Search PubMed⌕ Search

Biomedical subjects

K Stewart

Publications and source records attributed to K Stewart.

At least 37 records · Page 2Linked to original sources

Care management and the care programme approach: towards integration in old age mental health services.

OBJECTIVE: To examine the relationship between care management arrangements and the Care Programme Approach (CPA) in the context of old age mental health services and, particularly, dementia services. METHOD: The information reported is from a national study of care management arrangements, funded by the Department of Health. A response rate of 77% was obtained from local authority social services departments. RESULTS: In old age mental health services over half of the respondents reported joint screening arrangements for health and social care, almost four-fifths reported both joint criteria for the allocation of key workers and a clear definition of monitoring responsibilities. Of the latter over two-fifths were reported as being the same in care management and the CPA. Forty-six per cent of respondents provided a specialist service for people with dementia. Three-fifths of respondents reported that they did not apply CPA to people with dementia who were in receipt of care management or did so in less than 20% of cases. Where the CPA was applied it was more likely that a priority would be accorded to care management. A quarter of respondents reported the shared use of assessment documentation for people with dementia. DISCUSSION: The findings are set in the context of service developments to date and the implementation of the two systems of community based coordinated care for older people with mental health problems. Inter-authority variations are noted and the potential for greater service integration within the current legislative framework assessed.

Aged↗

Intensive care-management at home: an alternative to institutional care?

BACKGROUND: Care management and assessment of need are the cornerstones of the community care reforms in the UK. Although much of the research base has been on highly vulnerable older people, in practice, care management has been implemented for a wider group. OBJECTIVE: To examine how intensive care-management at home has developed. DESIGN: Postal survey of all local authority social services departments in England. METHOD: We used an overview questionnaire (85% response) and an old-age services questionnaire (77% response). We classified local authorities according to the presence or absence of seven indicators of intensive care management at home. RESULTS: 97% of social services departments had a goal of providing a community-based alternative to residential and nursing-home care. However, only 5% had specialist intensive care-management services for older people. Other key indicators of intensive care-management, such as devolved budgets, health service care managers, small caseloads and clear eligibility criteria, were uncommon. CONCLUSIONS: There was little evidence of intensive care-management at home in older peoples' services. This is of concern, given the move towards community-based provision for frail older people. Closer links between secondary health-care services (such as geriatric medicine) and intensive care-management at home may promote more effective care at home for those who are most vulnerable.

Aged↗

High concentrations of dexamethasone suppress the proliferation but not the differentiation or further maturation of human osteoblast precursors in vitro: relevance to glucocorticoid-induced osteoporosis.

OBJECTIVE: The use of glucocorticoids (GCs) in the treatment of RA is a frequent cause of bone loss. In vitro, however, this same class of steroids has been shown to promote the recruitment and/or maturation of primitive osteogenic precursors present in the colony forming unit-fibroblastic (CFU-F) fraction of human bone and marrow. In an effort to reconcile these conflicting observations, we investigated the effects of the synthetic GC dexamethasone (Dx) on parameters of growth and osteogenic differentiation in cultures of bone marrow stromal cells derived from a large cohort of adult human donors (n=30). METHODS: Marrow suspensions were cultured in the absence and presence of Dx at concentrations between 10 pm and 1 microm. After 28 days we determined the number and diameter of colonies formed, the total number of cells, the surface expression of receptors for selected growth factors and extracellular matrix proteins and, based on the expression of the developmental markers alkaline phosphatase (AP) and the antigen recognized by the STRO-1 monoclonal antibody, the proportion of cells undergoing osteogenic differentiation and their extent of maturation. RESULTS: At a physiologically equivalent concentration, Dx had no effect on the adhesion of CFU-F or on their subsequent proliferation, but did promote their osteogenic differentiation and further maturation. These effects were independent of changes in the expression of the receptors for fibroblast growth factors, insulin-like growth factor 1, nerve growth factor, platelet-derived growth factors and parathyroid hormone/parathyroid hormone-related protein, but were associated with changes in the number of cells expressing the alpha(2) and alpha(4), but not beta(1), integrin subunits. At supraphysiological concentrations, the effects of Dx on the osteogenic recruitment and maturation of CFU-F and their progeny were maintained but at the expense of a decrease in cell number. CONCLUSIONS: A decrease in the proliferation of osteogenic precursors, but not in their differentiation or maturation, is likely to be a key factor in the genesis of GC-induced bone loss.

Adult↗

Thy1 glomerulonephritis induced in young lewis rats accelerates age-related glomerulosclerosis.

Age-related and disease-induced glomerulosclerosis (GS) in rats have both been well defined in a number of strains and experimental models, but the inter-relationship between the two is not clear. The present study was undertaken to compare the pattern of glomerular injury in these two types of GS. One- and two-shot Thy1 glomerulonephritis (GN) was induced at 2 months of age and followed for 12 months. At 12 months histological injury in proteinuric rats was characterized by segmental hyaline lesions. Two-shot Thy1 GN resulted in accelerated, but morphologically identical injury at 8 months. Histological lesions predictive of subsequent accelerated GS were evaluated at 1, 2, 4 and 6 months. In this regard, glomerular hypercellularity, rather than hypertrophy or matrix increase, was the most consistent histological index of later accelerated disease. The profibrotic cytokines transforming growth factor (TGF)-beta(1) and -beta(3) were localized distinctly to segmental hyaline lesions, but not to areas of matrix increase within the glomerular tuft. This study reveals that GS after Thy1 GN represents acceleration of an age-related disease, presents evidence for use of prolonged glomerular hypercellularity as the best histological index of future disease progression, and correlates the key lesion of GS in these animals, the segmental hyaline lesion, with the presence of TGF-beta peptides.

Aging↗

Candida proteases and their inhibition: prospects for antifungal therapy.

The rationale for inhibition of the secreted acid proteases (SAP) of Candida fungal species as a novel antifungal strategy is outlined. Enzyme structure-activity relationship data regarding the inhibitor A-70450 are described along with results from in vivo antifungal assays. Developments from protein X-ray crystallographic studies, SAP knock-out genetic studies, and the importance of these new results for drug discovery are reviewed. Finally, inhibition of the Candida SAP enzymes with HIV protease inhibitors and a proposed role in candidiasis of AIDS patients is discussed.

Antifungal Agents↗

Structure-directed discovery of potent non-peptidic inhibitors of human urokinase that access a novel binding subsite.

BACKGROUND: Human urokinase-type plasminogen activator has been implicated in the regulation and control of basement membrane and interstitial protein degradation. Because of its role in tissue remodeling, urokinase is a central player in the disease progression of cancer, making it an attractive target for design of an anticancer clinical agent: Few urokinase inhibitors have been described, which suggests that discovery of such a compound is in the early stages. Towards integrating structural data into this process, a new human urokinase crystal form amenable to structure-based drug design has been used to discover potent urokinase inhibitors. RESULTS: On the basis of crystallographic data, 2-naphthamidine was chosen as the lead scaffold for structure-directed optimization. This co-crystal structure shows the compound binding at the primary specificity pocket of the trypsin-like protease and at a novel binding subsite that is accessible from the 8-position of 2-napthamidine. This novel subsite was characterized and used to design two compounds with very different 8-substituents that inhibit urokinase with K(i) values of 30-40 nM. CONCLUSIONS: Utilization of a novel subsite yielded two potent urokinase inhibitors even though this site has not been widely used in inhibitor optimization with other trypsin-like proteases, such as those reported for thrombin or factor Xa. The extensive binding pockets present at the substrate-binding groove of these other proteins are blocked by unique insertion loops in urokinase, thus necessitating the utilization of additional binding subsites. Successful implementation of this strategy and characterization of the novel site provides a significant step towards the discovery of an anticancer clinical agent.

Binding Sites↗

The expression and secretion of atrial natriuretic factor and brain natriuretic peptide by rat proximal tubular cells.

We examined the expression of both the natriuretic peptides and natriuretic peptide receptors (NPR) in primary cultures of rat proximal tubular (RPT) cells using Northern blot assay for peptides and receptors and radioimmunoassay and immunohistochemical analysis for atrial natriuretic factor (ANF), brain natriuretic peptide (BNP), and C-type natriuretic peptide. Freshly isolated cells expressed mRNA coding for ANF, BNP, and the NPR-C. The presence of ANF and BNP in freshly isolated cells was confirmed by immunocytochemical staining. As cells approached confluence, there was a marked increase in mRNA expression for ANF and BNP. Immunocytochemical analysis and radioimmunoassay confirmed that both these peptides were co-localised in RPT cells and present in the cell supernatant. These changes in peptide expression were associated with a concurrent decrease in the expression of the NPR-C and the appearance of the NPR-A and -B. These results confirm that freshly isolated RPT cells possess the components of an autocrine natriuretic peptide system and that growth in primary culture is associated with changes in both peptide system and that growth in primary culture is associated with changes in both peptide and receptor subtype expression, raising the possibility that the endogenous production of ANF and BNP may be involved in the control of control cell growth.

Animals↗

Follicular dendritic cells in scrapie pathogenesis.

Scrapie pathogenesis was studied in chimaeric mice that carried the prion protein (PrP) gene only in particular cells of the immune system. These mice were produced by grafting bone marrow from PrP expressing donors into PrP deficient recipients and vice versa. As follicular dendritic cells are not replaced significantly from the bone marrow in adult mice, this procedure resulted in a mismatch in PrP genotype between these cells and bone marrow derived cells such as lymphocytes. Using these models we obtained strong evidence that follicular dendritic cells produced high levels of the normal form of PrP in uninfected mice. Furthermore, the replication of a mouse-passaged scrapie strain in the spleen depended only on the presence of PrP expressing follicular dendritic cells. PrP expression by lymphocytes or other bone marrow derived cells had no influence on replication in spleen or on neuroinvasion in these models. These results indicate that the follicular dendritic cell is a potential target for prophylactic or therapeutic intervention in transmissible spongiform encephalopathies.

Animals↗

Macrophages from inflamed but not normal glomeruli are unresponsive to anti-inflammatory cytokines.

This study examined the properties and responsiveness to cytokines of macrophages purified from normal and nephritic glomeruli to ascertain whether macrophages activated in vivo develop programmed unresponsiveness to cytokines as do bone marrow-derived macrophages in vitro when activated by interferon-gamma (IFN-gamma), tumor necrosis factor (TNF), interleukin-4 (IL-4), or transforming growth factor-beta (TGF-beta). Macrophages from normal glomeruli did not generate nitric oxide (NO) spontaneously but only after treatment with IFN-gamma and TNF-alpha. NO generation by these macrophages was abrogated by administering IL-4, TGF-beta, or TNF-alpha before but not after IFN-gamma treatment. Glomerular macrophages also expressed beta-glucuronidase, which was increased by TGF-beta and decreased by IFN-gamma and TNF. By contrast, glomerular macrophages from rats with nephrotoxic nephritis did not express beta-glucuronidase even after exposure to TGF-beta. Furthermore, they generated NO spontaneously, and this spontaneous generation of NO was not suppressed by IL-4, TGF-beta, or TNF-alpha. Systemic treatment of nephritic rats with IL-4 reduced NO generation by 40% but did not prevent activation, which is similar to the effect of IL-4 on bone marrow-derived macrophages in vitro when given simultaneously with IFN-gamma. We conclude that macrophages infiltrating inflamed glomeruli have developed programmed unresponsiveness to activating cytokines. This may enable them to function appropriately in the complex conditions within an inflammatory focus.

Animals↗

Expression of the developmental markers STRO-1 and alkaline phosphatase in cultures of human marrow stromal cells: regulation by fibroblast growth factor (FGF)-2 and relationship to the expression of FGF receptors 1-4.

Autologous marrow stromal cells have been proposed as an adjuvant in the treatment of bone defects and diseases. This will require the development of culture conditions that permit their rapid expansion ex vivo while retaining their potential for further differentiation. Fibroblast growth factor (FGF)-2 has been proposed as a candidate for the ex vivo expansion of cells with enhanced osteogenic potential, and we have explored this possibility further using cells obtained from a large cohort of adult human donors. Treatment with FGF-2 (0.001-2.5 ng/mL) had no detectable effect on colony formation, but markedly increased their proliferative potential and that of their immediate progeny, as shown by the increases in colony size and cell number. Based on the observed increase in the expression of the developmental markers STRO-1 and alkaline phosphatase (AP), a major target for the actions of FGF-2 appears to be the more primitive cells of the osteoblast lineage, and that, when added in combination with the synthetic glucocorticoid dexamethasone (Dx), it interacts positively to promote further cell maturation. The maintenance of adequate levels of ascorbate was shown to be a critical component in determining the nature of the effect of FGF-2 on AP expression. Variation in the response (predominantly in the magnitude and/or sensitivity) of the cultured cell populations to treatment with FGF-2 was apparent, but a preliminary analysis indicated that this was not due to differences in the age or gender of the donors used. The cultured cell populations were found to express multiple FGF receptors (FGFRs; 1-4) and the observed changes in the spectrum and abundance of FGFRs expressed in relation to that of STRO-1 and AP are consistent with their expression being developmentally regulated during the process of osteogenic differentiation. These results provide novel insights into the mechanism of action of FGF-2 on human cells of the osteoblast lineage and support the use of this factor, alone or in combination with Dx, for the rapid, ex vivo expansion of cell populations with enhanced osteogenic potential.

Adult↗

Biphasic release of immunoreactive endothelins following acute pulmonary thromboembolism in pigs.

The purpose of this investigation was to study the role of endothelins (ETs) in the pathogenesis of acute pulmonary thromboembolism (PTE). Eighteen piglets (20 +/- 3 kg) were anesthetized and ventilated with 100% oxygen, five of them then served as controls. Acute thromboembolic injury in the lung was induced by injecting 15-25 ml of preformed clots into the left lower lobar pulmonary artery during thoracotomy. Pulmonary arterial pressure (Ppa) increased by at least 2.5-fold from baseline. During the subsequent 8 h, seven blood samples were collected from the left atrium and assayed for immunoreactive ETs. The results showed that following PTE: (1) Ppa remained elevated but cardiac output remained constant throughout the experiments; (2) plasma level of immunoreactive ETs increased in the embolized group compared to controls and the profile of immunoreactive ET release suggested a biphasic response. We conclude that the release of these vasocontractile and bronchoconstrictive mediators after PTE may contribute to ventilation perfusion mismatching and account for the pulmonary hypertension and deterioration of gas exchange that are often seen clinically.

Acute Disease↗

Intubation conditions and postoperative myalgia in outpatient dental surgery: a comparison of succinylcholine with mivacurium.

Ninety-four patients undergoing elective outpatient third molar extraction were recruited into a double-blind, randomized, prospective trial comparing mivacurium (group M) with succinylcholine (Group S) for conditions for endotracheal intubation and the occurrence of postoperative myalgia. Anaesthesia was induced with fentanyl 1 microgram.kg-1 and propofol 2.5 micrograms.kg-1 in all patients. Group S patients were given gallamine 20 mg while group M patients were given mivacurium 0.2 mg.kg-1. Manual ventilation was commenced and anaesthesia maintained with nitrous oxide 70% and isoflurane 1 to 2% in oxygen. After two minutes, group S patients were given succinylcholine 1.5 mg.kg-1 and group M patients 0.9% saline. Nasotracheal intubation was performed 30 seconds later. Intubating conditions in group M were significantly better than those in group S (P < 0.001). The incidence of postoperative myalgia was 9.5% in group M and 26% in group S but this was not statistically significant (P = 0.09). We propose that mivacurium is a suitable neuromuscular blocker to use for endotracheal intubation in outpatient dental surgery.

Adolescent↗

Phase I/II trial of cyclophosphamide, mitoxantrone, and escalated doses of carboplatin supported by peripheral-blood stem cells in women with metastatic breast cancer.

PURPOSE: To intensify a regimen of high-dose cyclophosphamide, mitoxantrone, and carboplatin that had previously produced high complete and overall response rates in metastatic breast cancer (MBC). PATIENTS AND METHODS: Forty-four patients with a median age of 43 years (range, 25 to 57 years) and previously untreated MBC who were responding to anthracycline-based or single-agent taxane chemotherapy received cyclophosphamide 1.5 g/m(2)/d and mitoxantrone 16 mg/m(2)/d combined with escalating doses of carboplatin 200 to 500 mg/m(2)/d, each given daily from days -6 to -3. Hematopoiesis was supported by mobilized peripheral-blood stem cells infused on day 0 and by use of granulocyte-macrophage colony-stimulating factor 300 microg/d subcutaneously starting on day 1. RESULTS: A total of six dose levels of carboplatin were examined. Grades 3 and 4 toxicity occurred in 10 patients and one patient, respectively, with grade 3 toxicity occurring in only five of 31 patients treated with < or = 400 mg/m(2) of carboplatin. Major dose-limiting toxicities were cardiac, pulmonary, and renal. Four patients developed congestive heart failure: two had persistently low ejection fraction 11 and 36 months after peripheral-blood stem-cell transplantation (PBSCT), and two recovered. Hematologic recovery to an absolute neutrophil count of greater than 0.5 x 10(9)/L occurred at a median of 11 days (range, 8 to 25 days) and to a platelet count of greater than 20 x 10(9)/L at a median of 10.5 days (range, 6 to 60 days). There were two toxic deaths from sepsis: one on day 27 (level 5) and one from cardiac arrest on day 42 (level 6). CONCLUSION: The maximum-tolerated dose of carboplatin was 400 mg/m(2)/d in combination with mitoxantrone 16 mg/m(2)/d and cyclophosphamide 1,500 mg/m(2), all drugs given over 4 days. This regimen is being tested in a phase III trial of high-dose chemotherapy and PBSCT versus standard treatment.

Adolescent↗

Economic impact of increased clinical intervention rates in community pharmacy. A randomised trial of the effect of education and a professional allowance.

OBJECTIVE: To determine the economic impact of an interventional programme aimed to increase the rate of clinical interventions undertaken in community pharmacy. STUDY DESIGN AND PERSPECTIVE: A randomised controlled trial of 4 parallel groups of pharmacies, conducted from a government perspective. Economic evaluations were based on savings/costs attributable to healthcare costs avoided, healthcare costs incurred by the pharmacists' actions, change in medication costs, pharmacy time and telephone calls made by the pharmacist. The study was conducted during November and December 1996 and costings were based on 1997 figures. INTERVENTIONS: A professional fee-for-service [10 Australian dollars ($A; $A1 = 6.50 US dollars) per intervention] and education (an intensive 1-week course or advanced education) were implemented in an attempt to increase clinical interventions by the pharmacists. Group A pharmacies (n = 10) served as a control group and received neither education nor remuneration; group B received education and professional remuneration (n = 9); group C had received prior continued education and now received advanced education and professional remuneration (n = 11); and group D received professional remuneration with no education. MAIN OUTCOME MEASURES AND RESULTS: The proactive clinical interventions in group C saved a mean of $A85.35 per 1000 prescriptions [95% confidence interval (CI)-$A157.11 to $A24.95). This was 4 times greater than savings generated by pharmacies in group B (mean savings of $A25.65 per 1000 prescriptions) and 6 times greater than control pharmacies. A sensitivity analysis which extrapolated results to Australian prescription figures showed that the control group was capable of generating savings in the order of $A2.4 million per year while pharmacists in group C would save the healthcare system $A15 million per year. CONCLUSIONS: These results provide the first economic estimates for the provision of clinical interventions in Australian community pharmacies. It is believed that they illustrate the value of pharmaceutical services to the healthcare system and to the Australian community in terms of both quality of care and savings.

Australia↗

Assessment approaches for older people receiving social care: content and coverage.

BACKGROUND: Assessment was identified as one of the 'cornerstones' of community care. This study presents findings from the first nationally representative analysis of assessment documents used by social services agencies in the UK. METHOD: In this paper analysis is made of 50 assessment documents used for the 'comprehensive' assessment of older people. The documents were examined in the extent to which they covered 33 assessment domains, grouped into four areas: functional domains; cognitive, mood and psychosocial domains; social environment domains; and clinico-medical domains. The documents were analysed on three dimensions: whether the domains were covered at all; whether the domain was covered in sufficient detail; and whether it would elicit a structured response. RESULTS: Activities of daily living were covered to some extent on the majority of documents, as were the instrumental activities of daily living. Very few documents were designed to elicit information on the potential for rehabilitation. Whilst the majority of forms were designed to collect some information on cognitive patterns, mood state and social activity, very few were designed to collect this in any detail. Although functional activities of daily living were covered in greater detail than the other domains overall, there was enormous variability between the documents, thus hampering their ability to generate any standardized information.

Activities of Daily Living↗