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Biomedical subjects

B G Mills

Publications and source records attributed to B G Mills.

At least 19 recordsLinked to original sources
PubMed1997

Robertsonian translocations in Paget's disease of bone.

The karyotypes of 14 patients with Paget's disease of bone were studied. The patients were recruited from our bone metabolism clinic where they received specific therapy for their skeletal disease. Eight of the 14 patients had chromosomal translocations localized to the D and G groups. None of the patients were related to one another, nor had any had the same lifelong environment. Thus, 57% of a sample of active patients with Paget's disease had Robertsonian translocations. By comparison, an age and sex-matched group of eight controls and 13 patients with osteoporosis who had been treated with bisphosphonates demonstrated no Robertsonian translocations. The prevalence of Robertsonian translocations in 14,000 newborns was reported to be 0.1%. These data suggest that a factor from the environment introduced during the lifetime of the patient could be present and could, in addition to genetic factors, affect gene replication during the development of Paget's disease.

Aged↗
PubMed1997

Cytokines expressed in multinucleated cells: Paget's disease and giant cell tumors versus normal bone.

Human osteoclasts are well characterized multinucleated cells whose function is the directed resorption of normal bone (NB). Osteoclastic bone destruction accompanies lytic solid tumors and myeloma as well as Paget's disease (PD) of bone and giant cell tumors of bone (GCTB). The mechanism of this stimulation of osteoclastic bone resorption is unknown. This study was designed to detect cytokines present in the multinucleated cells of PD and GCTB in order to determine whether cytokine abnormalities exist to account for bone lysis. Nine cytokines, representing the functions of bone resorption, angiogenesis, tumor necrosis, bone cell proliferation, and osteoblast-osteoclast coupling, were examined by immunohistochemistry using tissue samples from 15 NB, 17 PD, and 19 GCTB patients. Standard nonparametric statistical analysis showed a significant increase (P < 0.01 to 0.05) in immunostaining between osteoclasts of PD and NB for interleukin-6 (Il-6), tumor necrosis factor beta (TNFbeta), epidermal growth factor (EGF), platelet derived growth factor (PDGF), and basic fibroblast growth factor (bFGF). There was a statistically significant decrease in immunostaining of giant cells of GCTB as compared with NB for transforming growth factor beta (TGFbeta), but no other differences from normal osteoclasts. The increase in staining of PD osteoclasts over the giant cells of GCTB was significant (P < 0.01) for Il-6, TNFbeta, PDGF, bFGF and insulin growth factor-1 (IGF-1), and (P < 0. 05) for Il-1 and EGF. It was concluded that marked cytokine differences exist in vivo between osteoclasts of NB and PD lesions consistent with stimulated resorption. Alternatively, "osteoclastoma" cells in the center of the tumor did not overexpress the cytokines associated with bone lysis, suggesting some other mechanism for stimulated resorption.

Adolescent↗
PubMed1996

Juvenile Paget disease: life-long features of a mildly affected young woman.

Unusually mild Juvenile Paget Disease (JPD) was extensively investigated in a mentally retarded 21-year-old white woman. Progressive bowing deformitity of her lower limbs began at age 1 1/2 years. Nontraumatic fractures of both femora and both tibias occurred between ages 9 and 14 years. During adulthood, cortical thickening, osteosclerosis, and bowing affected these bones. Serum alkaline phosphatase (ALP) activity was persistently elevated. We found her serum osteocalcin and urinary hydroxyproline and pyridinoline/deoxypyridinoline to also be increased. The iliac crest histology, at ages 14 and 21 years, showed wide cortices and enhanced skeletal remodeling yet the bone was exclusively lamellar. Features of classic Paget Bone Disease (PBD)--such as hypermultinucleated osteoclasts, peritrabecular fibrosis, and mosaic or woven bone--were absent. Electron microscopy revealed no cytoplasmic or nuclear inclusions. Her dermal fibroblasts in culture synthesized unremarkable levels of ALP with proper membrane topography and lipid anchoring; ALP released into the medium also appeared normal. Six months of synthetic human calcitonin therapy daily appeared to reduce here lower limb pain and warmth, but the radiographs, biochemical parameters of skeletal turnover, and bone scintigraphy were unaltered. Lamellar bone has been reported in JPD but accompanied by excessive amounts of woven bone. Our patient reveals that lamellar bone without features of PBD can characterize the skeletal histopathology of the especially rare case of mild JPD.

Adult↗
PubMed1993

Giant cell tumor arising in Paget's disease of bone. Recurrences after 36 years.

A 96-year-old woman had both Paget's disease and a giant cell tumor of the same bone, the left scapula. Despite five surgical procedures, a full course of radiation therapy, and treatment with salmon calcitonin, human calcitonin, and finally disodium etidronate, the tumor has recurred over a 36-year period. The characteristic viral-like nuclear and cytoplasmic inclusions found in the osteoclasts of Paget's disease were found in the tumor giant cells, in specimens excised over an eight-year period, and in specimens obtained during orthopedic procedures on her other pagetic bone lesions over 12 years.

Aged↗
PubMed1990

Ultrastructural and immunohistochemical evidence of measles virus in active otosclerosis.

Because of the similarity between otosclerosis and Paget's disease of bone, and the mounting evidence of a viral cause in Paget's disease, we have investigated a possible viral cause for otosclerosis. Transmission electron microscopy of stapes footplate fragments with active otosclerosis has revealed structures morphologically identical with measles virus nucleocapsid in osteoblasts and preosteoblasts. Immunofluorescence and immunoperoxidase studies have confirmed the presence of measles nucleocapsid antigen in active lesions. Application of sera from patients with subacute sclerosing panencephalitis, a defective measles virus infection of the central nervous system, resulted in positive immunoreaction in areas of active otosclerosis.

Antigens, Viral↗
PubMed1989

Immunohistochemical evidence of measles virus antigens in active otosclerosis.

Despite intensive investigation, the cause of otosclerosis remains uncertain. Recent studies of Paget's disease of bone have revealed a possible viral origin. Because of similarities between otosclerosis and Paget's disease, we have pursued investigation of a possible viral cause of otosclerosis. Four temporal bone specimens from patients with otosclerosis, processed for immunohistochemistry, demonstrated positive specific reactivity with monoclonal antibodies to measles virus antigens using the indirect immunofluorescent and immunoperoxidase techniques. Reactivity was most intense in active foci. Reactivity in the peroxidase assay was also observed in areas of acting otosclerosis with application of primary antisera from patients with subacute sclerosing panencephalitis, a disorder of the central nervous system in which a defective measles virus has been isolated. Other related paramyxoviruses, including mumps and respiratory syncytial virus, were negative, as were negative controls.

Antibodies, Monoclonal↗
PubMed1988

Osteoclasts in human osteopetrosis contain viral-nucleocapsid-like nuclear inclusions.

We report the discovery of nuclear inclusions in the osteoclasts of three unrelated patients with benign osteopetrosis that resemble the osteoclast inclusions characteristic of Paget's disease of bone. These inclusions are morphologically and dimensionally identical to the nucleocapsids of a virus of the Paramyxoviridae family. Supporting a possible viral association with benign osteopetrosis in the observation of the presence of antigens of respiratory syncytial virus, measles virus, and/or mumps virus in the cells of all five patients whose paraffin-embedded bone specimens were tested. These included two patients whose osteoclasts contained nuclear inclusions. No patients with the malignant form of the disease have been studied. There is as yet no proof that a virus is causally related to human osteopetrosis even though a virus can produce an avian form of the disease.

Adult↗
PubMed1988

Gallium-67 citrate localization in osteoclast nuclei of Paget's disease of bone.

Gallium-67 citrate scintigraphy has been used to indicate the extent of bone involvement in patients with Paget's disease of bone and is an excellent marker in monitoring the effects of specific therapy. Since gallium uptake is dependent on cellular function, autoradiographic techniques can be applied to cells of Paget's lesions to understand better the mechanism of [67Ga]citrate uptake. Bone biopsies were obtained from sites of increased uptake using [67Ga]citrate scintigraphy in two patients with Paget's disease. In both patients electron microscopic autoradiographs demonstrated a high concentration of silver grains over the nuclei of osteoclasts. The cellular mechanism is unknown but may be related to the known inhibitory effect of calcitonin on osteoclast activity. The association of [67Ga]citrate with the nucleus of the osteoclasts is unique and different from tumor cells in which there is a high association of [67Ga]citrate with the lysosome fraction within the cytoplasm.

Autoradiography↗
PubMed1987

Critical evaluation of viral antigen data in Paget's disease of bone.

This study evaluates previous viral antigen data obtained from fixed tissue sections and cells grown in culture from bone affected by Paget's disease. Finding antigens to both respiratory syncytial virus (RSV) and measles virus (MV) in the same osteoclasts of ten patients could not be explained on the basis of any previously known cross-reactivity. Therefore, possible causes for these observations were sought. Monoclonal antibodies to viral proteins of RSV and MV were used to label proteins. Polyclonal antibodies that were monospecific and were produced exclusively in nonhuman species were used to rule out nonspecific reaction with human proteins. Antivimentin antibody was used to test the possibility of cross-reactivity with a cytoskeletal protein, as a second antibody F(ab')2 conjugated to fluorescein was used to rule out nonspecific reactivity with Fc receptors. Electron microscopy was used to evaluate bone cell cultures derived from Paget's bone in comparison with Paget's osteoclasts. Results showed that the pattern of monoclonal viral antibody labeling followed different patterns in different patients. Nonspecific reactivity was ruled out by significant negative and positive controls. Cross-reactivity with vimentin could not account for the positive immunofluorescent results because of an entirely different pattern of fluorescence in the same samples of live and fixed cells after colchemid treatment. It was concluded that specific viral antigens are present in osteoclasts and in cells grown from Paget's bone and that the present data are compatible with the possibility that Paget's disease of bone is a slow virus infection.

Antibodies, Monoclonal↗
PubMed1986

Filamentous structures morphologically similar to viral nucleocapsids in otosclerotic lesions in two patients.

Two of four patients with active stapedial otospongiosis had abnormal filamentous structures in osteoblast-like cells. These structures were rare in these cells and did not occur in any other cells. The structures were 17 nm wide and clustered in a loose skein in dilated cisternae of the rough endoplasmic reticulum. They resembled the nucleocapsids of subacute sclerosing panenecephalitis, a variant of measles virus.

Capsid↗
PubMed1985

A viral antigen-bearing cell line derived from culture of Paget's bone cells.

This study documents the characteristics of a viral antigen-bearing cell line derived from co-culture of the bone from a 71-year-old woman with Paget's disease of bone and HEp-2 cells. The cell line has survived in continuous culture for 3 1/2 years and 185 subcultures. The cells are epithelioid in appearance, produce alkaline and acid phosphatase, increase alkaline phosphatase activity in response to 1,25-(OH)2-D3 and contain receptors for 1,25-(OH)2-D3. Immunofluorescent studies utilizing antisera to respiratory syncytial virus and measles virus reveal antigens of both viruses in the cells. These cells do not produce bone in culture and the adenylate cyclase activity found in their plasma membrane does not increase significantly in response to parathyroid hormone or calcitonin. The cells are not contact inhibited and form spherical colonies in agarose. They are aneuploid and have a modal number of 62-74 as well as HeLa markers. When injected into athymic mice, osteosarcomas are produced. These tumors continue to bear viral antigens. The availability of this cell line should aid in further studies of the viral antigens associated with Paget's disease of bone.

Aged↗
PubMed1984

Evidence for both respiratory syncytial virus and measles virus antigens in the osteoclasts of patients with Paget's disease of bone.

Recent ultrastructural and immunohistochemical evidence supports the hypothesis that Paget's disease of bone is a slow viral infection of the Paramyxoviridae family. Conflicting evidence for the presence of respiratory syncytial virus (RSV), a pneumovirus, or measles, a morbillivirus, has been reported. By the indirect fluorescent antibody assay, four RSV antisera were compared with four measles antisera on serial sections of pagetic bone or replicate coverslips of cells from pagetic bone grown in culture from 30 patients. Results produced positive immunofluorescence for RSV in 28 of 29 patients and positive immunofluorescence for measles in 11 of 22 patients. Of the 20 patients from whom comparable samples could be tested for antigens, 11 were found to harbor both antigens. These studies support the hypothesis that Paget's disease of bone is a slow viral infection of the Paramyxoviridae family more closely related to the pneumoviruses than the morbilliviruses.

Antigens, Viral↗
PubMed1983

Evidence for a viral etiology of Paget's disease of bone.

Ultrastructural studies of the bone cells in patients with Paget's disease of bone have revealed the presence of nuclear and cytoplasmic inclusions that resemble the nucleocapsids of Paramyxoviridae virus. Immunocytologic studies of bone biopsy specimens and cultured bone cells have demonstrated positive responses with antisera against measles virus and/or respiratory syncytial virus. These observations suggest that Paget's disease may be a slow viral infection of bone. The exact nature of the putative viral agent has yet to be established.

Animals↗
PubMed1981

Immunohistological demonstration of respiratory syncytial virus antigens in Paget disease of bone.

Respiratory syncytial virus antisera have been found to produce a positive immunohistologic response in osteoclasts in bone sections or in cells cultured from Paget disease lesions in 12 out of 12 patients tested. These experiments were carefully controlled by several means. Use of experimentally infected cells served as positive controls. Adsorption of antisera on human bone powder and KB cells did not remove the specific immunologic stain, but adsorption of the antisera by the virus did. Negative results were also obtained in osteoclasts of patients with primary or secondary hyperparathyroidism. In addition, negative results in specimens of Paget disease were found with antisera to measles; parainfluenza 1, 2, and 3; influenza A, B and C; rubella; and herpes simplex. These results are consistent with the hypothesis that the nuclear and cytoplasmic inclusions in the osteoclasts of Paget disease are a result of viral activity.

Antigens, Viral↗
PubMed1981

Comparison of the ultrastructure of a malignant tumor of the mandible containing giant cells with Paget's disease of bone.

Distinction between lesions of the jaws containing giant cells can be difficult. This study reports the results of the study of the ultrastructure of 30 patients with Paget's disease in comparison with a patient diagnosed as having malignant giant cell tumor of the mandible. The ultrastructure of the malignant giant cell tumor of the mandible was found to contain nuclear inclusions morphologically identical with the 12-15 nm tubules characteristic of the nuclei of osteoclasts in Paget's disease of bone. No clinical or laboratory signs of Paget's disease was found in this patient. A search of the literature failed to produce reports of identical nuclear inclusions in soft tissue giant cell tumors, osteosarcomas, reparative granulomas containing giant cells or in osteitis fibrosa cystica. Such nuclear inclusions have been reported in benign giant cell tumors of bone, one another in malignant giant cell tumor and cases of polymyositis. These observations raise the question of a possible virus associated with the tumor since there are recent reports of immunological evidence for the presence of a virus in Paget's disease, and viruses have been suspected in polymyositis.

Adult↗
PubMed1980

Cell cultures from bone affected by Paget's disease.

Cells obtained from Paget's bone specimens were maintained in culture for up to 8 1/2 months. The cells had several characteristics of bone cells including the presence of alkaline phosphatase, acid phosphatase, or succinic dehydrogenase as demonstrated histochemically. Electron microscopy revealed nuclear inclusions similar to those found in the osterclasts of Paget's disease in 4 or 11 cultures. Immunohistology utilizing specific antisera demonstrated the presence of respiratory syncytial virus antigen(s) in 7 or 7 patients. Negative results were obtained with antisera to a variety of paramyxoviruses.

Aged↗
PubMed1979

Long-term culture of cells from bone affected by Paget's disease.

Cells obtained from surgical bone specimens of eight patients with Paget's disease of bone were maintained in culture for up to 8 months and seven passages. The doubling time during the period of maximal cell growth ranged from 4 to 12 days. Evidence consistent with the hypothesis that many of the cells were bone cells included the following: (a) histochemical techniques demonstrated staining of some cells for alkaline phosphatase or acid phosphatase and succinic dehydrogenase; (b) parathyroid extract stimulated increased uptake of 3H-thymidine and 3H-uridine; (c) parathyroid extract suppressed and salmon calcitonin stimulated uptake of 3H-proline; and (d) crystalline calcium deposits were found within cells and extracellularly. Ultrastructural analysis revealed that three of the eight cultures contained cells whose nuclei had inclusions which were almost identical to those found in the osteoclast nuclei of all patients with Paget's disease. The maintenance of cells derived from pagetic bone in long-term culture should aid in testing the hypothesis that Paget's disease represents a slow virus infection of bone.

Aged↗