Faculty Bibliography

OBJECTIVE: Tamoxifen reduces the risk of developing breast cancer but also affects the risks of certain vascular and neoplastic events. Our purpose was to estimate the effects of tamoxifen on potentially life-threatening vascular and neoplastic outcomes. DESIGN: Random effects meta-analysis of published randomized controlled trials. PATIENTS: Participants in all trials in which a treatment arm that included tamoxifen was compared to a similar control arm. Breast cancer risk reduction and treatment trials were included. INTERVENTIONS: Tamoxifen at variable dose and duration. MEASUREMENTS AND MAIN RESULTS: Thirty-two trials (52,929 patients) reported one or more outcomes of interest. Tamoxifen was associated with significantly increased risks of endometrial cancer (relative risk [RR] 2.70; 95% CI, 1.94 to 3.75), gastrointestinal cancers (RR 1.31; 95% CI, 1.01 to 1.69), strokes (RR 1.49; 95% CI, 1.16 to 1.90), and pulmonary emboli (RR 1.88; 95% CI, 1.77 to 3.01). Tamoxifen had no effect on secondary malignancies other than endometrial and gastrointestinal cancers (RR 0.96; 95% CI, 0.81 to 1.13). In contrast, tamoxifen significantly decreased myocardial infarction deaths (RR 0.62; 95% CI, 0.41 to 0.93) and was associated with a statistically insignificant decrease in myocardial infarction incidence (RR 0.90; 95% CI, 0.66 to 1.23). Postmenopausal women had greater risk increases for neoplastic outcomes. CONCLUSIONS: This meta-analysis of randomized trials found tamoxifen use to be significantly associated with several neoplastic and vascular outcomes. Consideration of tamoxifen use requires balance of potential benefits and risks

PURPOSE: Serious clinical deterioration precedes most cardiopulmonary arrests, and there is evidence that organized responses to this deterioration may prevent a substantial proportion of in-hospital deaths. We aimed to increase the utilization of our medical crisis response team (Condition C) to impact this source of mortality. METHODS: We have examined the change in numbers of Condition Cs and the main alternative response strategy (sequential stat pages) after the implementation of 4 strategies to increase Condition C utilization: (1) immediate reviews of all sequential STAT pages, (2) feedback to caregivers responsible for delays in Condition C activation, (3) creation of objective criteria for invoking a crisis response, and (4) dissemination of objective criteria through posting in units, e-mail, and in-service oral presentations. RESULTS: Over a 3-year period, interventions were followed by increased use of organized responses to medical crises (Condition Cs) and decreased numbers of disorganized responses (sequential STAT pages). The interventions that involved objective definition and dissemination of criteria for initiating the Condition C response were followed by 19.2 more Condition Cs monthly (95% confidence interval [CI], 12.1-26.3; P<0001) and 5.7 fewer sequential STAT pages monthly (95% CI, 3.2-8.2). The interventions that involved giving feedback to medical personnel based on review of their care were not associated with changes in the measures. CONCLUSION: Utilization of an important patient safety measure may be increased by focused interventions at an urban tertiary care hospital

A distinct group of metalloproteases has been identified in the developing sea urchin embryo by gelatin substrate gel zymography, a highly sensitive protease detection assay. The developing Arbacia embryo exhibited four prominent bands of gelatinase activity with apparent molecular masses of 55, 50, 42 and 38 kDa. The activity of the 55, 42 and 38 kDa tissue gelatinases increased and that of the 50 kDa tissue gelatinase decreased during embryonic development. All four enzymes were EDTA- and 1,10-phenanthroline sensitive and phenyl methyl sulphonyl fluoride (PMSF) insensitive. None of the enzymes had detectable caseinolytic activity in casein substrate gels. Although the Arbacia enzymes possessed a number of properties that are characteristic of the mammalian matrix metalloprotease family, they did not appear to be converted to lower molecular weight forms by organomercurial treatment and are distinct in this aspect. The Arbacia metalloproteases are candidate enzymes for the tissue and matrix remodeling that occurs during sea urchin embryo development

In rabbit ileum, Ca2+/calmodulin (CaM) appears to be involved in physiologically inhibiting the linked NaCl absorptive process, since inhibitors of Ca2+/CaM stimulate linked Na+ and Cl- absorption. The role of Ca2+/CaM-dependent phosphorylation in regulation of the brush-border Na+/H+ antiporter, which is believed to be part of the neutral linked NaCl absorptive process, was studied using purified brush-border membrane vesicles, which contain both the Na+/H+ antiporter and Ca2+/CaM-dependent protein kinase(s) and its phosphorprotein substrates. Rabbit ileal villus cell brush-border membrane vesicles were prepared by Mg precipitation and depleted of ATP. Using a freezethaw technique, the ATP-depleted vesicles were loaded with Ca2+, CaM, ATP and an ATP-regenerating system consisting of creatine kinase and creatine phosphate. The combination of Ca2+/CaM and ATP inhibited Na+/H+ exchange by 45 +/- 13%. This effect was specific since Ca2+/CaM and ATP did not alter diffusive Na+ uptake, Na+-dependent glucose entry, or Na+ or glucose equilibrium volumes. The inhibition of the Na+/H+ exchanger by Ca2+/CaM/ATP was due to an effect on the Vmax and not on the Km for Na+. In the presence of CaM and ATP, Ca2+ caused a concentration-dependent inhibition of Na+ uptake, with an effect 50% of maximum occurring at 120 nM. This Ca2+ concentration dependence was similar to the Ca2+ concentration dependence of Ca2+/CaM-dependent phosphorylation of specific proteins in the vesicles. The Ca2+/CaM/ATP-inhibition of Na+/H+ exchange was reversed by W13, a Ca2+/CaM antagonist, but not by a hydrophobic control, W12, or by H-7, a protein kinase C antagonist. We conclude that Ca2+, acting through CaM, regulates ileal brush-border Na+/H+ exchange, and that this may be involved in the regulation of neutral linked NaCl absorption

Brush-border vesicles purified from rabbit ileal villus cells were used to evaluate how Ca++/calmodulin (CaM) regulates the neutral linked NaCl absorptive process, part of which is a Na+/H+ exchanger. After freezing and thawing to allow incorporation of macromolecules into the vesicles, the effect of Ca++/CaM on brush-border Na+ uptake with an acid inside pH gradient, and on Na+/H+ exchange was determined. Freezing and thawing vesicles with 0.85 microM free Ca++ plus 5 microM exogenous CaM failed to alter Na+/H+ exchange as did the addition of exogenous ATP plus an ATP regenerating system, which was sufficient to elevate intravesicular ATP to 47 microM from a basal level of 0.4 microM. However, the combination of Ca++/CaM plus ATP inhibited Na+ uptake in the presence of an acid inside pH gradient and inhibited Na+/H+ exchange, while Na+ uptake in the absence of a pH gradient was not altered. This effect required a hydrolyzable form of ATP, and did not occur when the nonhydrolyzable ATP analogue, AMP-PNP, replaced ATP. Under the identical intravesicular conditions used for the transport studies, Ca++ (0.85 microM) plus exogenous CaM (5 microM), in the presence of magnesium plus ATP, increased phosphorylation of five brush-border peptides. These data are consistent with Ca++/CaM acting via phosphorylation to regulate the ileal brush-border Na+/H+ exchanger