Lithography and doping in strained Si towards atomically precise device fabrication.

We investigate the ability to introduce strain into atomic-scale silicon device fabrication by performing hydrogen lithography and creating electrically active phosphorus δ-doped silicon on strained silicon-on-insulator (sSOI) substrates. Lithographic patterns were obtained by selectively desorbing hydrogen atoms from a H resist layer adsorbed on a clean, atomically flat sSOI(001) surface with a scanning tunnelling microscope tip operating in ultra-high vacuum. The influence of the tip-to-sample bias on the lithographic process was investigated allowing us to pattern feature-sizes from several microns down to 1.3 nm. In parallel we have investigated the impact of strain on the electrical properties of P:Si δ-doped layers. Despite the presence of strain inducing surface variations in the silicon substrate we still achieve high carrier densities (>1.0 × 10(14) cm(-2)) with mobilities of ∼100 cm(2) V(-1) s(-1). These results open up the possibility of a scanning-probe lithography approach to the fabrication of strained atomic-scale devices in silicon.

Relationships of occupational and non-occupational physical activity to abdominal obesity.

HYPOTHESIS: Physically active occupations may protect against the risk of abdominal obesity. OBJECTIVES: This study assessed the interaction between non-occupational physical activity (NOA) (leisure-time, transport and domestic activity) and occupational activity (OA) in relation to abdominal obesity. METHODS: A total of 3539 adults over the age of 20, with no work limitations, employed in one of the 17 occupations classified as low OA (LOA) or high OA (HOA) were identified in the 1999-2004 National Health and Nutrition Examination Survey. Waist circumference (WC) was used to categorize individuals into either non-obese or abdominally obese (WC>88 cm in women and >102 cm in men) categories. NOA was divided into three categories based upon physical activity guidelines: (1) no NOA; (2) insufficient NOA; and (3) sufficient NOA. Logistic regression was used to examine possible associations between NOA, OA and abdominal obesity. RESULTS: In those who are sedentary outside of work, a high-activity occupation reduces the odds risk ratio of being categorized with abdominal obesity to 0.37 in comparison with those who work in low-activity occupations. For people working in low-activity occupations, there was a clear association with activity outside of work and the odds risk ratio of being categorized with abdominal obesity. In these adults, a reduced odds ratio was found only among those who met the physical activity guidelines through NOA (odds ratio=0.55; 95% confidence interval (CI)=0.40-0.75). CONCLUSION: HOA is associated with a reduced risk of abdominal obesity. Thus, it is important to include OA in studies seeking to understand the association between physical activity and abdominal adiposity.

Plasma prolactin, thyroid-stimulating hormone, melanocyte-stimulating hormone, and adrenocorticotropin responses to thyrotropin-releasing hormone in mares treated with detomidine and butorphanol.

Stress or excitement is a concern when performing endocrine tests on fractious horses. Sedation may be a solution; however, perturbation of test results may preclude useful information. Thyrotropin-releasing hormone (TRH) is a known stimulator of prolactin, thyroid-stimulating hormone (TSH), melanocyte-stimulating hormone (MSH), and ACTH. Thyrotropin-releasing hormone-induced ACTH is a diagnostic tool for the assessment of endocrinopathies such as pituitary pars intermedia dysfunction. It is unknown if drugs commonly used for sedation alter endocrine responses. The objective of this study was to assess the effects of detomidine (DET) and butorphanol on endocrine responses to TRH. Nine light horse mares were used in a replicated 3 × 3 Latin square with the following treatments: saline, DET, and detomidine + butorphanol (DET/BUT), all administered intravenously at 0.01 mg/kg BW. A 1-wk washout period was allowed between phases, all of which were performed in December. Blood samples were collected at -10 and 0 min before treatment and 5 and 10 min post-treatment. Administration of 1 mg TRH occurred 10 min post-treatment, and blood sampling continued 5, 10, 20, and 30 min post-TRH. Data were analyzed by ANOVA as a replicated Latin square with repeated sampling. Plasma prolactin increased (P < 0.0001) after TRH in all groups, rapidly peaking at 5 min in drug-treated mares and 40 min in saline-treated mares. The peak prolactin response to TRH was 2-fold higher (P < 0.0001) in saline-treated mares compared with those drug-treated. A peak rise in plasma TSH was observed in DET/BUT-treated mares 10 min after TSH and was greater (P ≤ 0.007) compared with DET- and saline-treated mares. Plasma MSH was stimulated (P = 0.001) by DET and DET/BUT before TRH, and the peak MSH response to TRH was greater (P < 0.0001) in drug-treated mares, although not hastened as observed with prolactin and TSH. A peak rise in ACTH was observed in drug-treated mares 5 min after administration of TRH, whereas a peak rise was observed in control mares 10 min post-TRH and was almost 2-fold lower (P = 0.05) than the peak observed in DET and DET/BUT-treated mares. Basal ACTH concentrations were not affected by DET or DET/BUT, indicating that sedation with these compounds may be achieved when needing to measure basal plasma ACTH. Treatment with DET and DET/BUT did alter the prolactin, TSH, MSH, and ACTH responses to TRH; therefore, the use of these drugs may not be advisable when assessing endocrine responses to TRH stimulation.

Validity of the Nike+ device during walking and running.

We determined the validity of the Nike+ device for estimating speed, distance, and energy expenditure (EE) during walking and running. Twenty trained individuals performed a maximal oxygen uptake test and underwent anthropometric and body composition testing. Each participant was outfitted with a Nike+ sensor inserted into the shoe and an Apple iPod nano. They performed eight 6-min stages on the treadmill, including level walking at 55, 82, and 107 m x min(-1), inclined walking (82 m x min(-1)) at 5 and 10% grades, and level running at 134, 161, and 188 m x min(-1). Speed was measured using a tachometer and EE was measured by indirect calorimetry. Results showed that the Nike+ device overestimated the speed of level walking at 55 m x min(-1) by 20%, underestimated the speed of level walking at 107 m x min(-1) by 12%, but closely estimated the speed of level walking at 82 m x min(-1), and level running at all speeds (p<0.05). Similar results were found for distance. The Nike+ device overestimated the EE of level walking by 18-37%, but closely estimated the EE of level running (p<0.05). In conclusion the Nike+ in-shoe device provided reasonable estimates of speed and distance during level running at the three speeds tested in this study. However, it overestimated EE during level walking and it did not detect the increased cost of inclined locomotion.

Hemodynamics of the corpus luteum in mares during experimentally impaired luteogenesis and partial luteolysis.

The aim of the current project was to characterize the luteal vascularity and the plasma concentrations of progesterone (P4), prolactin (PRL) and 13,14-dihydro-15-keto-PGF2α (PGFM) in mares with luteal disturbances during early and mid-diestrus. In Experiment 1, twenty-one mares were treated with 2 mL of 0.9% NaCl, or 1 mg Dinoprost, or 10 mg Dinoprost on day two after ovulation (Control-D2, 1/10PGF-D2 and PGF-D2 groups, respectively; n = 7 mares/group). In Experiment 2, similar treatments were performed eight days post-ovulation using a different cohort of 21 mares (Control-D8, 1/10PGF-D8 and PGF-D8 groups, respectively; n = 7 mares/group). Blood samples were collected hourly and power-Doppler examinations of the corpus luteum (CL) were performed every 6 h from H0 (moment immediately before treatment) to H48. Data collection was also done once a day from D0 (day of ovulation) to D20. In Experiment 1, the PGF-D2 and 1/10PGF-D2 groups had lower increase of plasma concentration of P4 until H48 and reduced maximum P4 concentrations on D8-D11 than mares from the Control-D2 group. However, no differences among groups were detected for luteal vascularity during early and mid-diestrus. In Experiment 2, complete and partial luteolysis were detected in mares from the PGF-D8 and 1/10PGF-D8 groups, respectively. Luteal vascularity and plasma P4 concentrations differed among Control-D8, PGF-D8 and 1/10PGF-D8 groups on H48. Partially regressed CLs (1/10PGF-D8 group) generated more Doppler signals than completed regressed CLs (PGF-D8 group) between D10 and D13. In both experiments, a transient increase in PRL activity was observed in parallel to the PGFM pulse in mares receiving 1 or 10 mg Dinoprost. The use of prostaglandin on D2 at conventional or 1/10 of the dose impaired the luteal development in mares. Moreover, the low dose of prostaglandin lead to partial regression of mature CLs. The blood supply was reduced in partially regressed CLs, but not in CLs undergoing impaired luteogenesis.

Influence of two ovulation-inducing agents on the pituitary response and follicle blood flow in mares.

The objective of the current study was to evaluate the effects of deslorelin and hCG, two ovulation-inducing therapies, on LH surge and follicle vascularity in mares. Thirty mares were either treated with 1.5 mg IM of deslorelin, 2,500 IU IV of hCG or 2 mL IM of NaCl 0.9% (GnRH, hCG and Saline groups, respectively). Power-flow Doppler examination and blood collection were performed every hour during the first 12 hours after treatment (H0) and every six hours between hours 12 (H12) and 30 (H30) after treatment. Moreover, endpoints were evaluated every hour through the last six hours before ovulation (OV-6 to OV-1). In GnRH group, plasma LH concentration progressively increased (P < 0.001) during the first 6 hours after treatment and remained high (P > 0.1) until OV-1. A significant increase in LH concentrations was first detected (P < 0.05) at 24 hours after treatment in hCG group, while no changes (P > 0.1) on LH levels were found during H0-H30 and between OV-6 and OV-1 in the Saline group. Independent of the treatment, significant variations on the percentage of the follicle wall with Doppler signals were not observed (P > 0.1) throughout the entire experiment. A weak correlation between the preovulatory follicle vascularity and the plasma LH concentration was found in GnRH, hCG and Saline groups (r = +0.29, +0.29 and -0.23, respectively; P ˂ 0.0001). These results described for the first time the immediate and continuous pituitary response to ovulation-inducing therapy with injectable deslorelin. Moreover, spontaneous and induced ovulations were not preceded by an increased follicle vascularity, which differs from previous reports in large animals.

Leptin secretion in horses: effects of dexamethasone, gender, and testosterone.

Five experiments were performed to evaluate the effects of dexamethasone (DEX), gender, and testosterone on plasma leptin concentrations in horses. In experiment 1, plasma leptin, insulin, glucose, and IGF-1 concentrations were increased (P < 0.01) in stallions following five daily injections of DEX (125 microg/kg BW). In experiment 2, leptin concentrations increased (P < 0.01) in mares, geldings, and stallions following a single injection of DEX, and the response was greater (P < 0.01) in mares and geldings than in stallions. The gender effect was confounded by differences in body condition scores and diet; however, based on stepwise regression analysis, both BCS and gender were significant sources of variation in the best fit model for pre-DEX leptin concentrations (R(2) = 0.65) and for maximum leptin response to DEX (R(2) = 0.75). In experiment 3, in which mares and stallions were pair-matched based on age and body condition and fed similar diets, mares again had higher (P < 0.01) leptin concentrations than stallions after DEX treatment as used in experiment 2. In experiment 4, there was no difference (P > 0.1) in plasma leptin response in mares following four single-injection doses of DEX from 15.6 to 125 microg/kg BW. In experiment 5, treatment of mares with testosterone propionate every other day for 5 days did not alter (P > 0.1) plasma leptin concentrations or the leptin response to DEX. In conclusion, multiple injections of DEX increase leptin concentrations in stallions, as does a single injection in mares (as low as 15.6 microg/kg BW), geldings and stallions. The greater leptin levels observed in mares and geldings relative to stallions were due partially to their greater body condition and partially to the presence of hyperleptinemic individuals; however, even after accounting for body condition and diet, mares still had greater leptin concentrations than stallions after DEX administration. Elevation of testosterone levels in mares for approximately 10 days did not alter leptin concentrations in mares.

Real-time characterization of the uterine blood flow in mares before and after artificial insemination.

The present experiment was divided into two studies to investigate the effect of age and endometrial degeneration on uterine blood flow of mares throughout the immediate post-breeding period. In study 1, uterine blood flow was characterized in mares (n = 7 mares/group) with minimal, moderate or severe endometrial degenerative changes (GI, GII and GIII, respectively). In study 2, the effect of age was investigated using young (≤ 6 years) and old (≥ 15 years) mares (n = 7 mares/group). Uterine vascular perfusion and mesometrial pulsatility index (PI) were evaluated every hour from H0 (moment immediately before AI) to H12. In study 1, a pronounced and transitory increase on uterine vascular perfusion was detected (P < 0.001) between H1 and H3 in the three endometrial groups. In addition, GIII mares had greater (P < 0.05) mesometrial PI than GI mares during the post-breeding period, denoting reduced uterine blood flow. In study 2, a transitory increase on uterine vascular perfusion was also observed in both age groups during the first hour after mating. However, mesometrial PI of young and old mares was similar (P > 0.05) and constant (P > 0.7) through the first 12h after AI. Results demonstrated, for the first time, the immediate changes on uterine vascular perfusion and mesometrial PI in response to semen infusion. Moreover, reduced blood flow of the uterus during the post-breeding period was strongly associated with endometrial degenerative changes in mares, regardless of age.

The derivation and characterization of stromal cell lines from the bone marrow of p53-/- mice: new insights into osteoblast and adipocyte differentiation.

We have derived a series of clonal cell lines from the bone marrow of p53-/- mice that represent different stages of osteoblast and adipocyte differentiation. All cell lines show indefinite growth potential (>300 population doublings) and have generation times of 12-20 h. These cell lines have been grouped into three categories. The least mature clones are heterogeneous and appear to contain a subpopulation of stem cells, which can spontaneously generate foci that contain either adipocytes or mineralizing osteoblasts. The second category of clones are homogeneous and clearly correspond to mature osteoblasts because they express high levels of the anticipated osteoblastic markers in a stable fashion and cannot differentiate into adipocytes even in the presence of inducers. The clones in the third category are the most unique. Initially they appeared to correspond to mature osteoblasts because they express alkaline phosphatase in a homogeneous manner, secrete type I collagen, show a significant cyclic adenosine monophosphate response to parathyroid hormone, secrete osteocalcin, and mineralize extensively after only 4-7 days. However, in contrast to the mature osteoblasts, these clones can be induced to undergo massive adipocyte differentiation, and this differentiation is accompanied by the complete loss of expression of all osteoblastic markers except alkaline phosphatase. These observations indicate that some cells that have acquired all of the characteristics of mature osteoblasts can be diverted to the adipocyte pathway. Further characterization of these clones may be particularly relevant to osteoporotic conditions where increased adipocyte formation appears to occur at the expense of osteoblast formation.

Ontogeny of Phex/PHEX protein expression in mouse embryo and subcellular localization in osteoblasts.

PHEX, a phosphate-regulating gene with homologies to endopeptidases on the X chromosome, is mutated in X-linked hypophosphatemia (XLH) in humans and mice (Hyp). Although recent observations indicate that Phex protein is expressed primarily in bone and may play an important role in osteoblast function and bone mineralization, the pattern of the Phex protein expression in the developing skeleton and its subcellular localization in osteoblasts remain unknown. We examined the ontogeny of the Phex protein in the developing mouse embryo and its subcellular localization in osteoblasts using a specific antibody to the protein. Immunohistochemical staining of mouse embryos revealed expression of Phex in osteogenic precursors in developing vertebral bodies and developing long bones on day 16 postcoitum (pc) and thereafter. Calvaria from day 18 pc mice showed Phex epitopes in osteoblasts. No Phex immunoreactivity was detected in lung, heart, hepatocytes, kidney, intestine, skeletal muscle, or adipose tissue of mouse embryos. Interestingly, embryonic mouse skin showed moderate amounts of Phex immunostaining. In postnatal mice, Phex expression was observed in osteoblasts and osteocytes. Moderate expression of Phex was seen in odontoblasts and slight immunoreactivity was observed in ameloblasts. Confocal microscopy revealed the presence of immunoreactive PHEX protein in the Golgi apparatus and endoplasmic reticulum of osteoblasts from normal mice and in osteoblasts from Hyp mice transduced with a human PHEX viral expression vector. PHEX protein was not detected in untransduced Hyp osteoblasts. These data indicate that Phex protein is expressed in osteoblasts and osteocytes during the embryonic and postnatal periods and that within bone, Phex may be a unique marker for cells of the osteoblast/osteocyte lineage.

Separate negative feedback effects of estrogen on the pituitary and the central nervous system in the ovariectomized rhesus monkey.

The site(s) of the negative feedback action of estrogen on gonadotropin secretion were studied in the ovariectomized rhesus monkey by observing the serum LH and FSH responses to intravenous GnRH injections at various times after implantation of Silastic capsules filled with estrogen. Circulating estrogen concentrations produced by the capsules were within the normal midcycle range for this species. Four h after estrogen implantation, no LH or FSH response was seen to the GnRH injection, indicating a suppressive effect of the steroid directly on the pituitary. Twelve and 22 h after estrogen implantation, however, the LH and FSH responses were equal to or larger than control responses. Since preinjection LH and FSH levels were below control values at these times and the pituitary responded to exogenous GnRH, it appears that endogenous GnRH secretion was affected, indicating an inhibitory action of estrogen on the central nervous system. Thus these experiments suggest 2 separate negative feedback actions of estrogen: a transient one directly on the pituitary and a longer lasting effect on the central nervous system.

Preferential metabolism of dihydrotestosterone to androstanediol 17-glucuronide in rat prostate.

Androstanediol glucuronide (Adiol G), a marker of peripheral dihydrotestosterone (DHT) metabolism and action, may be conjugated through the hydroxyl group at either the 3-carbon (Adiol 3-G) or 17-carbon (Adiol 17-G) position. Adiol 17-G is the predominant Adiol G isomer derived from DHT in normal men. To determine whether peripheral tissues may be responsible for this selective conversion of DHT to Adiol 17-G, a glucuronyl transferase assay was developed using rat prostate cells. Adiol 17-G was separated from Adiol 3-G by HPLC and selective precipitation with an antibody specific for Adiol 3-G. Using androstanediol (Adiol) as a substrate, enzyme kinetics were linear with respect to time and enzyme concentration. In the presence of 0 or 5 microM Adiol and 1 microCi [3H]Adiol, greater than 99% of the resulting Adiol G was Adiol 17-G. The percent conversions of DHT, Adiol, and androsterone to their glucuronide conjugates were 0.22%, 3.5%, and 0.24%/10(6) prostate cells, respectively. Using DHT as an inhibitor of Adiol glucuronidation, the Ki was 39.1 microM, compared to an apparent Km for Adiol of 15 microM. We conclude that rat prostate cells can selectively convert Adiol to Adiol 17-G, and that Adiol glucuronidation is favored over that of DHT or androsterone under these experimental conditions. Since DHT and Adiol are readily interconvertable, these results suggest that Adiol 17-G is the major DHT metabolite in the rat prostate.

Testicular androgen and estrogen secretion and benign prostatic hyperplasia in the beagle.

The natural history of benign prostatic hyperplasia (BPH) in the dog is characterized by a slow progression through two phases. The early phase of the disease process is characterized by glandular hyperplasia and occurs as early as 2.5 yr of age. The late phase of the disease is characterized by cystic hyperplasia and occurs after 4 yr. The results of the present study are the first to compare Leydig cell structure and steroidogenic function in dogs with BPH with those in age-matched controls. It was discovered that glandular BPH can occur in young dogs (2.5 yr) in which Leydig cell mass and ultrastructure and maximally stimulated androgen secretion are indistinguishable from those in age-matched controls. These results support the concept that the early phase of BPH (glandular hyperplasia) is not related temporally to some defect in the Leydig cell. In contrast, the late phase of BPH (cystic hyperplasia) in beagles 6 yr of age is associated with diminished smooth endoplasmic reticulum in the Leydig cell and with diminished production of androgens by perfused testes in vitro. During the course of these studies, we discovered that the testes of young beagles with BPH, but not age-matched controls or old beagles with BPH, secrete an unidentified molecule (putative estrogen). This molecule was characterized partially in that it is extractable from testicular venous effluent with diethyl ether, elutes in a discrete fraction in several different high performance liquid chromatographic systems, reacts with an antibody that recognizes 17 beta-estradiol, estrone, and estriol, and competes with 17 beta-[3H]estradiol for the rat uterine estrogen receptor. Based on the elution volume from high performance liquid chromatography, the unknown molecule (putative estrogen) is not estriol, estradiol, or estrone.

Effect of leuprolide and dexamethasone on hair growth and hormone levels in hirsute women: the relative importance of the ovary and the adrenal in the pathogenesis of hirsutism.

Ten hirsute women with polycystic ovarian syndrome (PCO) and nine with idiopathic hirsutism (IH) underwent selective ovarian suppression with leuprolide for 5-6 months and then were randomized to receive, in addition, dexamethasone or placebo for 4 more months. Serum hormone levels and hair growth rates were determined before and after each treatment period. During the initial treatment period with leuprolide alone, testosterone decreased by 54 +/- 6% (mean +/- SEM) in PCO and by 36 +/- 3% in IH (P = 0.02). Androstenedione decreased by 53 +/- 6% in PCO and by 31 +/- 7% in IH (P = 0.02). Androstanediol glucuronide (Adiol-G) decreased by 14 +/- 6% in PCO and by 7 +/- 3% in IH. There was no change in dehydroepiandrosterone sulfate (DHEAS). While initial serum androgen levels were higher in PCO than in IH, they were similar after ovarian suppression in the two groups. After ovarian suppression, Adiol-G was more consistently correlated with testosterone and androstenedione than was DHEAS, suggesting that Adiol-G may be a better marker than DHEAS of adrenal androgen secretion. Hair growth rates decreased by 37 +/- 6% in PCO and by 14 +/- 10% in IH (P = 0.07). The change in hair growth correlated with the change in androstenedione (r = 0.66; P = 0.002), but not significantly with the change in testosterone (r = 0.29; P = 0.2). After the addition of dexamethasone therapy (0.5 mg daily), testosterone, androstenedione, and DHEAS levels fell to near or below assay detection limits, while Adiol-G decreased by 80 +/- 3%. Hair growth rates decreased slightly more in women during dexamethasone (46 +/- 6%) than during placebo (26 +/- 9%; P = 0.18). In summary, the ovary was the major source of circulating testosterone and androstenedione in PCO. The adrenal contributed a substantial minority of these hormones in PCO and was the major source of androgen secretion in IH. Adrenal hyperandrogenism was common in both IH and PCO. Hair growth rates correlated best with changes in serum androstenedione levels. Adiol-G, which was derived primarily from adrenal precursors, was a better marker of adrenal androgen secretion than was DHEAS in these subjects.

Androstanediol glucuronide isomers in normal men and women and in men infused with labeled dihydrotestosterone.

3 alpha-Androstanediol glucuronide (Adiol G) is a major metabolite of dihydrotestosterone (DHT). Adiol G actually represents 2 different compounds, since the glucuronide can be conjugated at the 3-carbon position (Adiol 3-G) or at the 17-carbon position (Adiol 17-G). To determine which glucuronide represents the predominant physiological DHT metabolite and which isomer is the major circulating form, we developed a RIA to directly measure Adiol 3-G in serum extracts. In 10 normal men, mean serum Adiol 3-G and total Adiol G levels were 4.44 +/- 0.49 (+/- SE) nmol/L (208 +/- 23 ng/dL) and 27.9 +/- 2.8 nmol/L (1310 +/- 129 ng/dL), respectively (13.9 +/- 3.0% of Adiol G was Adiol 3-G). In 10 normal women sampled during the early follicular phase, mean serum Adiol 3-G and total Adiol G levels were 2.64 +/- 0.64 nmol/L (124 +/- 30 ng/dL) and 14.9 +/- 1.5 nmol/L (697 +/- 69 ng/dL), respectively (17.4 +/- 3.6% of Adiol G was Adiol 3-G). In 4 normal men infused for 8 h with tritiated DHT, 17.4 +/- 3.4% of the resulting tritiated Adiol G was Adiol 3-G. These results indicate that Adiol 17-G is the predominant circulating form of Adiol G in normal men and women and that it is also the major Adiol G isomer derived from DHT.

Androstanediol glucuronide production in human liver, prostate, and skin. Evidence for the importance of the liver in 5 alpha-reduced androgen metabolism.

Androstanediol glucuronide (Adiol G) has been reported to be a marker of peripheral androgen metabolism and action. It consists of two isomers, Adiol 3-G and Adiol 17-G. Adiol G is formed from unconjugated precursors by the enzyme glucuronyl transferase. To determine the likely source of Adiol G formation in man, we developed a glucuronyl transferase assay and measured the activity of this enzyme in human liver, abdominal and scalp skin, and prostate. In human liver, glucuronyl transferase activity was linear with respect to time (up to 120 min) and tissue concentration (up to 1 mg/ml). Apparent Michaelis-Menten constant Km (micromolar) and maximum velocity (Vmax) (picomoles per mg/30 min) were 5.6 and 140 for dihydrotestosterone, 8.9 and 1300 for androstanediol, and 3.1 and 46 for androsterone, respectively. Conversion of androstanediol to Adiol G (/0.5 mg tissue.30 min) was 5.8-13.2%. Over 80% of the Adiol G formed in human liver was Adiol 17-G, similar to what has been previously found in human serum. Glucuronyl transferase activity was present at low levels in human prostate (conversion of androstanediol to Adiol G was 0.04-4.6%/50 mg tissue.120 min). Analogous conversion rates (/50 mg tissue.120 min) for human scalp skin were 0.2-0.4% and for human abdominal skin were 0.07-0.14%. Although dihydrotestosterone may be converted to androstanediol in peripheral tissues such as skin and prostate, our results suggest that the principal site of androgen conjugation to glucuronic acid is the liver. The present results cast doubt upon the role of androstanediol glucuronide as a specific marker of cutaneous androgen metabolism.

Low dose estrogen and calcium have an additive effect on bone resorption in older women.

Previous studies have shown that treatment with estrogen or calcium decreases bone turnover in older women. The mechanisms by which estrogen and calcium exert their effects are probably different. We therefore examined the possibility of an additive or synergistic effect of combined treatment with calcium and low dose estrogen on bone turnover in older women, using biochemical markers. Thirty-one healthy women over 70 yr of age were randomized to 12 weeks of treatment with either micronized 17beta-estradiol [0.5 mg/day Estrace (E2)] or 1500 mg/day elemental calcium, given as carbonate plus vitamin D (800 IU/day; Ca+D). At the end of the initial 12-week treatment period, both groups received both Ca+D and E2 for an additional 12 weeks. Eleven older women were followed for 36 weeks without any treatment and served as a control group. Serum and urine were collected at baseline, at 12 and 24 weeks on treatment, and at 12 weeks after treatment was terminated for measurement of biochemical markers of bone turnover. Markers of bone formation were bone alkaline phosphatase, osteocalcin, and type I procollagen peptide; markers of bone resorption were urinary cross-linked C-telopeptides and N-telopeptides of type I collagen, serum cross-linked N-telopeptides of type I collagen, urinary free deoxypyridinoline cross-links, and serum bone sialoprotein. Repeated measures ANOVA was used to determine changes in bone turnover measures over time by group. All markers of bone resorption decreased with initial treatment and decreased further with combination therapy (P < 0.001). Markers of bone formation decreased with Ca+D treatment, but not with E2 alone; there was no additional effect of combination therapy on formation markers compared to Ca+D alone. Neither markers of formation nor resorption changed in the control group. These results suggest that there is an additive effect of low dose estrogen and calcium on bone resorption, but not on bone formation, in older women. Thus, the combination of low dose estrogen plus calcium is likely to be more effective in older women than either treatment alone.

Effects of finasteride (MK-906), a 5 alpha-reductase inhibitor, on circulating androgens in male volunteers.

Finasteride, a 5 alpha-reductase inhibitor, was administered to normal male volunteers in a blinded placebo-controlled study at daily oral doses of 25, 50, and 100 mg for 11 days (part 1) and daily oral doses of 0.04, 0.12, 0.2, and 1.0 mg for 14 days (part 2). Results from part 1 showed a significant reduction in dihydrotestosterone (DHT) at all doses and a significant increase in both testosterone (T) and delta 4-androstenedione at the 50- and 100-mg doses. No change was seen in LH, FSH, cortisol, or estradiol levels. Serum lipids, including total cholesterol, low density lipoprotein, high density lipoprotein, and triglycerides were not affected by treatment. Results from part 2 again showed significant reduction in DHT at all doses. DHT levels returned to pretreatment values within 14 days of discontinuing treatment. Significant increases in T were observed only in the 1.0 mg group and only during the first 8 days of treatment. The T/DHT ratio increased with all doses and returned to baseline when drug was discontinued. The DHT metabolites and androstanediol glucuronide and androsterone glucuronide were significantly reduced at all doses. There were no significant adverse experiences reported during part 1 or 2. In conclusion, finasteride is well tolerated by normal volunteers and results in significant suppression of serum DHT at all doses tested.

Swimming training lowers the resting blood pressure in individuals with hypertension.

BACKGROUND: Despite the fact that swimming is often recommended for the prevention and treatment of hypertension, no study has examined the potential efficacy of regular swimming exercise for lowering the blood pressure in hypertensive humans. OBJECTIVE: To test the hypothesis that regular swimming exercise lowers the resting blood pressure. DESIGN: A 10-week closely supervised swimming training program compared with a non-exercising control group. PATIENTS: Eighteen previously sedentary men and women [aged 48 +/- 2 years (mean +/- SEM)] with stage 1 or 2 essential hypertension. RESULTS: The resting heart rated, an index of cardiovascular adaptation, decreased in the swimming training group from 81 +/- 4 to 71 +/- 3 beats/min (P < 0.01). The body mass and body fat percentage did not show statistically significant changes. The systolic blood pressure of patients in the seated position fell significantly (P < 0.05) from 150 +/- 5 to 144 +/- 4 mmHg. The seated diastolic blood pressure did not change significantly. A similar magnitude of reductions in systolic blood pressure (P < 0.05) was also found in patients in the supine position. No significant changes in plasma catecholamine concentrations, casual forearm vascular resistance, plasma volume and blood volume were observed. There were no significant changes in any of these variables in the control group. CONCLUSION: Swimming training elicits significant reductions in arterial blood pressure at rest in individuals with hypertension. This is a clinically important finding since swimming can be a highly useful alternative to land-based exercises for hypertensive patients with obesity, exercise-induced asthma, or orthopedic injuries.