Bicycle helmets. Mountain biking is particularly dangerous.
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Adult↗
Biomedical subjects
S Hay
Publications and source records attributed to S Hay.
Osteoprotegerin inhibits osteoclast formation and bone resorbing activity in giant cell tumors of bone.
Osteolysis is a common complication of tumors that arise in, or metastasize to, bone. The recent discovery of key regulators of osteoclast formation and activity, including receptor activator of nuclear factor of kappaB ligand (RANKL), RANK, and osteoprotegerin (OPG), may facilitate new treatment regimes for certain tumors associated with excessive bone loss. We recently showed that the stromal cells of osteolytic giant cell tumors (GCT) of bone express high levels of mRNA encoding RANKL, relative to mRNA for the RANKL antagonist, OPG, compared with the expression patterns of other lytic and nonlytic bone tumors. In this study, we found that expression of RANKL and OPG mRNA continued by the stromal element of these tumors in a constitutive manner for at least 9 days in the absence of giant cells. Immunostaining of unfractionated GCT cultured in vitro revealed punctate cytoplasmic/membranous staining for RANKL and both cytoplasmic and extracellular matrix staining for OPG in stromal cells. Giant cells (osteoclasts) were negative for RANKL staining, but stained brightly for cytoplasmic OPG protein. We also investigated the functional relevance of these molecules for GCT osteolysis by adding recombinant OPG and RANKL to cultured GCT cells. We found that OPG treatment potently and dose-dependently inhibited resorption of bone slices by GCT, and could also inhibit the formation of multinucleated osteoclasts from precursors within the GCT. These effects of OPG were reversed by stoichiometric concentrations of exogenous RANKL. These data indicate that both the processes of osteoclast formation and activation in GCT are promoted by RANKL. Therefore, GCT represent a paradigm for the direct stimulation of osteoclast formation and activity by tumor stromal cells, in contrast to the mechanisms described for osteolytic breast tumors and multiple myeloma. The demonstration of these relationships is important in developing approaches to limit tumor-induced osteolysis.
Bone Neoplasms↗
Expression of alternatively-spliced MDM2 transcripts in giant cell tumours of bone.
Giant cell tumours of bone (GCT) are characterized histologically by multinucleated bone resorbing giant cells in a background of ovoid spindle-shaped mesenchymal cells. Current evidence suggests that the latter comprise the tumour element of these lesions, although there are basic questions as to the factors that contribute to the tumourigenesis and progression of GCT. The deregulation of the p53/MDM2 pathway is an important pathogenetic event in many tumour types, prompting us to assess the expression of MDM2 by the stromal cells and giant cells of GCT. Northern blot analysis demonstrated that most of the GCT samples examined expressed increased levels of MDM2 when compared to normal human bone cells. However, Southern analysis failed to show any evidence of MDM2 gene amplification in the same samples, suggesting that increased levels of MDM2 mRNA were not a direct result of gene amplification, but rather due to altered transcriptional regulation of MDM2 gene. By RT-PCR analysis we found that 7/8 giant cell tumours expressed strongly a short alternatively spliced variant of MDM2, whereas other tumours of bone and normal human bone cells expressed predominantly full length MDM2. Sequence analysis confirmed this variant to be MDM2-b, a variant previously reported to confer a transformed phenotype. Cell fractionation of the GCTs has shown that the MDM2-b splice variant was expressed exclusively in the stromal population, whereas the full length MDM2 was expressed in the multinucleated giant cells of these lesions. Overexpression of a green fluorescent protein-tagged MDM2-b in human embryonic kidney cells (HEK-293), demonstrated predominantly nuclear localisation. Immunoprecipitation studies showed that MDM2-b is unable to physically associate with the p53 tumour suppressor protein. These results are consistent with the hypothesis that the stromal cells comprise the tumour element in giant cell tumours of bone and we speculate that expression of the MDM2-b splice variant contributes to their transformed phenotype in a p53 independent manner.
Alternative Splicing↗
Expression of fibrillins and other microfibril-associated proteins in human bone and osteoblast-like cells.
Fibrillin-containing microfibrils are structural components of extracellular matrices of a diverse range of tissues, including bone. Their importance in bone biology is illustrated by the skeletal abnormalities manifest in the congenital disorder, Marfan syndrome, which results from mutations in the fibrillin-1 gene. We investigated the expression of fibrillins and other microfibril-associated proteins in human bone and bone-derived osteoblasts. Analysis of RNA extracted from cancellous bone showed expression of mRNAs encoding fibrillin-1 and -2, MAGP-1 and -2, LTBP-2, and MP78/70 (Big-h3). In demineralized normal mature bone, fibrillin-1 was immunolocalized to fibrils within the bone matrix and pericellularly to cells lining the endosteal surfaces of trabecular bone, some osteocytes, and cells associated with blood vessels. LTBP-2 was also identified at the endosteal surface and within the bone matrix in a lamellar fashion. In addition, primary osteoblast-like cells cultured from human trabecular bone (obtained from patients at joint replacement surgery) were found to express abundant mRNA for fibrillins and associated glycoproteins. Moreover, using western blot analysis, fibrillin-1 protein was shown to be secreted into the medium and to be deposited into the cell layer. Immunofluorescence staining of the cell layer visualized fibrillin-1 in the matrix as a three-dimensional network of fine filaments. Expression of fibrillin-1 by osteoblast-like cells was constitutive, and a number of skeletally active agents had little effect on mRNA or protein levels. These results show that human osteoblasts from mature bone express fibrillins and other microfibril-associated proteins, and suggest a role for these molecules in adult human bone.
Adult↗
Condom promotion in women attending inner city general practices for cervical smears: a randomized controlled trial.
BACKGROUND: Although condom promotion schemes have been widely piloted in UK general practices, there have been no rigorous evaluations of their effectiveness. OBJECTIVES: To see if a practice-based sexual health education intervention increases the number of women having smears who are given condoms and advice on avoiding STDs. To see if this low cost intervention affects subsequent condom use. METHOD: We conducted a cluster randomized trial of condom promotion in 1382 women aged <35 years attending 28 South London general practices for cervical smear tests. RESULTS: More women in intervention than control practices reported receiving advice on avoiding sexually transmitted infections (27% versus 10%) and being given condoms (28% versus 1%, P < 0.05). However, there was no difference in subsequent condom use, even in the 22% of women reporting >/=2 sexual partners in the previous year. CONCLUSIONS: To provide evidence of effectiveness, future interventions may need to be more intensive or focus on higher risk groups.
Adolescent↗
Expression of osteoclast differentiation signals by stromal elements of giant cell tumors.
The mechanisms by which primary tumors of the bone cause bone destruction have not been elucidated. Unlike most other lytic bone tumors, osteoclastomas, otherwise known as giant cell tumors (GCT), contain osteoclast-like cells within the tumor stroma. A new member of the TNF-ligand superfamily member, osteoclast differentiation factor (ODF/OPGL/RANKL/TRANCE), was recently identified. ODF was shown to directly stimulate osteoclastogenesis, in the presence of M-CSF. In this study, the expression of ODF was examined in a number of tumor samples associated with bone lysis in vivo. In addition, we investigated expression of the ODF receptor on osteoclast precursors, RANK, as well as the ODF inhibitor osteoprotegerin (OPG), and another TNF-ligand superfamily member, TRAIL, previously shown to abrogate the inhibitory effects of OPG. We report here the novel finding that GCT stromal cells contain abundant ODF mRNA, whereas the giant cell population exclusively expresses RANK mRNA. These results are consistent with the osteoclast-mediated bone destruction by these tumors. We also report the expression of OPG and TRAIL mRNA in GCT samples. A comparison with other lytic and nonlytic tumors of bone showed that GCT express more ODF and TRAIL mRNA relative to OPG mRNA. In addition, GCT were found to express a number of cytokines previously reported to play central roles in osteoclastogenesis, namely, IL-1, -6, -11, -17, as well as TNF-alpha. Importantly, GCT were also found to express high levels of M-CSF mRNA, a cytokine shown to be an essential cofactor of ODF, and a survival factor for mature and developing osteoclasts. Furthermore, expression of these molecules by stromal cells isolated from GCT continued in vitro. Thus GCT constitutively express all of the signals that are currently understood to be necessary for the differentiation of osteoclasts from precursor cells.
Apoptosis Regulatory Proteins↗
Sexual lifestyle of women attending inner-city general practices for cervical smears.
Despite high prevalences of sexually transmitted infections, little is known about the sexual lifestyles of women attending inner-city general practices. Responses from a 1996 questionnaire showed that age at first intercourse and numbers of sexual partners were similar to the national survey five years earlier. However, only 49% of women reporting > or = 2 sexual partners in the past year said their partner had used a condom at the last sexual intercourse.
Adolescent↗
Opportunistic screening for chlamydial infection at time of cervical smear testing in general practice: prevalence study.
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Adolescent↗
Integrin expression and function on human osteoblast-like cells.
The integrin family of cell adhesion molecules are a series of cell surface glycoproteins that recognize a range of cell surface and extracellular matrix (ECM)-associated ligands. To date, the precise role of individual integrin molecules in bone cell-ECM interactions remains unclear. Cell binding assays were performed to examine the ability of normal human bone cells (NHBCs) to adhere to different ECM proteins in vitro. NHBCs displayed preferential adhesion to fibronectin over collagen types I, IV, and vitronectin and showed low affinity binding to laminin and collagen type V. No binding was observed to collagen type III. The integrin heterodimers alpha 1 beta 1, alpha 2 beta 1, alpha 3 beta 1, alpha 5 beta 1, alpha v beta 3, and alpha v beta 5 were found to be constitutively expressed on the cell surface of NHBCs by flow cytometric analysis. The integrins alpha 4 beta 1 and alpha 6 beta 1 were not expressed by NHBCs. Subsequent binding studies showed that NHBC adhesion to collagen and laminin was mediated by multiple integrins where cell attachment was almost completely inhibited in the presence of a combination of function-blocking monoclonal antibodies (Mabs) to alpha 1 beta 1, alpha 2 beta 1, alpha 3 beta 1, and beta 1. In contrast, the adhesion of NHBCs to fibronectin was only partially inhibited (50%) in the presence of blocking Mabs to alpha 3 beta 1, alpha 5 beta 1, and beta 1. The attachment of NHBCs to collagen, laminin, fibronectin, and vitronectin was also found to be unaffected in the presence of a function-blocking Mab to alpha v beta 3. The results of this study indicate that beta 1 integrins appear to be the predominant adhesion receptor subfamily utilized by human osteoblast-like cells to adhere to collagen and laminin and in part to fibronectin.
Adult↗
Rationing in the NHS. Public does not always favour lifesaving, acute interventions.
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Attitude to Health↗
Dispensing medicines without first visiting the farm.
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Drug Prescriptions↗
Technical basis for EPA's proposed regulation on the cleanup of sites contaminated with radioactivity.
The U.S. Environmental Protection Agency is proposing a regulation for the protection of the public from radioactive contamination at sites that are to be cleaned up and released for public use. The rule will apply to sites under the control of Federal agencies, and will impose limits on radiation doses to individuals living or working on a site following cleanup; it will thereby provide site owners and managers with uniform, consistent cleanup criteria for planning and carrying out remediation. This paper presents an overview of EPA's approach to assessing some of the beneficial and adverse effects associated with various possible values for the annual dose limit. In particular, it discusses the method developed to determine how the choice of cleanup criterion affects (1) the time-integrated potential numbers of non-fatal and fatal radiogenic cancers averted among future populations, (2) the occurrence of radiogenic cancers among remediation workers and the public caused by the cleanup process itself, and (3) the volumes of contaminated soil that may require remediation. The analytic methods described here were used to provide input data and assumptions for the Regulatory Impact Analysis (RIA) that supports the proposed regulation; the RIA also considered non-radiological benefits and costs (i.e., public health, economic, and ecological) of the standards.
Radiation Injuries↗
Clinical guidelines in primary care: a survey of general practitioners' attitudes and behaviour.
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Chlamydia Infections↗
[Clinical and therapeutic aspects of hepatic amebiasis in Cambodia].
Amoebic liver abscess is a common disease in developing countries. Although therapy is now perfectly standardized, errors and inaccuracies are frequent in daily practice. A study was performed at the Calmette Hospital in Phnom Penh (Cambodia) to evaluate and improve this situation. Diagnostic criteria and the outcome of treatment with oral or parenteral metronidazole were analyzed in 38 patients presenting amoebic liver abscess. Hepatalgia was observed in 100% of cases. Hyperleukocytosis and enhancement of the sedimentation rate occurred in 95% of cases. Diagnosis was confirmed by ultrasonography. Serodiagnosis, given its high cost, was not indispensable. Metronidazole was of comparable effectiveness and tolerance (90%) whether administered by the oral or parenteral route. The parenteral route should be used only for patents presenting digestive intolerance. Drainage of the abscess is necessary in cases characterized by immediate complications, abscesses with diameters greater than 120 mm and absence of improvement after 5 days of treatment.
Adult↗
Serum ionised calcium and its relationship to parathyroid hormone after tibial fracture.
The changes in serum adjusted ionised calcium and parathyroid hormone (PTH) were prospectively studied in 32 patients with isolated tibial fractures, treated conservatively. We measured serum albumin, adjusted total calcium, phosphate, pH, adjusted ionised calcium and PTH at intervals until the fractures had healed. The mean ionised calcium adjusted for pH fell within 24 hours of injury, and then rose to a peak at between four and six weeks. These changes cannot be explained by changes in serum pH or PTH. The restoration of normal ionised calcium levels after fracture coincided with the period when the callus was being calcified. Analysis of the changes in ionised calcium, phosphate and PTH suggests that PTH levels alter in response to changes in ionised calcium levels. PTH is highest immediately after fracture and lowest, often not recordable, at six weeks. The cause of the changes in the ionised calcium level has yet to be elucidated.
Adolescent↗
The differences in toxicity and release of bone-resorbing mediators induced by titanium and cobalt-chromium-alloy wear particles.
We investigated the relationship between the toxic effects of metal wear particles and their ability to stimulate the release of inflammatory mediators implicated in bone resorption. In vitro studies were carried out with use of rat peritoneal macrophages, which were exposed to either cobalt-chromium-alloy or titanium-aluminum-vanadium particles, milled from the metal components of hip prostheses. The particles were in the size-range of, and at concentrations similar to, those found in the tissues surrounding failed prostheses in humans. The titanium-aluminum-vanadium particles showed little toxicity even at high concentrations, while the cobalt-chromium particles were very toxic. The titanium-aluminum-vanadium particles induced significantly more release of prostaglandin E2 than did the cobalt-chromium particles, and this was true for a wide range of concentrations. Exposure to titanium-aluminum-vanadium increased the release of prostaglandin E2, interleukin-1, tumor necrosis factor, and interleukin-6. In contrast, exposure to cobalt-chromium particles was associated with a decreased release of prostaglandin E2 and interleukin-6, and it had little effect on the release of interleukin-1 and tumor necrosis factor.
Alloys↗
The synovial response to intraarticular injection in rats of polyethylene wear particles.
To study the effect on tissues of wear particles commonly released from the articulating surfaces of joint prostheses, ultra-high-molecular-weight polyethylene particles were prepared in a joint simulator and injected into rat knees. The particles caused synovial proliferation and induced a macrophage and multinucleate giant-cell response in the subsynovium. Of particular interest was the macrophage response to particles ranging from 5 microns in maximum dimension to the limits of resolution of the light microscope; the multinucleate giant-cell response occurred in response to larger particles and aggregates of small particles. These findings emphasize the importance of wear particles in causing an adverse tissue response around joint replacements having a polyethylene component. The difference in cellular response to wear particles of different size suggests that not only the prosthesis material but also the pattern of wear and size of wear particles produced at the articulating surfaces of a prosthesis will determine the type of cellular response.
Animals↗
Effect of different carbohydrates on growth, polysaccharidase and glycosidase production by Bacteroides ovatus, in batch and continuous culture.
Bacteroides ovatus was grown in batch culture on 12 different carbon sources (five polysaccharides, seven monosaccharides and disaccharides). Specific growth rates were determined for each substrate together with polysaccharidase and glycosidase activities. Growth rates on polymerized carbohydrates were as fast or faster than on corresponding simple sugars, demonstrating that the rate of polysaccharide depolymerization was not a factor limiting growth. Bacteroides ovatus synthesized a large range of polymer-degrading enzymes. These polysaccharidases and glycosidases were generally repressed during growth on simple sugars, but arabinose was required for optimal production of alpha-arabinofuranosidase. Polysaccharidase and glycosidase activities were measured in continuous cultures grown with either xylan or guar gum under putative carbon limitation. With the exception of beta-xylosidase, activities of the polymer-degrading enzymes were inversely related to growth rate. This correlated with polysaccharide utilization which was greatest at low dilution rates. These results show that Bact. ovatus is highly adapted for growth on polymerized carbohydrate in the human colon and confirm that the utilization of polysaccharides is partly regulated at the level of enzyme synthesis.
Bacteroides↗