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Biomedical subjects

I R Reid

Publications and source records attributed to I R Reid.

At least 145 records · Page 8Linked to original sources
PubMed1989

Insulin-like growth factor 1 and bone turnover in glucocorticoid-treated and control subjects.

The role of the growth hormone-somatomedin axis in the genesis of steroid osteoporosis has been studied by measuring circulating insulin-like growth factor 1 (IGF-1) levels in asthmatic subjects either receiving or not receiving therapy with oral glucocorticoids. There was no difference in IGF-1 levels between the two groups (60.6 micrograms/l (95% confidence interval 47.3-77.8) in the control subjects vs 69.1 micrograms/l (49.3-96.9) in the steroid-treated group). IGF-1 declined with age in the control subjects but not in those taking steroids. When IGF-1 levels were correlated with biochemical indices of bone turnover, a significant relationship was found with urine hydroxyproline in the control subjects (r = 0.55, P less than 0.02) but not in those taking steroids. It is concluded that glucocorticoid therapy does not alter mean circulating levels of IGF-1 but that the growth hormone-somatomedin axis may influence bone turnover in normal subjects. Interference by glucocorticoids with the normal regulation of IGF-1 and its influence on bone turnover is suggested.

Adult↗
PubMed1989

Hypercalcemia and squamous cell carcinoma complicating chronic osteomyelitis.

A case of chronic osteomyelitis complicated by the development of squamous cell carcinoma in the sinus tract is described. This complication was itself associated with the development of humoral hypercalcemia of malignancy, a phenomenon not previously described in this context. Common misconceptions relating to the interpretation of serum parathyroid hormone levels led to the misdiagnosis of hyperparathyroidism and parathyroid exploration. Forced saline diuresis, mithramycin and oral phosphate supplements were not able to provide long-term control of the hypercalcemia but the patient was subsequently managed successfully with intravenous (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate (APD) and resection of the causative tumour.

Adolescent↗
PubMed1989

X-linked hypophosphatemia in adults: prevalence of skeletal radiographic and scintigraphic features.

The radiologic studies of 38 essentially untreated adults with X-linked hypophosphatemia (XLH) were reviewed to determine the prevalence of radiologic features, to compare the findings in men and in women, and to elucidate the natural history of the disease by comparing the findings in young, intermediate-age, and older patients. Bone-reinforcement lines were common, but no characteristic mineral mass alteration was established. Looser zones were more prevalent in older subjects. Osteoarthritis was common, occurring in the ankles, knees, feet, sacroiliac joints, and wrists. Enthesopathy was infrequent in the younger group but was present in every member of the intermediate and older groups and was often accompanied by extra ossicles. Curvatures of the lower-extremity long bones were common in all age groups. Three new skeletal alterations in XLH were found to be common: flaring of the iliac wings, trapezoidal distal femoral condyles, and alterations in talar morphology, including shortening of the talar neck and flattening of the talar dome. Technetium-99m methylene diphosphonate scintigrams of 17 subjects were often abnormal, depicting bowing deformity and focal tracer accumulation in diaphyseal cortices and in periarticular and extraarticular regions. The mean metabolic index was moderately elevated (4.0). Both radiographic and scintigraphic findings were more severe in men, consistent with hemizygosity. The natural history of untreated XLH in both sexes is characterized by the development of a variety of age-related skeletal abnormalities during adulthood.

Adult↗
PubMed1989

X-linked hypophosphatemia: a clinical, biochemical, and histopathologic assessment of morbidity in adults.

Research and management of XLH have concentrated on the disease in childhood, and the natural history and morbidity of XLH in adult life are thus poorly understood. We have studied 22 adults (6 men) with XLH to clarify these aspects of this most common inherited form of rickets and osteomalacia. Most study participants had presented with rickets in early childhood and had undergone tibial osteotomies on at least 1 occasion. Seventeen individuals had genu varum, 1 had genu valgum, and 4 had straight legs, attributable to successful osteotomies in 2. Five subjects reported increasing lower limb deformity in the late teens or subsequently. Eight subjects complained of bone pain, 6 of whom had radiologic evidence of pseudofractures; pseudofractures were found in 4 additional asymptomatic individuals. None of 16 subjects who underwent transiliac bone biopsy had normal double tetracycline labeling; accordingly, all were considered to have osteomalacia. Bone pain was associated with a relative osteoid volume in excess of 25%. Relative osteoid volume was inversely related to serum 1,25(OH)2D concentration (r = -0.74, p less than 0.02), but unrelated to serum concentrations of calcium and phosphate or their product. Eighteen participants complained of joint pain, predominantly in the knees and ankles. The severity of joint pain correlated with the degree of lower limb deformity (p = 0.011) which, in turn, was related to fasting serum phosphate concentration (r = -0.56, p less than 0.025) and TmP/GFR (r = -0.70, p less than 0.005). Enthesopathy affected 33% of those younger than 30 years, and all those above this age. Nineteen individuals had experienced significant dental problems, most commonly abscess formation. Eight had required complete dental clearance. Twelve women from the group had a total of 22 live births. Fifteen of these were by cesarean section, although radiologic evidence of pelvic narrowing was not found in any subject. Serum ALP was elevated in all but 3 of the 18 untreated subjects. Levels correlated with those of other indices of bone turnover (BGP r = 0.82, p less than 0.005; urine total HP r = 0.60, p less than 0.025; urine free HPr = 0.78, p less than 0.005), but were not related to the degree of osteomalacia found on bone biopsy. Serum levels of iPTH, 25(OH)D, 1,25(OH)2D, and thyroid hormones were generally normal in the untreated patients. We conclude that adults with untreated XLH have osteomalacia that is frequently symptomatic. Even greater morbidity is caused by degenerative joint disease arising from lower limb deformities.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1988

Prevention of steroid-induced osteoporosis with (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate (APD).

In a prospective, randomised, placebo-controlled trial comparing the effect of (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate (APD) (150 mg/day) plus calcium (1 g/day) with that of calcium alone on the bone mass of patients receiving long-term glucocorticoid therapy, the mean metacarpal cortical area in patients receiving APD increased by 1.2% between 0 and 6 months (p less than 0.06) and then remained stable between 6 and 12 months. In contrast, this index progressively declined in the placebo group (p less than 0.05 at 12 months). The two groups differed significantly in the changes at both 6 and 12 months (p less than 0.01). Mean vertebral mineral density, as measured by quantitative computed tomography, increased by 19.6% over 12 months in the APD group (p less than 0.02) but showed a non-significant decline of 8.8% in controls. The differences between the changes were again significant (p less than 0.005). Biochemical indices and bone histomorphometry indicated a reduction in bone resorption and bone formation but there was no evidence of osteomalacia. APD may thus prevent bone loss in glucocorticoid-treated patients over a year.

Calcium↗
PubMed1988

Parathyroid hormone depresses cytosolic pH and DNA synthesis in osteoblast-like cells.

It has recently become apparent that a number of hormones and growth factors modulate cytosolic pH (pHi), and there is some evidence that this in turn may influence cell growth. We have examined the effects of parathyroid hormone (PTH) on both these parameters in an osteoblast-like cell line, UMR 106. Preliminary studies, using the pH-sensitive fluorescent probe 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein indicated that these cells regulate pHi by means of an amiloride-inhibitable Na+-H+ exchanger. Rat PTH-(1-34) (rPTH) caused a progressive dose-related decrease in pHi with a half-maximal effect at 10(-11) M. At 1 h, the maximal depression of pHi was 0.1 +/- 0.01 U. This effect was reproduced by forskolin, but neither agent influenced pHi in the presence of amiloride. Incorporation of [3H]thymidine was reduced by rPTH (half-maximal dose approximately 10(-11) M), forskolin, and N6,2'-O-dibutyryladenosine 3',5'-cyclic monophosphate. The diacylglycerol analogue, phorbol 12-myristate 13-acetate, increased both pHi and [3H]thymidine incorporation, and amiloride reduced both indexes. However, rPTH remained a potent inhibitor of [3H]thymidine incorporation in the presence of amiloride, even though it did not affect pHi in these circumstances. It is concluded that PTH decreases pHi and growth in UMR 106 cells but that these changes can be dissociated. Depression of pHi may have other important effects on bone metabolism, such as reducing cell-cell communication, and may be associated with alkalinization of the bone fluid compartment.

Amiloride↗
PubMed1988

PTH elevates inositol polyphosphates and diacylglycerol in a rat osteoblast-like cell line.

Parathyroid hormone (PTH)-stimulated signal transduction through mechanisms alternate to adenosine 3',5'-cyclic monophosphate (cAMP) production were studied in UMR 106-01 cells, a cell line with an osteoblastic phenotype. PTH produced transient, dose-related increases in cytosolic calcium [( Ca2+]i), inositol trisphosphates, and diacylglycerol (DAG). Both inositol 1,4,5-trisphosphate (Ins-1,4,5P3) and inositol 1,3,4-trisphosphate (Ins-1,3,4P3) production were rapidly stimulated by PTH. Consistent with the production of Ins-1,3,4P3, rapid stimulation of late eluting inositol tetrakisphosphate was observed. The effects on the inositol phosphates were induced rapidly, consistent with roles as signals for changes in [Ca2+]i. In saponin-permeabilized UMR 106-01 cells, Ins-1,4,5P3 stimulated 45Ca release from a nonmitochondrial intracellular pool. Thus the hypothesis that PTH-stimulated Ins-1,4,5P3 production initiates Ca2+ release and contributes to transient elevations of [Ca2+]i is supported. Pretreatment of UMR 106-01 cells with pertussis toxin had no effect on PTH stimulation of inositol phosphates. Pertussis toxin reduced PTH-stimulated elevations of [Ca2+]i, but cAMP analogues had an even greater effect than pertussis toxin. These data suggest that stimulation of cAMP production during PTH stimulation may negatively affect production of rises in [Ca2+]i during PTH stimulation. The inactivation of the inhibitory G protein of adenylate cyclase by pertussis toxin could explain its action similar to cAMP analogues. Cyclic nucleotides diminish the effects of PTH on [Ca2+]i, probably interacting on a biochemical step subsequent to or independent of Ins-1,4,5P3 release.

Adenylate Cyclase Toxin↗
PubMed1987

Membrane potential and cation content of osteoblast-like cells (UMR 106) assessed by fluorescent dyes.

A number of cellular functions have recently been associated with alterations of the membrane potential in non-excitable cells. To assess the electrophysiologic regulation of osteoblast function, a method for measuring the membrane potential (Em) of a rat osteogenic sarcoma cell line (UMR 106) by the voltage-sensitive oxonol dye di-BA-C4(3) was developed. The fluorescent signal of di-BA-C4(3) was calibrated through a null point method using the protonophore FCCP. At null point, Em is equivalent to H+ equilibrium potential, and may be calculated by the Nernst equation. Intracellular pH (pHi) changes induced by the protonophore were monitored using BCECF, a pH-sensitive fluorescent probe. In the presence of FCCP, intracellular pH was found to be linearly correlated to extracellular pH (pHo). Therefore, the value of pHi at null point was extrapolated as well. With this technique, we estimated the plasma membrane potential of the "putative" rat osteoblasts (UMR 106) as -28.3 +/- 4.0 mV (n = 10). This method corrected the 16% overestimation of Em derived from the assumption that pHi does not change during the calibration procedure, as described in previous studies employing pH null point techniques. With null point methods, using BCECF and the carboxylic ionophores nigericin and monensin, intracellular concentrations of potassium and sodium were also measured and found to be 125 +/- 0.7 mM (n = 3) and 24 +/- 5.3 mM (n = 3), respectively. Although the Em of UMR 106 cells was dependent on extracellular potassium concentration, these cells did not behave as a potassium electrode. The sodium/potassium permeability ratio, calculated by the Goldman equation, was estimated at 0.317. This high membrane permeability to sodium may contribute to the genesis of the low plasma membrane potential of UMR 106 cells.

Animals↗
PubMed1987

Hypercalcemic hyperparathyroidism complicating oncogenic osteomalacia. Effect of successful tumor resection on mineral homeostasis.

Described herein is a case of oncogenic osteomalacia that ran a course of at least 16 years before curative resection of a mixed mesenchymal tumor. Hypercalcemic hyperparathyroidism developed in the patient, and review of the literature indicated that this occurs in about 10 percent of reported cases. Changes in serum parathyroid hormone levels with and without phosphate supplement therapy and before and after tumor resection suggested that both the high intake of phosphate and the effect of the neoplasm on vitamin D bioactivation engendered the parathyroid overactivity. Despite marked hyperparathyroidism, serum 1,25-dihydroxyvitamin D levels were subnormal preoperatively but showed a sevenfold increase within 48 hours of tumor resection. Thereafter, a gradual increase in the maximal tubular reabsorption of phosphate occurred during several months. Biopsy of the iliac crest confirmed that tumor removal was followed by resolution of osteomalacia, but there was no accompanying increase in vertebral mineral density as assessed by quantitative computed tomography or in total-body bone mineral as measured with dual-photon absorptiometry. The findings presented are consistent with secretion by the tumor of a factor with a short half-life that is potent enough to inhibit renal 25-hydroxyvitamin D-1 alpha-hydroxylase despite hyperparathyroidism. The resulting subnormal circulating 1,25-dihydroxyvitamin D levels may have secondarily contributed to decreased renal tubular reabsorption of phosphate.

Chronic Disease↗
PubMed1987

Cytoplasmic pH regulation in canine renal proximal tubule cells.

The precise mechanisms by which the mammalian kidney proximal tubule transports H+ and HCO3- and regulates cytosolic pH (pHi) remain in doubt, though both a H+-ATPase pump and Na+/H+ exchange at the luminal membrane are known to function in the export of protons. The mechanisms of HCO3- transport are less clear though recent reports suggest an important role for an electrogenic Na+/HCO3- symport in the basolateral membrane. The importance of chloride-dependent bicarbonate transport is unknown. In the present studies, the pH-sensitive fluorescent dye, bis-(carboxyethyl)-carboxyfluorescein (BCECF) has been used to study pHi changes in suspensions of canine proximal tubule cells following acidification or alkalinization of the cytosol. Cells were acid-loaded to pH 6.5 by exposure to the H+/K+ ionophore, nigericin. Following removal of nigericin, pHi returned to basal levels (pHi = 7.1) when the cells were resuspended in a buffer containing 100 mM Na+. This recovery was blocked by removal of Na+ or addition of 0.2 mM amiloride to the cell suspension. In the presence of 0.2 mM amiloride and Na+, partial excretion of the acid load occurred if the buffer also contained HCO3-/CO2, but this effect was blocked by the removal of Na+ or the addition of 1 mM 4-acetomido-4'-isothiocyano-2,2'-stilbene disulfonic acid (SITS). When cell membrane potential was monitored in these experiments using the potential-sensitive fluorescent dye, bis-(1,3-dibutylbarbiturate) trimethine oxonol, the increase in pHi seen in the presence of Na+ was found to be electroneutral, whereas when that occurred in the presence of Na+, amiloride and HCO3-/CO2 was associated with membrane hyperpolarization.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Parathyroid hormone acutely elevates intracellular calcium in osteoblastlike cells.

Changes in cytoplasmic calcium concentration ([Ca2+]i) activate numerous cellular processes thus mediating the effects of a number of hormones, but whether this mechanism is involved in the activation of osteoblasts by parathyroid hormone (PTH) remains uncertain. To examine this question, [Ca2+]i has been measured in suspensions of UMR 106 cells, a rodent osteosarcoma cell line with an osteoblastic phenotype. Basal [Ca2+]i was 137 +/- 3.7 nM (n = 60) and after the addition of rat PTH-(1-34) [rPTH-(1-34)] there was a rapid, dose-related increase with return to base line within 1 min. Half-maximal stimulation was produced by 5 X 10(-8) M rPTH-(1-34). Complexing of intracellular calcium by EGTA addition immediately before that of rPTH did not affect the calcium transient; neither did MnCl2 (10(-4) M) nor diltiazem (10(-4) M). Verapamil (10(-5) M) reduced the [Ca2+]i peak height after rPTH to 0.48 +/- 0.14 of control (n = 7). 8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoic acid and dantrolene both reduced the [Ca2+]i response to rPTH (0.65 +/- 0.08 and 0.29 +/- 0.13 of control, respectively). Forskolin (10(-6) and 10(-5) M) produced a slight [Ca2+]i transient smaller in amplitude than seen with PTH. It is concluded that PTH mobilizes an intracellular calcium pool in these osteoblastlike cells, and the predominant mechanism for this is independent of cAMP.

Animals↗
PubMed1987

Evidence for decreased tubular reabsorption of calcium in glucocorticoid-treated asthmatics.

Fasting urine calcium excretion was measured in 15 asthmatic patients receiving long-term glucocorticoid therapy (steroid group) and in age- and sex-matched asthmatics not receiving these drugs. In the steroid group, the mean urinary calcium/creatinine ratio and the mean calcium excretion per liter of glomerular filtrate (CaE) were both approximately twice the control values (p less than 0.005). When CaE was plotted as a function of serum calcium it more often exceeded the mean normal value in the steroid-treated patients than in the controls (p less than 0.05), suggesting a reduction in tubular calcium reabsorption. Calculation of the tubular maximum for calcium reabsorption confirmed a significant reduction in the glucocorticoid-treated patients (p less than 0.005). It is concluded that glucocorticoid drugs probably inhibit the tubular reabsorption of calcium and that this is likely to contribute to the development of osteoporosis in patients receiving this treatment.

Asthma↗