Buprenorphine abuse among opiate addicts.
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Buprenorphine↗
Biomedical subjects
R Travers
Publications and source records attributed to R Travers.
Defective bone formation by transplanted Hyp mouse bone cells into normal mice.
The hypophosphatemic (Hyp) mouse is a model for human X-linked hypophosphatemia (XLH). To test the hypothesis of an abnormal osteoblast function in XLH, periostea and osteoblasts isolated from normal and Hyp mice were transplanted im into normal and mutant mice. The thickness of the osteoid seams at the periphery of the bone nodules and the osteoid volume were measured in transplants as an index of bone formation. Impaired mineralization was evidenced in transplants of Hyp cells into Hyp mice by excessive osteoid thickness and volume compared with transplants of normal cells into normal mice. When normal cells were transplanted into mutant mice, the osteoid thickness and volume were markedly increased, demonstrating that the extracellular environment is critical for bone formation. In contrast, when Hyp cells were transplanted into normal mice, reduction, but not normalization, of the osteoid thickness and volume was observed. This abnormal bone formation supports the hypothesis of an osteoblast defect in the Hyp mouse.
Animals↗
Pharmaceutical advertising--a new era?
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Advertising↗
Michael Kelly, MD (Adel.): pioneer Australian rheumatologist.
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Arthritis↗
Continuous infusion of 1,25-dihydroxyvitamin D3 stimulates bone turnover in the normal young mouse.
The effects of continuous administration of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] on mineral and bone metabolism have been examined in the normal mouse. Four doses (0.05-0.25 micrograms/kg/day) of 1,25(OH)2D3 were infused continuously for 4 weeks in 21-day-old intact animals. Mineral and skeletal changes were evaluated by analytical methods and by histomorphometric analysis of endosteal bone formation and resorption parameters. All doses of 1,25(OH)2D3 increased the fractional osteoclastic surface and the osteoclast number in conjunction with increased hydroxyproline excretion. 1,25(OH)2D3 induced a dose-dependent elevation of the calcification rate, reduction of the mean osteoid seam thickness, and shortening of the mineralization lag time. In addition, there was a dose-related increase in the extent of tetracycline double-labeled osteoid surface and a concurrent rise in the fractional osteoblastic surface associated with elevated serum alkaline phosphatase levels. Increased bone formation appeared to have been balanced by increased bone resorption since the trabecular bone volume remained unchanged. Except at the highest dose given, serum calcium and phosphate concentrations remained normal in spite of increased bone mobilization and presumably enhanced intestinal absorption of minerals. Urinary cAMP and TmP/GFR remained normal, suggesting that parathormone secretion was not altered. The results show that continuous 1,25(OH)2D3 infusion in the young mouse produces a dose-dependent stimulation of bone mineralization rate in response to increased osteoclastic bone resorption. The data indicate that 1,25(OH)2D3 can regulate bone turnover as well as mineral homeostasis in the young mouse.
Alkaline Phosphatase↗
Influence of magnesium supplementation on bone turnover in the normal young mouse.
The effect of magnesium (Mg) supplementation on bone metabolism has been studied in the normal young mouse. Weanling male mice were given Mg-supplemented drinking water (5 mM or 32 mM Mg) for 4 weeks. Mineral and skeletal changes were assessed by biochemical methods and by histomorphometric analysis of endosteal bone formation and resorption parameters evaluated on tetracycline double-labeled, undecalcified caudal vertebrae. Magnesium supplementation increased serum and urinary Mg concentrations and bone Mg content. Both the calcification rate and the extent of tetracycline double-labeled osteoid surface increased progressively in Mg-treated mice, whereas the mineralization lag time was shortened. The osteoblastic surface was reduced, leading to a fall in osteoid surface. Stimulation of bone mineralization was associated with a rise in extracellular calcium (Ca) and phosphorus (P) concentrations whereas serum 25-OHD and 1,25(OH)2D levels remained normal. The Mg supplementation increased the number of acid phosphatase stained chondroclasts and osteoclasts and the extent of resorbing surface showing histochemically stained osteoclasts. Although urinary OH-proline increased above normal, Ca, P, and cyclic adenylic acid (cAMP) excretion and phosphate concentration (TmP/GFR) remained normal, suggesting that parathyroid hormone (PTH) secretion was not altered. The trabecular bone volume remained normal, showing that the increased bone resorption was balanced by the stimulated bone mineralization. The results show that Mg supplementation influenced both bone formation and resorption in the young mouse, and that the stimulation of bone mineralization was the result of increased extracellular mineral availability.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Effects of magnesium and lactose supplementation on bone metabolism in the X-linked hypophosphatemic mouse.
Besides rickets and osteomalacia, the X-linked hypophosphatemic male mouse (Hyp/Y) presents with low serum calcium (Ca) and increased urinary hydroxyproline (OH-Pro) excretion, suggesting a parathyroid hormone (PTH)-stimulated bone resorption despite reduced magnesium (Mg) bone content. In this study, we have investigated by histochemical methods the state of bone resorption in 50-day-old untreated Hyp/Y mice and the effects of 4 wk of Mg therapy or dietary lactose supplementation on bone formation and resorption. Mineral and skeletal changes were evaluated on serum, urinary and bone ash concentrations of Ca, phosphorus (P) and Mg, and by histomorphometric analysis of tetracycline double labeled undeclalcified caudal vertebrae. The number of acid phosphatase stained chondroclasts and osteoclasts was lower than normal in untreated Hyp/Y and was restored after Mg therapy while the osteoclastic surface was increased above normal. Accordingly, serum P and urinary Ca, P, Mg, cAMP and OH-Pro were increased while TmP/GFR was unchanged. On the other hand, dietary lactose corrected serum Ca which probably suppressed PTH secretion since the renal P conservation was improved and the osteoclast number and the osteoclastic surface were decreased. Both treatments reduced the growthplate and osteoid seam thickness and increased the bone calcification rate. The results indicate that the low skeletal Mg present in Hyp/Y partially impairs bone responsiveness to PTH since Mg therapy restored the osteoclastic bone resorption which secondarily provided new minerals for bone mineralization. The greater than normal bone resorption found in Mg treated-Hyp/Y and the decreased bone resorption observed in lactose treated animals indicate that the chronic hypocalcemia induces secondary hyperparathyroidism in Hyp/Y mice.
Animals↗
Florey and Cairns--early work on penicillin.
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Africa↗
Septic arthritis caused by Pasteurella multocida.
A patient with rheumatoid arthritis developed an infection in the right hand after she administered an antibiotic capsule to her cat. Two weeks after this, septic arthritis developed in her right knee. The organism isolated was Pasteurella multocida, which is part of the feline normal oral flora. The infection was treated with penicillin and drainage.
Anti-Bacterial Agents↗
Bone response to phosphate and vitamin D metabolites in the hypophosphatemic male mouse.
The hypophosphatemic male mouse (Hyp/y), the proposed model for human vitamin D-resistant rickets (VDRR), is characterized by chronic hypophosphatemia, dwarfism, and rachitic and osteomalacic bone lesions. We have reported that treatment of Hyp/y mice with phosphate salts (Pi) heals rickets but does not correct the defective endosteal bone mineralization. In an attempt to cure osteomalacia, mutant male animals were treated with Pi combined with 25-hydroxyvitamin D3 (25OHD3, 1 microgram/kg/day), 24,25-dihydroxyvitamin D3 [24,25(OH)2D3, 0.5 microgram/kg/day], or 1,25-dihydroxyvitamin D3 [1,25(OH)2D3, 0.05--0.25 microgram/kg/day] infused constantly for 3 weeks. The biochemical and skeletal effects of treatment were assessed by analytical methods and bone histomorphometry. The results show that only 1,25(OH)2D3 produced a dose-dependent elevation of serum calcium and phosphorus, and greatly improved bone mineralization at doses high enough to increase serum calcium and phosphorus concentrations within or above the normal range. Better improvement of bone mineralization was obtained when Pi was combined to 1,25(OH)2D3. In conjunction with the correction of hypocalcemia, Pi + 1,25(OH)2D3 suppressed the stimulation of bone turnover induced by Pi supplementation. The results show that, as in VDRR children, 1,25(OH)2D3 produces beneficial effects on bone lesions in Hyp/y mice, mainly through enhancement of mineral availability. However, the persistence of osteomalacia despite correction of serum mineral concentrations suggests that there is a specific bone cell resistance to mineral and/or hormonal influences in Hyp/y mice.
24,25-Dihydroxyvitamin D 3↗
Healing of bone lesions with 1,25-dihydroxyvitamin D3 in the young X-linked hypophosphatemic male mouse.
The X-linked hypophosphatemic (Hyp) mouse presents with biochemical and skeletal abnormalities similar to those of human vitamin D-resistant rickets and hence is considered as a model of the human disease. In an attempt to correct osteomalacia, young (21-day-old) mutant male mice were infused continuously for 4 weeks with 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3; 0.05--0.25 microgram/kg . day]. Mineral and skeletal changes were assessed by serum, urinary, and bone ash concentrations of calcium, phosphorus, and magnesium and by histomorphometric analysis of bone formation measured on histological sections of tetracycline dual labeled undecalcified caudal vertebrae. Treatment with 1,25-(OH)2D3 produced a dose-dependent elevation of serum phosphorous that could be assigned to increased intestinal phosphate absorption. Concomitantly, epiphyseal, endosteal, and periosteal bone mineralization were improved in correlation with both the dosage of 1,25-(OH)2D3 and the serum phosphorus level. Normalization of serum calcium and phosphorus but not of urinary phosphate excretion were achieved together with complete healing of bone mineralization when the highest doses of 1,25-(OH)2D3 (0.175--0.35 microgram/kg . day) were given. The data show that rickets and osteomalacia, which characterize the young Hyp mouse, can be healed by 1,25-(OH)2D3 in doses high enough to normalize serum mineral concentrations. Unlike the renal phosphate leak, the phenotypic expression of the Hyp gene pertaining to bone mineralization is then corrected by 1,25-(OH)2D3 supplementation.
Animals↗
Induction of bone resorption by parathyroid hormone in congenital malignant osteopetrosis.
A male patient, afflicted with malignant congenital osteopetrosis, was studied over a 5 year period. Hypocalcemia (less than 8 mg/dl) with lack of an appropriate increase in serum immunoreactive parathyroid hormone (iPTH) prevailed at all times. Under a calcium restricted diet, a 6-hour infusion of parathyroid extract normalized serum calcium, and increased the urinary hydroxyproline excretion suggesting that bone resorption had been induced. A second attempt to induce resorption was made by infusing a synthetic amino terminal fragment of bovine PTH over a period of 3 weeks at the dose of 1.5 units/kg/hr. This infusion evoked an increase in serum calcium (8.1 to 10.5 mg/dl), urinary calcium (0.03 to 0.65 mg/g creatinine) and urinary hydroxyproline (160 to 372 mg/g creatinine); and urinary hydroxyproline (160 to 372 mg/g creatinine); increases which were reversed by calcitonin administration. Iliac crest bone biopsies were obtained before and on the last day of the 3-week infusion. Quantitative comparison of the two specimens showed that, during PTH infusion, there was a 23% decrease in bone volume due to the increase in marrow space, a 93% increase in the number of osteoclasts and 136% increment in the osteoclastic resorption surface. Electron microscopic examination of the osteoclasts in the first tissue sample showed no evidence of ruffled borders, while in the second biopsy, numerous cytoplasmic processes indicative of resorptive activity were visible at the matrix-cell interface. It is proposed that, in our patient, the osteopetrotic phenotype is the consequence of an abnormality in the interaction between PTH and osteoclasts that may be related to the synthesis of a physiologically "defective" PTH.
25-Hydroxyvitamin D 2↗
Healing of rickets with phosphate supplementation in the hypophosphatemic male mouse.
The hypophosphatemic male mouse, an animal model for human vitamin D-resistant rickets, is characterized by low serum phosphorus concentration due to increased urinary phosphate excretion, rickets, osteomalacia, and dwarfism. Because phosphate administration can heal rickets but not osteomalacia in the human disease, we have compared the effect of phosphate supplementation on the epiphyseal and endosteal bone mineralization in the mutant animal. Phosphate was given in drinking water for 137 d and the biochemical and bone responses were assessed by analytical and histomorphometric methods. Treatment with phosphate normalized the endochondral calcification (vertebral growthplate thickness: 83 +/- 5 SD vs. controls [+/Y] 73 +/- 8 micrometers, NS), but did not correct the endosteal bone mineralization (mineralization front: 13.6 +/- 2.7 vs. +/Y 67.1 +/- 6.9% osteoid surface, P less than 0.001, endosteal mean osteoid seam thickness: 46.4 +/- 6.1 vs. +/Y 3.3 +/- 0.3 micrometers, P less than 0.001). In addition, both osteoblastic and osteoclastic recruitment and activity were stimulated, as a result of a probable increase in parathyroid hormone secretion following the phosphate induced fall in serum calcium. Our results show that in the hypophosphatemic mouse, phosphate supplementation can heal the epiphyseal, but not the endosteal defective bone mineralization. Then, the biochemical and skeletal response to phosphate therapy appear to be similar to what we have observed in the human disease, further stressing the interest of the animal model.
Animals↗
Inadequate bone response to phosphate and vitamin D in familial hypophosphatemic rickets (FHR).
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Bone and Bones↗
Intestinal phosphate transport in familial hypophosphatemic rickets.
The present report outlines an attempt to characterize inorganic phosphate uptake by human jejunal mucosa using biopsy material obtained from six patients affected by the X-linked form of vitamin D-resistant rickets and six control subjects. The tissue from control subjects accumulated 32P actively in a linear fashion against time. The incorporation of inorganic phosphate into organophosphate derivatives is rapid and equilibrates after 10 min at an inorganic over total phosphate ratio of 0.45. Concentrative uptake and incorporation were both suppressed by anaerobiosis or cyanide. Rates of phosphate uptake and incorporation into the organic derivatives by the tissue of hypophosphatemic patients are comparable with normal values. Saturation kinetics observed over a wide range of substrate concentrations (0.003 to 3 mM) elicits only one transport system with an apparent Michaelis constant of 0.2 mM and a maximum velocity of 0.7 mmol/liter/40 min. The kinetic data obtained from the patients do not strikingly differ from the control values. The chemical analysis of the phosphate content of intestinal mucosa from two patients and two control subjects indicates that the tissue is not specifically phosphate-depleted in the mutant individuals. These results are in accordance with the positive results obtained with the oral replacement therapy in familial hypophosphatemia.
Adolescent↗
Movement of lipids into and out of the blood during hyperlipidemia induced in rabbits by pituitary extract and fraction H.
Rabbits were rendered hyperlipidemic by the subcutaneous injection of an alkaline aqueous extract of mammalian pituitary gland or a partially purified, concentrated fraction derived therefrom, designated Fraction H. Eight hours after the injection of Fraction H, arteriovenous (A-V) differences in plasma triglyceride (TG) were measured across five body areas. A large negative A-V difference in plasma TG was consistently found across the liver (increase in plasma concentration), and a moderate positive A-V difference across the perirenal fat depot (decrease in plasma concentration). Most values obtained across the intestines and mesentery and the leg were positive. Differences across the kidney were mostly small and almost equally divided between positive and negative values. Similar results were obtained 7-12 and 16-18 hr after injection of the pituitary extract. It is concluded that the liver is the principal source of the TG for this kind of hyperlipidemia, and that the plasma TG levels are reduced principally in passage through adipose tissue. A consistent negative A-V difference in plasma free fatty acid concentration (net increase) was found across the kidney 7-12 hr after injection, suggesting that the kidney hydrolyzes its accumulated TG and mobilizes it in the form of free fatty acids.
Animals↗
Osteogenesis imperfecta: comparison of molecular defects with bone histological changes.
Osteogenesis imperfecta (OI) is a group of inherited disorders characterized by a predisposition to bone fracturing, and usually resulting from mutations in the genes encoding type I collagen. This report describes the molecular defects in a patient with type II OI and another with type III OI. These patients were demonstrated to possess point mutations resulting in glycine-->arginine substitutions within the triple helical domain of the alpha 1(I) or alpha 2(I) collagen polypeptide chain. The defect in the type II OI patient affected residue 211 of the alpha 1(I) triple helical domain, and constitutes the most amino-terminal lethal glycine-->arginine substitution described to date. The substitution in the type III OI patient affected residue 427 of the alpha 2(I) triple helical domain. Both defects were informative in that they identified the regions of the alpha 1(I) and alpha 2(I) collagen chains in which the phenotypes associated with glycine-->arginine substitutions undergo a transition between lethal and nonlethal forms, thereby allowing a more reliable prognosis of disease severity. The histological examination of bone from these patients revealed striking abnormalities in the quantity and organization of mineralized bone structures, compared with age-matched controls. Although the patients were differently classified, no major differences in the magnitude of bone architectural changes could be perceived, consistent with the presence of their defects near a common phenotypic transition. The results are compatible with there being a gradient in severity between OI types II and III, and that parameters external to the gene mutations might account for the survival differences in the 2 cases presented in this study.
Base Sequence↗