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This study examined the efficacy of a National Cholesterol Education Program (NCEP) step II diet (25% fat with < 7% saturated fat [SFA]) with and without moderate energy restriction. We tested the hypothesis that moderate energy restriction would improve the lipid profile resulting from an isoweight NCEP step II diet. Twenty hypercholesterolemic subjets (10 men and 10 postmenopausal women) consumed the following three controlled diets, each of 4 weeks' duration, as outpatients: (1) high-fat, high-saturated-fat diet to establish baseline lipids and isoweight energy requirements, (2) NCEP step II diet at isoweight energy, and (3) NCEP step II diet with an energy level 15% less than isoweight. The NCEP step II diet at isoweight energy reduced total cholesterol (TC) by 4% (P = .015), high-density lipoprotein cholesterol (HDL-c) by 13% (P < .0001), and HDL2-c by 40% (P < .0001). The TC:HDL-c ratio increased from 4.9 to 5.5 (P < .0001) and was increased in 19 of 20 subjects. Apolipoprotein B (apo B)-containing lipoproteins changed reciprocally: low-density lipoprotein cholesterol (LDL-c) decreased 4% (P = .008) and very-low-density lipoprotein cholesterol (VLDL-c) increased 29% (P < .0001). Apo B levels did not change. Compared with the NCEP isoweight diet the NCEP hypocaloric diet significantly reduced VLDL-c (-9%, P = .014) and apo B (-5%, P = .015). There was an additional reduction in TC (-4%, P = .073) and LDL-c (-4%, P = .126) with no change in HDL-c (P = .807). These data indicate that a NCEP step II diet with energy restriction produces a more desirable lipoprotein response than a NCEP step II isoweight diet. Neither NCEP step II diet improved the TC:HDL-c ratio.

Hip fractures are common and devastating events. The apolipoprotein E*4 (APOE) allele, associated with Alzheimer's disease, has also been associated with osteoporosis in hemodialysis patients. We prospectively studied 1750 women, age >/=65 years, who underwent measurements of hip and calcaneal bone mineral density (BMD), were typed for APOE and followed for approximately 7.0 years for the occurrence of fractures and falls. Women with at least one APOE*4 allele had an increased risk of hip fracture, relative hazard (RH) (95% confidence interval) = 1.90 (1.05-3.41) and wrist fracture, RH = 1.67 (1.01-2.77) compared with women without APOE*4, even after adjusting for age, cognitive function, falling, and BMD. The effect of APOE*4 on hip fracture was greatest among women with additional (>/=3) other risk factors. Women with an APOE*4 allele were also likely to report a maternal history of fracture. The average number of falls per year did not differ by APOE*4: 0.46 for APOE*4 women and 0.41 for women without an APOE*4 allele. Women with an APOE*4 allele experienced greater weight loss which contributed to faster rates of bone loss. We conclude that women with the APOE*4 polymorphism are at substantially increased risk of hip and wrist fracture that is not explained by bone density, impaired cognitive function, or falling. Possible alternate explanations include an effect of APOE on vitamin K, bone turnover, or weight loss. The APOE polymorphism may be a candidate gene for hip fractures among community dwelling nondemented women.

Background: The purpose of this study was to evaluate the cross-sectional and longitudinal association of oral estrogen replacement therapy (ERT) and cognitive function in an older, nondemented sample of women., Methods: In a prospective cohort of 9651 white women aged 65 years and older enrolled in the Study of Osteoporotic Fractures, a modified Mini-Mental Status Exam (mMMSE), and digit symbol substitution and Trails B tests were administered twice, 4 to 6 years apart. History and current use of oral ERT was documented. Age, educational attainment, and activity limitations were the primary covariates in the analyses; in addition, stroke and depression scores were adjusted in subsets of women with available data., Results: Current and past users of ERT had better initial scores on the mMMSE than did never users, P < .05 and .001, respectively, with better scores for current estrogen hormone users being most apparent among the older and less educated women. The percentages of women scoring < or = 23 of a possible 26 on the mMMSE were 14.3 for current users, 14.5 for past users, and 20.5 for never users, P < .001. However, only past users exhibited smaller declines upon retesting in mMMSE and Trails B performance, P < .05, than did never users. Educational attainment predicted both initial test scores and change scores and was, next to age, the most powerful predictor of cognitive function., Conclusions: Current oral ERT does not protect against age-related declines in cognitive function in older nondemented women, whereas formal education does protect, even though it had been completed many years earlier. The influence of education in late-life on cognitive function should be tested.

A polymorphism at the first of two potential translation initiation codons in the vitamin D receptor (VDR) gene defined by the FokI restriction endonuclease has been associated with reduced bone mineral density (BMD) among Caucasian, Asian, and Mexican-American women. We tested the hypothesis that the FokI polymorphism is related to markers of osteoporotic risk in 104 community-dwelling African-American women aged 65 years and older. Six percent of the African-American women had the ff genotype, 32% were heterozygous, and 63% had the FF genotype. FokI genotype frequencies did not differ from Hardy-Weinberg expectations. Hip and calcaneal BMD, calcaneal ultrasound attenuation and hip geometry from pelvic radiographs did not differ significantly by FokI genotypes or between women with and without the rare FokI allele. There was also no association between the FokI polymorphism and biochemical markers of bone turnover or fractional calcium absorption. We conclude that the VDR start codon polymorphism does not have a major influence on osteoporotic risk in older African-American women.

Family and twin studies have established a genetic contribution to the etiology of osteoporosis. The genes and allelic variants conferring osteoporotic risk are largely undefined, but the number of candidates has increased steadily in recent years (Table I). Osteoporosis is a complex disease, and allelic variation in many other candidate-genes including those that encode growth factors, cytokines, calciotropic hormones, and bone matrix proteins are likely to also play a role and warrant systematic investigation. Most family and association studies to date have focused on the genetic contributions to bone density, a major determinant of bone strength and fracture risk. Bone density is not the only determinant of skeletal fragility, however, and genetic influences on fracture risk are independent of bone density [Cummings et al., 1995]. The microarchitectural properties and overall size and geometry of bone also influence skeletal strength [Bouxsein et al., 1996], and the genetic influences on these phenotypes should be investigated more rigorously. Even fewer studies have assessed the association between candidate-gene variation and the risk of fracture, the most important clinical outcome of osteoporosis. Large-scale molecular epidemiologic studies will be increasingly necessary in the future to quantify the relative, absolute and attributable risks of fracture associated with specific genetic variants. Osteoporosis is a complex, multifactorial disease, and most candidate-gene association studies have had limited statistical power to assess gene-gene and gene-environment interaction. Although gender plays an important role in the development of osteoporosis, genetic studies have almost exclusively focused on women, and have not tested whether gender modifies the association between genetic variation and osteoporotic risk. Therefore, future genetic studies will need to recruit larger samples of individuals including men. Rapid additional progress in our understanding of the molecular basis of osteoporosis can be expected in the near future as ongoing genome-wide linkage [Spotila et al., 1996] and candidate-gene association analyses are completed. Linkage analyses in families at high-risk for rare metabolic bone diseases should also yield important clues to the pathogenesis of osteoporosis. Recent examples are the mapping of loci for both high [Johnson et al., 1997] and low [Gong et al., 1996] bone mass to chromosome 11q and osteopetrosis to chromosome 1p [Van Hul et al., 1997]. Similar ongoing studies in baboons [Rogers and Hixson, 1997] and mice [Beamer et al., 1997] may reveal additional loci whose human homologs contribute to osteoporotic risk. The improved understanding of osteoporosis that will emerge from these genetic studies should lead to better diagnosis of this disease and new treatment and prevention strategies.

Cultured cerebellar granule neurons develop their characteristic axonal and dendritic morphologies in a series of discrete temporal steps highly similar to those observed in situ, initially extending a single process, followed by the extension of a second process from the opposite pole of the cell, both of which develop into axons to generate a bipolar morphology. A mature morphology is attained following the outgrowth of multiple, short dendrites [Powell et al., 1997: J. Neurobiol. 32:223-236]. To determine the relationship between the localization of the Golgi apparatus, the site of microtubule nucleation (the centrosome), and the sites of initial and secondary axonal extension, the intracellular positioning of the Golgi and centrosome was observed during the differentiation of postnatal mouse granule neurons in vitro. The Golgi was labeled using the fluorescent lipid analogue, C5-DMB-Ceramide, or by indirect immunofluorescence using antibodies against the Golgi resident protein, alpha-mannosidase II. At 1-2 days in vitro (DIV), the Golgi was positioned at the base of the initial process in 99% of unipolar cells observed. By 3 DIV, many cells began the transition to a bipolar morphology by extending a short neurite from the pole of the cell opposite to the initial process. The Golgi was observed at this site of secondary outgrowth in 92% of these "transitional" cells, suggesting that the Golgi was repositioned from the base of the initial process to the site of secondary neurite outgrowth. As the second process elongated and the cells proceeded to the bipolar stage of development, or at later stages when distinct axonal and somatodendritic domains had been established, the Golgi was not consistently positioned at the base of either axons or dendrites, and was most often found at sites on the plasma membrane from which no processes originated. To determine the location of the centrosome in relation to the Golgi during development, granule neurons were labeled with antibodies against gamma-tubulin and optically sectioned using confocal microscopy. The centrosome was consistently co-localized with the Golgi during all stages of differentiation, and also appeared to be repositioned to the base of the newly emerging axon during the transition from a unipolar to a bipolar morphology. These findings indicate that during the early stages of granule cell axonal outgrowth, the Golgi-centrosome is positioned at the base of the initial axon and is then repositioned to the base of the newly emerging secondary axon. Such an intracellular reorientation of these organelles may be important in maintaining the characteristic developmental pattern of granule neurons by establishing the polarized microtubule network and the directed flow of membranous vesicles required for initial axonal elaboration.

This study tested the hypothesis that exercise in combination with a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor produces greater creatine kinase (CK) elevations, an index of skeletal muscle injury, than exercise alone, using a double-blind, placebo-controlled design. Fifty-nine healthy men aged 18 to 65 years with low-density lipoprotein cholesterol (LDL-C) levels greater than 3.36 mmol/L (130 mg/dL) despite diet therapy were studied. Subjects were randomly assigned to receive lovastatin (40 mg/d) or placebo for 5 weeks. Subjects completed 45 minutes of downhill treadmill walking (-15% grade) at 65% of their predetermined maximum heart rate after 4 weeks of treatment. During the subsequent week, they completed four 10-repetition sets of one-arm biceps curl exercise using 50% of their maximum capacity. CK levels were measured before exercise and daily for 4 and 5 days after the treadmill and biceps exercises, respectively. Age, body weight, and blood lipid and lipoprotein levels were similar in lovastatin and placebo groups. Resting CK levels were 33% higher in the lovastatin group before treatment (P < .05), but were not significantly altered by lovastatin. CK levels were 62% and 77% higher (P < .05) in the lovastatin group 24 and 48 hours after treadmill exercise after adjusting for initial CK differences. There were no significant CK differences between lovastatin and placebo groups after biceps curl exercise. We conclude that HMG-CoA reductase inhibitors exacerbate exercise-induced skeletal muscle injury.

Bone mineral density (BMD) is under genetic control. Some studies in Caucasian and Asian women suggest that polymorphisms in the vitamin D receptor (VDR) gene are associated with BMD and the rate of postmenopausal bone loss. We determined if similar associations exist in 101 African-American women aged 65 years and older (71 +/- 5 years, mean +/- SD). We also examined the relation between VDR genotype and fractional 45Ca absorption and markers of bone formation (osteocalcin) and resorption (N-telopeptides) in these women. BMD was measured at the proximal femur and whole body at baseline and after 1.9 +/- 0.4 years (femur only) on a Hologic QDR-2000 densitometer using dual-energy X-ray absorptiometry. Calcaneal BMD was measured with single x-ray absorptiometry. VDR gene polymorphisms were defined by the endonucleases BsmI, ApaI, and TaqI. These polymorphisms were not associated with BMD at any skeletal site or with markers of bone turnover. There was a significant interaction between age and VDR genotype where the oldest women (> 70 years) with the TT genotype experienced greater hip bone loss than women with the TT genotype (-2.1%/year vs. -0.4%/year, respectively), whereas heterozygous women experienced an intermediate rate of bone loss (-1.3%/year). Women homozygous for the B allele had 14% lower fractional 45Ca absorption compared with women homozygous for the b allele, although this difference was not statistically significant (p = 0.08). We conclude that VDR gene polymorphisms are not associated with BMD or indices of bone turnover in this population of older African-American women. However, DNA sequence variation in the VDR gene or a nearby locus may influence intestinal calcium transport and the rate of postmenopausal bone loss in African-American women.

This study examined the effect of exercise training without weight loss on high-density lipoprotein (HDL) metabolism in overweight men. We evaluated HDL metabolism using 125I-radiolabeled autologous HDL in 17 overweight men aged 40 +/- 7 years (mean +/- SD) before and after 1 year of exercise training. Subjects consumed defined diets in a metabolic kitchen during the metabolic studies. They performed endurance exercise under supervision for 1 hour four times weekly and maintained their pretraining body weight. Maximal oxygen uptake (VO2max) increased 27% (P < .001) with exercise training. HDL-cholesterol (HDL-C) and apolipoprotein (apo) A-I increased 10% and 9%, respectively (P < .001 for both), whereas triglycerides and apo B decreased 7% and 10%, respectively (P < .05). Postheparin lipoprotein lipase increased 11% (P = NS). Hepatic triglyceride lipase activity (HTGLA) decreased 12% (P < .05). The fractional catabolic rate (FCR) of HDL protein and of apo A-I decreased 5% and 7%, respectively (P < .05 for both). The synthetic rate of apo A-I increased 13% (P < .01). Increased HDL after exercise training is associated with both decreased HDL protein catabolism and increased HDL apo A-I synthesis. Weight loss is not required to increase HDL-C with exercise training in overweight men, but without weight loss, even prolonged exercise training produces only modest changes in HDL-C concentrations.

The lower fracture rates among African-American women relative to Caucasian women may reflect their higher bone mass. However, bone mass is not the only determinant of bone strength: the quality and microarchitecture of the bone are also important. Quantitative ultrasound is believed to measure properties of bone strength that are independent of bone mass. To test the hypothesis that there are racial differences in quantitative ultrasound measures of bone, we recruited 154 African-American women age > or = 65 years. A random sample of 300 Caucasian women participating in the Study of Osteoporotic Fractures in Pittsburgh, Pennsylvania, was chosen for comparison. The Walker Sonix UBA 575+ was used to measure calcaneal broadband ultrasonic attenuation (BUA). Duplicate BUA measurements were obtained with a reproducibility of 5%. We measured bone mineral density (BMD) of the hip and calcaneus using single (calcaneus) or dual (hip) energy X-ray absorptiometry. The correlation between BUA and calcaneal BMD was similar in Caucasians (r = 0.66, p < 0.001) and African-Americans (r = 0.58, p < 0.001). Age-adjusted BUA (dB/MHz) was higher among the African-American women than Caucasian women (69.1 and 66.2, respectively), but these differences were not statistically significant, (p = 0.12). Adjustment for calcaneal BMD completely attenuated the racial differences in BUA. BMD at the femoral neck and calcaneus was higher among the African-American women, even after adjusting for age, height and weight. In conclusion, our results suggest that racial differences in rates of fracture cannot be explained by differences in bone quality as assessed by ultrasound attenuation.

Few studies have examined the effect of prolonged exercise training on left ventricular diastolic function in previously sedentary subjects. We performed M-mode, 2-D, and Doppler echocardiography on 16 previously sedentary men before and after 1 yr of exercise training. Six men served as controls. Exercise subjects participated in four 1-h supervised sessions weekly at 60-80% of their measured maximal heart rate. Maximal oxygen uptake, maximal exercise cardiac output, and resting left ventricular systolic and diastolic function were determined before and after training. Maximal oxygen uptake and peak cardiac output increased 27.3% and 8.5% in the trainers (P < 0.001 for both) and 1.3% and 1.0% in the controls. Left ventricular diastolic and systolic dimensions changed slightly in both groups. Maximal early inflow velocity decreased in both trainers (-9.9 +/- 14.0 cm.s-1, mean +/- SD, P < or = 0.01) and controls (-7.2 +/- 10.2 cm.s-1). Maximal atrial inflow velocity decreased (-7.8 +/- 10.9 cm.s-1, P < or = 0.01) only in the trainers possibly because of a reduction in resting heart rate (-6 +/- 11 beats.m-1, P < or = 0.05). Acceleration and deceleration times were unchanged in both groups. These results demonstrate that substantial increases in exercise performance and exercise cardiac output can occur without detectable changes in resting cardiac dimensions or left ventricular systolic and diastolic function.

To test the hypothesis that substrate utilization during mild-intensity exercise differs in non-insulin-dependent diabetes mellitus (NIDDM) compared with nondiabetic subjects, seven lean healthy subjects (L), seven obese healthy subjects (O), and seven individuals with NIDDM were studied during 40 min of mild-intensity cycling (40% of peak O2 uptake). Systemic utilization of plasma glucose (Glc Rd) was determined by using isotope dilution methods. Gas exchange was measured to determine rates of carbohydrate (CHO) and lipid oxidation. During exercise, when CHO oxidation was greater than Glc Rd, the net oxidation of glycogen was calculated as the difference: CHO oxidation - Glc Rd. During mild-intensity cycling, the respiratory exchange ratio was similar across groups (0.87 +/- 0.02, 0.85 +/- 0.02, and 0.86 +/- 0.01 in L, O, and NIDDM subjects, respectively), and CHO oxidation accounted for one-half of total energy expenditure during exercise. Glc Rd increased during exercise and was greatest in subjects with NIDDM (3.0 +/- 0.2, 2.9 +/- 0.2, and 4.5 +/- 0.4 ml.kg-1.min-1 in L, O, and NIDDM subjects, respectively, P < 0.05), yet Glc Rd was less than CHO oxidation during exercise, indicating net oxidation of glycogen. Glycogen oxidation was greater in L and O than in NIDDM subjects (3.4 +/- 1.0, 2.5 +/- 0.9, and 1.7 +/- 0.8 ml.kg-1.min-1; P < 0.05). In summary, during mild-intensity exercise, NIDDM subjects have an increased Glc Rd and a decreased oxidation of muscle glycogen.

We examined the effects of moderate physical activity on serum luteinizing hormone (LH), sex hormone-binding globulin (SHBG), and testosterone levels in seven sedentary but otherwise healthy men aged 66 to 76 years (mean +/- SD, 70 +/- 4). Blood samples were obtained at 10-minute intervals for 4 hours before, during, and 4 hours after 60 minutes of cycle ergometry. Blood samples were also obtained every 10 minutes for 9 hours during a separate day to control for normal diurnal variation in serum testosterone levels. Serum testosterone increased 39%, SHBG 19%, total serum protein 13%, and the free testosterone index 23% during exercise (P < .01 for all). Testosterone and SHBG levels during the 4-hour sampling period after exercise were similar to values obtained before exercise and on the morning and afternoon of the control day. LH concentrations were unaltered during or after exercise. The change in SHBG levels during exercise correlated positively with the change in testosterone concentrations (r = .74, P = .09). We conclude that short-term exercise produces a transient elevation in serum testosterone levels in elderly men, which is partly due to an increase in serum SHBG concentrations. The concomitant increase in total protein and the rapid return of total protein and SHBG to baseline values after exercise indicate that hemoconcentration partly contributes to the exercise-associated increase in circulating testosterone levels.

The effects of doxazosin or atenolol on exercise capacity in 15 male distance runners (mean age +/- SD 43 +/- 10 years) were compared in a double-blind, crossover study. Subjects performed a maximal treadmill test and a timed 2-mile run before and after each drug treatment. Cardiac output was determined by acetylene rebreathing at rest and at 30%, 50%, and 75% of maximal oxygen consumption. Oxygen consumption was determined at the above-mentioned workloads and at maximal effort. Both drugs were titrated to produce similar reductions in blood pressure and the final doses of atenolol and doxazosin were 43 +/- 22 and 6 +/- 6 mg, respectively. Atenolol reduced cardiac output (p < 0.05) and heart rate (p < 0.001) at rest and at all exercise intensities compared with the prior placebo phase, whereas doxazosin increased cardiac output at rest and at 50% effort (p < 0.05). Consequently, cardiac output was higher (p < 0.01) with doxazosin than with atenolol at rest and at 30% and 50% effort. Heart rate was higher with doxazosin (p < 0.01) during all exercise workloads. Despite these changes in cardiovascular function, there were no significant differences between the effect of the 2 study drugs on maximal oxygen consumption or 2-mile run times. We conclude that atenolol decreases rest and exercise heart rate and cardiac output compared with doxazosin, but that at modest doses neither drug adversely affects exercise performance in male hypertensive runners.

Numerous studies have examined factors regulating high-density lipoprotein cholesterol (HDL-C) levels in male endurance athletes, but few studies have examined HDL-C regulation in female athletes. The present study compared lipid and lipoprotein concentrations, postheparin lipolytic activities, and the clearance rate (K2) of triglycerides following an intravenous fat infusion in 12 female distance runners (aged 33 +/- 9 years, mean +/- SD) and 13 sedentary women (33 +/- 9 years). Runners were leaner and had greater maximum oxygen uptake values than controls. Runners also had nonsignificantly lower triglyceride (53 +/- 15 v 65 +/- 13 mg/dL) and higher HDL-C (62 +/- 14 v 52 +/- 8 mg/dL, P = .06). Lipoprotein lipase activity (LPLA) was 33% greater (P < .05) and fat clearance (K2) was 27% faster (P < .01) in the trained women, and LPLA correlated directly with K2 (r = .61) and HDL-C (r = .62) in this group (P < .05 for both). K2 was directly related to HDL-C in the athletes (r = .57, P = .06), and also when the active and sedentary women were combined (r = .43, P < .05). These results suggest that increased LPLA and enhanced plasma triglyceride clearance may contribute to the HDL-C levels of physically active premenopausal women.

Stanozolol, an oral 17 alpha-alkylated androgen, increases hepatic triglyceride lipase activity (HTGLA) and decreases high-density lipoprotein cholesterol (HDL-C) levels, whereas intramuscular testosterone has comparatively little effect. In the present study, we tested the hypothesis that aromatization of androgen to estrogen blunts the lipid and lipase effects of exogenous testosterone. Fourteen male weightlifters received testosterone enanthate (200 mg/wk intramuscularly), the aromatase inhibitor testolactone (250 mg four times per day), or both drugs together in a randomized cross-over design. Serum testosterone level increased during all three drug treatments, whereas estradiol level increased only with testosterone alone (+47%, P < .05), demonstrating that testolactone effectively inhibited testosterone aromatization. Testosterone decreased HDL-C(-16%, P < .05), HDL2-C(-23%, NS), and apoprotein (apo) A-I (-12%, P < .05) levels, effects that were consistently but not significantly greater with simultaneous testosterone and testolactone administration (HDL-C, -20%; HDL2-C, -30%; apo A-I, -15%; P < .05 for all). In contrast, both testosterone regimens decreased HDL3-C levels by 13% (P < .05 for both). HTGLA increased 21% during testosterone treatment and 38% during combined testosterone and testolactone treatment (P < .01 for both). Lipoprotein lipase activity (LPLA) increased only during combined testosterone and testolactone treatment (+31%, P < .01), suggesting that estrogen production may counteract the effects of testosterone on LPLA. Testolactone alone had little effect on any lipid, lipoprotein, apoprotein, or lipase concentration.(ABSTRACT TRUNCATED AT 250 WORDS)