Showing papers by "Arthur M. Feldman published in 2008"

Regulation of cardiac myocyte contractility by phospholemman: Na+/Ca2+ exchange versus Na+-K+-ATPase

Abstract: Phospholemman (PLM) regulates cardiac Na+/Ca2+ exchanger (NCX1) and Na+-K+-ATPase in cardiac myocytes. PLM, when phosphorylated at Ser68, disinhibits Na+-K+-ATPase but inhibits NCX1. PLM regulates ...

Does academic culture support translational research

Abstract: Volume 1 • Issue 2 www.ctsjournal.com t he fulfillment of the promise of translational research for improving the health and longevity of the world’s populations depends on the development of broad-based teams of scientists and scholars who are able to focus their efforts on linking basic scientific discoveries with the arena of clinical investigation, as well as taking the results of clinical trials and translating them into changes in clinical practice. This type of team approach is quite common in large, successful businesses. However, investigators within academic medical centers often face impediments that inhibit collaborative interactions across the silos of academia. Academic medical centers must build new structures and modify their cultures to facilitate the development of seamless collaboration and cooperation among diverse groups of investigators.

Cardiac-Restricted Overexpression of the A2A-Adenosine Receptor in FVB Mice Transiently Increases Contractile Performance and Rescues the Heart Failure Phenotype in Mice Overexpressing the A1-Adenosine Receptor

Abstract: In the heart, adenosine binds to pharmacologically distinct G protein-coupled receptors (R) located on the cardiomyocyte (A1-R, A2A-R and A3-R). While the role of the A1- and A3-Rs in the heart has been clarified by selective overexpression or ablation in murine hearts, the effects of genetically manipulating the A2A-R has not been defined. Thus, we created mice overexpressing a cardiac-restricted A2A-R transgene. Mice with both low (Lo) and high (Hi) levels of A2A-R overexpression demonstrated a marked increase in cardiac contractility at 12 weeks-of-age. These changes were associated with a significantly higher systolic but not diastolic [Ca2+]i, higher maximal contraction amplitudes, maximal shortening and re-lengthening velocities, and a significantly enhanced sarcoplasmic reticulum Ca2+ uptake activity. The alterations in Ca2+ handling were associated with an increase in the level of sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA2). At 20 weeks-of-age, the effects of A2A-R overexpression on cardiac contractility diminished. The positive effects elicited by A2A-R overexpression differ from the heart failure phenotype we observed with A1-R overexpresson. Interestingly, co-expression of A2A-R TGHi, but not A2A-R TGLo, enhanced survival, prevented the development of left ventricular dysfunction and heart failure and improved Ca2+ handling in mice overexpressing the A1-R. These results suggest that adenosine-mediated signaling in the heart requires a balance between A1- and A2A-Rs – a finding that may have important implications for the ongoing clinical evaluation of adenosine receptor subtype-specific agonists and antagonists for the treatment of cardiovascular diseases.

Myocardial Fas and cytokine expression in end-stage heart failure: impact of LVAD support.

Abstract: Left ventricular assist device (LVAD) support may facilitate myocardial recovery. We evaluated the impact of LVAD support on Fas expression in a cohort with end-stage heart failure. Myocardial gene expression was assessed pre- and post-LVAD by RNase protection assay and compared to control donor hearts. The expression of Fas is markedly elevated at the time of LVAD support and is tightly correlated with TNF expression. While interleukin (IL)-6 was significantly reduced by LVAD support, the impact of support on Fas was highly variable and tightly linked to tumor necrosis factor (TNF). The role of Fas in predicting recovery after LVAD support requires further investigation.

Compositions and methods for the treatment and prevention of cardiovascular diseases

Abstract: The present invention is directed to a pharmaceutical composition, and methods of use thereof, comprising at least one agent which target multiple adenosine receptors (AR) simultaneously in a stoichiometric relationship (i.e. each AR receptor is targeted to an equal extent). Aspects of the present invention relate to pharmaceutical compositions, and uses thereof, comprising at least one agent which co-activates an A 1 -adenosine receptor (A 1 -AR) and an A 2A -adenosine receptor (A 2A -AR) or a combination of at least one agent which activates an A 1 -AR and at least one agent which activates an A 2A -AR, where both the A 1 -AR and A 2A -AR are activated in a stoichiometric relationship such that the level of biological activation of A 1 -AR is approximately the same level of biological activation of A 2A -AR. Other aspects of the present invention relates to methods for the therapeutic and prophylactic treatment of cardiac dysfunction in a subject having or at risk of having a cardiac dysfunction, for example, but not limited to, for the treatment of a subject with myocardial infarction, such as acute myocardial infarction, coronary ischemia or congestive heart failure and other cardiac dysfunctions.

CTS: a new discipline to catalyze the transfer of information.

Abstract: Volume 1 • Issue 1 www.ctsJouRNAl.com Forty years ago, the editors of the New England Journal of Medicine first used the term “bench-bedside interface” to describe the diffusion of information that needed to occur between the clinical arena and the basic science laboratories assessing the biochemical, morphologic, and genetic phenomenon that characterized the phagocytic process in patients with chronic granulomatous disease.1 This concept of “translating” novel discoveries found at the laboratory bench into the clinical investigation of new technologies and methodologies to both diagnose and treat human disease at the bedside gained increasing focus over the past decade as an explosion of innovative technology supported scientific advances in numerous fields, including genomics, proteomics, gene transfer, stem cell biology, structural biology, and imaging. As these new fields of biology leapt onto the scientific stage, scientists became increasingly aware

TNF alpha—Still a Therapeutic Target

Abstract: 4. Mann DL, McMurray JJV, Packer M, Swedberg K, Borer JS, Colucci WS, Dijan J, Drexler H, Feldman A, Kober L, Krum H, Liu P, Nieminen M, Tavazzi L, van Veldhuisen DJ, Waldenstrom A, Warren M, Westheim A, Zannad F, Fleming T. Targeted anti-cytokine therapy in patients with chronic heart failure: results of the Randomized Etancercept worldwide evaluation (RENEWAL). Circulation. 2004; 109: 1594–1602. 5. Bozkurt B, Torre-Amione G, Warren MS, Whitmore J, Soran OZ, Feldman AM, Mann DL. Results of targeted ant-tumor necrosis factor therapy with etanercept (ENBREL) in patients with advanced heart failure. Circulation. 2001; 103: 1044–1047.

Relationship of Inferior Vena Cava Filter Usage in Post-Surgical Patients by Various Surgical and Medical Subspecialists

Abstract: Venous thromboembolism is a common and often fatal problem in postsurgical patients. These patients are usually treated with either therapeutic anticoagulation or the placement of inferior vena cava (IVC) filters. Controversy surrounds the use of IVC filters, because no data exist proving survival benefit. In this study, 264 inpatient medical records of patients who underwent major surgical procedures and had the diagnosis of deep venous thrombosis or pulmonary embolism were examined. Among these patients, those who received IVC filters were identified, and the documented indications for filter placement were reviewed. Rates of IVC filter placement per venous thromboembolism event and specific indications were examined across surgical subspecialties and by type of medical consultant. Sixty percent of patients received IVC filters. IVC filter placement rates varied significantly across surgical subspecialties (p <0.0001), with the highest rate in the orthopedic surgery subgroup (80%). Rates of IVC filter use also differed significantly (p <0.0007) between medical consultants who specialized in antithrombotic medicine (46.8%) and those who did not (68.3%). Significant differences also existed in specific indications for filter placement between medical and surgical subspecialties. In conclusion, most of this study's population received IVC filters. Rates of IVC filter placement varied by the specialties of surgeons and medical consultants. The heterogeneity of treatment strategies coupled with the lack of data for this patient population highlights the need for future prospective studies to guide evidence-based treatment.

Re‐envisioning Our Approach to Research in Academia

Abstract: DOI: 10.1111/j.1752-8062.2008.00064.x L ike every profession, scientists have always faced nonfinancial pressures that could bias the interpretation of their results: the need to compete for extramural grants, the desire to climb the academic ladder, and the desire to receive accolades from peers and to win prestigious research awards.1 However, there was little oversight as there was an incredibly high level of trust in the integrity of scientific discovery and a reliance on the ethical attitudes of individual investigators.2 In 1980, the playing field changed with the passage of the Bayh-Dole Act.3 This act not only provided the opportunity for academic investigators who were funded by federal grants and their institutions to commercialize their discoveries but actually encouraged them to do so. Scientists had both an academic and an entrepreneurial interest in their work, and relationships between academicians and industry blossomed.4 American medical colleges (AMCs) also profited as they developed technology transfer offices to oversee the patenting of discoveries and the out-licensing of patents to existing pharmaceutical or device companies, start-up companies founded by university investigators, or the universities themselves. Over the past decade, scandals in biomedical research at major AMCs have made the front pages of newspapers across the United States, leading the public to question whether physicians and scientists who populate America’s academic centers have “conflicts of interest” that cause them to make decisions regarding patient care or the presentation of research studies that are biased by their own personal financial interest. These highly publicized cases were not isolated events, as studies showed a strong association between a positive outcome and the presence of a conflict of interest among the authors of clinical studies.5 Studies also showed that authors who had financial relationships with pharmaceutical companies were significantly more likely to reach supportive conclusions.6 In 2000, only 47% of high-impact journals had policies requiring disclosure of conflicts of interest.7 Among journals that had conflict-of-interest policies, few articles actually included conflictof-interest disclosures.8,9 In addition, in a survey of 100 institutions with the most funding from the National Institutes of Health in 2000, only 55% required their faculty to disclose conflicts of interest.10 Responding to the public outcries, prestigious journals instituted new policies for authors, and AMCs undertook efforts to mitigate the problem. Unfortunately, these efforts appear to have been only partially successful. A research team from Duke University Medical Center in Durham, North Carolina; Wake Forest University in Winston-Salem, North Carolina; and Johns Hopkins University in Baltimore, Maryland, reported that only 48% of U.S. AMCs had a formal policy requiring that financial conflicts of interest be disclosed to participants in industrysponsored clinical trials.11 Even when conflicts of interest did exist, participants in clinical studies were informed about the conflicts less than half of the time12 and there was little agreement among institutions about whether disclosures should include the amount of a particular financial interest held by an investigator.13 Thus, almost a decade after the first public disclosures of conflicts of interest in clinical trials, the problem has not been solved. Issues regarding conflicts of interest also have surfaced in the context of published articles and, in particular, practice guidelines. For example, the publication in July 2004 of the National Cholesterol Education Programs (NCEP) that recommended the use of statins14 was tarnished by the subsequent disclosure in the Los Angeles Times that one of the authors of the NCEP update had received $114,000 in consulting fees from pharmaceutical companies that produced the drugs.15 In Minnesota, requirements for public disclosure of industry payments brought additional conflicts to light. Indeed, 87% of guideline authors had some form of interaction with the pharmaceutical industry, and 58% of authors had relationships with companies whose drugs were recommended by the guidelines they authored. Responding to concerns on the part of the public, state legislatures have taken action. In 1993, Minnesota mandated that all pharmaceutical and device companies needed to report relationships with physicians—a mandate that was later passed in Vermont, Maine, West Virginia, California, and the District of Columbia.16 More recently, Senators Charles Grassley (R-IA) and Herb Kohl (D-WI) introduced the Physician Payments Sunshine Act, a bill that would require manufacturers of pharmaceutical and medical devices to disclose the amount of money they give to individual physicians. In many respects, this bill would be beneficial for patients, physicians, and the pharmaceutical and device companies. However, in some states, governmental actions have simply gone too far. Recent proposals by the Massachusetts Senate would ban all gifts and freebies to doctors from pharmaceutical companies, a move that would make Massachusetts the first state in the country to ban such gifts outright.17 Failure to adhere to the ruling could result in a fine up to $5,000 and jail sentences up to 2 years for practicing physicians who accept a pen, a pad of paper, or a slice of pizza from a company representative. The proposed Massachusetts ban has been criticized for negatively impacting information flow to practitioners.17 Academic leaders have also noted that, “the language of the legislature’s proposed anti-gifting bill is both severe and vague, inviting inquisitors and individuals with personal grievances to harass Re-envisioning our Approach to Research in Academia