PubMed Health⌕ Search

Biomedical subjects

M D Fallon

Publications and source records attributed to M D Fallon.

At least 37 records · Page 2Linked to original sources
PubMed1989

Analysis of liver/bone/kidney alkaline phosphatase mRNA, DNA, and enzymatic activity in cultured skin fibroblasts from 14 unrelated patients with severe hypophosphatasia.

Hypophosphatasia is a heritable disorder characterized by defective bone mineralization and a deficiency of liver/bone/kidney alkaline phosphatase (L/B/K ALP) activity in serum and tissues. Severe forms of the disease, which are generally lethal in infancy, are inherited in an autosomal recessive fashion. The gene defects that produce hypophosphatasia are poorly understood, but many are likely to occur at the L/B/K ALP locus. To investigate these gene defects, we analyzed L/B/K ALP DNA, RNA, and enzyme activity in cultured dermal fibroblasts from 14 patients with perinatal or infantile hypophosphatasia and from 12 normal individuals. Southern blot analyses of the L/B/K ALP genes from patients and controls revealed identical restriction patterns. Control fibroblast ALP activity correlated with the corresponding L/B/K ALP mRNA levels estimated by blot hybridization analysis and densitometry (r = .94, P less than .0001). In contrast, fibroblasts from the hypophosphatasia patients were deficient in ALP enzyme activity but expressed apparently full-sized L/B/K ALP mRNA at normal levels. Bone specimens from one of the patients were examined and found to be deficient in histochemical ALP but contained immunologic cross-reactive material detected by anti-human liver ALP antiserum. Our results demonstrate that the deficiency of ALP activity in fibroblasts from 14 patients with severe hypophosphatasia is not due to decreased steady-state levels of the corresponding mRNA. The presence of enzymatically inactive L/B/K ALP protein in one of these patients is consistent with a point mutation or small in-frame deletion in the coding region of L/B/K ALP gene.

Alkaline Phosphatase↗
PubMed1989

Proximal femoral focal deficiency. Evidence for a defect in proliferation and maturation of chondrocytes.

Proximal femoral focal deficiency is a rare congenital malformation, characterized by a failure of normal development of the proximal part of the femur. To our knowledge, there have been no reports on the histology of fetal growth plates that are affected by this disorder. To characterize this focal developmental anomaly further, we studied the histopathology of the growth plates and epiphyses from a twenty-one-week fetus with unilateral proximal femoral focal deficiency. Although the shape of the cartilaginous anlage of the fetus appeared normal, the growth plate of the proximal part of the involved femur was markedly abnormal. The major findings were: (1) striking failure of the proximal growth plate to migrate proximally, away from the central part of the diaphysis, and failure of formation of a normal growth plate; (2) failure of organization of proliferative and hypertrophic chondrocytes into longitudinal columns; (3) truncation of an immature hypertrophic zone that had abnormal septal architecture; and (4) disorganized vascular invasion with a honeycomb rather than a columnar pattern of primary trabeculae. In contrast, the histological characteristics of the growth plates from the distal part of the femur and from all other long bones were normal.

Cartilage↗
PubMed1988

Serum bone gla protein and the vitamin D endocrine system in the oophorectomized rat.

Because of the importance of estrogen in osteoporosis, the effects of decreased estrogen production using sensitive measurements of bone mineral metabolism were studied in oophorectomized rats. Serum levels of ionized calcium, bone gla protein (BGP), vitamin D metabolites (25-hydroxyvitamin D and 1,25-dihydroxyvitamin D), and estradiol were measured before and serially for 6 weeks after oophorectomy in the rat. In addition, static and dynamic indices of bone histomorphometry were determined after double tetracycline labeling. Fifty Sprague-Dawley female rats (approximately 250 g) were studied. Twenty-five rats underwent oophorectomy (O), while the remaining rats were sham operated. Estrogen deficiency was noted in the O group within a week after surgery (estradiol, 2.45 +/- 0.78 vs. 27.9 +/- 4.15 pg/ml; P less than 0.05). Serum ionized calcium levels, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and PTH levels did not differ between the two groups during the length of the study. Serum BGP levels were the same in both groups until the second week postoophorectomy, after which BGP remained significantly elevated in the O animals (121.7 +/- 5.95 vs. 76.7 +/- 3.87; P less than 0.001). Bone histomorphometry revealed increased osteoid volume (4.4 +/- 0.9% vs. 2.3 +/- 0.7%), osteoblast surface (26.5 +/- 2.4% vs. 3.2 +/- 1.2%), tetracycline surface (18.9 +/- 4.1% vs. 6.8 +/- 2.2%), as well as osteoclast surface (8.2 +/- 1.4% vs. 2.5 +/- 2%) in all O animals compared with those in the sham-operated group. These data indicate that oophorectomy and decreased estrogen result in increased bone turnover with elevated BGP levels. The marked BGP elevation within 2 weeks postoophorectomy suggests that estrogen withdrawal results in rapid altered bone mineral metabolism. The lack of concomitant increase in circulating PTH levels suggests that other factors may be mediating the bone loss following surgical oophorectomy.

Animals↗
PubMed1988

MR imaging of soft-tissue hemangiomas: correlation with pathologic findings.

Soft-tissue hemangiomas have been described in MR imaging, but a histopathologic correlation to better understand the MR appearance has not been reported. Five patients with intramuscular soft-tissue hemangiomas were imaged in orthogonal planes on a 1.5-T system with spin-echo (SE) short-TR/TE sequences (600/20) and long-TR/TE sequences (2500/20-80). Complete intact surgical specimens were obtained, and gross and histopathologic findings were compared with MR findings. A striated-septated configuration with a high signal intensity on long-SE sequences (TE greater than 75 msec) correlated with endothelial-lined vascular channels separated by fibrous and/or fatty linear strands. An awareness of the morphologic MR pattern of soft-tissue hemangiomas may aid in recognition of these lesions.

Adolescent↗
PubMed1988

Long term administration of prostaglandin inhibitors in vivo fail to influence cartilage and bone mineral metabolism in the rat.

Non-steroidal anti-inflammatory drugs are potent inhibitors of prostaglandin synthesis. Prostaglandins have been reported to stimulate bone resorption and to enhance 1,25(OH)2D3 production in vitro. In patients with osteoarthritis of the hip, non-steroidal anti-inflammatory drugs are associated with localized accelerated bone destruction. The mechanisms for some of the in vivo effects are unknown. The effects of prostaglandin inhibitors on normal bone and mineral homeostasis has not been established. Therefore 15 male Sprague-Dawley rats were given daily injections of indomethacin, 2 mg/kg s.c., for either 4 or 8 weeks (a dose known to inhibit fracture healing) and compared to 13 control rats given vehicle alone. Serum Ca, BGP and 1,25(OH)2D were measured serially until day 56 in nine of those administered indomethacin and in seven of the control animals. Bone histomorphometry with double tetracycline labelling and cartilage histology were performed after sacrifice on days 28 and 56. Compared to control animals serum ionized calcium, BGP and 1,25(OH)2D levels were not altered by indomethacin administration. Quantitative histomorphometric indices of bone formation and resorption as well as cartilage histology were not significantly different between the two groups. With time, however, serum bone Gla protein fell in the control and indomethacin-treated groups, while calcium and 1,25-dihydroxyvitamin D remained stable. The age related decline in this serum marker of bone turnover was accompanied by a parallel reduction in the level of bone remodelling activity. These reductions in bone formation and bone resorption were not retarded or enhanced by indomethacin.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Osteomalacia as a very late manifestation of primary hyperparathyroidism.

An 86-year-old woman with a history of treated hyperthyroidism and a 20-year history of untreated primary hyperparathyroidism developed generalized bone pain and a pseudofracture of the midshaft of the left femur. Laboratory examinations revealed elevated serum calcium, alkaline phosphatase, and C-terminal parathyroid hormone levels. Serum inorganic phosphate was below normal and 25-hydroxyvitamin D levels were low-normal. An undecalcified transiliac bone biopsy specimen following tetracycline double labeling revealed osteomalacia and osteitis fibrosa. Following treatment with vitamin D and phosphate, the serum inorganic phosphate level rose to normal. There was a decrease in bone pain, and the pseudofracture healed. However, the serum calcium, alkaline phosphatase, and C-terminal parathyroid hormone levels remained elevated. Longstanding primary hyperparathyroidism causes chronic hypophosphatemia and may lead to osteomalacia. Osteomalacia and its consequences may be part of the spectrum of bone disease seen in patients with longstanding primary hyperparathyroidism.

Aged↗
PubMed1987

The magnetic resonance imaging appearance at 1.5 tesla of cartilaginous tumors involving the epiphysis.

Three cases of lytic, calcified epiphyseal lesions with plain film and computed tomography features suggestive of chondroblastoma were imaged by magnetic resonance imaging. Histopathologic correlation was obtained in each case. Two cases of chondroblastoma showed low signal intensity on both short (TR600/TE20ms) and long (TR2500/TE80ms) spin echo (SE) images. The third case, a clear cell chondrosarcoma, demonstrated increased signal intensity on moderately T2 weighted (TR2500/TE40ms) images. These findings suggest that magnetic resonance imaging may be helpful in distinguishing these lesions.

Adolescent↗
PubMed1987

Controlled study of renal osteodystrophy in patients undergoing dialysis. Improved response to continuous ambulatory peritoneal dialysis compared with hemodialysis.

To assess the effect of different dialysis modalities on renal osteodystrophy, a controlled study was performed in six patients undergoing continuous ambulatory peritoneal dialysis and six hemodialysis-treated patients. All patients were enrolled at the initiation of dialysis, and age, sex, cause of renal failure, prior treatment of renal osteodystrophy, and baseline serum and bone histologic variables were similar in the two groups. After initial blood samples and bone biopsy specimens (with double-tetracycline labels) were obtained, renal osteodystrophy in both groups received comparable treatment with aluminum hydroxide to maintain serum phosphorus levels between 3.5 and 5.5 mg/dl, and with calcium carbonate and calcitriol to maintain total serum calcium levels between 10 and 11 mg/dl. Blood and bone samples were obtained again after nine months. All patients were asymptomatic at the beginning and end of the study. Phosphorus values were well controlled, and total calcium increased similarly in both groups. Although ionized calcium levels increased in both groups, the final level was higher in hemodialysis-treated patients than in patients undergoing continuous ambulatory peritoneal dialysis (2.82 +/- 0.07 meq/liter and 2.5 +/- 0.05 meq/liter, respectively; p = 0.005). Amino-terminal parathyroid hormone levels normalized in both groups, and histologic improvement of osteitis fibrosa occurred in a similar proportion of patients in both groups; however, quantitative improvement was greater in the hemodialysis-treated patients. Osteomalacia, assessed qualitatively and by dynamic histomorphometric measurements, was ameliorated to a much greater degree in patients undergoing continuous ambulatory peritoneal dialysis compared with hemodialysis-treated patients. Bone aluminum staining was absent in all biopsy specimens. Overall, bone histologic findings improved to a greater degree in patients undergoing continuous ambulatory peritoneal dialysis. When patients undergoing continuous ambulatory peritoneal dialysis or hemodialysis and receiving similar treatment for renal osteodystrophy were compared, patients treated with continuous ambulatory peritoneal dialysis appeared to have a greater improvement in their metabolic bone disease.

Aluminum Hydroxide↗
PubMed1987

Carbonic anhydrase activity of chick osteoclasts is increased by parathyroid hormone.

Embryonic chick osteoclasts were harvested, cultured for 18 h, and separated from erythrocytes, and carbonic anhydrase (CA) activity was assayed. Cultures contained 75-85% osteoclasts by acid phosphatase stain. CA activity was also determined after exposure to parathyroid hormone (PTH). Two methods of measurement were used: a delta pH method, which detects the generation of hydrogen ion by carbonic anhydrase, and a mass spectrometric method, which follows the disappearance of 18O-enriched CO2. Unstimulated osteoclasts showed CA activity that was one-third that of erythrocytes but was comparable with macrophages and chondrocytes. Osteoclasts exposed to PTH showed a twofold increase in activity, which occurred after 30 min. Ethoxzolamide (10(-8) M) inhibited enzyme activity by 90%. Treatment of osteoclasts with calcitonin did not prevent the PTH-associated increase in CA activity. The doubling of CA activity with PTH stimulation supports the hypothesis that osteoclastic CA is intimately involved in bone resorption.

Animals↗
PubMed1987

1,25-Dihydroxyvitamin D3 modulates glucocorticoid-induced alteration in serum bone Gla protein and bone histomorphometry.

Glucocorticoid excess is associated with alterations in the vitamin D endocrine system. The aim of this study was to assess change in serum bone Gla protein (BGP) after low and high dose cortisone acetate treatment and to assess whether these alterations are altered or attenuated by 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] administration. Five groups of rats were studied and compared to a control group [cortisone acetate in doses of 0.2, 3.3, and 5.0 mg/100 g BW; 1,25-(OH)2D3 in a dose of 100 ng/100 g BW; and a combination of 1,25-(OH)2D3 (100 ng/100 g BW) plus cortisone acetate (3.3 mg/100 g BW)]. Each animal received daily sc injections for 27 days. BGP decreased significantly by day 7 in the two groups receiving high doses of cortisone acetate compared to control group values (65.20 +/- 4.38 vs. 150.18 +/- 6.13 ng/ml in the intermediate dose group and 91.57 +/- 5.30 vs. 150.18 +/- 6.13 ng/ml in the high dose group; P less than 0.01); this effect persisted until day 28. Histomorphometry revealed decreased formation and resorption in the two high dose cortisone acetate groups, whereas low dose cortisone acetate produced no histological change. The combination therapy lessens any change in BGP until day 28 when BGP was lower than the control value (P less than 0.01); histomorphometry showed that combination therapy prevents the effect of cortisone acetate by increasing bone formation and resorption. The data demonstrate that high doses of cortisone acetate suppress bone formation and that this is reflected in the low serum BGP values. Thus, BGP may be a marker of glucocorticoid-induced bone disease. 1,25-(OH)2D3 protects against glucocorticoid-induced bone disease and the normal BGP level reflects this.

Animals↗
PubMed1987

Metatropic dwarfism. Uncoupling of endochondral and perichondral growth.

Metatropic dwarfism is a rare heritable skeletal dysplasia that is thought to result from a defect in endochondral ossification. Histological studies have been few and have yielded inconsistent findings. In addition, no investigator has commented on the structure and function of the perichondral portion of the growth plate in patients who have metatropic dysplasia. To further characterize this disturbance, histological studies were carried out on autopsy specimens from the proximal part of the femur and the iliac crest of a patient who had this disorder. The major findings were: the absence of formation of normal primary spongiosa in the metaphysis; the presence of a thin seal of bone at the chondro-osseous junction, with abnormal metaphyseal vascular invasion and arrest of endochondral growth; and normal-appearing perichondral ring structures with persistence of circumferential growth. These findings suggest an uncoupling of endochondral and perichondral growth and offer an explanation for the dumbbell-shaped morphological structure of the osseous metaphysis that is seen in patients who have metatropic dysplasia. Other observations included prominence of the cartilaginous canals and vascular channels in the reserve zone; clumping of chondrocytes with enhanced staining of the pericellular matrix in the proliferative zone; a decreased ratio of cells to matrix in the hypertrophic zone, with intracellular metachromatic granules and incomplete evolution of chondrocytes; complete absence of an alcian-blue-positive zone of provisional calcification; and, finally, islands of dysplastic chondrocytes in the metaphysis. These abnormalities suggest that metatropic dysplasia is not simply a disorder of endochondral ossification. There appear to be associated defects in the longitudinal proliferation and maturation of chondrocytes and in the production of normal matrix.

Achondroplasia↗
PubMed1987

Multiple pathologic fractures of the appendicular skeleton in a patient with Cushing's disease.

A 33-year-old woman with asymptomatic osteoporosis sustained a spontaneous middiaphyseal fracture of the femur as the initial sign of Cushing's disease. Subsequently, she incurred a fracture of the ipsilateral hip and both bones of the forearm. All four fractures failed to unite. There were no symptoms of involvement of the axial skeleton. Although axial osteopenia is the most common skeletal finding in hypercortisolism, fractures exclusively limited to the appendicular skeleton should not preclude detailed diagnostic investigations of hypercortisolism.

Adult↗
PubMed1986

Idiopathic familial acroosteolysis: histomorphometric study of bone and literature review of the Hajdu-Cheney syndrome.

We describe a 27-year-old man with familial acroosteolysis involving 9 fingers. Bone biopsy of an affected digit showed osteolysis with no tetracycline deposition, rare osteoclasts, increased vascularity, and numerous mast cells. In contrast, the iliac crest bone showed active bone remodeling and normal double-tetracycline labeling. We believe mast cells deserve further study as possible factors in this form of localized osteolysis.

Adult↗
PubMed1986

Infantile hypophosphatasia: normalization of circulating bone alkaline phosphatase activity followed by skeletal remineralization. Evidence for an intact structural gene for tissue nonspecific alkaline phosphatase.

After a 3-month course of weekly intravenous infusions of pooled normal plasma in an attempt at enzyme replacement therapy, we observed gradual and prolonged normalization of circulating alkaline phosphatase (AP) activity in a boy with infantile hypophosphatasia. During this 4-month period, when hypophosphatasemia had been corrected, electrophoretic and heat denaturation studies suggested that the AP in serum was skeletal in origin. Serial radiographic and histologic studies of bone demonstrated skeletal remineralization and the appearance of AP activity in osteoblasts and chondrocytes after the infusions. Considerable clinical improvement coincided with the skeletal remineralization. Our observations indicate that in one patient with infantile hypophosphatasia the structural gene for the tissue-nonspecific (bone/liver/kidney) AP isoenzyme was intact and could be expressed with marked physiologic effect. Infantile hypophosphatasia may result from absence or inactivation of a circulating factor(s) that regulates the expression of the gene for tissue nonspecific AP.

Alkaline Phosphatase↗