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Background: Discussions about advance directives should be offered to all nursing home residents. Managed Medicare programs for nursing home residents allow for the development of performance improvement initiatives to ensure that these discussions occur and are documented., Purpose: To assess the effectiveness of an intervention to increase discussion and documentation of advance directives for enrollees in a managed Medicare program for nursing home residents, and to evaluate whether this intervention affected preferences for cardiopulmonary resuscitation (CPR) and hospitalization among enrollees., Subjects: Participants were 4,248 enrollees in a managed Medicare program in 1996, and 6,598 enrollees in 1997, in Georgia, Maryland, Massachusetts, Minnesota, Arizona, and Florida., Design: Descriptive study of a quality improvement initiative., Methods: A chart review was conducted in the fall of 1996 to determine the prevalence of documented advance directive discussions among all enrollees, and the preferences regarding CPR and hospitalization. Because the discussion rates varied across sites, and were lower than expected, each site developed strategies to improve advance directive discussion and documentation. One year later, a similar survey was conducted to determine the efficacy of the interventions, as well as to assess the impact, if any, on rates of desire for CPR and hospitalization., Results: Documented discussions of advance directives increased across the six sites from 73% to 85% (P < 0.001). The overall percentage of patients desiring CPR did not change following the intervention (18%). However, there were geographical differences in the desire for CPR among enrollees, with those in Minnesota (8%), Arizona (11%), and Florida (12%) desiring it the least, and those in Massachusetts (20%), Georgia (29%), and Maryland (29%) desiring it the most. The overall percentage of desire for hospitalization decreased from 65% to 62% (P < 0.001). Enrollees in Georgia were most likely to want hospitalization (87%), and enrollees in Minnesota were the least likely to want hospitalization (57%)., Conclusions: In a managed care program, documentation of advance directive discussions can be increased with focused efforts. Overall, most enrollees did not desire CPR, but a majority desired hospitalization. Despite the similarity of interventions and program philosophy across sites, significant geographic variations in desire for CPR and hospitalization remained.

Objectives: To describe a cluster of cases of proximal deep vein thrombosis among nursing home residents treated with megestrol acetate, to identify other risk factors for deep vein thrombosis development among these patients, and to alert physicians to this potential complication of megestrol acetate therapy., Design: Retrospective review., Setting: A 129-bed Maryland nursing home., Participants: Nineteen residents prescribed megestrol acetate between November 1997 July 1998, identified by computerized pharmacy records., Measurements: Demographic data (including identification of known risk factors for deep vein thrombosis development) were collected along with information on the indications for megestrol acetate therapy and its duration, diagnostic studies related to detection of deep vein thrombosis and their results, and patient outcomes following diagnosis of deep vein thrombosis., Results: Megestrol acetate was prescribed for 18 nutritionally at-risk patients and one with uterine cancer. Six (32%) patients developed deep vein thrombosis signs and symptoms, and all diagnoses were confirmed as proximal deep vein thromboses with Doppler studies. (No diagnosis of deep vein thrombosis were made among any nursing home patients not being treated with megestrol acetate during the observation period.) All patients diagnosed with deep vein thrombosis were hospitalized and anticoagulated, but none were diagnosed with pulmonary embolus or died. The length [median (range)] of megestrol acetate treatment was similar regardless of whether deep vein thrombosis developed [117 (57-244) versus 143 (2-294) days, respectively, P = 0.83]. Stratification by length of treatment in 50-day increments revealed that most patients who developed deep vein thrombosis did so after 50 days of treatment (P = 0.046)., Conclusion: A high incidence of deep vein thrombosis was identified among nursing home residents treated with megestrol acetate, even among ambulatory individuals with no other known risk factors. Because the efficacy of megestrol acetate treatment in nursing home residents with weight loss is unproven, the risk of deep vein thrombosis must be considered when prescribing megestrol acetate, and its use to treat nutritionally at-risk nursing home residents should be limited.

Insulin decreases cellular protein degradation, but the mechanism of this action is poorly understood. We have shown that insulin can have an inhibitory effect on the action of the proteasome in vitro, which requires the presence of insulin degrading enzyme (IDE). In this study we have used an antibody which inhibits the activity of IDE to show that IDE is required for insulin inhibition of protein degradation in intact cells. The anti-IDE antibody blocked the insulin effect on cellular degradation of proteins prelabeled with radioactive amino acids. The anti-IDE antibody also decreased insulin inhibition of proteasome degradation of a specific substrate in intact cells. These data suggest that insulin works intracellularly via IDE to inhibit protein degradation by the proteasome. Thus, IDE may function as an intracellular mediator for insulin effects on protein degradation. This is a novel signal transduction mechanism for peptide hormones.

Cellular homeostasis requires regulation of protein turnover. Protein degradation is an essential component of this process and is inhibited by insulin. The importance of cytosolic proteolysis in overall cellular protein degradation is increasingly apparent and an insulin effect on this system has been suggested but not proven. The present study shows that a membrane permeable substrate of the proteasome is degraded in HepG2 cells and that insulin inhibits its degradation both by isolated proteasomes and by intact cells. Inhibitors of the proteasome suppress degradation, and in the presence of these inhibitors insulin has no further effect. This is the first demonstration that insulin inhibition of cellular protein degradation is due to an effect on proteasomes.

The insulin degrading enzyme (IDE) is the first recognized member of a new class of metalloproteinases. Studies on the purification and the properties of this enzyme have led to divergent results and conclusions from different laboratories. The present manuscript suggests that many of the divergent results may be due to the interaction of this enzyme with other proteins as part of a proteolytic complex. IDE co-isolates with the multicatalytic proteinase (MCP) during a wide variety of purification approaches including affinity chromatography and conventional purification approaches. Ion exchange chromatography will partially or completely separate IDE and MCP. The SDS-PAGE protein bands at various purification steps suggest the presence of a cytosolic proteolytic complex containing IDE, MCP and other unidentified components and raise the possibility of a functional interaction among these proteins.

Insulin degrading enzyme (IDE) is a thiol-dependent metalloendoprotease that is responsible for initiation of cellular insulin degradation. However, its exact mode of action and the factors controlling it are poorly understood. Since IDE is a metal requiring enzyme, we have examined which metal(s) is(are) endogenously associated with it. Using neutron activation analysis, we studied the metal content of a partially purified enzyme from three different tissues: rat skeletal muscle, rat liver, and human placenta. Our results indicate that zinc and manganese are associated with the enzyme with approximately 10 times more zinc as manganese being present. These results suggest that one or both of these two metals are endogenously associated with this enzyme and are a means of controlling the enzyme's activity.

A commercially available radial immunodiffusion assay was used to measure serum alpha-1-antitrypsin levels in stool samples from subjects aged over 60 years as a marker of protein-losing enteropathy. alpha 1-antitrypsin was found in all of 12 patients with colonoscopy-confirmed pseudomembranous colitis, 6 of 14 (43%) patients with Clostridium difficile diarrhoea without pseudomembranes, 6 of 12 (50%) nursing-home patients culture-positive for Cl difficile but negative for its cytotoxin, and none of 15 healthy control subjects. It is concluded that serum protein loss into the gastrointestinal tract can occur as a result of Cl difficile infection, that its presence correlates with the severity of disease, and that it may occur even in the absence of diarrhoea. The diagnosis of protein-losing enteropathy should be considered for all patients with Cl difficile infection, particularly elderly nursing-home patients, in whom the risk of Cl difficile disease and the frequency of severe malnutrition are high.

Sclerosing or morphea-like variant of basal cell carcinoma (BCC) is characterized by an extensive connective tissue stroma, and histopathology has suggested that the extracellular matrix is largely composed of collagen. In addition, fibronectin deposition has been proposed to modulate tumor growth in BCC. In this study, we examined the expression of genes coding for type I, III, and IV procollagens, as well as for fibronectin, in tissue from 10 patients with sclerosing BCC. For comparison, tissues from 5 patients with nodular BCC and 4 controls were examined. Total RNA was isolated by CsCl density gradient centrifugation, and messenger RNA (mRNA) steady-state levels were determined by slot-blot hybridizations with human sequence specific complementary DNAs (cDNAs). The abundance of type I procollagen mRNA in sclerosing BCC tissue was increased to 233.6 +/- 36.7% of the controls (mean +/- SEM). The corresponding value for type III procollagen mRNA in sclerosing BCC was 281.8 +/- 54.8% of the controls. Consequently, the steady-state ratio of type I/III procollagen mRNAs in sclerosing BCCs (5.0 +/- 1.2; mean +/- SD) was within the control range. Thus, there is a coordinate increase in type I and type III procollagen mRNA levels in sclerosing BCC. In contrast, the values for type I and type III procollagen mRNAs in nodular BCC were not different from the controls. In addition, type IV procollagen and fibronectin mRNA levels were not different from the controls either in sclerosing or nodular BCCs, attesting to the selectivity of the increase in type I and III procollagen mRNA levels in sclerosing BCC. These observations may relate to the excessive deposition of the extracellular matrix stroma surrounding the tumor cells in sclerosing BCC.