Idiopathic osteoporosis: is the osteoblast to blame?
Explore the source record for details and available documents.
Humans↗
Biomedical subjects
R S Weinstein
Publications and source records attributed to R S Weinstein.
Osteoblast programmed cell death (apoptosis): modulation by growth factors and cytokines.
Once osteoblasts have completed their bone-forming function, they are either entrapped in bone matrix and become osteocytes or remain on the surface as lining cells. Nonetheless, 50-70% of the osteoblasts initially present at the remodeling site cannot be accounted for after enumeration of lining cells and osteocytes. We hypothesized that the missing osteoblasts die by apoptosis and that growth factors and cytokines produced in the bone microenvironment influence this process. We report that murine osteoblastic MC3T3-E1 cells underwent apoptosis following removal of serum, or addition of tumor necrosis factor (TNF), as indicated by terminal deoxynucleotidyl transferase-mediated dUTP-nick end labeling and DNA fragmentation studies. Transforming growth factor-beta and interleukin-6 (IL-6)-type cytokines had antiapoptotic effects because they were able to counteract the effect of serum starvation or TNF. In addition, anti-Fas antibody stimulated apoptosis of human osteoblastic MG-63 cells and IL-6-type cytokines prevented these changes. The induction of apoptosis in MG-63 cells was associated with an increase in the ratio of the proapoptotic protein bax to the antiapoptotic protein bcl-2, and oncostatin M prevented this change. Examination of undecalcified sections of murine cancellous bone revealed the presence of apoptotic cells, identified as osteoblasts by their proximity to osteoid seams and their juxtaposition to cuboidal osteoblasts. Assuming an osteoblast life span of 300 h and a prevalence of apoptosis of 0.6%, we calculated that the fraction that undergo this process in vivo can indeed account for the missing osteoblasts. These findings establish that osteoblasts undergo apoptosis and strongly suggest that the process can be modulated by growth factors and cytokines produced in the bone microenvironment.
Animals↗
Band 1p36 abnormalities and t(1;17) in ovarian carcinoma.
In a series of 128 karyotyped ovarian carcinomas, 42% of cases with chromosome 1 clonal structural abnormalities had breaks at band 1p36 (usually involving translocations of unknown material). Fluorescent in situ hybridization (FISH) studies using combinations of 1 centromere and 1p36.3-specific probes (16 cases) or 1 centromeric and 17 whole-chromosome paint probes (11 cases with 1p+) revealed a trend toward deletion of 1pter relative to 1 centromere (63%); intratumor heterogeneity; and the origin of 1p+ in 3/11 cases (27%) from chromosome 17 [t(1;17)(p36;?)]. The frequency of this specific breakpoint and its involvement in recurrent translocations suggest that these regions are loci for genes important in the pathogenesis of a subset of sporadic ovarian carcinomas.
Adenocarcinoma↗
Advances in the treatment of Paget's bone disease.
Remission is now possible for many patients. The underlying aggressiveness of osteoclast-mediated bone resorption can be inhibited- and often abrogated-with the new aminobisphosphonates. Long-term complications of Paget's disease may thus be substantially reduced in frequency and severity.
Aged↗
Telepathology: a ten-year progress report.
Explore the source record for details and available documents.
Feasibility Studies↗
Dynamic-robotic telepathology: Department of Veterans Affairs feasibility study.
In this retrospective study, we assess the accuracy, confidence levels, and viewing times of two generalist pathologists using both dynamic-robotic telepathology and conventional light microscopy (LM) to render diagnoses on a test set of 100 consecutive routine surgical pathology cases. The objective is to determine whether telepathology will allow a pathology group practice at a diagnostic hub to provide routine diagnostic services to a remote hospital without an on-site pathologist. For TP, glass slides were placed on the motorized stage of the robotic microscope of a telepathology system by a senior laboratory technologist in Iron Mountain, MI. Real-time control of the motorized microscope was then transferred to a pathologist in Milwaukee, WI, who viewed images of the glass slides on a video monitor. The telepathologists deferred rendering a diagnosis in 1.5% of cases. Clinically important concordance between the individual diagnoses rendered by telepathology and the "truth" diagnoses established by rereview of glass slides was 98.5%. In the telepathology mode, there were five incorrect diagnoses out of a total of 197 diagnoses. In four cases in which the telepathology diagnosis was incorrect, the pathologist's diagnosis by LM was identical to that rendered by telepathology. These represent errors of interpretation and cannot be ascribed to telepathology. The certainty of the pathologists with respect to their diagnoses was evaluated over time. Results for the first 50 cases served as baseline data. For the second 50 cases, confidence in rendering a diagnosis in the telepathology mode was essentially identical to that of making a diagnosis in the LM viewing mode. Viewing times in the telepathology mode also improved with more experience using the telepathology system. These results support the concept that an off-site pathologist using dynamic-robotic telepathology can substitute for an on-site pathologist as a service provider.
Feasibility Studies↗
Diagnostic accuracy of an international static-imaging telepathology consultation service.
Static-image and dynamic- (real-time) image telepathology are competing technologies. Although some studies suggest that the diagnostic accuracy of the dynamic-image telepathology approaches the accuracy of light microscopy, few reports have documented the diagnostic accuracy of static-image telepathology as used in the setting of an actual surgical pathology consultation practice. We report the results of an analysis of 171 telepathology consultation cases submitted to the Arizona-International Telemedicine Network (AITN). Digital images were submitted by pathologists from six participating institutions in Arizona, Mexico, and China. Telepathologists could render a telepathology diagnosis (TP) or defer rendering a diagnosis to obtain additional video images, glass slides for detailed analysis, or to obtain tissue blocks for special studies such as immunohistochemistry. The telepathologists rendered diagnoses for 144 cases and deferred 27 cases. Two pathologists retrospectively evaluated-glass slides from each case and rendered a consensus glass slide (GS) "truth" diagnosis. There was 88.2% concordance between TP and GS diagnoses (127 of 144 diagnoses). Concordance of 96.5% was achieved for clinically important diagnoses (139 of 144 diagnoses). Telepathologists deferred making a diagnosis to obtain glass slides for conventional light microscopy in 14 cases (8.1%) and for results of immunohistochemistry studies in 13 cases (7.6%). Thus, correct diagnoses were rendered by static-image telepathology in 127 of 171 cases (74.3%) at the time of telepathology diagnostic sessions. Inappropriate field selection and sampling biases of referring pathologists, as well as a tendency of static-image telepathologists to underestimate the complexity of some cases, may reduce the value of consultations based on the viewing of static images.
Humans↗
Volunteer participation in context: motivations and political efficacy within three AIDS organizations.
Employed quantitative and qualitative data in a contextual examination of participation in three San Francisco-area HIV/AIDS organizations: an urban, gay community-based social change setting; an urban, broadly focused information/referral setting; and a suburban individual support setting. The settings attracted different kinds of volunteers and engaged them differently with the setting, each other, and community. In quantitative analyses external political efficacy (belief in the responsiveness of sociopolitical systems to change efforts) significantly distinguished settings, but was best predicted by setting-moderated relationships to scaled motivations. Qualitative data more clearly illuminated volunteers' motivations for participation, as well as complex, embedded relationships between setting, motivations, attitudes about sociopolitical participation, and personal and community experience and identification. Together the findings underscore three unique but related stories for the three AIDS organizations, and the value of contextual approaches to participation and empowerment.
Acquired Immunodeficiency Syndrome↗
Adolescent AIDS prevention in context: the impact of peer educator qualities and classroom environments on intervention efficacy.
Peer-led, school-based interventions show promise for preventing AIDS among adolescents, but little is known about the processes underlying effective peer education or the conditions that promote its efficacy. This study examined the implementation in one school of an effective, peer-led AIDS prevention program for inner-city 7th-grade participants (n = 123) and identified the qualities of peer educators (n = 15) and classroom environments (n = 5) that contributed to improvement in participants' postintervention AIDS-related attitudes. The Peer Educator Rating Scale was developed to assess two dimensions of participants' perceptions of peer educators: "positive regard" and "perceived similarity." Participants reported greater positive regard for more highly individuated and less shy peer educators, and participants' positive regard for peer educators in turn was associated with lowered AIDS risk as measured by perceptions of peer norms regarding sexual activity and self-efficacy for peer communication regarding sexual topics and condoms. Participants' perceived similarity was not associated with any postintervention improvements in AIDS-related knowledge and attitudes. Participants' classroom membership was associated with improvements in all 5 knowledge and attitude scales, and exploratory classroom-level findings indicated that classroom intervention environments perceived as more organized by participants showed slightly greater overall improvements across AIDS-related knowledge and attitudes scales. Consistent with individual-level findings regarding participants' positive regard for peer educators, the two classrooms with the greatest positive regard for their peer educator teams showed the most student improvement. Implications for further research and the design of future prevention and promotion programs for adolescents are discussed.
Acquired Immunodeficiency Syndrome↗
Use of telepathology for routine surgical pathology review in a test bed in the Department of Veterans Affairs.
BACKGROUND: Routine surgical pathology review by telepathology could be an important service component of multi-institutional pathology laboratory systems. Such service networks would increase access for rural hospitals without on-site pathologists to a broader range of pathology services on a daily basis. METHODS: In this clinical trial, we analyzed the diagnostic accuracy, deferral rates, and viewing times of two generalist pathologists using a hybrid dynamic/store-and-forward (HDSF) telepathology (TP) system to render diagnoses in real time on 200 consecutive surgical cases. The objective was to assess the efficacy of TP in providing diagnostic surgical pathology services to a remote hospital without an onsite pathologist. Surgical pathology specimens underwent gross preparation by specially trained personnel. When appropriate, this was done under the video supervision of a telepathologist. For TP, glass slides were placed on the stage of a robotic microscope at the Iron Mountain (MI) Department of Veterans Affairs Medical Center (VAMC) (remote site); control of the motorized microscope was then transferred to a pathologist located 220 miles away at the Milwaukee VAMC (host site). For each case, the telepathologist had the option of rendering a diagnosis or deferring the case for later analysis by conventional light microscopy (LM). After the slides were read by TP and a surgical pathology report had been generated, the slides were transported to Milwaukee, where they were reexamined by the telepathologist using LM and then by the pathology group practice or, when there was no consensus, by an outside consultant to establish a "truth" diagnosis. RESULTS: Compared with the consensus ("truth") diagnosis, clinically important and overall concordance were 99.0% and 97.4%, respectively, by TP, and clinically important and overall concordance were 100.0% and 98.5%, respectively, by LM. The deferral rate was 2.5%. Examining glass slides by HDSF telepathology took an average of 4.43 minutes per slide and 12.09 minutes per case. CONCLUSION: The high diagnostic accuracy and low rate of case deferral support the proposal that an offsite pathologist using HDSF telepathology can substitute effectively for an onsite pathologist as a service provider.
Biopsy↗
The effects of androgen deficiency on murine bone remodeling and bone mineral density are mediated via cells of the osteoblastic lineage.
Both estrogens and androgens act on bone marrow stromal/osteoblastic cells to inhibit the production of local factors that promote osteoclast development. Based on this and the evidence that loss of sex steroids up-regulates not only osteoclastogenesis but also osteoblastogenesis, we have hypothesized that cells of the osteoblastic lineage are the mediators of the adverse effects of sex steroid deficiency on bone. To test this hypothesis, we used the senescence-accelerated mouse (SAMP6), a model of defective osteoblast development, and examined the effects of orchidectomy on static and dynamic histological features of bone remodeling and on bone mineral density. After orchidectomy in SAMP6 mice, the expected increases in osteoblast precursors, cancellous osteoclasts and osteoblasts, frequency of remodeling events, trabecular spacing, and rate of bone formation were absent or greatly attenuated. Moreover, whereas bone mineral density decreased in orchidectomized controls, it did not change in SAMP6. Our data indicate that when osteoblast development is defective, orchidectomy fails to result in bone loss. This evidence suggests that cells of the osteoblastic lineage are essential mediators of the changes in the rate of bone remodeling and loss of bone mass that ensue following loss of androgens.
Androgens↗
Dose-response relationships for alendronate treatment in osteoporotic elderly women. Alendronate Elderly Osteoporosis Study Centers.
Alendronate (ALN) is an aminobisphosphonate employed as an antiresorptive agent in the treatment of osteoporosis. The present study was carried out to determine dose-response relationships, particularly the effects of relatively low doses of ALN, on bone mineral density (BMD), biochemical indexes of bone and mineral metabolism, and bone histology, with particular attention to effects in elderly women. This prospective, randomized, double blind, 2-yr multicenter study compared the effects of placebo with those of 1.0, 2.5, or 5.0 mg ALN daily. All subjects received supplemental calcium (500 mg daily) as the carbonate. We studied 359 women with lumbar spine BMD at least 2.0 SD below the peak young adult mean. Subjects were stratified by age, with 135 aged 60-69 yr and 224 aged 70-85 yr. Histomorphometry was performed on transiliac bone biopsies obtained from 104 subjects after 1 yr and from 83 subjects after 2 yr. This study elucidated the previously uninvestigated lower region of the dose-response curve for ALN in osteoporosis. Over 2 yr, treatment with 1.0, 2.5, or 5.0 mg/day increased lumbar spine BMD, on the average, by 0.65%, 3.54%, and 5.67%, respectively, compared with that in the placebo group (P < 0.001 vs. placebo for the 2.5 and 5 mg groups). Significant dose-related increases were also seen in BMD at appendicular sites and in total body BMD. Dose-dependent reductions in bone turnover to new steady states were indicated by serum and urine biochemical markers as well as by histomorphometry. There was also a dose-related reduction in the proportion of subjects suffering nonvertebral fractures (P < 0.05). Safety profiles were similar for the ALN and placebo groups and for both age strata. Efficacy was similar for both age strata. There was no evidence of impaired mineralization or other histological abnormalities due to ALN treatment. We conclude that treatment with ALN over a period of 2 yr was well tolerated and produced dose-dependent increases in BMD without evidence of a plateau over the dose range of 1.0-5.0 mg daily. One milligram daily did not result in a significant effect on BMD, and 5.0 mg daily produced favorable effects at all sites measured. Other studies have demonstrated somewhat greater effects on 10 mg daily. ALN, was equally effective and well tolerated in osteoporotic women over 70 yr old as in younger women with the same condition.
Aged↗
Quantification of vitamin D receptor mRNA by competitive polymerase chain reaction in PBMC: lack of correspondence with common allelic variants.
It has been recently claimed that polymorphism for the vitamin D receptor (VDR) influences several aspects of calcium and bone metabolism. To evaluate the physiologic plausibility of these claims, we compared the abundance of the VDR mRNA in peripheral blood mononuclear cells (PBMCs) between different VDR genotypes using a quantitative reverse transcribed polymerase chain reaction-based method. The method is based on the coamplification of VDR cDNA and an internal standard consisting of known concentrations of a human VDR CDNA mutated at a BglII restriction site; the interassay coefficient of variation is 11%. To validate the method, we made use of earlier receptor binding studies indicating that normal human monocytes and activated, but not resting, lymphocytes expressed the VDR. The concentration of the VDR mRNA was 10(-8) to 10(-7) g/g of total RNA in cell-sorted monocytes and in in vitro activated lymphocytes, but only 10(-12) g/g of total mRNA in resting lymphocytes, establishing that the VDR mRNA determined by our method in PBMCs is due to constitutive expression in monocytes. Following an initial genotype screening of 85 normal volunteers by polymerase chain reaction or restriction fragment length polymorphism analysis, 14 individuals with the Bb genotype, 12 with the bb genotype, and 12 with the BB genotype were selected. The concentration of the VDR mRNA, corrected for the number of monocytes, was similar among the three genotype groups, as were the other variables examined: serum calcitriol, serum osteocalcin, and vertebral and hip bone density. We conclude that VDR polymorphism does not affect the abundance of the VDR mRNA.
Aged↗
Long-term aminobisphosphonate treatment of fibrous dysplasia: spectacular increase in bone density.
Explore the source record for details and available documents.
Adult↗
Treating panic disorder.
Explore the source record for details and available documents.
Benzodiazepines↗
Human ehrlichiosis.
Human ehrlichiosis is a newly emergent, tick-borne, zoonotic infection caused by members of the genus Ehrlichia. These rickettsia-like, obligate intracellular, gram-negative bacteria produce two similar yet distinct diseases. Human monocytic ehrlichiosis is caused by Ehrlichia chaffeensis. Human granulocytic ehrlichiosis is caused by an organism closely related to Ehrlichia equi. The most common initial clinical findings include fever, malaise, myalgia, headaches and rigors, while the most common laboratory findings are thrombocytopenia, leukopenia, anemia and elevated liver enzyme levels. Both diseases can produce intracytoplasmic morulae, in either monocytes or neutrophils, which may be visible on Wright-stained peripheral smears. Treatment consists of tetracycline or doxycycline. Rifampin or chloramphenicol can be tried when tetracycline is absolutely contraindicated. Treatment should never be delayed pending serologic or polymerase chain reaction confirmation of the diagnosis because of the 5 to 10 percent mortality rate.
Anti-Bacterial Agents↗
Linkage of decreased bone mass with impaired osteoblastogenesis in a murine model of accelerated senescence.
Bone marrow is the principal site for osteoclastogenesis and osteoblastogenesis; and an increase in the former has been linked with bone loss caused by acute loss of gonadal steroids. We have now used an established murine model of accelerated senescence and osteopenia (SAMP6) to test the hypothesis that reduced osteoblastogenesis is linked with decreased bone mass. At 1 mo of age, the number of osteoblast progenitors in SAMP6 marrow was indistinguishable from controls; however a threefold decrease was found at 3-4 mo of age. Impaired osteoblast formation was temporally associated with decreased bone formation and decreased bone mineral density, as determined by histomorphometric analysis of tetracycline-labeled cancellous bone and dual-energy x-ray absorptiometry, respectively. Osteoclastogenesis determined in ex vivo bone marrow cultures was also decreased in these mice, as was the number of osteoclasts in histologic sections. Moreover, unlike controls, senescence-accelerated mice failed to increase osteoclast development after gonadectomy. The osteoclastogenesis defeat was secondary to impaired osteoblast formation as evidenced by the fact that osteoclastogenesis could be restored by addition of osteoblastic cells from normal mice. These findings provide the first demonstration of a link between low bone mineral density and decreased osteoblastogenesis in the bone marrow and validate the senescence-accelerated mouse as a model of involutional osteopenia.
Aging↗
Development of an orthotopic SCID mouse-human tumor xenograft model displaying the multidrug-resistant phenotype.
Multiple myeloma is a plasma cell malignancy which is generally incurable in spite of a high initial response to chemotherapy. While animal models of myeloma are known, the recent developments of human xenografts in nude and SCID mice suggests a promising experimental model. The SCID model, in particular, holds promise because these animals readily accept hematopoietic and lymphoid transplantation and do not generally develop graft versus host reaction. We have developed two drug-resistant variants of the human multiple myeloma cell line ARH-77 by in vitro exposure to gradually increasing concentrations of doxorubicin (ARH-D60) or mitoxantrone (ARM-80). When injected into irradiated SCID mice, the ARH-D60 cell line grew in an orthotopic pattern with the development of osteolytic lesions. This is in contrast to the 8226/C1N human myeloma cell line which grows in a disseminated but nonorthotopic manner in the SCID mouse. Both the ARH-D60 and ARM-80 cell lines are resistant to doxorubicin and cross-resistant to mitoxantrone, vinca alkaloids, taxol and m-AMSA while maintaining sensitivity to antimetabolites and alkylating agents. Growth characteristics and cell cycle kinetics, including S-phase, were not altered in the resistant sublines. The ARH-D60 and ARM-80 cell lines both displayed a classic multidrug-resistance (MDR) phenotype which was partially reversed by the addition of verapamil. These two cell lines represent the first MDR human myeloma cell lines which have demonstrated an orthotopic growth pattern in the SCID mouse and thus may be of value in studying the pathophysiology of this disease.
Animals↗