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Biomedical subjects

T Foster

Publications and source records attributed to T Foster.

At least 19 recordsLinked to original sources
PubMed2004

A phase II study of sequential carboplatin, paclitaxel and topotecan in patients with previously untreated advanced ovarian cancer.

We evaluated the sequential use of carboplatin, paclitaxel and topotecan in patients with advanced, previously untreated ovarian cancer. In total, 43 patients with advanced ovarian cancer and >1 cm residual disease were treated with sequential carboplatin (area-under-the-curve (AUC) 5 days 1 and 22), paclitaxel (175 mg m(-2) days 43 and 64) and topotecan (1.5 mg m(-2) daily for 5 days from days 85, 106, 127 and 148). Median age of patients was 61 years. Median follow-up was 22.2 months (range 0.76-50.6 months). In all, 34 (79%) patients received all eight cycles of treatment and nine (21%) withdrew. Of the 29 evaluable patients, 19 (66%) responded according to WHO and 30 of 36 (83%) patients according to CA125. The best overall response (CA125 and/or WHO) was 77% (33 of 43 patients). The response rates to sequential drugs based on >50% fall in CA125 were as follows: carboplatin, 77% (30 of 39 patients); paclitaxel, 65% (15 of 23 patients); topotecan, 38% (five of 13 patients). Two patients responded to paclitaxel and one to topotecan after failure to respond to preceding chemotherapy. Median survival and time to progression was 22.24 and 10.61 months, respectively. This study demonstrates that sequential chemotherapy with just two initial courses of carboplatin is a reasonable way to introduce new agents into first-line therapy for poor prognostic ovarian cancer patients.

Adult↗
PubMed2004

Results of an evaluation of the effectiveness of triage and direct transportation to minor injuries units by ambulance crews.

OBJECTIVE: To evaluate triage and transportation to a minor injury unit (MIU) by emergency ambulance crews. METHODS: Ambulance crews in two services were asked to transport appropriate patients to MIU during randomly selected weeks of one year. During all other weeks they were to treat such patients according to normal practice. Patients were followed up through ambulance service, hospital and/or MIU records, and by postal questionnaire. Semi-structured interviews were undertaken with crews (n = 15). Cases transferred from MIU to accident and emergency (A&E) were reviewed. RESULTS: 41 intervention cluster patients attended MIU, 303 attended A&E, 65 were not conveyed. Thirty seven control cluster patients attended MIU, 327 attended A&E, 61 stayed at scene. Because of low study design compliance, outcomes of patients taken to MIU were compared with those taken to A&E, adjusted for case mix. MIU patients were 7.2 times as likely to rate their care as excellent (95% CI 1.99 to 25.8). Ambulance service job-cycle time and time in unit were shorter for MIU patients (-7.8, 95% CI -11.5 to -4.1); (-222.7, 95%CI -331.9 to -123.5). Crews cited patient and operational factors as inhibiting MIU use; and location, service, patient choice, job-cycle time, and handover as encouraging their use. Of seven patients transferred by ambulance from MIU to A&E, medical reviewers judged that three had not met the protocol for conveyance to MIU. No patients were judged to have suffered adverse consequences. CONCLUSIONS: MIUs were only used for a small proportion of eligible patients. When they were used, patients and the ambulance service benefited.

Accidents↗
PubMed2003

Phase I study of temozolamide (TMZ) combined with procarbazine (PCB) in patients with gliomas.

Temozolomide (TMZ) is an oral alkylating agent with a good safety profile and proven efficacy in the treatment of malignant glioma. Procarbazine (PCB) has been used for treating gliomas for many years and here both agents were combined in the treatment. This phase I study was designed to evaluate the efficacy and safety of TMZ alone (course 1) and TMZ in combination with PCB in subsequent courses in chemotherapy-naïve patients with malignant glioma. Patients with anaplastic astrocytoma (AA), glioblastoma multiforme (GBM) and low-grade glioma were treated with TMZ 200 mg m(-2) on days 1-5 on a 28-day cycle for course 1. Beginning with course 2, cohorts of patients received TMZ at full dose with escalating doses of PCB (50/75/100/125 mg m(-2) days 1-5 given 1 h prior to TMZ). A total of 28 patients were enrolled with three patients each at dose level 1 and 2, 16 patients at dose level 3 and six patients at dose level 4 received 182+ cycles of treatment and were included in this analysis. In all, 16 patients had GBM, seven patients had AA, five had grade 1 or 2 glioma and the median age was 47 years. The patients had received prior surgery and radiotherapy. Responses were seen at all dose levels. Overall, there were 10 (36%) responses lasting from 2 to 17+ months. Treatment was generally well tolerated with few grade 3 or 4 toxicities, except at dose level 4, where four patients had grade 3/4 had thrombocytopaenia at this dose and several patients had moderate-to-severe lethargy. TMZ 200 mg m(-2) and PCB 100 mg m(-2) were well tolerated on a daily 5 x and four weekly cycle in patients with malignant glioma and clearly had antitumour activity.

Administration, Oral↗
PubMed2003

Computer assisted assessment and advice for "non-serious" 999 ambulance service callers: the potential impact on ambulance despatch.

OBJECTIVE: To investigate the potential impact for ambulance services of telephone assessment and triage for callers who present with non-serious problems (Category C calls) as classified by ambulance service call takers. DESIGN: Pragmatic controlled trial. Calls identified using priority dispatch protocols as non-serious were allocated to intervention and control groups according to time of call. Ambulance dispatch occurred according to existing procedures. During intervention sessions, nurses or paramedics within the control room used a computerised decision support system to provide telephone assessment, triage and, if appropriate, offer advice to permit estimation of the potential impact on ambulance dispatch. SETTING: Ambulance services in London and the West Midlands. SUBJECTS: Patients for whom emergency calls were made to the ambulance services between April 1998 and May 1999 during four hour sessions sampled across all days of the week between 0700 and 2300. MAIN OUTCOME MEASURES: Triage decision, ambulance cancellation, attendance at an emergency department. RESULTS: In total, there were 635 intervention calls and 611 controls. Of those in the intervention group, 330 (52.0%) were triaged as not requiring an emergency ambulance, and 119 (36.6%) of these did not attend an emergency department. This compares with 55 (18.1%) of those triaged by a nurse or paramedic as requiring an ambulance (odds ratio 2.62; 95% CI 1.78 to 3.85). Patients triaged as not requiring an emergency ambulance were less likely to be admitted to an inpatient bed (odds ratio 0.55; 95% CI 0.33 to 0.93), but even so 30 (9.2%) were admitted. Nurses were more likely than paramedics to triage calls into the groups classified as not requiring an ambulance. After controlling for age, case mix, time of day, day of week, season, and ambulance service, the results of a logistic regression analysis revealed that this difference was significant with an odds ratio for nurses:paramedics of 1.28 (95% CI 1.12 to 1.47). CONCLUSIONS: The findings indicate that telephone assessment of Category C calls identifies patients who are less likely to require emergency department care and that this could have a significant impact on emergency ambulance dispatch rates. Nurses were more likely than paramedics to assess calls as requiring an alternative response to emergency ambulance despatch, but the extent to which this relates to aspects of training and professional perspective is unclear. However, consideration should be given to the acceptability, reliability, and cost consequences of this intervention before it can be recommended for full evaluation.

Adolescent↗
PubMed2001

Protection against experimental Staphylococcus aureus arthritis by vaccination with clumping factor A, a novel virulence determinant.

The importance of the fibrinogen-binding adhesin clumping factor A (ClfA) in the pathogenesis of Staphylococcus aureus septic arthritis was examined in an animal model. The protective effect of active and passive immunization with ClfA also was investigated in S. aureus infection models. The severity of arthritis was markedly reduced in mice challenged intravenously with a clfA mutant, compared with mice infected with the wild-type strain. Mice immunized with recombinant ClfA and challenged with S. aureus developed less-severe arthritis than did mice immunized with a control antigen. Passive immunization of mice with rat and rabbit anti-ClfA antibodies protected against S. aureus arthritis and sepsis-induced death, indicating that the protection by active immunization is antibody mediated. Taken together, these data strongly suggest that ClfA is a crucial virulence determinant for septic arthritis and an excellent target for the generation of immune therapies directed against S. aureus.

Animals↗
PubMed2001

The organizational costs of preventable medical errors.

BACKGROUND: Preventable medical errors are associated with additional costs that tend to be borne by patients, but little is known about organizational costs associated with such errors. Two composite case studies (a fall and a delay in diagnosis) were used to identify the organizational costs of preventable medical errors. ANALYSIS: Legal, marketing, and organizational costs--direct, indirect, and long term--were associated with each of the preventable medical errors. A model was generated to examine the theoretical relationship between the costs and four determinants of corporate performance--price, wages, cost of capital, and efficiency. DISCUSSION: Organizations may also have a financial incentive to improve patient safety, for beyond patient and societal costs, preventable medical errors appear to account for significant legal, marketing, and operational costs for the organizations that deliver health care. Some of these costs are not so much the cost of the error but the costs of organizational responses to the error. Three broad areas of inquiry could be used to test the model and improve our understanding of the organizational costs of errors: market response to patient safety interventions, before/after studies of interventions, and case-control studies. SUMMARY AND CONCLUSION: Health care leaders have a moral imperative to implement systems that reduce medical errors and improve patient safety. An understanding of the costs associated with medical errors may help leaders understand the importance of patient safety from a financial perspective, develop measures to evaluate the impact of patient safety initiatives, and efficiently allocate resources to address this important health concern.

Female↗
PubMed2000

Pharmacokinetics of flunisolide administered via metered dose inhaler with and without a spacer device and following oral administration.

BACKGROUND: After inhalation of a glucocorticoid from a meter dose inhaler (MDI), a certain portion of the delivered dose is deposited in the lungs, and the remainder is deposited in the oropharynx. OBJECTIVE: To examine the absolute bioavailability of flunisolide given orally via metered dose inhaler, and metered dose inhaler with a commercially available spacer device as well as to determine the fraction of drug deposited in the lungs following inhalation. METHODS: Twenty-four healthy volunteers were enrolled in the study; twenty-two completed the study. The IRB approved the study protocol, and informed consent was obtained. Volunteers received four treatments: treatment A (MDI), 1.0 mg inhaled flunisolide; treatment B (MDI-S), 1.0 mg inhaled flunisolide with a spacer device; treatment C, 1.0 mg of orally administered flunisolide with 240 mL of water; and treatment D, 1.0 mg intravenous flunisolide by IV push in the antecubital vein over 60 seconds. Plasma and urine flunisolide were quantified by HPLC/mass spectrometry/mass spectrometry. RESULTS: Flunisolide is a corticosteroid with low oral bioavailability (6.7%), which was found to be lower than previously reported. Similar AUCs were observed between the MDI and MDI-S groups, but by using mass balance equations, it appears that more flunisolide was delivered to the lungs in the MDI-S group (410 microg versus 280 microg). Oropharyngeal deposition was an important difference between the two inhaler groups. Approximately an 11-fold reduction in the oropharyngeal deposition of flunisolide through use of the spacer device was observed. CONCLUSIONS: Use of a spacer device improved pulmonary delivery of flunisolide by almost 50% and significantly decreased the oropharyngeal exposure to drug.

Administration, Oral↗
PubMed1999

Angiogenesis gene therapy: phase I assessment of direct intramyocardial administration of an adenovirus vector expressing VEGF121 cDNA to individuals with clinically significant severe coronary artery disease.

BACKGROUND: Therapeutic angiogenesis, a new experimental strategy for the treatment of vascular insufficiency, uses the administration of mediators known to induce vascular development in embryogenesis to induce neovascularization of ischemic adult tissues. This report summarizes a phase I clinical experience with a gene-therapy strategy that used an E1(-)E3(-) adenovirus (Ad) gene-transfer vector expressing human vascular endothelial growth factor (VEGF) 121 cDNA (Ad(GV)VEGF121.10) to induce therapeutic angiogenesis in the myocardium of individuals with clinically significant coronary artery disease. METHODS AND RESULTS: Ad(GV)VEGF121.10 was administered to 21 individuals by direct myocardial injection into an area of reversible ischemia either as an adjunct to conventional coronary artery bypass grafting (group A, n=15) or as sole therapy via a minithoracotomy (group B, n=6). There was no evidence of systemic or cardiac-related adverse events related to vector administration. In both groups, coronary angiography and stress sestamibi scan assessment of wall motion 30 days after therapy suggested improvement in the area of vector administration. All patients reported improvement in angina class after therapy. In group B, in which gene transfer was the only therapy, treadmill exercise assessment suggested improvement in most individuals. CONCLUSIONS: The data are consistent with the concept that direct myocardial administration of Ad(GV)VEGF121.10 to individuals with clinically significant coronary artery disease appears to be well tolerated, and initiation of phase II evaluation of this therapy is warranted.

Adenoviridae↗
PubMed1999

Gnarley1 is a dominant mutation in the knox4 homeobox gene affecting cell shape and identity.

Maize leaves have a stereotypical pattern of cell types organized into discrete domains. These domains are altered by mutations in knotted1 (kn1) and knox (for kn1-like homeobox) genes. Gnarley (Gn1) is a dominant maize mutant that exhibits many of the phenotypic characteristics of the kn1 family of mutants. Gn1 is unique because it changes parameters of cell growth in the basal-most region of the leaf, the sheath, resulting in dramatically altered sheath morphology. The strongly expressive allele Gn1-R also gives rise to a floral phenotype in which ectopic carpels form. Introgression studies showed that the severity of the Gn1-conferred phenotype is strongly influenced by genetic background. Gn1 maps to knox4, and knox4 is ectopically expressed in plants with the Gn1-conferred phenotype. Immunolocalization experiments showed that the KNOX protein accumulates at the base of Gn1 leaves in a pattern that is spatially and temporally correlated with appearance of the mutant phenotype. We further demonstrate that Gn1 is knox4 by correlating loss of the mutant phenotype with insertion of a Mutator transposon into knox4.

Alleles↗
PubMed1999

Alpha-toxin and gamma-toxin jointly promote Staphylococcus aureus virulence in murine septic arthritis.

Septic arthritis is a common and feared complication of staphylococcal infections. Staphylococcus aureus produces a number of potential virulence factors including certain adhesins and enterotoxins. In this study we have assessed the roles of cytolytic toxins in the development of septic arthritis by inoculating mice with S. aureus wild-type strain 8325-4 or isogenic mutants differing in the expression of alpha-, beta-, and gamma-toxin production patterns. Mice inoculated with either an alpha- or beta-toxin mutant showed degrees of inflammation, joint damage, and weight decrease similar to wild-type-inoculated mice. In contrast, mice inoculated with either double (alpha- and gamma-toxin-deficient)- or triple (alpha-, beta-, and gamma-toxin-deficient)-mutant S. aureus strains showed lower frequency and severity of arthritis, measured both clinically and histologically, than mice inoculated with the wild-type strain. We conclude that simultaneous production of alpha- and gamma-toxin is a virulence factor in S. aureus arthritis.

Animals↗
PubMed1999

Risk factors for suicide independent of DSM-III-R Axis I disorder. Case-control psychological autopsy study in Northern Ireland.

BACKGROUND: The vast majority of suicides suffer from at least one mental disorder at the time of death. AIMS: To identify risk factors for suicide, particularly those independent of current DSM-III-R Axis I disorder(s). METHOD: A case-control psychological autopsy study comparing suicides with matched community controls. RESULTS: Independent risk factors for suicide included: Axis II (personality) disorder (particularly antisocial, avoidant and dependent); at least one of 12 life events (from the List of Threatening Experiences) during the previous 52 or 4 weeks (in particular, a 'serious problem with close friend, neighbour or relative'); current unemployment; previous history of deliberate self-harm; and contact with a GP within 26 weeks. Relative to individuals with no current mental disorder, the estimated risk of suicide in those with Axis I-Axis II comorbidity (OR 346.0) was significantly greater than that in those with Axis I disorder(s) only (OR 52.4). CONCLUSIONS: Suicide risk assessment may be enhanced by enquiry about the aforementioned independent risk factors, and attention to Axis I-Axis II comorbidity.

Case-Control Studies↗
PubMed1999

Mosaic analysis of the dominant mutant, Gnarley1-R, reveals distinct lateral and transverse signaling pathways during maize leaf development.

Maize leaves are organized into two major domains along the proximal-distal axis: a broad flat blade at the distal end of the leaf, and a narrow, thickened sheath that encircles the stem. Between the blade and sheath are two wedge-shaped tissues called auricles, and the ligule, an epidermally derived fringe. Members of the Knotted1 (Kn1) family of mutations change the shape and position of both ligule and auricle, thus disturbing the overall pattern of the leaf. Here we present the results of a mosaic analysis of Gnarley1-R (Gn1-R), which like members of the Kn1 family, affects the ligule and auricle. Gn1-R is distinct, however, in altering the dimensions of cells that make up sheath tissue. To gain insight into the Gn1-R phenotype, we performed a mosaic analysis using X-ray induced chromosome breakage to generate wild-type (gn1+/-) sectors in otherwise Gn1-R leaves. These sectors allowed us to determine whether Gn1-R acts non-autonomously to influence adjacent cells. Most aspects of the Gn1-R phenotype, such as ligule position, inhibition of auricle development, and sheath thickness showed autonomy in the lateral dimension (leaf width). In contrast, all aspects of the Gn1-R phenotype were non-autonomous in the transverse dimension (leaf thickness), suggesting that signaling occurs between cell layers in the leaf. These results support a model for distinct signaling pathways along lateral versus transverse axes of a developing leaf.

Chromosome Breakage↗
PubMed1998

The psychological autopsy approach to studying suicide: a review of methodological issues.

The psychological autopsy approach to studying suicide is becoming an increasingly used research method. It presents considerable methodological problems. In order to assist future researchers in this field and to help readers assess reports of psychological autopsy studies the authors have reviewed these issues on the basis of their own experience and those of other workers. The areas covered include research design, identification of subjects, sources of information and the particular issues concerned with approaching relatives and other informants, choice and recruitment of controls, the difficulties of conducting psychological autopsy interviews with relatives, problems for interviewers, the selection of appropriate measures to obtain information, and achieving valid and reasonably reliable conclusions from diverse information sources.

Autopsy↗
PubMed1998

Role of Staphylococcus aureus surface-associated proteins in the attachment to cultured HaCaT keratinocytes in a new adhesion assay.

Colonization of human skin with Staphylococcus aureus is a common feature in a variety of dermatologic diseases. In order to reproducibly investigate the adherence of Staphylococcus aureus to human epidermal cells, an in vitro assay was established using the biotin/streptavidine labeling system and the HaCaT cell line. This assay was used to define the role of several Staphylococcus aureus surface proteins with regard to their function in the staphylococcal adhesion process. Our studies included the standard laboratory strain Newman as well as its genetically constructed mutants DU5873, DU5852, DU5854, and DU5886 generated by allele replacement or transposon mutagenesis, which are deficient in the elaboration of staphylococcal protein A (spa), clumping factor (clfA), coagulase (coa), and the fibronectin-binding proteins A and B (fnbA/B), respectively. In comparison with strain Newman all mutants showed remarkably reduced adherence to the HaCaT keratinocyte cell line in our assay, yielding only between 43% and 60% of the adherence capacity of strain Newman after 60 min. Bacterial adherence could be re-established by introducing the cloned wild-type genes for the surface proteins on shuttle plasmids into the chromosomally defective mutants, thus suggesting a pathogenetic role of these proteins in the attachment of Staphylococcus aureus to human keratinocytes. Bacterial adherence was additionally enhanced by alkaline pH-values that are characteristic for skin conditions with epidermal barrier dysfunction. The use of Staphylococcus aureus mutant strains, deficient in the elaboration of defined proteins, allows specific investigation of colonization and virulence factors of this dermatologic relevant microorganism.

Bacterial Adhesion↗
PubMed1997

Characterization of the interaction between the Staphylococcus aureus clumping factor (ClfA) and fibrinogen.

The ability of Staphylococcus aureus to adhere to adsorbed fibrinogen and fibrin is believed to be an important step in the initiation of biomaterial and wound-associated infections. In this study, we show that the binding site in fibrinogen for the recently identified S. aureus fibrinogen-binding protein clumping factor (ClfA) is within the C-terminus of the fibrinogen gamma chain. S. aureus Newman cells expressing ClfA adhered to microtitre wells coated with recombinant fibrinogen purified from BHK cells, but did not adhere to wells coated with a purified recombinant fibrinogen variant where the 4 C-terminal residues of the gamma chain were replaced by 20 unrelated residues. In addition, a synthetic peptide corresponding to the 17 C-terminal amino acids of the fibrinogen gamma chain effectively inhibited adherence of ClfA-expressing cells to fibrinogen. In western ligand blots, a recombinant truncated ClfA protein called Clf33 (residues 221-550) recognized intact recombinant fibrinogen gamma chains, but failed to recognize recombinant fibrinogen gamma chains where the 4 C-terminal amino acids were altered by deletion or substitution. Previous studies have shown that the C-terminal domain of fibrinogen gamma chains contains a binding site for the integrin alphaIIb beta3 (glycoprotein gpIIb/IIIa) receptor on platelets [Kloczewiak, M., Timmons, S., Bednarek, M. A., Sakon, M. & Hawiger, J. (1989) Biochemistry 28, 2915-1919; Farrell, D. H., Thiagarajan, P., Chung, D. W. & Davie, E. W. (1992) Proc. Natl. Acad. Sci. USA 89, 10729-10732; Hettasch, J. M., Bolyard, M. G. & Lord, S. T. (1992) Thromb. Haemostasis 68, 701-706]. We now show that Clf33 inhibits ADP-induced, fibrinogen-dependent platelet aggregation in a concentration-dependent manner and inhibits adhesion of platelets to immobilized fibrinogen under fluid shear stress, indicating that the binding sites for the platelet integrin and the staphylococcal adhesin overlap. The interaction between Clf33 and fibrinogen was further characterized using the BIAcore biosensor. When soluble Clf33 was allowed to bind to immobilized fibrinogen, a Kd of 0.51 +/- 0.19 microM was experimentally determined using equilibrium binding data. It was also shown that the synthetic C-terminal gamma-chain peptide effectively inhibited this interaction.

Adenosine Diphosphate↗