Postmenopausal hormone therapy and subclinical cerebrovascular disease: the WHIMS-MRI Study.

OBJECTIVE: The Women's Health Initiative Memory Study (WHIMS) hormone therapy (HT) trials reported that conjugated equine estrogen (CEE) with or without medroxyprogesterone acetate (MPA) increases risk for all-cause dementia and global cognitive decline. WHIMS MRI measured subclinical cerebrovascular disease as a possible mechanism to explain cognitive decline reported in WHIMS. METHODS: We contacted 2,345 women at 14 WHIMS sites; scans were completed on 1,424 (61%) and 1,403 were accepted for analysis. The primary outcome measure was total ischemic lesion volume on brain MRI. Mean duration of on-trial HT or placebo was 4 (CEE+MPA) or 5.6 years (CEE-Alone) and scans were conducted an average of 3 (CEE+MPA) or 1.4 years (CEE-Alone) post-trial termination. Cross-sectional analysis of MRI lesions was conducted; general linear models were fitted to assess treatment group differences using analysis of covariance. A (two-tailed) critical value of alpha = 0.05 was used. RESULTS: In women evenly matched within trials at baseline, increased lesion volumes were significantly related to age, smoking, history of cardiovascular disease, hypertension, lower post-trial global cognition scores, and increased incident cases of on- or post-trial mild cognitive impairment or probable dementia. Mean ischemic lesion volumes were slightly larger for the CEE+MPA group vs placebo, except for the basal ganglia, but the differences were not significant. Women assigned to CEE-Alone had similar mean ischemic lesion volumes compared to placebo. CONCLUSIONS: Conjugated equine estrogen-based hormone therapy was not associated with a significant increase in ischemic brain lesion volume relative to placebo. This finding was consistent within each trial and in pooled analyses across trials.

Effect of postmenopausal hormone therapy on glucose and insulin concentrations. PEPI Investigators. Postmenopausal Estrogen/Progestin Interventions.

OBJECTIVE: To characterize the long-term impact of four hormone therapy regimens on insulin and glucose concentrations measured during a standard oral glucose tolerance test. RESEARCH DESIGN AND METHODS: The Postmenopausal Estrogen/Progestin Intervention Study was a 3-year placebo-controlled randomized trial to assess effects of four hormone regimens on cardiovascular risk factors. This efficacy analysis describes glucose and insulin concentrations from 788 adherent women at baseline and at 1 and 3 years' postrandomization. RESULTS: When compared with women taking placebo, those taking conjugated equine estrogen (CEE) at 0.625 mg/day with or without a progestational agent had mean fasting insulin levels that were 16.1% lower, mean fasting glucose levels 2.2 mg/dl lower, and mean 2-h glucose levels 6.4 mg/dl higher (each nominal P < 0.05). No significant differences were apparent between women taking CEE only versus the three progestin regimens: medroxyprogesterone acetate (MPA) at 2.5 mg daily (continuous MPA), MPA at 10 mg on days 1-12 (cyclical MPA), and micronized progesterone (MP) (cyclical) at 200 mg on days 1-12. The impact of hormone therapy on insulin and glucose depended on baseline levels of fasting insulin and 1-h glucose (P < 0.05). However, the treatment effects on carbohydrate metabolism appeared to be consistent across participant subgroups formed by lifestyle, clinical, and demographic characteristics. CONCLUSIONS: Oral hormone therapy involving 0.625 mg/day of CEE may modestly decrease fasting levels of insulin and glucose. Postchallenge glucose concentrations are increased, however, which may indicate delayed glucose clearance.

Analysis of complications in patients with endometrial carcinoma receiving adjuvant irradiation.

We analyzed the complications in 310 patients with pathologically documented endometrial carcinoma who received adjuvant radiation therapy (RT) at Fox Chase Cancer Center between 1970 and 1986. Variables included timing of treatment, technique, total dose, age, diabetes, previous abdominal surgery, hypertension, prior bowel pathology, and lymphadenectomy. According to the FIGO (1985) system, 258 patients had Stage I disease, 48 had Stage II, and one had Stage III. One hundred seventy patients received preoperative (preop) RT, 138 received postoperative (postop) RT, and 2 received preop and postop RT. A 4-field technique was used for 212 of 235 patients receiving external-beam (EX) RT, and 75 patients were treated with intracavitary (IC) RT only. Median follow-up was 5.5 years. Actuarial survival of all 310 patients was 78% at 5 years. Thirty-two complications occurred, involving the rectum, small bowel, femur, or lower extremity. Complications were graded according to the ECOG scoring system as grade 2 (mild) and grades 3, 4, or 5 (serious). One of 75 patients treated with IC RT only experienced a grade-2 complication (proctitis). Of 71 patients receiving 4-field EX RT only, 25 preop (16%) and 14 postop (14%) patients had complications. Of 139 patients treated with both EX and IC RT, grade-2 complications were seen in 5% of 87 preop patients and 12% of 52 postop patients (p = 0.17), whereas serious complications were observed in 4% of each group. Univariate analysis of the variables of interest revealed that the incidence of complications was associated with a lymphadenectomy (p = .03), use of external RT (p less than .01), and decreasing age (p = .04). Multivariate analysis confirmed that use of external RT was the most significant predictor for complications. In conclusion, similar complication rates were found in patients treated with either preop or postop 4-field EX RT. While pelvic RT clearly decreases pelvic relapse in patient with endometrial carcinoma, the risk benefit ratio for treatment of these patients should be carefully considered when recommending adjuvant RT for pelvic control.

Preoperative and intraoperative predictors of inotropic support and long-term outcome in patients having coronary artery bypass grafting.

The prognostic value of preoperative symptoms, preoperative left ventricular function, and intraoperative factors as related to postoperative outcome in coronary artery bypass grafting is unclear. This study was performed to identify risk factors that could be used as markers to predict immediate and long-term outcome, knowledge of which might allow physicians to modify these factors to decrease the likelihood of an adverse outcome. We retrospectively evaluated preoperative factors (including age, sex, New York Heart Association [NYHA] classification of symptoms, ejection fraction [EF], wall motion abnormalities, baseline left ventricular end-diastolic pressure [LVEDP], postradiographic contrast injection LVEDP, change in LVEDP with contrast injection, cardiac enlargement, and collateral vessels) and intraoperative factors (duration of bypass and aortic cross-clamp time) in 128 patients. The need for inotropic drug support was used as a marker of immediate outcome. A 36-mo follow-up used death and the postoperative NYHA classification of symptoms as markers of long-term outcome. The various factors associated with the use of inotropes and immediate outcome were analyzed by logistic regression. The factors related to inotrope use (and presumed adverse short-term outcome) in order of decreasing significance were lower EF, older age, cardiac enlargement, female sex, and higher baseline and postcontrast LVEDP. Patients with EF greater than or equal to 55%, but also having wall motion abnormalities and LVEDP change greater than or equal to 10 mm Hg, and all patients with EF less than 55% were more likely to require inotropic drug stimulation after cardiopulmonary bypass. Neither the change in LVEDP nor the presence of wall motion abnormalities independently predicted the need for postoperative inotropic support.(ABSTRACT TRUNCATED AT 250 WORDS)

Cross-sectional and longitudinal reliability for clinical measurement of attachment loss.

Progression of marginal periodontitis in humans is characterized by acute exacerbations during short periods of time followed by periods of remission. The analytical procedures used to distinguish actively progressing sites from non-progressing sites within an individual's dentition are controversial. The purpose of the present investigation was to use measurements of probing depth and attachment level from a prospective longitudinal study of episodic periodontal disease progression to examine measurement and diagnostic reliability. In 10 systemically healthy adult human subjects with untreated advanced periodontitis, probing depth and attachment levels were measured at baseline and every 30 days for 10 to 12 months. Measurements were made at 6 sites of each tooth using an acrylic onlay as a reference point and a pressure sensitive probe. Replicate measurements were made on sites showing apparent changes in attachment loss of 2 mm or more in a month, and their contralateral counterparts. Cross-sectional reliability was described by means and standard deviations for the absolute differences between replicate measurements: 0.63 +/- 0.87 mm for anterior teeth, 0.58 +/- 0.80 mm for premolars and 0.69 +/- 0.91 mm for molars. The mean differences tended to decrease with increasing time on study and tended to be greater in deeper pockets. Longitudinal reliability was described by analyzing site-specific serial attachment level measurements across the study time period. Maximum likelihood methods were used to estimate false positive and false negative diagnostic rates associated with the diagnosis of attachment loss based on minimum threshold levels of 1 and 2 mm. The use of a 1 mm threshold resulted in estimated false positive rates of 0.08 to 0.11 and false negative rates of 0.11 to 0.15.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypothermia with and without end-expiratory pressure in canine oleic acid pulmonary edema.

An important goal in managing patients with respiratory failure using mechanical ventilatory support and positive end-expiratory pressure (PEEP) is to optimize tissue oxygen delivery relative to oxygen consumption. To this end, systemic hypothermia has been reported to reduce oxygen consumption. Cooling, however, may antagonize hypoxic pulmonary vasoconstriction and depress cardiac output. To determine whether these potentially adverse effects of cooling on tissue oxygen delivery would outweigh any potential benefits, we studied the effects of systemic hypothermia and end-expiratory pressure on venous admixture, intrapulmonary blood distribution, and oxygenation variables in 40 dogs with oleic acid-induced pulmonary edema of the right lung. The dogs were randomly assigned to four treatment groups of 10 dogs each: normothermia and zero end-expiratory pressure (ZEEP); normothermia and 10 cm H2O PEEP; hypothermia and ZEEP; hypothermia and PEEP. Hypothermia to 31.9 +/- 0.1 degree C (mean +/- SEM) caused no adverse effects on intrapulmonary blood flow distribution (measured by radioactive microspheres) or on venous admixture. Tissue oxygen delivery and arterial oxygenation did not improve with hypothermia, the latter being 109 +/- 13 mm Hg and 70 +/- 8 mm Hg with PEEP and ZEEP, respectively. However, hypothermia significantly reduced oxygen consumption, so that the coefficient of oxygen delivery (i.e., the ratio of oxygen supply to consumption) increased from 2.5 +/- 0.1 to 3.2 +/- 0.2 (p less than 0.01) with ZEEP and from 2.0 +/- 0.1 to 2.6 +/- 0.3 with PEEP (p = 0.016). Thus, although systemic hypothermia failed to improve arterial oxygenation and tissue oxygen delivery, it decreased systemic oxygen demands, thereby improving the oxygen supply-demand balance.

Clinical responses following periodontal treatment by local drug delivery.

A 4-quadrant, single-blind study was designed to test the efficacy of periodontal disease therapy by local drug delivery. A delivery system made of extruded ethylene vinyl acetate fibers loaded with 25% USP tetracycline hydrochloride was placed and maintained in periodontal pockets for 10 days. The clinical effects of this form of therapy were compared with treatment by periodontal scaling. In addition, the effect of treatment by combined local delivery and scaling was investigated. Untreated quadrants were included as control. Placement of tetracycline-loaded ethylene vinyl acetate fibers into periodontal pockets established a drug concentration of approximately 0.06%. By covering the delivery system with a periodontal dressing, this concentration level was maintained throughout the 10-day therapeutic period. The average tetracycline dose used was 2.4 mg/tooth treated. Following fiber therapy, treated sites improved clinically, as evidenced by a gain in periodontal attachment and a decrease in periodontal pocket depth. The rate of new lesion formation at fiber-treated sites decreased from a pretreatment rate of 26.5% of sites/year to a posttreatment rate of 4.8% of sites/year. Periodontal scaling also produced clinical improvement, as indicated by significant attachment gain, pocket depth reduction and a decreased rate of new lesion formation. However, in no case were clinical results by scaling superior to results by local drug delivery, and by several measures local drug delivery was found to provide a better clinical response. Principal measures by which the clinical response using local drug delivery exceeded that by scaling were in early (3-6 months) attachment gain and in the degree of reduction of new lesion formation.(ABSTRACT TRUNCATED AT 250 WORDS)

Periodontal disease treatment by local drug delivery.

The subgingival microbiologic composition of diseased periodontal sites was evaluated by darkfield microscopy before and after scaling or local delivery of tetracycline. A standardized sampling and counting method using a crevicular washing technique was developed to determine both numbers and proportions of morphotypes using darkfield microscopy. Tetracycline-loaded hollow fibers established an initial intrasulcular concentration of 200,000 micrograms/ml, which decreased exponentially to 15 micrograms/ml in 24 hours. Repetitive intrasulcular placement of these fibers at periodontitis sites produced an incremental reduction in bacterial counts over a 10-day period. Monolithic fibers made of ethylene vinyl acetate loaded with 25% tetracycline hydrochloride provided sustained release for 10 days under in vitro test conditions. Ten patients were treated in a study comparing the effects of these fibers with scaling. Fibers were placed subgingivally to fill pockets to their probable depth and covered with a periodontal dressing which was maintained for 10 days. The average intrasulcular tetracycline concentration measured at the end of the 10-day period was 643 micrograms/ml. At these sites, total counts, spirochetes, motile rods and nonmotile rods were significantly reduced immediately following treatment. Total counts were depressed to levels near the detection limit of darkfield microscopy. In comparison, scaling produced much smaller alterations of darkfield counts which were not statistically significant.

Clinical Responses Following Periodontal Treatment by Local Drug Delivery.

A 4-quadrant, single-blind study was designed to test the efficacy of periodontal disease therapy by local drug delivery. A delivery system made of extruded ethylene vinyl acetate fibers loaded with 25% USP tetracycline hydrochloride was placed and maintained in periodontal pockets for 10 days. The clinical effects of this form of therapy were compared with treatment by periodontal scaling. In addition, the effect of treatment by combined local delivery and scaling was investigated. Untreated quadrants were included as control. Placement of tetracycline-loaded ethylene vinyl acetate fibers into periodontal pockets established a drug concentration of approximately 0.06%. By covering the delivery system with a periodontal dressing, this concentration level was maintained throughout the 10-day therapeutic period. The average tetracycline dose used was 2.4 mg/tooth treated. Following fiber therapy, treated sites improved clinically, as evidenced by a gain in periodontal attachment and a decrease in periodontal pocket depth. The rate of new lesion formation at fiber-treated sites decreased from a pretreatment rate of 26.5% of sites/year to a posttreatment rate of 4.8% of sites/year. Periodontal scaling also produced clinical improvement, as indicated by significant attachment gain, pocket depth reduction and a decreased rate of new lesion formation. However, in no case were clinical results by scaling superior to results by local drug delivery, and by several measures local drug delivery was found to provide a better clinical response. Principal measures by which the clinical response using local drug delivery exceeded that by scaling were in early (3-6 months) attachment gain and in the degree of reduction of new lesion formation. The combination of fiber therapy with scaling reduced the rate of new lesion formation; however, attachment gain appeared delayed in comparison with either scaling alone or fiber therapy alone. This delay in healing was probably due to mechanical interference by the delivery system, which was packed into the periodontal pocket immediately following scaling. Although delayed, the final attachment gain was equal to that of other treatment modalities. Untreated sites exhibited clinical signs of significant improvement which appeared 6 to 12 months after the therapeutic period. Attachment level gains were consistently less than at periodontal sites which had been treated but were nevertheless significant when compared to pretreatment levels. It is suggested that host response mechanisms triggered by periodontal scaling may have been responsible for this effect.