Biomedical subjects

A Kabcenell

Publications and source records attributed to A Kabcenell.

6 recordsLinked to original sources

PubMed2001

Nonpeptidic, monocharged, cell permeable ligands for the p56lck SH2 domain.

p56lck is a member of the src family of tyrosine kinases and plays a critical role in the signal transduction events that lead to T cell activation. Ligands for the p56lck SH2 domain have the potential to disrupt the interaction of p56lck with its substrates and derail the signaling cascade that leads to the production of cytokines such as interleukin-2. Starting from the quintuply charged (at physiological pH) phosphorylated tetrapeptide, AcpYEEI, we recently disclosed (J. Med. Chem. 1999, 42, 722 and J. Med. Chem. 1999, 42, 1757) the design of the modified dipeptide 3, which carries just two charges at physiological pH. Here we present the elaboration of 3 to the nonpeptidic, monocharged compound, 9S. This molecule displays good binding affinity for the p56lck SH2 domain (K(d) 1 microM) and good cell permeation, and this combination of properties allowed us to demonstrate clear-cut inhibitory effects on a very early event in T cell activation, namely calcium mobilization.

Caco-2 Cells↗

PubMed1999

Ligands for the tyrosine kinase p56lck SH2 domain: discovery of potent dipeptide derivatives with monocharged, nonhydrolyzable phosphate replacements.

p56lck is a member of the src family of tyrosine kinases. Through modular binding units called SH2 domains, p56lck promotes phosphotyrosine-dependent protein-protein interactions and plays a critical role in signal transduction events that lead to T-cell activation. Starting from the phosphorylated dipeptide (2), a high-affinity ligand for the p56lck SH2 domain, we have designed novel dipeptides that contain monocharged, nonhydrolyzable phosphate group replacements and bind to the protein with KD's in the low micromolar range. Replacement of the phosphate group in phosphotyrosine-containing sequences by a (R/S)-hydroxyacetic (compound 8) or an oxamic acid (compound 10) moiety leads to hydrolytically stable, monocharged ligands, with 83- and 233-fold decreases in potency, respectively. This loss in binding affinity can be partially compensated for by incorporating large lipophilic groups at the inhibitor N-terminus. These groups provide up to 13-fold increases in potency depending on the nature of the phosphate replacement. The discovery of potent (2-3 microM), hydrolytically stable dipeptide derivatives, bearing only two charges at physiological pH, represents a significant step toward the discovery of compounds with cellular activity and the development of novel therapeutics for conditions associated with undesired T-cell proliferation.

Crystallography, X-Ray↗

PubMed1998

Lessons in cooperation: an update on improving the quality of hospital care.

BACKGROUND: Between 1989 and 1997 the Robert Wood Johnson Foundation (Princeton, NJ) launched a demonstration project, the Improving the Quality of Hospital Care Program, to test a consortium approach to quality improvement. As part of the project, four hospital consortia in various parts of the United States shared quality resources (for example, training) and collaborated on improvement efforts. Although cooperation was not a natural approach for enhancing quality in hospitals, the consortia mounted improvements in multiple clinical areas, such as diabetes care, the intensive care unit (ICU), prevention of wound infections, and care in rural areas. WHERE ARE THEY NOW? Of the four consortia that received implementation funding, all are continuing some explicit focus on improving quality, but only two have retained the organizational form of a consortium. Based at the University of Iowa (Iowa City), the Institute for Quality Healthcare continues to operate as a free-standing consortium with more than 40 hospital members. The Vermont Program for Quality in Health Care (Montpelier) provides information and education to improve quality of care statewide. LESSONS FROM THE PROGRAM: The program taught valuable lessons about what hospitals can do together and what they can achieve when they cooperate around quality of care issues. Sharing resources for education, providing a forum for quality improvement professionals to work together on specific issues, and identifying means of improving specific aspects of care in the group are all feasible in the consortium model. Even a chaotic environment can support cooperation.

Academies and Institutes↗

PubMed1998

Reducing cesarean section rates safely: lessons from a "breakthrough series" collaborative.

BACKGROUND: Almost one million cesarean operations are performed each year in the United States. The objective of this project was to test the hypothesis that a structured collaborative effort can help participating health care organizations to reduce their cesarean delivery rates safely. METHODS: Experts associated with the collaborative helped participant organizations to explore several categories of change concepts and to develop action plans for safely reducing their cesarean delivery rates. Over the course of one year participants attended three two-day learning sessions. In the interval between these sessions, collaborative participants communicated by weekly conference calls and a dedicated Internet site. RESULTS: Of 28 participating organizations, 15 percent achieved cesarean delivery rate reductions of 30 percent or more during the 12-month period of active collaborative work. An additional 50 percent achieved reductions between 10 and 30 percent. CONCLUSIONS: The Healthy People 2000 goal of a cesarean delivery rate below 15 percent by the year 2000 is attainable. Clinical leadership from doctors and nurses toward the achievement of that goal is timely, ethical, and in the best interests of childbearing women in the United States.

Academies and Institutes↗

PubMed1998

Beyond survival: toward continuous improvement in medical care.

Using the scientific method, continuous improvement strives to attain unprecedented levels of performance - improved patient outcomes while maintaining or reducing costs. The needs for, and benefits of, continuous improvement are discussed along with a description of its basic elements. The approaches outlined can serve to greatly increase the pace of improvement in health care.

Critical Care↗

PubMed1988

Organized practice and the quality of medical care.

Larger, more complex medical care organizations have the inherent capability to improve the quality of the care they deliver because of the improved competency that follows higher volumes of service, the interdependence of staff, and the emergence of responsible leadership in large organizations. The potential for slackened physician-patient relationships, however, could jeopardize that quality. We suggest that professional associations can counterbalance the negative influences of large organizations. We envision that the changing political and economic environment of medical practice, along with the greater professional and public scrutiny of care in highly visible large organizations, will act together to exert pressure on organized practices to examine and demonstrate quality clinical practice.

Economic Competition↗