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Biomedical subjects

S M Ott

Publications and source records attributed to S M Ott.

At least 19 recordsLinked to original sources
PubMed2003

Bone histology at autopsy and matched bone scintigraphy findings in patients with hormone refractory prostate cancer: the effect of bisphosphonate therapy on bone scintigraphy results.

Bisphosphonates (BisP) are non-metabolized compounds with high bone affinity used in bone metastasis diagnosis and treatment. Currently, BisP are used to treat hypercalcemia of malignancy as well as to prevent, minimize, or delay skeletal morbidity. These compounds have a long half-life in bone. Thus long-term BisP treatment might saturate bone and interfere with a single-dose scanning agent used for bone scintigraphy when visualizing bone metastases. In an effort to answer this question, this study evaluated the concordance of histology and Technetium99 methylene diophosphonate (Tc99 MDP) bone scintigraphy in the diagnosis of bone metastases in prostate cancer patients. We assessed the concordance of findings between bone scintigraphy and histology using 188 bone biopsies from 11 autopsied patients who died with metastatic prostate cancer, 5 of whom were treated with pamidronate for 2 to 13 months before death. Overall agreement between histology and bone scintigraphy was 84%, 86% in non-pamidronate-treated patients and 82% in pamidronate-treated patients. Scintigraphic bone metastases without histological metastasis (false negatives = 12.7%) were observed in 24 anatomic locations; half of these were in one patient who had been treated with pamidronate and had no histological bone response to the carcinoma. There were only 4 sites where a positive bone scan was not associated with histologic metastasis (false positives = 2.21%). There was no statistical difference between the treated and non-treated group for concordance, specificity, sensitivity, positive and negative predictive values of bone scintigraphy and prevalence of histological abnormality. Long-term pamidronate treatment of prostate cancer bone metastases does not generally affect the ability to detect bone metastases with Tc99 MDP bone scintigraphy.

Antineoplastic Agents↗
PubMed2003

Contribution of raloxifene and calcium and vitamin D3 supplementation to the increase of the degree of mineralization of bone in postmenopausal women.

Raloxifene has been shown to increase bone mineral density and reduce the risk of vertebral fracture in postmenopausal women with osteoporosis. In this study, we report the results of the first prospective longitudinal study to evaluate the mean degree of mineralization of bone (MDMB) in a group of patients enrolled in the Multiple Outcomes of Raloxifene Evaluation trial. Patients were randomly assigned to one of three treatment groups: placebo (n = 24), raloxifene 60 mg/d (RLX60; n = 22), or raloxifene 120 mg/d (RLX120; n = 18). All patients received daily calcium (500 mg) and vitamin D(3) (400-600 IU) supplementation for the duration of the study. Iliac crest biopsies were taken at baseline and after 2 yr of treatment. Quantitative microradiography was used to analyze the biopsy specimens and revealed a statistically significant (P < 0.05) mean percentage increase in total MDMB of 7.0, 5.3, and 5% for RLX60-, RLX120-, and placebo-treated patients, respectively, compared with baseline. Raloxifene treatment was found to shift the distribution of total bone mineral to higher values of MDMB (RLX60, 29%; RLX120, 8%) with greater heterogeneity, compared with placebo. The profile of MDMB observed in biopsies after treatment with placebo and raloxifene, compared with baseline, closely resembles physiological premenopausal bone.

Aged↗
PubMed2001

Nitric oxide inhibition of cAMP synthesis in parotid acini: regulation of type 5/6 adenylyl cyclase.

The nitric oxide (NO) donor, GEA 3162, inhibited isoproterenol-induced cyclic AMP (cAMP) accumulation in a concentration- and time-dependent manner in mouse parotid acini; SIN-1 mimicked these effects. Inhibition of stimulated cAMP accumulation was independent of phosphodiesterase activity. GEA 3162 also inhibited forskolin-induced cAMP accumulation. Removal of extracellular Ca(2+), addition of La(3+), or the calmodulin (CaM) inhibitor, calmidazolium, did not prevent the NO-mediated response, and addition of the soluble guanylyl inhibitor, ODQ, did not reverse GEA 3162-induced inhibition of cAMP accumulation. GEA 3162 also inhibited adenylyl cyclase in vitro independently of Ca(2+)/CaM. Further studies revealed that the NO synthase (NOS) inhibitor, 7-nitroindazole (7-NI), reduced significantly thapsigargin-induced Ca(2+) release and capacitative Ca(2+) entry and reversed thapsigargin inhibition of the AC Type 5/6 isoform (AC5/6). Data suggest that NO produced endogenously has dual effects on cAMP accumulation in mouse parotid acini, an inhibitory effect on AC activity and a modulatory effect on capacitative Ca(2+) entry resulting in AC5/6 inhibition.

Adenylyl Cyclases↗
PubMed2001

Bone density loss after allogeneic hematopoietic stem cell transplantation: a prospective study.

The incidence and course of bone density abnormalities following hematopoietic stem cell transplantation are poorly understood and complicated by the impact of multiple factors. Hip, spine, and wrist bone mineral densities (BMDs) were measured in 104 adults (54 women, 54 men; mean age, 40 years [range, 18-64 years]) at 3 and 12 months after allogeneic transplantation. Clinical and laboratory variables were evaluated using univariate and multivariate analyses to determine risk factors for osteoporosis, fracture, and avascular necrosis. At 3 months posttransplantation, combined (male and female) hip, spine, and wrist z scores were -0.35, -0.42, and +0.04 standard deviations, respectively. At 12 months both men and women experienced significant loss of hip BMD (4.2%, P < .0001); changes in the spine and wrist were minimal. The cumulative dose and number of days of glucocorticoid therapy and the number of days of cyclosporine or tacrolimus therapy showed significant associations with loss of BMD; age, total body irradiation, diagnosis, and donor type did not. Nontraumatic fractures occurred in 10.6% of patients and avascular necrosis in 9.6% within 3 years posttransplantation. The decrease in height between pretransplantation and 12 months posttransplantation was significant (P = .0001). Results indicate that loss of BMD after allogeneic stem cell transplantation is common and accelerated by the length of immunosuppressive therapy and cumulative dose of glucocorticoid. An increased incidence of fracture and avascular necrosis may adversely impact long-term quality of life. Prevention of bone demineralization appears warranted after stem cell transplantation.

Adolescent↗
PubMed2001

Effects of contraceptive use on bone biochemical markers in young women.

The purpose of this study was to compare biochemical markers of bone resorption and formation in young women using different hormonal contraceptive methods. Women aged 18-39 yr who were using depot medroxyprogesterone acetate (DMPA) contraception were recruited for the study; comparison women were matched by age and clinic location. There were 116 women using DMPA, 39 using oral contraceptives containing estrogen and progestin, and 72 not currently using hormonal contraceptives. Biochemical measurements were serum calcium, PTH and osteocalcin, and urine N-telopeptide. Bone density was measured using dual-energy x-ray absorptiometry. The N-telopeptide levels, adjusted for age and other risk factors, were 42.4 +/- 2.3 nmol/mmol creatinine in the DMPA group, 26.2 +/- 3.3 nmol/mmol in the oral contraceptive group, and 35.4 +/- 2.9 nmol/mmol in the nonusers; significant differences were seen in all pairwise comparisons. Osteocalcin levels showed the same pattern, although the difference between the DMPA users and nonusers was not statistically significant. There were no differences among groups in the PTH levels. The bone density at the spine was 1.086 +/- 0.085 g/cm(2) in the DMPA group, 1.103 +/- 0.095 g/cm(2) in the oral contraceptive group, and 1.093 +/- 0.090 g/cm(2) in nonusers (P = 0.051). The results suggest that in women using DMPA bone resorption exceeded bone formation.

Adult↗
PubMed2001

Osteoporosis in women with spinal cord injuries.

Decreased bone density and increased fracture risk are seen in patients with SCI. The bone resorption rate is markedly increased. Hypercalciuria, low PTH, and low 1,25 (OH)2 vitamin D are commonly seen. Bed-rest studies show similar findings, but of lesser magnitude. Therapies to treat or prevent osteoporosis include optimal nutrition (with care to avoid exacerbating hypercalciuria). Weight-bearing or functional electrical stimulation cycle ergometry may prevent some of the bone loss, especially in acutely injured patients. Estrogen should be considered in postmenopausal or amenorrheic women, but not if they are at high risk of thromboembolism. More research on effects of estrogen is needed in this population. Bisphosphonates may also help prevent the acute bone loss; oral routes must not be used in recumbent patients. Thiazides could be useful as adjunct therapy.

Absorptiometry, Photon↗
PubMed2000

Low-dose hydrochlorothiazide and preservation of bone mineral density in older adults. A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Thiazide may have beneficial effects on bone mineral density and may reduce risk for hip fracture. However, the existence of a causal role remains uncertain because experimental evidence is limited. OBJECTIVE: To determine the effect of hydrochlorothiazide on rates of bone loss in older adults. DESIGN: Randomized, double-blind, placebo-controlled trial with 3-year follow-up. SETTING: A large health maintenance organization in western Washington State. PARTICIPANTS: 320 healthy, normotensive adults (205 women, 115 men) 60 to 79 years of age. INTERVENTION: Random assignment to one of three study groups: 12.5 mg of hydrochlorothiazide per day, 25 mg of hydrochlorothiazide per day, or placebo. MEASUREMENTS: Bone mineral density using dual-energy x-ray absorptiometry at the total hip, posterior-anterior spine, and total body; blood and urine markers of bone metabolism; incident falls, clinical fractures, and radiographic vertebral fractures. RESULTS: 309 of 320 participants completed the 36-month visit (97%). Adherence to study medication throughout follow-up was high in all participants (81.6% to 89.7%) except men in the high-dose hydrochlorothiazide group (60.5%). According to intention-to-treat analysis, the 36-month differences in percentage change in total hip bone mineral density were 0.79 percentage point (95% CI, -0.12 to 1.71) for the 12.5-mg hydrochlorothiazide group and 0.92 percentage point (CI, -0.001 to 1.85) for the 25-mg group compared with placebo (P = 0.03). Percentage change at the posterior-anterior spine was significantly greater for the 25-mg hydrochlorothiazide group at 6 months (intergroup difference, 1.04 percentage points [CI, 0.22 to 1.86]) compared with placebo (P = 0.005); at 36 months, this difference was 0.82 percentage point (CI, -0.36 to 2.01; P = 0.12). No significant differences were seen in total-body bone mineral density between the treatment groups. Treatment effects were stronger in women than in men. CONCLUSIONS: In healthy older adults, low-dose hydrochlorothiazide preserves bone mineral density at the hip and spine. The modest effects observed over 3 years, if accumulated over 10 to 20 years, may explain the one-third reduction in risk for hip fracture associated with thiazide in many epidemiologic studies.

Aged↗
PubMed2000

The type 8 adenylyl cyclase is critical for Ca2+ stimulation of cAMP accumulation in mouse parotid acini.

Capacitative Ca(2+) entry stimulates cAMP synthesis in mouse parotid acini, suggesting that one of the Ca(2+)-sensitive adenylyl cyclases (AC1 or AC8) may play an important role in the regulation of parotid function (Watson, E. L., Wu, Z., Jacobson, K. L., Storm, D. R., Singh, J. C., and Ott, S. M. (1998) Am. J. Physiol. 274, C557-C565). To evaluate the role of AC1 and AC8 in Ca(2+) stimulation of cAMP synthesis in parotid cells, acini were isolated from AC1 mutant (AC1-KO) and AC8 mutant (AC8-KO) mice and analyzed for Ca(2+) stimulation of intracellular cAMP levels. Although Ca(2+) stimulation of intracellular cAMP levels in acini from AC1-KO mice was indistinguishable from wild type mice, acini from AC8-KO mice showed no Ca(2+)-stimulated cAMP accumulation. This indicates that AC8, but not AC1, plays a major role in coupling Ca(2+) signals to cAMP synthesis in parotid acini. Interestingly, treatment of acini from AC8-KO mice with agents, i.e. carbachol and thapsigargin that increase intracellular Ca(2+), lowered cAMP levels. This decrease was dependent upon Ca(2+) influx and independent of phosphodiesterase activation. Immunoblot analysis revealed that AC5/6 and AC3 are expressed in parotid glands. Inhibition of calmodulin (CaM) kinase II with KN-62, or inclusion of the CaM inhibitor, calmidazolium, did not prevent agonist-induced inhibition of stimulated cAMP accumulation. In vitro studies revealed that Ca(2+), independently of CaM, inhibited isoproterenol-stimulated AC. Data suggest that agonist augmentation of stimulated cAMP levels is due to activation of AC8 in mouse parotid acini, and strongly support a role for AC5/6 in the inhibition of stimulated cAMP levels.

Adenylyl Cyclases↗
PubMed2000

Depressive symptoms in users and non-users of depot medroxyprogesterone acetate.

To evaluate the possible effects of depot medroxyprogesterone acetate (DMPA) injectable contraception on depressive symptoms, we conducted a population-based prospective study with women aged 18-39 years old enrolled at a health maintenance organization. At baseline, 183 women used DMPA and 274 were non-users. Data on depressive symptoms and on factors potentially related to DMPA use and depression were collected by questionnaire at 6-month intervals for up to 3 years. In multivariate longitudinal analysis, we found an increased likelihood of reporting depressive symptoms among continuous DMPA users (OR = 1.44; 95% CI = 1.00-2.07) and discontinuers (OR = 1.60; 95% CI = 1.03-2.48) when compared to non-users. Women who discontinued DMPA use had elevated depressive symptoms prior to discontinuation (OR = 2.30; 95% CI = 1.42-3.70) and immediately following discontinuation (OR = 2.46; 95% CI = 1. 46-4.14), and depressive symptoms subsided at subsequent visits relative to non-users. Our prospective analyses found an association between DMPA use and depressive symptoms but further research is needed to determine whether the relationship is causal.

Adolescent↗
PubMed2000

The effects of pregnancy on the musculoskeletal system.

During pregnancy the female body undergoes many hormonal and anatomic changes that affect the musculoskeletal system. These changes may cause various musculoskeletal complaints, predispose to injury, or alter the course of preexisting conditions. The changes of pregnancy should be taken into account when counseling women who wish to exercise through their pregnancy. Treatment of musculoskeletal complaints during pregnancy must include the potential effects on mother and fetus.

Female↗
PubMed2000

Bone structure in patients with low bone mineral density with or without vertebral fractures.

Vertebral fractures (VFX) are caused by low bone mass and microstructural deterioration of bone tissue. The latter is not well defined. We investigated bone structure in transiliac biopsy specimens from 88 volunteers. Biopsy specimens were obtained at baseline in the Multiple Outcomes of Raloxifene Evaluation trail, a prospective study in osteoporotic (BMD < or = -2.5 T score) postmenopausal women without or with VFX on standardized lateral spinal radiographs. Bone biopsy specimens were embedded in methylmethacrylate (MMA). Histomorphometry was done in 8 microns (U.S.A.) or 5 microns (Europe) Goldner stained sections. Vertebral fracture status (yes/no) was the outcome variable in logistic regression models adjusted for age and biopsy specimen origin (U.S.A. vs. Europe). Patients with and without VFX (26/62) were similar regarding age (69.2 +/- 5.2 years vs. 67.3 +/- 6.7 years), bone volume (BV/TV; 17.7 +/- 4.7% vs. 19.0 +/- 5.8%), and bone surface (BS/TV; 2.7 +/- 0.6 mm2/mm3 vs. 2.8 +/- 0.6 mm2/mm3). A lower cortical thickness (C.Th; 652 +/- 267 microns vs. 822 +/- 325 microns), total strut length (TSL; 826 +/- 226 microns/mm2 vs. 922 +/- 256 microns/mm2), node-to-loop (Nd-Lp) strut length (10.1 +/- 10.3% vs. 15.0 +/- 13.6%), together with a higher node-to-terminus (Nd-Tm) strut length (45.6 +/- 9.7% vs. 39.1 +/- 9.3%) were each associated with prevalent VFX (0.01 < p < 0.10). Differences in BV/TV did not explain these associations. In conclusion, cortical thinning and disruption of trabecular lattice are possible pathogenic mechanisms in patients with VFX.

Age Factors↗
PubMed1999

Bone mineral density in women using depot medroxyprogesterone acetate for contraception.

OBJECTIVE: To evaluate the possible effects of depot medroxyprogesterone acetate injectable contraception on bone mineral density in reproductive-age women. METHODS: We conducted a population-based cross-sectional comparison of bone mineral density levels in women using depot medroxyprogesterone acetate contraception and in women of similar age not using this method. The study recruited 457 nonpregnant women aged 18-39 years who were enrollees of a Washington state health maintenance organization. One hundred eighty-three women were receiving injections and 274 were not. Bone mineral density at several anatomic sites (spine, femoral neck, greater trochanter, and whole body) was measured using dual-energy x-ray absorptiometry. Data on other factors potentially related to bone density were collected through questionnaire and examination. RESULTS: Overall, age-adjusted mean bone density levels were lower for users of this method than for nonusers at all anatomic sites: The mean difference was 2.5% for the spine (P = .03) and 2.2% for the femoral neck (P = .12). Exposure to depot medroxyprogesterone acetate continued to be significantly (P < .01) associated with decreased bone density at the femoral neck, spine, and trochanter after multivariate adjustment for other risk factors related to bone density. Age-specific comparisons indicated that the major differences in bone density between users and nonusers occurred in the youngest age group (women 18-21 years); the mean femoral neck bone density was 10.5% lower (P < .01) for the exposed women, and differences were consistent (P < .01) across all anatomic sites. We also noted a significant dose-response relation between longer use of depot medroxyprogesterone acetate and decreased bone density levels in this age group (P < .01 for all sites). CONCLUSION: These results provide evidence that contraception with depot medroxyprogesterone acetate, particularly long-term use, may adversely affect bone mineral density levels in young women aged 18-21 years. The implications for future bone health need further study.

Absorptiometry, Photon↗
PubMed1999

Nitric oxide acts independently of cGMP to modulate capacitative Ca(2+) entry in mouse parotid acini.

Carbachol- and thapsigargin-induced changes in cGMP accumulation were highly dependent on extracellular Ca(2+) in mouse parotid acini. Inhibition of nitric oxide synthase (NOS) and soluble guanylate cyclase (sGC) resulted in complete inhibition of agonist-induced cGMP levels. NOS inhibitors reduced agonist-induced Ca(2+) release and capacitative Ca(2+) entry, whereas the inhibition of sGC had no effect. The effects of NOS inhibition were not reversed by 8-bromo-cGMP. The NO donor GEA-3162 increased cGMP levels blocked by the inhibition of sGC. GEA-3162-induced increases in Ca(2+) release from ryanodine-sensitive stores and enhanced capacitative Ca(2+) entry, both of which were unaffected by inhibitors of sGC but reduced by NOS inhibitors. Results support a role for NO, independent of cGMP, in agonist-mediated Ca(2+) release and Ca(2+) entry. Data suggest that agonist-induced Ca(2+) influx activates a Ca(2+)-dependent NOS, leading to the production of NO and the release of Ca(2+) from ryanodine-sensitive stores, providing a feedback loop by which store-depleted Ca(2+) channels are activated.

Animals↗
PubMed1999

Bone physiology during pregnancy and lactation in young macaques.

We used a nonhuman primate model (Macaca nemestrina) of adolescent human pregnancy to characterize bone remodeling at midpregnancy and at weaning and the associated changes in bone mass. In this longitudinal study, 125 nulliparous females were followed through pregnancy, 6 months of lactation, and 3 months postweaning; 13 nonpregnant females served as controls. Between early pregnancy and midpregnancy, the whole body bone mineral increased. There was no significant change between midpregnancy and parturition. Between parturition and 3 months lactation, the animals lost 3.0% of their bone mineral (p < 0.01), which was regained by 3 months after weaning. The vertebral bone mineral apparent density decreased during pregnancy and 6 months of lactation, followed by an increase during the 3 months after weaning. Calcium, phosphate, 25-hydroxyvitamin D, and osteocalcin increased significantly from midpregnancy to weaning whereas 1,25-dihydroxyvitamin D values showed significant decreases. Histomorphometric measurements from bone biopsies showed significant increases in most parameters of bone formation between pregnancy and weaning. These results are consistent with the hypothesis that at midpregnancy bone formation is decreased and cancellous bone resorption may have increased. During lactation, losses occur in both cortical and cancellous bone, partially depleting the maternal reservoir of calcium, but a subsequent increase in bone formation enables restoration of bone mineral after weaning to values similar to those in the control group.

Adolescent↗
PubMed1999

Augmenting simplified habit reversal in the treatment of oral-digital habits exhibited by individuals with mental retardation.

We investigated whether a simplified habit reversal treatment eliminates fingernail biting and related oral-digital habits exhibited by individuals with mild to moderate mental retardation. Although simplified habit reversal did little to decrease the target behaviors for 3 of 4 participants, simplified habit reversal plus additional treatment procedures decreased the behavior to near-zero levels for all participants. These procedures included remote prompting, remote contingencies involving differential reinforcement plus response cost, and differential reinforcement of nail growth. Limitations of habit reversal for individuals with mental retardation along with directions for future research involving therapist-mediated treatment procedures, particularly those involving remote prompting and remote contingencies, are discussed.

Adult↗