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Biomedical subjects

S M Ott

Publications and source records attributed to S M Ott.

At least 37 records · Page 2Linked to original sources
PubMed1998

Osteoporosis in patients with cystic fibrosis.

Decreased bone density and increased risk of fractures are seen in patients with cystic fibrosis. Suboptimal vitamin D levels, nutrition problems, hypogonadism, inactivity, corticosteroid use, and cytokines may contribute to the low bone mass seen in these patients. Treatment recommendations must be individualized and may include nutrition, vitamin D, estrogen or testosterone, and exercise. In high-risk patients calcitonin or growth hormone could be considered.

Absorptiometry, Photon↗
PubMed1998

Capacitative Ca2+ entry is involved in cAMP synthesis in mouse parotid acini.

Muscarinic receptor interaction leading to augmentation of isoproterenol-stimulated cAMP accumulation in mouse parotid acini involves Ca2+ (28). The effectiveness of capacitative Ca2+ entry and intracellular Ca2+ release on this response was determined in time course studies by using three independent tools to manipulate the free intracellular Ca2+ concentration: the muscarinic agonist carbachol, thapsigargin, and ionomycin. Time course studies revealed that Ca2+ release from intracellular stores by carbachol produced an early rapid increase (0.25-0.5 min) in stimulated cAMP levels, whereas capacitative Ca2+ entry resulted in a sustained increase in stimulated cAMP levels that was blocked by La3+. Capacitative Ca2+ entry, alone, was involved in thapsigargin and ionomycin augmentation of stimulated cAMP accumulation. The inability of phosphodiesterase inhibitors, 3-isobutyl-1-methylxanthine and milrinone, to prevent agonist augmentation of cAMP levels, as well as the finding that the type VIII adenylyl cyclase (ACVIII) is expressed in parotid acini, suggests that capacitative Ca2+ entry augments stimulated cAMP accumulation, at least in part, via activation of this adenylyl cyclase isoenzyme.

1-Methyl-3-isobutylxanthine↗
PubMed1998

Beta-adrenergic-induced cytosolic redistribution of Rap1 in rat parotid acini: role in secretion.

Rap1 has recently been identified on the secretory granule membrane and plasma membrane of rat parotid acinar cells (N. J. D'Silva, D. DiJulio, C. B. Belton, K. L. Jacobson, and E. L. Watson. J. Histochem. Cytochem. 45: 965-973, 1997). In the present study, we examined the cellular redistribution of Rap1 following treatment of acini with isoproterenol (ISO), the beta-adrenergic agonist, and determined the relationship between translocation and amylase release. In the presence of ISO, Rap1 translocated to the cytosol in a concentration- and time-dependent manner; this effect was not mimicked by the muscarinic agonist, carbachol. Translocation was maximal at 1 microM ISO and paralleled amylase release immediately after ISO stimulation. Rap1 translocation and amylase release were blocked by the beta-adrenergic antagonist, propranolol, whereas okadaic acid, a downstream secretory inhibitor, significantly blocked amylase release but did not inhibit Rap1 redistribution. Results suggest that the translocation of Rap1 is causally related to secretion and that the role of Rap1 in secretion is at a site proximal to the exocytotic event.

Adrenergic beta-Agonists↗
PubMed1998

Bone mineral, histomorphometry, and body composition in adults with growth hormone receptor deficiency.

Growth hormone (GH) and insulin-like growth factor I (IGF-I) deficiencies have been associated with osteopenia in both children and adults. To examine the effects of growth hormone resistance on bone mineral and body composition, we studied 11 adults (mean age 30 years) with growth hormone receptor deficiency (GHRD, Laron syndrome) and 11 age- and gender-matched controls from Southern Ecuador. Bone mineral and body composition were determined by dual-energy X-ray absorptiometry. Bone physiology was assessed with biochemical markers of bone turnover and dynamic bone histomorphometry. Bone size and body composition differed markedly between subjects with GHRD and controls. Affected adults were 40 cm shorter than controls, had significantly less lean body mass, and had increased percent body fat. Bone mineral content and density (BMD) at the spine, femoral neck, and whole body were significantly lower in adults with GHRD than in controls. Mean BMD Z scores were -1.5 to -1.6 at all sites in affected women and -2.2 to -2.3 in men with GHRD. Estimated volumetric bone density (BMAD) at the spine and femoral neck, however, was not reduced in GHRD. Spine BMAD was 0.210 +/- 0.025 versus 0.177 +/- 0.021 for affected women versus controls (p < 0.05) and 0.173 +/- 0.018 versus 0.191 +/- 0.025 for men with GHRD versus normals (p = 0.31). Urinary pyridinoline concentrations were significantly greater in adults with GHRD than in controls, while type I collagen C-telopeptide breakdown products and markers of bone formation did not differ. Differences in histomorphometry were limited to a reduction in trabecular connectivity; bone volume and formation rate were similar to controls. These data confirm the importance of the GH/IGF axis in regulating bone size and body composition. The contribution of these peptides to the acquisition and maintenance of bone mineral is less certain since volumetric bone density was preserved despite low levels of IGF-I and IGFBP-3 associated with GH resistance.

Absorptiometry, Photon↗
PubMed1997

Ryanodine receptor type III (Ry3R) identification in mouse parotid acini. Properties and modulation of [3H]ryanodine-binding sites.

Immunoblot analysis and [3H]ryanodine binding were used to characterize and identify ryanodine receptors (RyRs) in nonexcitable mouse parotid acini. Western analysis revealed ryanodine receptor type III (Ry3R) to be the only detectable isoform in parotid microsomal membranes. Binding of [3H]ryanodine to microsomal fractions was dependent on Ca2+, salt, pH, and temperature. At 23 degrees C, and in the presence of 0.5 M KCl and 100 microM Ca2+, [3H]ryanodine bound specifically to membranes with high affinity (Kd = 6 nM); maximum binding capacity (Bmax) was 275 fmol/mg protein. Mg2+ and ruthenium red inhibited [3H]ryanodine binding (IC50 = 1.4 mM and 0.5 microM, respectively). 4-Chloro-3-ethylphenol enhanced the binding of [3H]ryanodine 2.5-fold; whereas ATP and caffeine were much less efficacious toward activating Ry3R (56% and 18% maximal enhancement, respectively). Bastadin, a novel modulator of the 12-kDa FK506 binding protein.RyR complex, increased [3H]ryanodine binding 3-4-fold by enhancing Kd. The immunosuppressant FK506 enhanced [3H]ryanodine receptor occupancy at >100 microM and antagonized the action of bastadin, suggesting that an immunophilin modulates Ry3R in parotid acini. These results suggest that Ry3R may play an important role in Ca2+ homeostasis in mouse parotid acini.

Adenosine Triphosphate↗
PubMed1997

Skeletal status of men with early and late ankylosing spondylitis.

PURPOSE: To assess the influence of extent of disease on the skeletal status of men with ankylosing spondylitis (AS). PATIENTS AND METHODS: Fourteen men with AS were studied at entry and again after 15 months. Bone mineral density (BMD) was assessed by single photon absorptiometry (SPA), dual energy x-ray absorptiometry (DXA), and quantitative computed tomography (QCT). Calciotropic hormones and bone turnover were also assessed, and biopsies of iliac crest and skin were taken after tetracycline double-labeling from 10 subjects. Clinical evaluation and Health Assessment Questionnaires were used to assess functional status. RESULTS: Of the 14 participants, 7 had sacroiliitis alone without radiologic evidence of spinal involvement (early disease) and 7 had sacroiliitis with extensive vertebral calcifications and immobilization (late disease). QCT baseline lumbar spine BMD was very low in both groups compared with normative standards (Z score = -3.08 +/- 1.83, P < 0.0001) and did not change significantly over 15 months. This low BMD was more marked in late disease than in early disease subjects (P < 0.01). DXA BMD at the lumbar spine was lower than predicted in early disease subjects (Z score = -1.08 +/- 0.67, P = 0.005) but not in the late disease group. DXA BMD was also low at the all three hip sites (Z score = -0.96 +/- 0.86, P < 0.01). Significant differences between late disease group and normative values were apparent at all hip sites. Values in early disease subjects, however, did not differ from age-predicted norms. Bone mineral status did not change significantly over the 15-month period of observation. Circulating parathyroid hormone (PTH) and vitamin D metabolites were normal in both groups as were creatinine clearance and urinary excretion of calcium and hydroxyproline. Osteocalcin levels were normal in all but the two youngest subjects in the early disease group. Histomorphometry of the iliac crest showed no consistent change in bone turnover. Bone volume and trabecular width were low in many cases. Cancellous bone volume correlated with lumbar spine BMD by QCT (r = 0.69, P = 0.026) but not with DXA. Although beneficial changes occurred in exercise tolerance and pain over time, anthropometric measurements did not improve. CONCLUSION: BMD is low in both the axial and peripheral skeleton in men with AS and is independent of spinal immobilization. Anterioposterior lumbar spine DXA in late AS is less useful than QCT in determining the degree of osteopenia in late AS. Bone mineral deficits in AS do not reflect measurable metabolic derangement or hypogonadism. Although bone histomorphometry suggests both trabecular thinning and loss of structural elements as mechanisms involved in low bone volume, the exact cause of osteopenia in AS remains to be determined.

Absorptiometry, Photon↗
PubMed1997

Evaluation of vertebral volumetric vs. areal bone mineral density during growth.

Bone mineral "density" (BMD) measured by dual-energy X-ray absorptiometry (DEXA) does not represent the volumetric density (grams per cubic centimeter), but rather the areal density (grams per square centimeter). This distinction is important during growth. The purpose of this study was to measure vertebral dimensions in cadavers of young pigtail macaques (Macaca nemestrina), and to derive equations to predict the volumetric bone density from noninvasive measurements. We measured the areal bone density by DEXA, vertebral volume by underwater weighing, mineral content by ashing, dimensions of lumbar vertebrae by calipers, and dimensions of vertebrae by radiography. Somatometric measurements of the female lumbar vertebral bodies showed that the shape changed during growth. The bone mineral content from the densitometer correlated significantly with the ash weight (r = 0.99, error 8.7%). The correlation coefficient between the volumetric bone mineral density and areal BMD measurement was significant (r = 0.68, p < 0.0001) with a 9.5% error; this improved significantly to 0.82 (7.2% error) when the BMD was divided by the vertebral depth from the radiograph. A real BMD showed a strong correlation with age (r = 0.82, p < 0.0001), with an average increase of 7.4%/year. In contrast, volumetric mineral density showed a weak relationship with age (r = 0.43, p < 0.01), for an average increase of 1.5%/year. When studying bone mineral density during growth, the differences between volumetric and areal bone mineral density should be taken into consideration.

Absorptiometry, Photon↗
PubMed1996

Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group.

BACKGROUND: Previous studies have shown that alendronate can increase bone mineral density (BMD) and prevent radiographically defined (morphometric) vertebral fractures. The Fracture Intervention Trial aimed to investigate the effect of alendronate on the risk of morphometric as well as clinically evident fractures in postmenopausal women with low bone mass. METHODS: Women aged 55-81 with low femoral-neck BMD were enrolled in two study groups based on presence or absence of an existing vertebral fracture. Results for women with at least one vertebral fracture at baseline are reported here. 2027 women were randomly assigned placebo (1005) or alendronate (1022) and followed up for 36 months. The dose of alendronate (initially 5 mg daily) was increased (to 10 mg daily) at 24 months, with maintenance of the double blind. Lateral spine radiography was done at baseline and at 24 and 36 months. New vertebral fractures, the primary endpoint, were defined by morphometry as a decrease of 20% (and at least 4 mm) in at least one vertebral height between the baseline and latest follow-up radiograph. Non-spine clinical fractures were confirmed by radiographic reports. New symptomatic vertebral fractures were based on self-report and confirmed by radiography. FINDINGS: Follow-up radiographs were obtained for 1946 women (98% of surviving participants). 78 (8.0%) of women in the alendronate group had one or more new morphometric vertebral fractures compared with 145 (15.0%) in the placebo group (relative risk 0.53 [95% Cl 0.41-0.68]). For clinically apparent vertebral fractures, the corresponding numbers were 23 (2.3%) alendronate and 50 (5.0%) placebo (relative hazard 0.45 [0.27-0.72]). The risk of any clinical fracture, the main secondary endpoint, was lower in the alendronate than in the placebo group (139 [13.6%] vs 183 [18.2%]; relative hazard 0.72 [0.58-0.90]). The relative hazards for hip fracture and wrist fracture for alendronate versus placebo were 0.49 (0.23-0.99) and 0.52 (0.31-0.87). There was no significant difference between the groups in numbers of adverse experiences, including upper-gastrointestinal disorders. INTERPRETATION: We conclude that among women with low bone mass and existing vertebral fractures, alendronate is well tolerated and substantially reduces the frequency of morphometric and clinical vertebral fractures, as well as other clinical fractures.

Aged↗
PubMed1994

Bone histomorphometric changes after cyclic therapy with phosphate and etidronate disodium in women with postmenopausal osteoporosis.

The purpose of this study was to examine bone histomorphometry before and after 2 yr of a double blind trial of etidronate to determine whether etidronate was associated with the development of osteomalacia and to clarify the mechanism of action. Sixty-eight postmenopausal women with vertebral compression fractures from 3 clinical centers received 1 g phosphate or placebo twice daily on days 1-3, 400 mg etidronate or placebo daily on days 4-17, and 0.5 g calcium daily on days 18-91. This cycle was given eight times. Iliac crest bone was biopsied after tetracycline labeling. None of the patients developed osteomalacia. The placebo/placebo group lost significantly more bone volume than the other groups. The change in mineralizing surface was significantly different among groups due to the decrease in the placebo/etidronate group. Within groups, placebo/placebo showed a decrease in bone volume without other changes. Phosphate/placebo showed no changes. Placebo/etidronate showed decreases in osteoid volume, osteoid surface, mineralizing surface, bone formation rate, and activation frequency. The only change in phosphate/etidronate was a decrease in osteoid surface. We conclude that 2-yr treatment with cyclical etidronate does not cause osteomalacia and that the mechanism for the increased bone mass is probably a decreased activation frequency.

Bone and Bones↗
PubMed1993

Bone formation periods studied with triple tetracycline labels in women with postmenopausal osteoporosis.

In adult cancellous bone, cyclic remodeling occurs in discrete locations (BMUs, or basic multicellular units). Some aspects of these remodeling cycles are still not clear. Only about half the osteoid surface normally has tetracycline labels; the remainder is thought to be immature or in a resting phase. This study was designed to test the assumption that pauses occur during the bone formation periods. Iliac crest bone biopsies were performed in 84 women with postmenopausal osteoporosis. The subjects were given three tetracycline labels; the middle label had a distinctive color. The osteoid surface was 10 +/- 6% of the bone surface; the range was 0.6-24.4%. The mineralizing surface was 42 +/- 26% of the osteoid surface. Immature osteoid was 7.6 +/- 5.3% of the osteoid surface. There were no BMUs with the first and third tetracycline label but without the middle demeclocycline label. The expected length of double 1-3 label, based on an assumption that unlabeled mature osteoid was temporarily in a resting phase, was significantly higher than the observed length (68 +/- 77 microns/mm2 tissue area versus 0, p < 0.0001). The mean active formation period was 77 +/- 16 days calculated by standard methods but was only 55 +/- 26 days when calculated by label escape (p < 0.001). The correlation coefficient between these two methods was only modest (r = 0.27, p < 0.01). The failure to find any double 1-3 labels despite abundant triple labels provides strong evidence against the presence of pauses in bone mineralization between 3 and 34 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1993

Clinical effects of bisphosphonates in involutional osteoporosis.

The bisphosphonates are analogs of naturally occurring pyrophosphate. They appear to block bone resorption much more than mineralization. A series of compounds has been investigated. These have antiresorptive potencies ranging from 1 to 10,000. So far, structure-function relationships have eluded definition. These drugs increase the bone density in women with postmenopausal osteoporosis by about 5%-10% over 1 year. The bone density then appears to plateau, but most studies are of short duration. Improved bone density does not necessarily result in stronger bone, but no studies have had adequate power to assess fracture incidence. Bone formation rates decrease as measured histomorphometrically. This occurs while the bone density is improving, which implies an inhibition of bone resorption that is probably due to direct toxicity to the osteoclasts. Etidronate blocks mineralization as well as resorption and can cause osteomalacia, which is not seen with low-dose cyclical etidronate or with the second-generation compounds. The long-term effects of interfering with the remodeling cycle are still not known. Subtle side effects may be those on the bone itself. These might go undetected, since bone pain or fractures usually are attributable to the underlying disease.

Bone Density↗
PubMed1993

When bone mass fails to predict bone failure.

New technology for noninvasive measurement of bone mass has enabled many studies of bone mass and its relationship to fracture, which challenge the view that bone mass is the only relevant factor in the etiology of fractures. Several studies have reported ROC curves that generally show values of about 80%. No convincing evidence suggests that one technique is superior to another. The reported relative risks or odds ratios for a fracture usually range between 1.2 and 2.5 per SD. There is no doubt that the risk of a fracture increases as the bone density decreases. However, even with a low bone mass, the risk of not fracturing a bone over the next year is over 90%. Most of the data suggest that patients with severe vertebral fractures have lower bone mass than those with mild fractures, but some women with similarly low bone mass have mild or no fractures. The weight of the evidence suggests that age has an effect on fracture incidence which is independent of bone mass. Trauma is such a major factor that it is surprising to find almost no studies that have controlled for it. The relationship between bone mass and bone failure is strong, but other factors must also be contributing to the bone failure which, like heart failure or renal failure, is a complex, multifactorial disease.

Adolescent↗
PubMed1993

Transforming growth factor-beta accelerates osteoinduction in a craniofacial onlay model.

Recombinant human transforming growth factor beta 1 was added to a demineralized bone matrix (DBM) paste, formed into cylinders and implanted onto the cranial periosteum of New Zealand White rabbits. The TGF-beta was added at doses of 0, 0.3, 3, 30 and 75 micrograms per implant. When the implants were removed after six weeks, histomorphometric analysis of the implants showed that TGF-beta induced significantly higher levels of trabecular bone formation than in the controls (mineralized bone area 6.0 +/- 0.8, 6.0 +/- 1.2, 5.6 +/- 1.0, 10.1 +/- 1.5, and 10.8 +/- 1.4 mm2, respectively, P < 0.05), TGF-beta also caused greater resorption of the demineralized bone matrix carrier (matrix area 7.2 +/- 0.9, 6.8 +/- 1.4, 3.7 +/- 0.9, 2.7 +/- 1.2, 0.9 +/- 0.5 mm2, respectively, P < 0.02). Measurements of the osteoid demonstrated a more active bone surface and there was evidence of rapid bone remodeling. Similar results were obtained using TGF-5 beta, a new hybrid molecule. These results demonstrate the capacity of transforming growth factor beta in accelerating osteoinduction.

Analysis of Variance↗
PubMed1991

Methods of determining bone mass.

Bone disease is one of the most important clinical manifestations of primary hyperparathyroidism. Recent studies have shown that the loss of bone in "modern" hyperparathyroidism is not homogeneous throughout the skeleton. Whereas measurements of the spine and the trabecular portion of iliac crest are normal or even slightly increased, the wrist and the cortical bone of the iliac crest are significantly lower than expected. Thus, knowledge of the percentage of trabecular bone at each measurement site is important. These include distal radius, 80%; midradius, 5%; vertebrae, 19-25%; vertebral body, 33-42%; and femoral neck, 43%. Knowledge of the precision and its relationship to ranges and rates of change of bone mass are essential. For an individual, the bone mass should change by 2.8 times the precision before one can determine with 90% confidence that the change was real, not due to measurement error. Noninvasive methods of measuring bone mass that are commercially available include single- and dual-photon absorptiometry, quantitative computed tomography, and dual-energy x-ray absorptiometry. The precision of these techniques varies, with the best values reported using dual-energy x-ray absorptiometry. Research should be done to describe more completely the patterns of bone loss in this disease, including longitudinal studies on rates of loss at different skeletal sites. Studies that relate the bone mass at a particular site to fractures must be done in populations with hyperparathyroidism to see if the risk of fracture is similar to the risk in normal or osteoporotic individuals.

Absorptiometry, Photon↗