Publications

Three non-RGD-containing disintegrins, VLO5, EO5, and EC3, belong to the heterodimeric family of these snake venom-derived proteins. They are potent inhibitors of certain leukocyte integrins such as alpha4beta1, alpha4beta7, and alpha9beta1, and act through the MLD motif present in one of their subunits. However, the selectivity of these disintegrins to interact with integrins is related to the amino acid composition of the integrin-binding loop in the MLD-containing subunit. The most important amino acid is that preceding the MLD motif. In vitro experiments in adhesion and ELISA assays revealed that the TMLD-containing disintegrins, VLO5 and EO5, appeared to be very potent inhibitors of human alpha4beta1 and alpha9beta1 and less effective in inhibition of the alpha4beta7 integrin. The reverse effect was observed for the AMLD-containing disintegrin, EC3. The data with native disintegrins were confirmed by experiments with synthetic peptides displaying TMLD and AMLD motifs. The MLD-containing disintegrins showed differential activities to inhibit human and murine alpha4beta1 integrin. EC3 was a weaker inhibitor of human integrin, whereas VLO5 and EO5 less actively inhibited murine alpha4beta1. These data describe a useful set of potent and selective integrin antagonists and suggest conformational requirements of human and mouse integrins for interaction with ligands.

During the past several years much new evidence has accumulated regarding the molecular and biochemical mechanisms underlying cardiac responses to hypoxia and to ischemia/reperfusion injury. Studies have involved cell culture, and ex vivo and in vivo preparations. This review focuses on regulation of two transcription factors that are thought to be important in these processes, hypoxia-inducible factor1alpha (HIF-1alpha) and heat shock factor (HSF). Both of these molecules are expressed acutely and chronically in response to hypoxia and ischemia/reperfusion, and both have numerous targets that comprise part of integrated response to ischemic injury aimed at promoting cell survival. Emphasis is placed on new mechanisms of action that regulate HIF-1alpha, HSF, and heat shock proteins as key responses to hypoxia and ischemia, and possible approaches to therapy based on these data are discussed.

PURPOSE

Because limited audit/feedback of health status information has yielded mixed results, we evaluated the effects of a sustained program of audit/feedback on patient health and satisfaction.

METHODS

We conducted a group-randomized effectiveness trial in which firms within Veterans Administration general internal medicine clinics served as units of randomization, intervention, and analysis. Respondents to a baseline health inventory were regularly mailed the 36-Item Short Form (SF-36) and, as relevant, questionnaires about six chronic conditions (ischemic heart disease, diabetes, chronic obstructive pulmonary disease, depression, alcohol use, and hypertension) and satisfaction with care. Data were reported to primary providers at individual patient visits and in aggregate during a 2-year period.

RESULTS

Baseline forms were mailed to 34,050 patients; of the 22,413 respondents, 15,346 completed and returned follow-up surveys. Over the 2-year study, the difference between intervention and control groups (as measured by difference in average slope) was -0.26 (95% confidence interval [CI]: -0.79 to 0.27; P=0.28) for the SF-36 Physical Component Summary score and -0.53 (95% CI: -1.09 to 0.03; P=0.06) for the SF-36 Mental Component Summary score. No significant differences emerged after adjusting for deaths. There were no significant differences in condition-specific measures or satisfaction between groups after adjustment for provider type, panel size, and number of intervention visits, or after analysis of patients who completed all forms.

CONCLUSION

An elaborate, sustained audit/feedback program of general and condition-specific measures of health/satisfaction did not improve outcomes. To be effective, such data probably should be incorporated into a comprehensive chronic disease management program.