Low-dose contraceptive estrogen-progestin and coronary artery atherosclerosis of monkeys.

OBJECTIVE: To determine the separate and combined effects of the estrogen and progestin components of a modern triphasic oral contraceptive (OC) formulation on extent of coronary artery atherosclerosis. METHODS: Female cynomolgus monkeys (n = 81) were fed atherogenic diets for 32 months. After the first 7 months, they were randomized to four groups and treated triphasically for 21 of each 28 days with ethinyl estradiol (E2) (monkey equivalent of 30-40 microg), levonorgestrel (monkey equivalent of 50-125 microg), a combination of the two steroids, or placebo. RESULTS: Treatment with estrogen alone reduced coronary artery atherosclerosis extent 67% compared with untreated controls (P <.05). Treatment with progestin alone had no effect (P >.20). While atherosclerosis extent in monkeys treated with the combined OC was reduced 28%, this did not differ statistically from the other groups (P >.20). CONCLUSION: In doses used for oral contraception, E2, like all other estrogens studied to date, has a marked inhibitory effect on atherosclerosis progression. Levonorgestrel, at doses used in modern OC formulations, antagonizes this effect. When considered with other experimental evidence, these findings support the concept that progestins used in OCs and hormone replacement therapy can antagonize estrogen's atheroinhibitory effects. Whether this occurs seems to depend on a relative balance between estrogen and progestin with respect to dose, potency, route, and pattern of administration. However, when considered with evidence from previous studies, the findings also indicate a modest atheroinhibitory influence of combination (estrogen-progestin) OCs.

The costs versus the perceived benefits of an LCME institutional self-study.

PURPOSE: To calculate the costs versus the perceived benefits of an institutional self-study done to satisfy the requirements of the Liaison Committee on Medical Education's (LCME's) accreditation process. METHOD: From postcard questionnaires, the authors determined the hours spent over 18 months from 1994 to 1996 on the institutional self-study by 131 self-study committee members and 64 database compilers at the Medical College of Wisconsin. The committee members also rated the potential utility of the self-study process and the probability that the concerns identified by their subcommittees would be addressed. Administrative costs (self-study coordinating team's hours, supplies, and other expenses) were tracked using calendars and budget subaccount numbers. Personnel costs were calculated using salary data from the Association of American Medical Colleges and the College and Universities Personnel Administrators' survey. RESULTS: Supplies and equipment for the self-study cost $12,158, and the personnel costs, based on an 81% response rate, were estimated at $207,384, for a total of $219,542. The participants in the self-study rated the process as moderately useful, but believed that there was only a medium degree of probability that concerns they had identified would be addressed. CONCLUSION: Considering the costs of self-study, the process might be more useful if attention were focused less on identifying concerns and more on an institution's demonstrated ability to successfully respond to problems.

Conjugated equine estrogens alone, but not in combination with medroxyprogesterone acetate, inhibit aortic connective tissue remodeling after plasma lipid lowering in female monkeys.

The objective of this study was to determine the arterial responses to plasma lipid lowering alone or in combination with (1) estrogen replacement therapy or (2) hormone replacement therapy in surgically postmenopausal female monkeys with preexisting atherosclerosis. Eighty-eight female cynomolgus macaques were ovariectomized, fed an atherogenic diet for 24 months, and then assigned by randomized stratification into 4 groups. One group (baseline, n=20) was necropsied at the end of the atherogenic diet period; the remaining 3 groups were fed a plasma lipid-lowering diet (regression) for 30 months. These regression groups were control (diet only), CEE (receiving conjugated equine estrogens alone), and CEE+MPA (receiving CEE and continuous medroxyprogesterone acetate). A previous report described coronary artery functional and histological results; the present report describes biochemical and histological results from the abdominal aorta. Aortic plaque size was not different between groups, similar to previous findings in the coronary arteries. Aortic cholesterol content (milligrams per gram lipid-free dry weight) was lower in the regression groups compared with baseline, both for free cholesterol (mean, control=19.1, CEE=15.7, CEE+MPA=14.4, and baseline=32.7; P<0.001) and for esterified cholesterol (mean, control=18.9, CEE=15.4, CEE+MPA=14.2, and baseline=58.7; P<0.001). This cholesterol efflux could lead to increased plaque stability without changing the physical size of the lesion. Alterations in aortic connective tissue composition were observed in the regression groups. When expressed as a percentage of the lipid-free tissue weight, the aortic elastin content of the control (mean=14.9) and the CEE+MPA (mean=14.0) groups was lower than that of the baseline group (mean=19.0), which was not different from that of the CEE group (mean=15.8). Aortic collagen content, as estimated by hydroxyproline content per milligram of lipid-free tissue, was higher in the control group (mean=67.4) and the CEE+MPA group (mean=66.1) than in the baseline group (mean=56.2; P<0.05). Collagen content of the CEE group (mean=58.9) was not different from that of the baseline group. When the regression groups were considered separately, the aortic collagen content of the CEE group was lower than that of the control group (P<0.05) and tended to be lower than that of the CEE+MPA group (P=0.10), suggesting that CEE therapy (but not CEE+MPA) inhibits potentially detrimental connective tissue alterations that accompany lesion regression. These results have implications for combinations of lipid-lowering and hormone replacement therapies in relation to vascular remodeling and abdominal aortic aneurysm development.

Tamoxifen inhibits arterial accumulation of LDL degradation products and progression of coronary artery atherosclerosis in monkeys.

Estrogen replacement therapy reduces the risk of coronary heart disease in postmenopausal women and inhibits progression of coronary artery atherosclerosis in monkeys. Tamoxifen is a nonsteroidal compound with mixed estrogen agonist and antagonist properties. Its antagonist activity is useful in chemotherapy of breast cancer and may have protective effects on plasma lipid concentrations, but its effects on atherogenesis have not been defined. The goal of this study was to examine the effect of tamoxifen on plasma lipids, arterial and hepatic LDL metabolism, and progression of coronary artery atherosclerosis in surgically postmenopausal female monkeys. Thirty-five monkeys were fed an atherogenic diet containing 1.3 mg.kg-1.d-1 tamoxifen (equivalent to the usual dose of 20 mg/d given to women). Thirty-one monkeys were fed the same atherogenic diet with no tamoxifen. Ten monkeys from each treatment group were fed the test diets for 12 weeks to examine the short-term effects of tamoxifen on arterial LDL metabolism. The rest of the monkeys were fed the test diets for 3 years to study the long-term effects of tamoxifen on development of atherosclerosis. In the short term, tamoxifen inhibited the rate of arterial accumulation of LDL degradation products overall (P = .03) and decreased hepatic cholesterol content (P = .003). In the long term, tamoxifen increased plasma concentrations of triglycerides (0.60 +/- 0.67 versus 0.23 +/- 0.02 mmol/L, P = .001) and reduced average LDL molecular weight (5.3 +/- 0.2 versus 4.8 +/- 0.1 g/mumol, P = 0.004) but had no effects on plasma total, LDL, or HDL cholesterol concentrations. Coronary artery atherosclerosis (intimal area, mean +/- SEM) was 0.25 +/- 0.06 mm2 in control monkeys and 0.12 +/- 0.03 mm2 in tamoxifen-treated monkeys (P = .057). We conclude that tamoxifen has antiatherogenic effects that may be modulated in part through direct effects on arterial LDL metabolism.

Medroxyprogesterone acetate antagonizes inhibitory effects of conjugated equine estrogens on coronary artery atherosclerosis.

Although estrogen replacement therapy is associated with reduced risk of coronary heart disease and reduced extent of coronary artery atherosclerosis, the effects of combined (estrogen plus progestin) hormone-replacement therapy are uncertain. Some observational data indicate that users of combined hormone replacement consisting of continuously administered oral conjugated equine estrogens (CEE) and oral sequentially administered (7 to 14 days per month) medroxyprogesterone acetate (MPA) experience a reduction in risk similar to that of users of CEE alone. However, the effects of combined, continuously administered CEE plus MPA (a prescribing pattern that has gained favor) on the risk of coronary heart disease or atherosclerosis are not known. We studied the effects of CEE (monkey equivalent of 0.625 mg/d) and MPA (monkey equivalent of 2.5 mg/d), administered separately or in combination, on the extent of coronary artery atherosclerosis (average plaque size) in surgically postmenopausal cynomolgus monkeys fed atherogenic diets and treated with these hormones for 30 months. Treatment with CEE alone resulted in atherosclerosis extent that was reduced 72% relative to untreated (estrogen-deficient) controls (P < .004). Atherosclerosis extent in animals treated with CEE plus MPA or MPA alone did not differ from that of untreated controls. Although treatment had marked effects on plasma lipoprotein patterns, statistical adjustment for variation in plasma lipoproteins did not alter the between-group relationships in atherosclerotic plaque size, suggesting that these factors do not explain substantially the atheroprotective effect of estrogen or the MPA-associated antagonism. Although the mechanism(s) remains unclear, we conclude that oral CEE inhibits the initiation and progression of coronary artery atherosclerosis and that continuously administered oral MPA antagonizes this atheroprotective effect.

Application of an enzyme-multiplied immunoassay technique for determination of caffeine elimination kinetics as a test of liver function in clinically normal dogs.

A commercially available automated enzyme-multiplied immunoassay technique (EMIT) was used to determine serum caffeine concentration after oral and IV administrations of caffeine at dosage of 5 mg/kg of body weight to 12 clinically normal dogs. Dogs were allotted to 2 groups of 6 dogs each; 1 group initially received caffeine orally and the other received caffeine IV. After 72 hours, caffeine administration was repeated in all dogs in the alternate manner. Serum samples were obtained at multiple intervals over 24 hours to determine distribution and elimination kinetics. Analysis of the drug concentration-time data indicated IV elimination half-life (t1/2) of 6.39 +/- 1.87 hours, volume of distribution at steady state of 685.3 +/- 132.2 ml/kg, total body clearance of 1.31 +/- 0.38 ml/min/kg, absorption t1/2 of 1.02 +/- 0.68 hour, oral elimination t1/2 of 6.53 +/- 2.72 hours, lag time after oral administration of 0.0614 +/- 0.0661 hour, highest measured concentration of 5.29 +/- 1.17 micrograms/ml, time to peak concentration of 2.74 +/- 1.30 hours, and bioavailability of 99.4 +/- 19.4%. Data from 6 dogs best fit a 1-compartment open model and those from 6 other dogs best fit a 2-compartment open model. On the basis of data from the 6 dogs that best fit a 2-compartment model, t1/2 of distribution was 0.58 +/- 0.72 hour. Data for oral administration best fit a single absorption phase and a single elimination phase. The increased availability and simplicity of the EMIT offers an opportunity to study the application of caffeine elimination for clinical evaluation of dogs with liver disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Object relations and social functioning of schizophrenic and borderline patients: a cross-sectional developmental perspective.

Using a cross-sectional design, this study compared patients with schizophrenic and borderline personality disorders on measures of object relations and social functioning. Although we found that on measures of object relations the borderline group remained less impaired than the schizophrenics, during the course of the lifespan the schizophrenic patients appeared to surpass the borderlines on social functioning. These results are integrated with the literature that compares the long-term course and outcomes for these disorders and are discussed within the context of differential adaptive capacities, change mechanisms, and treatment interventions.

Renal failure attributable to atrophic glomerulopathy in four related rottweilers.

Atrophic glomerulopathy resulting in chronic renal failure was diagnosed in 4 related Rottweilers, each < 1 year old. All 4 dogs had severe azotemia and massive protein-losing nephropathy. Histologically, the glomerular lesion was characterized by mild dilatation of Bowman's space, with glomerular tufts absent or markedly atrophied. The lesion is distinct from the congenital glomerular changes described in Samoyeds or Doberman Pinschers.

Impact of long-term cyclosporine immunosuppressive therapy on native kidneys versus renal allografts: serial renal function in heart and kidney transplant recipients.

Aggregate analyses of the impact of long-term cyclosporine administration in kidney transplant recipients have reported generally impaired but stable allograft function. In contrast, experience in extrarenal transplantation has suggested that treatment with cyclosporine for periods in excess of 12 months causes a progressive native nephropathy often leading to dialysis dependence. The extent of this apparent discrepancy between native kidneys and renal allografts is the subject of this study, which examines the evolution of renal function in 119 kidney and 100 heart transplant recipients receiving 12 or more months of cyclosporine immunosuppressive therapy administered in uniform protocols by affiliated clinical transplantation programs. The evolution of renal function in both study cohorts was analyzed retrospectively on the basis of serial serum creatinine (Crs) determinations. Assessment of group mean Crs, reciprocal Crs (1/Crs), and slopes of the curves obtained by plotting 1/Crs versus time in individual patients revealed a significant decline of native kidney function over the first 6 posttransplant months in the cardiac allograft group. Thereafter, however, native kidney function stabilized in these patients, and the aggregate trend was suggestive of no further decline in function over a 3- to 4-year follow-up period. Kidney transplant recipients had an aggregate trend of slowly declining allograft function consistent with the effects of chronic immunologic injury. The data were not consistent with a uniform pattern of a progressive, cyclosporine-induced loss of renal function in either cohort. Long-term use of cyclosporine was found to be associated with impaired but generally stable aggregate renal function in both the heart and the kidney transplant cohorts.(ABSTRACT TRUNCATED AT 250 WORDS)

Stability of renal allograft function associated with long-term cyclosporine immunosuppressive therapy--five year follow-up.

To examine the evolution of renal allograft function in kidney transplant recipients receiving long-term cyclosporine therapy, we evaluated 50 cadaveric and 30 living-related renal transplant recipients having graft survival greater than or equal to 12 months and an opportunity for 5 years of follow-up. Linear analysis of long-term allograft function in each patient was undertaken by plotting reciprocal serum creatinine (1/Crs) values vs. time. Mean follow-up was 49 +/- 18 months. Actual 3-year and 5-year allograft survivals were 83.8% (n = 80) [corrected] and 73.3% (n = 75) [corrected], respectively. Collective analyses of values of 1/Crs measured at yearly intervals and of the slopes of the curves obtained by plotting 1/Crs vs. time for each patient suggested that long-term use of CsA is associated with impaired but generally stable allograft function 1-5 years posttransplant. The aggregate rate of decline of renal allograft function in the study population did not differ from that of a historical control group consisting of 59 renal transplant recipients treated with a conventional prednisone-azathioprine immunosuppressive regimen. Donor source, diabetes, and diastolic hypertension (diastolic BP greater than 95 mmHg in more than half the follow-up readings) were not correlated with a more rapid rate of decline of allograft function as reflected in the slopes of the 1/Crs vs. time curves between 12 months posttransplant and the end of follow-up. In contrast, a significantly greater rate of decline of cadaveric allograft function was observed in patients with 12-month Crs values greater than 2.5 mg% and recipients of greater than 2 HLA-A,B-mismatched cadaveric kidneys. The data do not support an indication for routine conversion from CsA to azathioprine following successful renal transplantation.

A retrospective study of aldosterone secretion in normal and adrenopathic dogs.

A retrospective study on stored plasma from normal dogs and dogs with pituitary dependent hyperadrenocorticism (PDH), pituitary dependent hyperadrenocorticism controlled by mitotane (o,p'-DDD),* iatrogenic hyperadrenocorticism, and hypoadrenocorticism was conducted to determine if alterations in aldosterone production exist in these disorders. The plasma aldosterone concentration (PAC) was measured by radioimmunoassay immediately before and 1 hour after adrenocorticotropic hormone (ACTH) administration (0.5 IU/kg, intravenously [IV]). PACs increased significantly when ACTH was administered to normal dogs. Dogs with PDH had a lower baseline PAC, but their PAC increased to levels similar to that of normal dogs after ACTH administration. In dogs with PDH controlled by o,p'-DDD therapy, the response to ACTH was significantly less than that of normal dogs or dogs with untreated PDH. Dogs with iatrogenic hyperadrenocorticism had a lower baseline and post-ACTH PAC than normal dogs. Dogs with hypoadrenocorticism had a normal basal PAC, but showed no significant increase in PAC following ACTH administration. These findings suggest that PACs are significantly altered in a variety of adrenal diseases, and that the ACTH stimulation test may be useful when evaluating aldosterone secretion in adrenopathic disorders. In addition, at therapeutic dosages, o,p'-DDD treatment was associated with a decrease in basal and post-ACTH PACs in dogs with PDH.

The impact of cytomegalovirus infection on seronegative recipients of seropositive donor kidneys versus seropositive recipients treated with cyclosporine-prednisone immunosuppression.

To assess the impact of cytomegalovirus (CMV) infection in D+R- patients treated with cyclosporine (CsA)-prednisone immunosuppression, we compared the incidence of CMV infection, severity of disease, and the 1, 2, and 3-year actual graft and patient survival rates of CMV-infected D+R- patients with R+ patients from a group of 516 renal allograft recipients at our center. CMV infection occurred more frequently in 27/56 D+R- patients (48%) versus 111/376 R+ patients (29%) (P less than 0.01). The incidence of CMV was also significantly greater in D+R- versus R- patients receiving CAD grafts (59% vs. 32%, P less than 0.01) and first transplants (47% vs. 30%, P less than 0.05). There were no significant differences in CMV disease severity between the aggregate D+R- and R+ patient groups and when subgroups of these patients receiving cadaveric donor (CAD), living-related donor (LRD), first, or retransplant allografts were compared. The actual 1, 2, and 3-year graft survival rates for D+R- patients (68%, 58%, 68%) were not significantly different from rates in R+ patients (83%, 77%, 63%) with CMV infection. When the 1, 2, and 3-year actual graft survival rates in subgroups of D+R- and R+ patients were compared in CAD, LRD, and first and retransplants, there were no significant differences. The actual 1, 2, and 3-year patient survival rates were not significantly different between D+R- (89%, 92%, 100%) and R+ patients (94%, 91%, 86%) with CMV infection, nor were they different when CMV infected D+R- and R+ patients with CAD, LRD, first or retransplant grafts were compared. These data do not support the policy of denying a seropositive kidney to a seronegative recipient, since the severity of CMV disease and the impact of CMV infection is not significantly different comparing D+R- and R+ patients receiving CsA-prednisone immunosuppression.