A role for the PTH-calcium axis in the normal bone-marrow response to bleeding or erythropoietin administration has been demonstrated in rats. We studied 20 autologous blood donors, each donating two units of blood, who served as a human bleeding model. Fifteen patients completed the study. Blood donations were followed by a significant increase in serum intact PTH (2.15 +/- 0.67 to 2.81 +/- 0.84 pmol/l; p = 0.0003) and protein-corrected total calcium (2.43 +/- 0.09 to 2.49 +/- 0.08 mmol/l; p = 0.2). All the individual values remained within the normal range. PTH weakly correlated with the reticulocyte count, but not with the corrected serum calcium. We conclude that moderate bleeding in humans is followed by a physiological increase in serum PTH and calcium.
Promotional properties of a high-fat diet in intestinal cancer were studied by feeding a 30% beef fat diet to 8 groups of rats (25 rats/group) for time periods varying from i to 2i weeks after8 weeklys.c. injectionsof azoxymethane (AOM)(8 mg/ kg). Two other groups were fed the high-fat diet, one for 8 weeks prior to and the other during AOM injections. A 5% fat diet was fed to matswhen not on the 30% fat diet and to a control group of 25 animals. High-fat diet increased intestinal tumor frequency up to 2fold when given for at least 4 weeks after but not during or prior to AOM injections; this increase occurred even after a prolonged interval (i 0 weeks) between the last AOM injection and the high-fat diet. In general, tumor frequency increased according to the length of time animals were fed the high-fat diet after AOM. Therefore, the high-fat diet in this model exhibited most of the properties of promoters developed from murine skin cancer, thus adding support to the concept that excess dietary fat acts at the promotionalphaseof carcinogen esis.
Obesity offers protection against osteoporosis in older women. The mechanisms are not well understood, but relate in part to increased aromatization of adrenal androgens to estrone in peripheral fat and muscle tissue. Two hundred and one white and 77 black women previously reported to be free of skeletal disease and to have normal bone mass had measurements of total body bone mineral (TBBM), fat mass (TBFM), and lean mass (TBLM) performed by dual energy x-ray absorptiometry. Serum estrone, androstenedione, and dihydroepiandrostenedione sulfate were measured on the same day. Body weight, body mass index, TBFM, and TBLM were all significantly higher in the black women. However, proportionately, there were no differences in body composition between the two groups. This suggests that the black women were not more obese despite their greater body mass index, and that future studies on the health impact of obesity in older black women should take this into consideration. Despite the greater TBFM and TBLM in the black women and no difference in serum androstenedione levels, the serum estrone level was not higher in the black women, and the higher bone mass in blacks was not related to serum estrone. In both ethnic groups, TBBM was significantly related to body weight (white, r = 0.80; black, r = 0.85; P < 0.001 for both). Both TBFM and TBLM were significantly related to TBBM in both ethnic groups. Serum estrone was significantly related to all measures of body mass in the white women, but to no measures of body mass in the black women, indicating apparent differences in the metabolism of estrone between older white and black women.
From a random sample of our institution's health maintenance organization (HMO), we recruited 250 white women and 112 black women, aged 55-75, all of whom were 10 or more years postmenospause with minimal estrogen exposure and free of osteoporosis, other metabolic bone disease, and medical, surgical, or therapeutic situations that may influence bone loss. Bone mass was measured in the radius, spine, and femur by DXA and in L1 by QCT. Serum samples were analyzed for parathyroid hormone, calcidiol, calcitriol, osteocalcin, and bone alkaline phosphatase and urine samples analyzed for creatinine, calcium, and hydroxyproline. Mean Z score, based on published reference data for forearm and femoral neck BMD in the white women, was not significantly different from zero, but mean Z score at the lumbar spine was 0.6 (p < 0.001), 17.2% of the individual values being > 2.0. In normal white women (BMI < 27.3, n = 143), Z score was still > 2.0 in 10.3%, suggesting that the upper bound of the published reference interval may be too low. After adjustment for body mass index, BMD was greater in the forearm (9.8%), spine (8.7%), and femoral neck (14.7%) in black women (p < 0.001 at all sites). At L1, adjusted BMC in the black women was 37.4% greater than in the white women (p < 0.001). Serum calcidiol was significantly lower and serum PTH and calcitriol significantly higher in the black women. Despite this, biochemical markers of bone resorption and formation were significantly lower in the black women. We conclude that skeletally healthy older black women have a greater bone mass and lower rates of bone remodeling than a comparable group of white women. These data can serve as reference intervals for the variables measured.
We have investigated the effect of age, a high-fat diet, sodium deoxycholate, and the ornithine analogue alpha-difluoromethylornithine on ornithine decarboxylase (ODC) activity in the rat colon. The relative levels of ODC activity were also determined in normal mucosa and tumor tissue from rat and human colon. The colonic ODC activity induced by intrarectal instillation of sodium deoxycholate in male Sprague-Dawley rats was highest in young animals, and it decreased with increasing age. A high level of dietary fat caused both an increased in basal colonic ODC activity and enhanced ODC induction by deoxycholate. alpha-Difluoromethylornithine given in drinking water inhibited, in a dose-dependent fashion, deoxycholate-induced ODC activity. The frequency of azoxymethane-induced intestinal tumors was also significantly reduced by alpha-difluoromethylornithine. Since colonic ODC activity is increased in carcinogenesis by known promoting agents and decreased by tumor inhibitors, this short-term assay may provide a useful system for identifying colon tumor promoters and inhibitors. The ODC activity in colon tumors of Sprague-Dawley rats was found to be significantly higher than in normal-appearing mucosa in the same animals. Similarly, ODC activity in human colon cancer was found to be higher than that of the normal-appearing mucosa in the same specimen. These results strengthen the utilization of the rat model for studies, the results of which may apply to the human situation.
Outbred male Sprague-Dawley CD rats were fed a complete semisynthetic diet and were given supplemental low doses (2 ppm) of selenium as H2SeO3 in their drinking water or 50 mg 13-cis-retinoic acid (13-cis-RA) and 2 g beta-sitosterol/kg diet either singly, in combinations of two, or in combinations of all three. Intestinal tumors were induced with eight weekly sc injections of 8 mg azoxymethane (AOM)/kg body weight, and inhibition of tumor formation was determined by tumor counts after 26 weeks. Noncarcinogen controls for each dietary group received eight injections of sterile water. Tumor inhibition was statistically significant in 2 groups of animals: Dietary control animals had a tumor frequency of 5.07 tumors/rat, rats receiving selenium- plus 13-cis-RA supplementation had a tumor frequency of 3.77, and those being given the combination of all three inhibitors had 2.75 tumors/rat. Analysis of fecal steroids from 3 AOM groups (dietary controls, the beta-sitosterol plus 13-cis-RA-supplemented group, and the group receiving all three additives) after 4 months of supplementation showed that the addition of beta-sitosterol to the diet had no effect on acidic or neutral steroids, regardless of the observed difference in tumor frequency. These results suggest that subpharmacologic doses of inhibitors, particularly those that inhibit the process by different mechanisms, while ineffective alone, may provide significant inhibition of tumorigenesis when used in combination.
Osteocalcin, the vitamin K-dependent protein in bone, can also be detected in serum and is receiving increased attention as a marker for bone turnover in evaluating patients with metabolic bone disease. We compared results for patients as determined with two commercial radioimmunoassay kits (Immuno Nuclear Corp. and Seragen Inc.) and with our in-house radioimmunoassay (Methods Enzymol 107: 517, 1984). Results by our assay correlated well (r greater than 0.9) with those by both kits, but the values by the Immuno Nuclear and Seragen methods were respectively 40% and 10% lower than by our radioimmunoassay. Within-run variation (CV) for the two kit methods was respectively 7.3% and 9.8%, run-to-run CV was 9.7% and 8.6%. The standard curve was linear from 1 to 25 micrograms/L for the Immuno Nuclear kit, from 4 to 100 micrograms/L for the Seragen equilibrium method, and from 1 to 25 micrograms/L for the Seragen nonequilibrium method. A second freeze-thaw cycle reduced the serum values by 20% to 40% for both kit methods. A third freeze-thaw cycle further reduced values and eliminated any correlation among methods.
