'What vision?': experiences of Team members in a community service for adults with intellectual disabilities.

BACKGROUND: In the UK, the closure of 'long-stay' hospitals was accompanied by the development of community teams (CTs) to support people with intellectual disabilities (IDs) to live in community settings. The self-reported experiences of staff working in such teams have been neglected. METHODS: Focusing on a single county-wide service, comprising five multi-disciplinary and inter-agency CTs, we measured perceptions among the health care and care management Team members of (1) their personal well-being; (2) the functioning of their team; and (3) the organisation's commitment to quality, and culture. RESULTS: Almost three-quarters of the questionnaires were returned (73/101; 72%). The scores of health care practitioners and care managers were very similar: (1) the MBI scores of more than half the respondents were 'of concern'; (2) similarly, almost four in ten respondents' scores on the Vision scale of the TCI were 'of concern'; (3) the perceived commitment to quality (QIIS-II Part 2) was uncertain; and (4) the organisational culture (QIIS-II, Part 1) was viewed as primarily hierarchical. DISCUSSION: The perceived absence of a vision for the service, combined with a dominant culture viewed by its members as strongly focussed on bureaucracy and process, potentially compromises the ability of these CTs to respond proactively to the needs of people with IDs. Given the changes in legislation, policy and practice that have taken place since CTs were established, it would be timely to revisit their role and purpose.

Fetal bovine bone cells synthesize bone-specific matrix proteins.

We isolated cells from both calvaria and the outer cortices of long bones from 3- to 5-mo bovine fetuses. The cells were identified as functional osteoblasts by indirect immunofluorescence using antibodies against three bone-specific, noncollagenous matrix proteins (osteonectin, the bone proteoglycan, and the bone sialoprotein) and against type 1 collagen. In separate experiments, confluent cultures of the cells were radiolabeled and shown to synthesize and secrete osteonectin, the bone proteoglycan and the bone sialoprotein by immunoprecipitation and fluorography of SDS polyacrylamide gels. Analysis of the radiolabeled collagens synthesized by the cultures showed that they produced predominantly (approximately 94%) type I collagen, with small amounts of types III and V collagens. In agreement with previous investigators who have employed the rodent bone cell system, we confirmed in bovine bone cells that (a) there was a typical cyclic AMP response to parathyroid hormone, (b) freshly isolated cells possessed high levels of alkaline phosphatase, which diminished during culture but returned to normal levels in mineralizing cultures, and (c) cells grown in the presence of ascorbic acid and beta-glycerophosphate rapidly produced and mineralized an extracellular matrix containing largely type I collagen. These results show that antibodies directed against bone-specific, noncollagenous proteins can be used to clearly identify bone cells in vitro.

Bone matrix mRNA expression in differentiating fetal bovine osteoblasts.

In the accompanying study, we report an in vitro culture system from bovine bone cells that can be applied to investigate bone cell growth and differentiation. In this system, bovine bone cells placed in mineralization medium formed multilayers (days 2-3), began deposition of mineral (days 5-6), and eventually acquired a mineralized matrix sheet (days 14-20) through the stages of mineralizing nodules and trabecular-like structure. In the current study we used this system to investigate the relative expression of bone matrix genes that may play an important role in bone development and metabolism. alpha 1(I)-collagen, alkaline phosphatase, osteonectin, biglycan (PgI), decorin (PgII), osteopontin, and bone sialoprotein mRNA gene expression were measured on days 0, 2, 6, 10, and 20 (date when the cells were placed in mineralization medium as day 0). Total RNA was purified and analyzed by northern blot using radiolabeled cDNA encoding these genes. To comprehend the relationship between gene expression and mineralization, total calcium content in the cultures was also measured. During the culture period we observed several very different gene expression profiles. The expression of both alpha 1(I)-collagen and biglycan increased 3- to 4-fold by day 6 and then returned to basal levels by day 20. The osteonectin gene was highly expressed throughout the culture, with no significant increase in induction found during any time of culture. A significant induction of alkaline phosphatase (13.8-fold) gene expression was observed by day 6. Osteopontin showed a similar profile to that of alkaline phosphatase but had a much greater level of relative expression (26-fold) compared to day 0. Interestingly, downregulation during mineral accumulation seemed a common occurrence among many of the genes measured. In contrast, the bone sialoprotein gene showed a significant and distinct expression pattern, increasing rapidly after the onset of mineralization on day 6 and ultimately reaching 140-fold that of day 0. Decorin (Pg II) showed an increasing pattern, with the final relative level of induction 5-fold on day 20. These data suggest that the development of the mature osteoblastic phenotype, complete with the ability to produce a thick mineralized matrix, requires the differential regulation of a series of genes and their gene products over the culture period.

Factors influencing synthesis and mineralization of bone matrix from fetal bovine bone cells grown in vitro.

This study of the in vitro synthesis and mineralization of bovine bone demonstrates that sheets of mineralized matrix can be produced consistently within 18-24 days of cell isolation. Mineralization surpasses that achieved by other systems with other species: The deposition of mineral extends beyond nodules to form branching trabeculae and then solid wafers of bone. Comparison of the fetal age of the bone source, enzyme digestion methods, seeding density, culture surface, nutritive media, and concentration of fetal calf serum and other additives, including insulin and ascorbic acid, has yielded a set of optimal culture conditions. In the presence of ascorbic acid and beta-glycerol phosphate, insulin has a dose-dependent effect on the morphology of the mineralized bone matrix produced. Quantitative analysis shows that in these cultures calcium accumulates most rapidly between days 6 and 10 after the introduction of mineralization medium but that mineral accretion continues throughout 14-16 days of culture. Alkaline phosphatase levels rise up to 200-fold, concomitant with a rapid increase in the number of cells per culture during the early mineralization phases; both fall as mineralization proceeds. This system has been used to study the induction of mRNA of type I collagen, alkaline phosphatase, and several noncollagenous bone proteins during the course of mineralization. Because of the degree of mineralization achieved with this system, it has many potential applications.

Spatiotemporal assessment of fetal bovine osteoblast culture differentiation indicates a role for BSP in promoting differentiation.

Fetal bovine mandible-derived osteoblasts were cultured for the purpose of obtaining a spatiotemporal assessment of bone matrix protein expression during in vitro differentiation. The results obtained from electron microscopic, immunohistological, biochemical, and molecular biological analyses indicated that these primary cultured osteoblasts produce an abundant extracellular matrix which mineralizes during a 14-day culture period. During this process, a restricted, spatiotemporal pattern of bone sialoprotein expression was indicated by immunohistological and molecular evaluations. To test the possibility that bone sialoprotein promoted the continued morphodifferentiation of osteoblastic cells, cultures were grown in the presence of anti-bone sialoprotein antibodies known to interfere with cell-bone sialoprotein attachment. Compared with cultures grown in the presence of normal rabbit serum (1:150), cultures grown in the media containing anti-bone sialoprotein antibody (1:150) failed to mineralize as demonstrated by von Kossa staining and failed to express osteocalcin and osteopontin as shown by the reverse transcription polymerase chain reaction. These results contribute to the growing evidence that bone sialoprotein is an important determinant of osteoblast differentiation and bone formation. Matrix protein-cell interactions may be examined using this spatiotemporally defined model.

A tetracycline study of cyclic longitudinal bone growth in the female rat.

This study shows that bone growth in the young female rat is cyclic. Using tetracycline labeling, measurements were taken for every possible 2-day growth interval during the 4-day estrous cycle. The slow phase of bone growth occurs when estrogen and glucocorticoid serum levels are elevated, whereas the rapid phase of growth occurs when estrogen serum levels are minimal. Parathyroidectomy or 1-microgram injections of exogeneous 17 beta-estradiol retard the rapid phase of growth. Adrenalectomy alters the rate of growth in that the slow phase no longer occurs but rather increases to a rate equal to the rapid phase. The results show that parathyroid hormone is an essential component of the cyclic growth pattern in the young adult female rat and that estrogen, which reduces the rate of longitudinal bone growth, has its effect primarily through its stimulation of glucocorticoid production. These findings are discussed in relation to other recent studies which show that there are no estrogen receptors in bone and that high levels of estrogen stimulate 1,25-dihydroxyvitamin D3 production in the kidney. A hypothetical model, interrelating these hormones to the cyclic longitudinal bone growth pattern found in the female rat, is proposed.

Restricted and coordinated expression of beta3-integrin and bone sialoprotein during cultured osteoblast differentiation.

In this study, the expression of beta3-integrin was examined in relationship to the restricted expression of bone sialoprotein (BSP). Immunohistochemical analysis indicated that the alpha(v)beta3-integrin was coincident and proximal to BSP expression in the fetal mandible bovine osteoblast culture model. Alpha(v)beta3-integrin expression was expressed predominantly in a region proximal to, but not including, the substrate adherent cells. In comparison, the alpha5beta1-integrin was expressed in a generalized pattern throughout the culture layers in a coordinated fashion to fibronectin. The temporal expression of beta1- and beta3-integrin was evaluated using RT-PCR and southern blot analysis. Unlike the generalized expression of beta1-integrin, beta3-integrin was restricted to days 3 and 5 of the culture period. The previous demonstration of similar restriction of BSP expression and the present colocalization of BSP suggests the potential coordinated expression of a specific extracellular matrix ligand with a select integrin. Beta3-integrin/BSP adhesion-mediated signaling may play a significant role in the process of osteoblast morphodifferentiation.

Non-coordinate control of bone formation displayed by growth factor combinations with IGF-I.

Polypeptide growth factors (GFs) promote osteogenesis by enhancing the mitogenesis, migration, and matrix synthesis of osteoblasts. Most previous investigators have evaluated only the effects of single GFs on these parameters. Studies on single GFs might overlook large biological responses comparable with those documented in the cell cycle literature when GFs are used in combinations that interact synergistically. In this study, we screened for synergistic interactions between IGF-I and three additional GFs (PDGF-BB, TGF-beta 1, and bFGF) on the regulation of bone growth and differentiation. Fetal bovine osteoblasts were assessed for osteoblast mitogenesis, collagenous and non-collagenous protein synthesis, and alkaline phosphatase activity (ALP). Our results show synergistic interactions between IGF-I and the other GFs on osteoblast mitogenic activity and protein synthesis. In contrast to synergistic mitogenic and protein synthesis. In contrast to synergistic mitogenic and protein synthesis effects, IGF-I failed to increase ALP activity when combined with TGF-beta 1, PDGF-BB, and bFGF in bovine osteoblast-like cells.

Isoproterenol-induced changes in glutathione metabolism in the rat parotid gland.

Rat parotid glands were removed at timed intervals after intraperitoneal injection of isoproterenol (IPR). Reduced/oxidized glutathione ratios, glutathione peroxidase, glutathione reductase and amylase activities were determined. Parotid gland amylase content fell to less than 5 per cent of control values within 1 h after IPR, then slowly returned to control levels by 24 h. The ratio of reduced/oxidized glutathione was decreased at 2 h after IPR injection, returned to near control values at 6 h, then increased above control levels at 9, 12 and 24 h. Glutathione peroxidase activity was increased only at 12 h after injection of IPR, whereas glutathione reductase activity initially decreased, then reached peak values at 12 h. These results indicate that alterations in metabolic activity during the secretory cycle are accompanied by changes in the reduced/oxidized glutathione ratio and the activity of glutathione-metabolizing enzymes. Cellular events contributing to these alterations in glutathione metabolism may include exocytosis, endocytosis and membrane recycling, increased amino-acid transport and resynthesis of secretory proteins.

Formation of mineralizing osteoblast cultures on machined, titanium oxide grit-blasted, and plasma-sprayed titanium surfaces.

Altering osseous responses at implant surfaces to enhance bone is a current goal of clinical therapy. Cell culture may be used to investigate surface-dependent responses of bone-forming cells. In this report, the ability of primary fetal bovine mandibular osteoblast cultures to form a mineralizing matrix on machined, titanium plasma-sprayed, and titanium oxide grit-blasted surfaces has been compared. Immunohistochemical markers associated with bone formation were used to define the differentiated state of the formed matrix using qualitative light microscopy, and von Kossa staining was used to demonstrate the presence of mineralization within this matrix. Compared to either titanium oxide grit-blasted or machined surfaces, titanium plasma-sprayed surfaces displayed a unique pattern of mineralized matrix formation. Scanning electron microscopy further revealed that each surface accumulated unique organic and inorganic deposits during matrix formation, suggesting that surface-dependent physicochemical and biochemical conditioning of implant surfaces takes place. Surface topographic features of commercially pure titanium substrates can alter cultured osteoblast extracellular matrix formation and mineralization. Similar molecular and cellular assessment of in vivo responses to implant surface topography may contribute to improved engineering of endosseous implants.

Correlative microscopic investigation of the interface between titanium alloy and the osteoblast-osteoblast matrix using mineralizing cultures of primary fetal bovine mandibular osteoblasts.

In this study, the primary culture of bovine mandibular osteoblast cells in a microculture assay has been used to further investigate the interaction of mineralizing osteoblast cultures with implant surfaces by using correlative microscopic techniques. Rapid differentiation and mineralization of osteoblast cultures grown on titanium alloy surfaces was observed. The successful short-term culture of mineralizing mandibular osteoblasts on titanium alloy surfaces occurred without the formation of a tenacious adhesive interface between the alloplastic material and the multilayered cell culture.

Drug watch.

AIDS: The latest information on drug development from the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) is presented. The drugs featured include several which are currently available, such as bleomycin (BLM) and Hydroxyurea (HU). Drugs which are being studied for the use in HIV treatment and are likely to be approved within the next 5 years are also discussed. Information provided includes the drug name, the class, and a profile of the drug's action.^ieng

The panacea of growth hormone.

AIDS: Growth hormone is one of the latest tools against AIDS. Serono's Serostim (somatropin) is the only growth hormone to receive Food and Drug Administration (FDA) approval to treat wasting. HIV-positive individuals show a dramatic suppression of growth hormone, and people with AIDS have practically none. The decrease in growth hormone is also associated with decreasing T-cell counts. The mechanisms in growth hormone production and their role in metabolism and nutrition are described. Serostim is very expensive, and the Serono SeroCare program has limited the cost to $36,000 per year. The program is managed by the National Organization for Rare Diseases. The method of creating growth hormone from the recombinant DNA proteins (rDNA) family is described.^ieng

Treatment issues in rural America.

AIDS: Rural HIV-positive populations are rapidly increasing in size and will present the health care system with formidable challenges. Treatment is sometimes difficult in rural communities, and ignorance and denial interfere with effective medical treatment. A Utah study of rural physicians found that of 169 respondents, 96 percent thought their communities had only a minor problem with HIV issues, and 30 percent would not treat a person with HIV. Rural adolescents are most at risk for the stigmatization and prejudice of their communities.^ieng

New data on IL-2.

AIDS: A new study to be presented at the 12th World AIDS Conference demonstrates that IL-2 dramatically restores immune function in people with AIDS. The study group included patients with fewer than 200 CD4-cells and a history of severe AIDS-related complications including CMV retinitis, PCP, wasting syndrome, KS, and Cryptococcal meningitis. In the study, CD4 counts rose 96 percent when IL-2 was added to protease inhibitor therapy. The increases were sustained, and naive cells increased as well. Most common side effects included fever, fatigue, sinus congestion, and headache; most side effects stopped within 24 hours of completing the treatment cycle. The findings represent new hope for people whose immune systems are substantially compromised. Contact information is provided.^ieng

Reflections on Geneva.

AIDS: The 12th World AIDS Conference in Geneva revealed two very different HIV epidemics in the world, marked by vast differences in wealth and technology availability. Ninety-five percent of people living with AIDS reside in Africa and Asia where funds are scarce. India has 4 million people infected with HIV, and HIV is now present in every province in China. Drug companies need to take the initiative, and help the Third World battle the epidemic. Another message delivered at Geneva was the idea of rebuilding the immune system to help control the virus. HIV is now being seen more as a chronic and difficult disease that is manageable, especially since simpler HIV regimens are appearing. Vaccines are being pursued, but an effective vaccine is believed to still be more than 10 years away.^ieng

Pipe dreams.

AIDS: A chart is presented listing new compounds that will become available to fight HIV. The chart lists compounds according to when they are expected to be available, their classification, the drug's significance, and the manufacturer. Contact information is provided for some of the manufacturers.^ieng

Updates from the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy.

AIDS: Selected highlights of the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy are presented. These include information on new investigational drugs for hepatitis B and discouraging results on using anti-HIV agents for hepatitis C. Highlights on anti-HIV drugs address patient compliance, salvage therapy for HIV infection, use of Thalidomide as an anti-HIV agent, immunologic reconstitution of highly active antiretroviral therapy (HAART), liver damage caused by Ritonavir, and the use of Gemfibrozil in a protease regimen to lower triglycerides.^ieng

Resistance A-Z.

AIDS: Testing is now available to show why certain drugs are or become ineffective in some patients. Key reasons for the drugs' ineffectiveness include (1) antiviral drugs that may not always reach places where the virus is concealed; (2) inconsistent dosing that may leave an opportunity for the virus to replicate; and (3) mutant strains of the virus that arise even when medications are being used. Phenotypic and genotypic testing can be used to search for mutations in the virus which reproduce despite the presence of antiviral drugs. A table depicts typical mutations and corresponding drugs. Understanding which mutations are present helps to determine an effective course of treatment before a drug regimen is begun. Although these tests, which are not covered by most insurance companies, are not foolproof, they do provide valuable information about the treatment of HIV.^ieng

Drug watch.

AIDS: Updates on promising investigational therapies are presented. A new drug, MDI-P, that could potentially destroy latent cell reservoirs infected with HIV, is in the preclinical phase. AG1549, a new non-nucleoside analog manufactured by Agouron, is entering Phase I-II trials. AG1549 has shown high potency and, in vitro, appears to have less chance for cross-resistance than other non-nucleosides. Other updates focus on the advance of WF10 to Phase III trials, and the ability of concurrent IL-2 and HAART treatment to significantly reduce latent HIV reservoirs. Contact information is provided.^ieng