. We then found that when recombinant OmpA was injected into mice as an active vaccine, and subsequently the vaccinated or control mice were infected with A. baumannii, thevaccine protected mice from otherwise lethal extreme drug resistant (XDR) A. baumannii infection. Next, we discovered that the mechanism of vaccine- mediated efficacy was induction of protective antibodies. We then raised 5 distinct types of monoclonal antibodies (MAbs) against OmpA isolated from A. baumannii. These MAbs enhance opsonophagocytic killing of A. baumannii in vitro and effectively protected mice given a lethal infection with XDR A. baumannii. While these MAbs are a promising new therapy for XDR A. baumannii infections, the feasibility of further clinical development will hinge upon successful humanization of the antibodies. Mouse MAbs cannot be used to treat humans, because humans mount an immune reaction to mouse MAbs that can cause rapid removal of the MAbs (hence lower efficacy), systemic inflammation, severe allergic reactions, and even a risk for death. The humanization process prevents these undesirable effects. We therefore propose to humanize the MAbs while retaining their anti-A. baumannii activity (as verified both in vitro and in vivo) in two AIMS: 1) Humanize 3 lead candidate MAbs, with class switching to human IgG3; 2) Define an optimally effective humanized MAb regimen based on in vitro surface binding and bacterial killing, and invivo efficacy in a mouse model of A. baumannii infection. A. baumannii infections pose a grave public health threat that urgently demands development of new treatments, but no new antibiotics to treat these infections will likely be available in the coming decade. MAbs hold great promise to treat A. baumannii infections. We propose conservative milestones (feasibility criteria) that are part of a standard, methodical development pathway for our unique MAbs as a novel treatment for such infections. Progression to Phase II depends on humanization of the MAbs without loss of efficacy. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: In the last decade, Acinetobacter baumannii has emerged as one of the most highly antibiotic-resistant and deadly pathogens in the United States (US) and throughout the world. Given the tremendous scientific barriers to developing new antibiotics to treat A. baumannii and the economic market failure of antibiotics, new treatments are critically needed for this bacterium.We have developed mouse monoclonal antibodies that successfully treat mice given otherwise lethal infections of A. baumannii, and seek to humanize the antibodies as a critical first step towards translation to clinical development.

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