The Intensive Diet and Exercise for Arthritis (IDEA) trial: 18-month radiographic and MRI outcomes.

PURPOSE: Report the radiographic and magnetic resonance imaging (MRI) structural outcomes of an 18-month study of diet-induced weight loss, with or without exercise, compared to exercise alone in older, overweight and obese adults with symptomatic knee osteoarthritis (OA). METHODS: Prospective, single-blind, randomized controlled trial that enrolled 454 overweight and obese (body mass index, BMI = 27-41 kg m(-2)) older (age ≥ 55 yrs) adults with knee pain and radiographic evidence of femorotibial OA. Participants were randomized to one of three 18-month interventions: diet-induced weight loss only (D); diet-induced weight loss plus exercise (D + E); or exercise-only control (E). X-rays (N = 325) and MRIs (N = 105) were acquired at baseline and 18 months follow-up. X-ray and MRI (cartilage thickness and semi-quantitative (SQ)) results were analyzed to compare change between groups at 18-month follow-up using analysis of covariance (ANCOVA) adjusted for baseline values, baseline BMI, and gender. RESULTS: Mean baseline descriptive characteristics of the cohort included: age, 65.6 yrs; BMI 33.6 kg m(-2); 72% female; 81% white. There was no significant difference between groups in joint space width (JSW) loss; D -0.07 (SE 0.22) mm, D + E -0.27 (SE 0.22) mm and E -0.16 (SE 0.24) mm (P = 0.79). There was also no significant difference in MRI cartilage loss between groups; D -0.10(0.05) mm, D + E -0.13(0.04) mm and E -0.05(0.04) mm (P = 0.42). CONCLUSION: Despite the potent effects of weight loss in this study on symptoms as well as mechanistic outcomes (such as joint compressive force and markers of inflammation), there was no statistically significant difference between the three active interventions on the rate of structural progression either on X-ray or MRI over 18-months.

Influences of alignment and obesity on knee joint loading in osteoarthritic gait.

OBJECTIVE: To determine the influences of frontal plane knee alignment and obesity on knee joint loads in older, overweight and obese adults with knee osteoarthritis (OA). METHODS: Cross-sectional investigation of alignment and obesity on knee joint loads using community dwelling older adults (age ≥ 55 years; 27 kg m(-2) ≥ body mass or body mass index (BMI) ≤ 41 kg m(-2); 69% female) with radiographic knee OA that were a subset of participants (157 out of 454) enrolled in the Intensive Diet and Exercise for Arthritis (IDEA) clinical trial. RESULTS: A higher BMI was associated with greater (P = 0.0006) peak knee compressive forces [overweight, 2411 N (2182, 2639), class 1 obesity, 2772 N (2602, 2943), class 2+ obesity, 2993 N (2796, 3190)] and greater (P = 0.004) shear forces [overweight, 369 N (322, 415), class 1 obesity, 418 N (384, 453), class 2+ obesity, 472 N (432, 513)], independent of alignment, and varus alignment was associated (P < 0.0001) with greater peak external knee adduction moments, independent of BMI [valgus, 18.7 Nm (15.1, 22.4), neutral, 27.7 Nm (24.0, 31.4), varus, 37.0 Nm (34.4, 39.7)]. CONCLUSION: BMI and alignment were associated with different joint loading measures; alignment was more closely associated with the asymmetry or imbalance of loads across the medial and lateral knee compartments as reflected by the frontal plane external adduction moment, while BMI was associated with the magnitude of total tibiofemoral force. These data may be useful in selecting treatment options for knee OA patients (e.g., diet to reduce compressive loads or bracing to change alignment).

Basal growth hormone concentration increased following a weight loss focused dietary intervention in older overweight and obese women.

OBJECTIVES: Growth and sex steroid hormones decrease with aging and obesity. The effect of dietary weight loss and exercise training lifestyle interventions was examined on hormones as well as determining their relationships with physical function in older obese and overweight adults. DESIGN: Individuals were randomized into one of four 18 month interventions: Healthy Lifestyle (HL), Exercise, Diet, and Exercise-Diet. SETTING: Clinical research setting with facility based exercise and nutrition education and behavior classrooms. PARTICIPANTS: Older (≥60 yrs) overweight and obese (BMI≥28 kg/m(2)) adults with knee osteoarthritis (n=309) were recruited for the study. INTERVENTION: Weight loss goal for Diet groups was ≥5%. Exercise groups trained (mostly walking and resistance training) 3 days/week for 60 min/session. MEASUREMENTS: Body weight, growth hormone (GH), corticosterone, sex-hormone binding globulin (SHBG), testosterone, and dehydroepiandrosterone (DHEA) were measured at baseline, 6, and 18 months. Physical function was determined through performance task (6-min walking distance) and self-reported questionnaires (Western Ontario McMaster University Osteoarthritis Index-WOMAC) at similar time points. RESULTS: Diet, Exercise, and Exercise-Diet groups lost 4.9%, 3.5%, and 6.2% of their weight at 18 months, respectively. There was a significant diet treatment effect on GH levels in women as higher concentrations of this hormone were apparent following dietary weight loss intervention (p=0.01). No other hormones were affected by either diet or exercise treatments in men or women. A significant inverse correlation between baseline 6-minute walking distance and SHBG (r=-0.33) was found in men. CONCLUSION: The increase in basal GH levels from the diet treatment in women suggests that this lifestyle behavior intervention may mitigate the age- and obesity-related decreases in growth hormone levels, to help preserve muscle mass, strength, and physical function in older adults.

Does high weight loss in older adults with knee osteoarthritis affect bone-on-bone joint loads and muscle forces during walking?

OBJECTIVE: The aim of this study was to examine the effects of high weight loss on knee joint loads during walking in participants with knee osteoarthritis (OA). DESIGN: Data were obtained from a subset of participants enrolled in the Arthritis, Diet, and Activity Promotion Trial (ADAPT). Complete baseline and 18-month follow-up data were obtained on 76 sedentary, overweight or obese older adults with radiographic knee OA. Three-dimensional gait analysis was used to calculate knee joint forces and moments. The cohort was divided into high (>5%), low (<5%), and no (0% or gain) weight loss groups. RESULTS: From baseline body weight, the high weight loss group lost an average of 10.2%, the low weight loss group lost an average of 2.7%, and the no weight loss group gained 1.5%. Adjusted 18-month outcome data revealed lower maximum knee compressive forces with greater weight loss (P=0.05). The difference in compressive forces between the high weight loss and no weight loss groups was due primarily to lower hamstring forces (P=0.04). Quadriceps forces were similar between the groups at 18-month follow-up. There was no difference between the groups in 18-month joint space width or Kellgren-Lawrence scores. CONCLUSIONS: These results suggest that a 10% weight loss in an overweight and obese osteoarthritic population elicits positive changes in the mechanical pathway to knee OA by having lower knee joint compressive loads during walking compared to low and no weight loss groups. The difference in compressive forces was due, in large part, to reductions in hamstring co-contraction during the initial portion of the stance phase.

Effect of an exercise and dietary intervention on serum biomarkers in overweight and obese adults with osteoarthritis of the knee.

OBJECTIVE: To determine the effects of exercise and weight loss interventions on serum levels of four biomarkers and to examine if changes in biomarker levels correlate with clinical outcome measures in obese and overweight adults with knee osteoarthritis (OA). METHODS: Serum was obtained at baseline, 6 and 18 months from 193 participants in Arthritis, Diet and Activity Promotion Trial. This was a single-blind 18-month trial with subjects randomized to four groups: healthy-lifestyle (HL), diet (D), exercise (E) and diet plus exercise (D+E). Serum levels of cartilage oligomeric matrix protein (COMP), hyaluronan (HA), antigenic keratan sulfate (AgKS), and transforming growth factor-beta1 (TGF-beta1) were measured by enzyme linked immunosorbent assay. RESULTS: At baseline there were no significant differences in biomarker levels between intervention groups. When results for all the intervention groups were combined, the levels of HA were found to be negatively correlated with medial joint space width and positively correlated with Kellgren-Lawrence scores (K-L scores) while TGF-beta1 levels negatively correlated with K-L scores. When biomarker levels measured at 6 and 18 months were adjusted for baseline values, age, gender, and body mass index, weak but significant differences between intervention groups were present for mean levels of COMP and TGF-beta1. Furthermore, AgKS levels averaged over all groups tended to decrease over time. There were no significant associations of baseline biomarkers and the follow-up outcomes. Weak associations were noted between change in the biomarkers at 18 months and change in outcome measures that included change in weight with AgKS and COMP and change in Western Ontario and McMaster Universities Osteoarthritis Index pain with AgKS. CONCLUSION: Overall, the E and D interventions did not show a consistent effect on levels of potential OA biomarkers. The four biomarkers showed differences in correlations with outcome measures suggesting that they may measure different aspects of disease activity in OA. The strongest correlations were between serum HA and radiographic measures of OA at baseline.

Glucosamine/chondroitin combined with exercise for the treatment of knee osteoarthritis: a preliminary study.

OBJECTIVE: This preliminary study sought to determine whether using 1500/1200mg of glucosamine hydrochloride and chondroitin sulfate (GH/CS) is effective, both separately and combined with exercise, compared to a placebo plus exercise program in improving physical function, pain, strength, balance, and mobility in older adults with knee osteoarthritis (OA). METHODS: This double-blind, placebo-controlled, randomized clinical trial lasted 12 months. Participants included 89 older adults (age>/=50 years) with knee OA randomized to either GH/CS or placebo group. Phase I was a 6-month trial comparing the effects of assignment to either GH/CS or placebo. Phase II added 6 months of exercise for both groups. The primary outcome measure was Western Ontario and McMaster University Osteoarthritis Index (WOMAC) function, and secondary outcome measures included WOMAC pain, 6-min walk, balance, and knee strength. RESULTS: Of the 89 randomized participants, 72 (81%) completed the study. The median pill compliance was 94% and 95% in Phase I, and, in Phase II, 97% and 91% for the GH/CS and placebo groups, respectively. Median exercise compliance during Phase II was 77% for the GH/CS group and 78% for the placebo group. WOMAC function and pain did not differ significantly between the groups at 6- or 12-month follow-up. There were also no significant differences between the groups in 6-min walk or knee strength; however, balance was better in the placebo group with approximately a 10% difference compared to the GH/CS group. CONCLUSIONS: The GH/CS group was not superior to the placebo group in function, pain, or mobility after both phases of the intervention (pill only and pill plus exercise).

Age and other risk factors for neuropsychologic decline in patients undergoing coronary artery bypass graft surgery.

OBJECTIVE: To evaluate if increasing age is a major determinant of long-term neuropsychologic (NP) dysfunction in patients undergoing coronary artery bypass graft (CABG) surgery. DESIGN: Prospective cohort study. SETTING: A single university hospital. PARTICIPANTS: Three hundred eighty-one patients undergoing elective CABG surgery. INTERVENTIONS: Baseline preoperative and intraoperative characteristics were assessed for all patients. A comprehensive NP test battery was conducted preoperatively and at 1 month postoperatively. MEASUREMENTS AND MAIN RESULTS: Of the initial 381 patients, 319 (84%) returned for the 1-month visit. The overall incidence of an NP deficit was 21.6%. There was no significant difference seen with increasing age, although a trend was observed with highest NP deficit rate in the older than 65 age group. Other preoperative risk factors, including gender, education level, and preexisting diseases, were nonsignificant. Intraoperative variables were evaluated and revealed no significant differences across the age groups. CONCLUSIONS: This cohort study did not find an increased incidence of NP deficits in elderly patients after CABG surgery. It has addressed the limitations of other studies, however, with (1) a comprehensive NP test battery, (2) longer-term follow-up, and (3) adequate sample size.

Postmenopausal hormone use following a 3-year randomized clinical trial.

Postmenopausal women often discontinue estrogen therapy within the first year. No studies have examined reasons why women continue or discontinue hormone replacement therapy (HRT) after several years of use, when hormone side effects have subsided. We wanted to identify determinants of estrogen use after participation in a 3-year randomized placebo-controlled trial. The Postmenopausal Estrogen/Progestin Intervention (PEPI) study compared the effects of estrogen alone or in combination with one of three progestogens with placebo. Post-PEPI use of hormone therapy was ascertained 1-4 years after the trial in 775 (90%) of the originally enrolled women. Potential correlates of treatment decisions were identified from sociodemographic characteristics, medical histories, and clinical measures ascertained at baseline and during and after the trial. Among women who had been assigned to placebo during PEPI, post-PEPI hormone use was significantly less common in women who were adherent to placebo during PEPI, older, or of non-Caucasian ethnicity. Hormone use was positively associated with hysterectomy. Among women assigned to an active regimen during PEPI, post-PEPI hormone use was significantly more common in women who used hormones before PEPI and in women who were adherent to hormones during PEPI. Older age, less education, and being non-Caucasian predicted less hormone use. Post-PEPI hormone use was highest in San Diego and lowest in Iowa City. Women on placebo who lost more bone mineral density (BMD) were more likely to begin hormones than women with less bone loss. Lipids, blood pressure, and other cardiovascular risk factors had relatively little influence on hormone use. The main predictors of post-PEPI hormone use were those associated with use in the general population (education, ethnicity, geographical region, hysterectomy, and prior use/adherence).

Genetic diversity of eleven European pig breeds.

A set of eleven pig breeds originating from six European countries, and including a small sample of wild pigs, was chosen for this study of genetic diversity. Diversity was evaluated on the basis of 18 microsatellite markers typed over a total of 483 DNA samples collected. Average breed heterozygosity varied from 0.35 to 0.60. Genotypic frequencies generally agreed with Hardy-Weinberg expectations, apart from the German Landrace and Schwäbisch-Hällisches breeds, which showed significantly reduced heterozygosity. Breed differentiation was significant as shown by the high among-breed fixation index (overall F(ST)= 0.27), and confirmed by the clustering based on the genetic distances between individuals, which grouped essentially all individuals in 11 clusters corresponding to the 11 breeds. The genetic distances between breeds were first used to construct phylogenetic trees. The trees indicated that a genetic drift model might explain the divergence of the two German breeds, but no reliable phylogeny could be inferred among the remaining breeds. The same distances were also used to measure the global diversity of the set of breeds considered, and to evaluate the marginal loss of diversity attached to each breed. In that respect, the French Basque breed appeared to be the most "unique" in the set considered. This study, which remains to be extended to a larger set of European breeds, indicates that using genetic distances between breeds of farm animals in a classical taxonomic approach may not give clear resolution, but points to their usefulness in a prospective evaluation of diversity.

Genetic parameters and genetic trends in the Chinese x European Tiameslan composite pig line. I. Genetic parameters.

Genetic parameters of body weight at 4 (W4w), 8 (W8w) and 22 (W22w) weeks of age, days from 20 to 100 kg (DT), average backfat thickness at 100 kg (ABT), teat number (TEAT), number of good teats (GTEAT), total number of piglets born (TNB), born alive (NBA) and weaned (NW) per litter, and birth to weaning survival rate (SURV) were estimated in the Chinese x European Tiameslan composite line using restricted maximum likelihood methodology applied to a multiple trait animal model. Performance data from a total of 4 881 males and 4 799 females from 1 341 litters were analysed. Different models were fitted to the data in order to estimate the importance of maternal effects on production traits, as well as genetic correlations between male and female performance. The results showed the existence of significant maternal effects on W4w, W8w and ABT and of variance heterogeneity between sexes for W22w, DT, ABT and GTEAT. Genetic correlations between sexes were 0.79, 0.71 and 0.82, respectively, for W22w, DT and ABT and above 0.90 for the other traits. Heritability estimates were larger than (ABT and TEAT) or similar to (other traits) average literature values. Some genetic antagonism was evidenced between production traits, particularly W4w, W8w and ABT, and reproductive traits.

Genetic parameters and genetic trends in the Chinese x European Tiameslan composite pig line. II. Genetic trends.

The Tiameslan line was created between 1983 and 1985 by mating Meishan x Jiaxing crossbred Chinese boars with sows from the Laconie composite male line. The Tiameslan line has been selected since then on an index combining average backfat thickness (ABT) and days from 20 to 100 kg (DT). Direct and correlated responses to 11 years of selection were estimated using BLUP methodology applied to a multiple trait animal model. A total of 11 traits were considered, i.e.: ABT, DT, body weight at 4 (W4w), 8 (W8w) and 22 (W22w) weeks of age, teat number (TEAT), number of good teats (GTEAT), total number of piglets born (TNB), born alive (NBA) and weaned (NW) per litter, and birth to weaning survival rate (SURV). Performance data from a total of 4,881 males and 4,799 females from 1,341 litters were analysed. The models included both direct and maternal effects for ABT, W4w and W8w. Male and female performances were considered as different traits for W22w, DT and ABT. Genetic parameters estimated in another paper (Zhang et al., Genet. Sel. Evol. 32 (2000) 41-56) were used to perform the analyses. Favourable phenotypic (DeltaP) and direct genetic trends (DeltaG(d)) were obtained for post-weaning growth traits and ABT. Trends for maternal effects were limited. Phenotypic and genetic trends were larger in females than in males for ABT (e.g. DeltaG(d) = - 0.48 vs. -0.38 mm/year), were larger in males for W22w (DeltaG(d) = 0.90 vs. 0.58 kg/year) and were similar in both sexes for DT (DeltaG(d) = - 0.54 vs. - 0.55 day/year). Phenotypic and genetic trends were slightly favourable for W4w, W8w, TEAT and GTEAT and close to zero for reproductive traits.

Effect of hormone replacement therapy on the validity of the Friedewald equation in postmenopausal women: the postmenopausal estrogen/progestins interventions (PEPI) trial.

The Friedewald equation is often used to estimate low-density lipoprotein cholesterol (LDL-C). Hormone therapy is known to raise triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C) and alter lipid contents of lipoproteins. We compared Friedewald estimated LDL-C to measured LDL-C in PEPI participants on placebo or four different hormone treatment groups. At baseline, the 0.2 coefficient for triglyceride (TG) was accurate for all five treatment groups. Among women who took >80% of their pills and whose TG was <4.5 mmol/l (400 mg/dl), LDL-C was underestimated for 69-82% of the participants in the active treatment groups, compared to 50% in the placebo group. After 3 years of therapy, the TG coefficient that offered a better fit of the Friedewald equation in the active treatment groups was 0.39 for the equation in mmol/l (0.17 for the equation in mg/dl). Using this coefficient is clearly warranted for greater accuracy in research studies.

Effect of postmenopausal hormones on inflammation-sensitive proteins: the Postmenopausal Estrogen/Progestin Interventions (PEPI) Study.

BACKGROUND: Observational studies in healthy women suggest postmenopausal hormone therapy reduces risk of coronary events. In contrast, in a recent clinical trial of women with coronary disease, a subgroup analysis demonstrated increased risk during the early months of therapy. Because higher levels of inflammation factors predict vascular disease outcomes, the effect of hormones on these factors is of interest. METHODS AND RESULTS: Four inflammation-sensitive factors, C-reactive protein, soluble E-selectin, von Willebrand factor antigen, and coagulation factor VIIIc were measured at baseline, 12, and 36 months in 365 participants of the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial, a randomized, placebo-controlled trial of the effects of 4 hormone preparations on cardiovascular disease risk factors. Compared with placebo, all 4 active preparations resulted in a large sustained increase in the concentration of C-reactive protein and a decrease in soluble E-selectin (P=0.0001). There were no effects of treatment on concentrations of von Willebrand factor or factor VIIIc. There were no differences in effects among treatment arms. Relative to placebo, when combining active treatment arms, final concentrations of C-reactive protein were 85% higher whereas E-selectin was 18% lower compared with baseline. CONCLUSIONS: Postmenopausal hormones rapidly increased the concentration of the inflammation factor C-reactive protein. Such an effect may be related to adverse early effects of estrogen therapy. In contrast, hormones reduced the concentration of soluble E-selectin, and this might be considered an anti-inflammatory effect. Because PEPI was not designed to assess clinical endpoints, studies of the impact of hormone-mediated changes in inflammation on risk of subsequent coronary events are needed.

A randomized, blinded trial of the antioxidant pegorgotein: no reduction in neuropsychological deficits, inotropic drug support, or myocardial ischemia after coronary artery bypass surgery.

OBJECTIVE: To determine whether patients receiving pegorgotein preoperatively would be less likely than patients receiving placebo to demonstrate postoperative cerebral or myocardial dysfunction and thus would be less likely to (1) demonstrate a decline in neuropsychologic testing after cardiopulmonary bypass, (2) receive inotropic drug support, or (3) demonstrate electrocardiographic signs of ischemia or infarction. DESIGN: Prospective, randomized, blinded clinical trial. SETTING: University teaching hospital and clinics. PARTICIPANTS: Sixty-seven patients with normal left ventricular function undergoing elective, primary coronary artery bypass surgery. INTERVENTIONS: Six to 18 hours before aortic cross-clamping, patients received a single dose of placebo (n = 22); pegorgotein, 2,000 IU/kg intravenously (n = 23); or pegorgotein, 5,000 IU/kg intravenously (n = 22). MEASUREMENTS AND MAIN RESULTS: Patients in the three groups were similar; the mean ages were 65, 66, and 67 years, and there were seven, eight, and seven women in the placebo; pegorgotein, 2,000 IU/kg; and pegorgotein, 5,000 IU/kg groups. Fifty-one of 67 patients demonstrated neuropsychologic deficit 5 to 7 days postoperatively (n = 17, 19, and 15 for placebo, 2,000 IU/kg, and 5,000 IU/kg; p = NS). Median duration of cardiopulmonary bypass was longer in patients with two or more deficits at 4 to 6 weeks than in those with fewer than two deficits (121 v. 98 minutes; p = 0.04). No patient demonstrated a perioperative stroke. Twenty-seven patients required inotropic drug support after cardiopulmonary bypass (n = 8, 11, and 8 for placebo, 2,000 IU/kg, and 5,000 IU/kg; p = NS). Inotropic drug support was associated with history of angina (p = 0.01) and increasing weight (p = 0.03). Nine patients demonstrated early postoperative ischemia or infarction (n = 1, 7, and 1 for placebo, 2,000 IU/kg, and 5,000 IU/kg; p = 0.07). CONCLUSIONS: This study showed no positive influence of pegorgotein on the incidence of any of the findings and showed a trend toward an increased incidence of myocardial ischemia or infarction.

Agreement in assessing endometrial pathology: the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial.

We report on agreement in interpreting endometrial biopsy specimens between the local and central pathologists of the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial. This trial was a 3-year, multicenter, randomized, double-masked, placebo-controlled trial of four groups taking estrogen or estrogen/progestin combinations. A total of 1804 follow-up biopsies were performed in 596 subjects. Relative sensitivity and relative specificity using the diagnosis from the central pathologist as the gold standard and overall agreement are presented. Almost 90% of the diagnoses were reported normal by both readers. There were significant differences in agreement among clinics and treatment arms (p < 0.0001). The visit at which the biopsy specimen was obtained, age at baseline, prior postmenopausal estrogen use, parity, and drug adherence were not associated with agreement between the two readers. Higher proportions of disagreement were seen in two clinics (13% and 11%) compared with the other five clinics (2%-5%). Biopsy specimens from participants who were taking conjugated equine estrogens (CEE) only were more likely to be diagnosed differently by both readers (11%) than biopsy specimens from women taking a placebo (2%) or CEE combined with progestins (5%). Relative specificity varied from 86.4% to 98.9% among the clinics (p < 0.0001). Relative sensitivity was based on a small number of diagnoses, as few biopsy specimens were classified abnormal by the central pathologist. In patients assigned to CEE combined with progestin, 5 of the 7 biopsy specimens that were recorded abnormal by the central pathologist received a normal diagnosis locally. Our findings show that sample size requirements for study designs in which a central reader is used can be at least threefold lower than the requirements for designs relying on local diagnoses. Centralized protocols for endometrial histopathology reading and staff training are highly desirable in multicenter trials.

Factors that predict the use of positive inotropic drug support after cardiac valve surgery.

UNLABELLED: Left ventricular dysfunction is common after cardiac surgery and is often treated with positive inotropic drugs (PIDs). We hypothesized that the use of PIDs after cardiac valve surgery would have significant associations with the valvular pathophysiology and surgical procedure, and unlike the case for patients undergoing coronary artery surgery, would be unrelated to duration of cardiopulmonary bypass (CPB) or of aortic clamping. One hundred forty-nine consenting patients undergoing cardiac valve surgery were studied. Patients with hepatic or renal failure, or New York Heart Association class IV cardiac symptoms, were excluded. Patients were considered to have received PIDs if they received an infusion of amrinone, dobutamine, epinephrine, or dopamine (> or = 5 microg x kg[-1] x min[-1]). PIDs were received by 78 patients (52%). In a univariate model, older age, history of congestive heart failure, decreasing left ventricular ejection fraction, longer durations of CPB, and concurrent coronary artery surgery significantly increased the likelihood of PID support. There was also significant variation by anesthesiologist in the administration of PIDs. The specific diseased valve and valvular stenosis or insufficiency did not influence the likelihood of receiving PID support. In a multivariable model, age, history of congestive heart failure, decreasing left ventricular ejection fraction, and anesthesiologist were significantly associated with the likelihood of PID support, but duration of CPB and concurrent coronary artery surgery were not. In conclusion, patient age and ventricular function, as well as physician preferences, predicted the need for inotropic drug support; however, neither the specific valvular lesion, nor duration of CPB were strongly predictive in a multivariable model. IMPLICATIONS: We evaluated factors related to use of positive inotropic drugs after cardiac valve surgery. The likelihood of a patient receiving these drugs increases with advancing age and with more severe preoperative left ventricular dysfunction, but was not influenced by the specific diseased valve or the duration of cardiopulmonary bypass.

The use of selection experiments for detecting quantitative trait loci.

Gene frequency changes following selection may reveal the existence of gene effects on the trait selected. Loci for the selected quantitative trait (SQTL) may thus be detected. Additionally, one can estimate the average effect (alpha) of a marker allele associated with an SQTL from the allele frequency change (delta q) due to selection of given intensity (i). In a sample of unrelated individuals, it is optimal to select the upper and lower 27% for generating delta q in order to estimate alpha. For a given number of individuals genotyped, this estimator is 0.25i2 times more efficient than the classical estimator of alpha, based on the regression of the trait on the genotype at the marker locus. The method is extended to selection criteria using information from relatives, showing that combined selection considerably increases the efficiency of estimation for traits of low heritability. The method has been applied to the detection of SQTL in a selection experiment in which the trait selected was pig litter size averaged over the first four parities, with i = 3. Results for four genes are provided, one of which yielded a highly significant effect. The conditions required for valid application of the method are discussed, including selection experiments over several generations. Additional advantages of the method can be anticipated from determining gene frequencies on pooled samples of blood or DNA.

Nimodipine neuroprotection in cardiac valve replacement: report of an early terminated trial.

BACKGROUND: We conducted a double-blind, randomized clinical trial in patients undergoing cardiac valve replacement to determine whether nimodipine, a dihydropyridine calcium antagonist, reduced the risk of new neurological, neuro-ophthalmologic, or neuropsychological deficits-common complications associated with cardiac surgery-1 week after surgery. METHODS AND RESULTS: Enrollment for a total of 400 patients started in May 1992 and was stopped in September 1994, with 150 patients randomized to the study. Nimodipine was given to the patients during the perioperative period. Patients underwent examinations before surgery and at approximately 1 week, 1 month, and 6 months after surgery. Major adverse events, including deaths and strokes, were monitored monthly. The trial was terminated early because of both an unexpected disparity in death rates between groups and a lack of evidence of a beneficial effect of nimodipine. New deficits were observed in 72% of the placebo group versus 77% of the nimodipine group (p=.55). In the 6-month follow-up period, 8 deaths (10.7%) occurred in the nimodipine group (n=75) compared with 1 death (1.3) in the placebo group (n=74) (p=.02). Major bleeding occurred in 10 patients in the nimodipine group versus 3 in the placebo group (13.3% versus 4.1%; P=.04). Six (46.2%) of the 13 patients with major bleeding died compared with 3 deaths (2.2%) among the 136 patients without major bleeding. CONCLUSIONS: Our findings add to the growing evidence that calcium antagonists have a prohemorrhagic effect in some patients and suggest that nimodipine use should be restricted perioperatively in patients scheduled for cardiac valve replacement.

Distribution and correlates of plasma fibrinogen in middle-aged women. Initial findings of the Postmenopausal Estrogen/Progestin Interventions (PEPI) study.

Fibrinogen levels have been reported in cohort and case-control studies to be positively related to the development of coronary heart disease. This report presents the distribution and determinants of fibrinogen in women enrolling in a 3-year randomized trial of hormone replacement therapy (HRT), the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial. Fasting plasma fibrinogen levels were measured in 874 postmenopausal women, aged 45 to 65 years, who had not used HRT for at least 3.5 months. Mean (+/- SD) fibrinogen level was 2.83 +/- 0.45 g/L. There was a significant positive association between fibrinogen and age (P = .03). Significantly higher (P < .005) fibrinogen levels were seen in current smokers versus nonsmokers (2.94 versus 2.81 g/L), in women who reported consuming fewer than 12 alcoholic drinks in the 12 months before the baseline visit versus higher consumption (2.90 versus 2.79 g/L), and in women who reported never versus ever having used HRT (2.90 versus 2.77 g/L). Self-reported leisure time physical activity (LTPA) was negatively associated (P = .0001) with fibrinogen levels as follows: inactive (2.84 g/L), light (2.89 g/L), moderate (2.80 g/L), and heavy (2.60 g/L), with significantly (P = .0001) lower levels in women who reported heavy LTPA versus each of the other categories and in women reporting moderate versus light LTPA. A strong positive correlation was found between fibrinogen and body mass index (BMI) (r = .32; P < .0001). In a model that included age, smoking, alcohol intake, prior HRT, LTPA, and BMI, LTPA was no longer a statistically significant predictor of fibrinogen level, while associations with other variables remained significant.(ABSTRACT TRUNCATED AT 250 WORDS)

Brain microemboli associated with cardiopulmonary bypass: a histologic and magnetic resonance imaging study.

Emboli in brain tissue after cardiopulmonary bypass were reported in the literature 30 years ago, but there is little objective evidence confirming the presence of emboli in the brain after cardiopulmonary bypass with more modern equipment and techniques. Recently, with alkaline phosphatase vascular staining, we found an acellular fatty material in brain microvasculature from autopsy material of patients who died shortly after cardiopulmonary bypass. These fatty intravascular collections range in diameter from 10 to 70 microns, a size that lodges in the smallest vessels of the microvasculature. They have been found in numbers sufficient to cause detectable neurologic dysfunction and are believed, but not proved, to be emboli. By sequentially injecting colored microspheres, we can determine when emboli occur during experimental cardiopulmonary bypass. In ongoing related studies, magnetic resonance imaging was performed before cardiac valve replacement in 39 patients for whom preoperative and postoperative neurologic and neuropsychologic testing was available. Preliminary results suggest that magnetic resonance imaging evidence of prior stroke is not a significant risk factor for cognitive or motor decrement after cardiopulmonary bypass.