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Biomedical subjects

G Knowles

Publications and source records attributed to G Knowles.

At least 19 recordsLinked to original sources
PubMed2006

Retrospective review of laser therapy for palliation of colorectal tumours.

Patients with inoperable colorectal tumours will often require symptomatic relief due to the nature of extensive disease spread or existing co-morbidities. The use of laser treatment for palliation of tumours in the lower gastrointestinal tract has become an attractive treatment option for such patients. This paper presents the results of a retrospective review of 58 case notes in order to determine the effectiveness of laser therapy in palliating symptoms of colorectal tumours. In addition, the paper aims to identify which colorectal symptoms laser is best used to palliate. The study was conducted in a regional coloproctology unit at the Western General Hospital in Edinburgh. The main findings show that 52% (n=30) of patients had successful (complete/good) resolution of symptoms, 36% (n=21) had a poor response and 12% (n=7) had no resolution of symptoms from laser therapy. Of all documented symptoms, this study found that laser is most effective at palliating obstructive symptoms. It also has beneficial application in the palliation of bleeding and mucous discharge. It is less effective for the anal symptoms of tenesmus and pain and for stool related symptoms such as diarrhoea, constipation, frequency and incontinence.

Adult↗
PubMed2003

The pathway study: results of a pilot feasibility study in patients suspected of having lung carcinoma investigated in a conventional chest clinic setting compared to a centralised two-stop pathway.

UNLABELLED: The best chance of cure in non-small cell lung cancer (NSCLC) is surgical resection, but UK rates of 8% compare poorly to 25% in the USA and Europe. Delays in diagnosis in the current UK system may be one reason for such discrepancy. To address this problem we set up a rapid diagnostic system and compared it to the conventional method of investigations in a pilot randomised trial. METHODS: Eighty-eight patients were prospectively enrolled from three District General Hospitals and randomised to either investigation locally or to the rapid system at The Royal Marsden Hospital. The pilot end-points were feasibility and audit of radical treatment rates to enable estimates for patient numbers for the full study. RESULTS: Forty-five and 43 patients were in the central and conventional arms, respectively (65% male, median age 69 years). There was a 4-week improvement in time to first treatment in those in the central arm (P=0.0025) with 13/30 (43%) and 9/27 (33%) patients having radical treatment in the central and conventional arms, respectively. Patients in the conventional arm felt the diagnostic process was too slow (P=0.02) while those in the central arm seemed to have a better care experience (P=0.01). There were significantly less visits to the general practitioner (GP) in the central arm (P=0.02). CONCLUSIONS: This pilot study demonstrates that the full study is feasible but would require the commitment and involvement of a large number of patients and physicians. The results show several advantages to investigations and diagnosis in the central arm, particularly in time to treatment initiation, patient satisfaction and rate of radical treatments. The improved rate of radical treatment could lead to an improved survival rate.

Aged↗
PubMed2001

5-fluorouracil steady state pharmacokinetics and outcome in patients receiving protracted venous infusion for advanced colorectal cancer.

PVI 5FU gives increased response rates and reduced toxicity when compared to bolus 5FU (J Clin Oncol 1989, 425-432). PVI 5FU administration was reported to give highly variable (>1000-fold) plasma 5FU concentrations at steady state (FU Css) which correlated with toxicity (Ann Oncol 1996, 47-53); but only 19 patients were studied. Therefore, we performed a study of PVI 5FU in 61 patients with advanced colorectal cancer to assess the variability (inter- and intra-subject) in 5FU Css associated with PVI 5FU (300 mg m(-2)day(-1)) and to attempt to correlate pharmacodynamic end-points (anti-tumour activity, toxicity) with 5FU Css as a prelude to 'exposure-guided' 5FU administration. All 5FU sampling was performed between 10 am and noon. PVI 5FU administration continued to 26 weeks in patients with disease improvement or stabilization. The response rate was 26% (33% stable disease) and median survival was 11 months. Hand-foot syndrome was the most common dose limiting toxicity. Variability in 5FU(300)Css was considerably less than previously reported; 94 +/- 25 ng ml(-1)(CV = 27%). No relationships were demonstrated between subject mean 5FU(300)Css and PD end-points such as response, mucositis, diarrhoea and hand-foot syndrome. The lack of correlation suggests that measurement of 5FU concentrations should not be used to individualize dosing in patients receiving PVI 5FU for advanced colorectal cancer.

Adult↗
PubMed2001

Intramural neurofibroma of the trachea treated by multiple stents.

The case history is presented of a patient in whom an intramural tracheal neurofibroma developed, causing severe airway stenosis. The patient was treated with multiple stents over a period of 5 years because of progression of the disease and associated airflow limitation. Clinicians should be aware of this rare complication of neurofibromatosis.

Bronchoscopy↗
PubMed2000

Survey of nurses' assessment of cancer-related fatigue.

Fatigue is now widely recognised as a significant' problem for patients with cancer. While research effort into this subject has grown considerably in recent years, the exact mechanisms underlying fatigue remain unclear. Therefore assessing and managing this symptom can be problematic. This paper describes the findings from a survey evaluating how nurses (n = 84) in a Cancer Centre in Edinburgh currently define and assess fatigue. The results demonstrate that while the problems associated with fatigue are acknowledged, assessment tools are not widely used and the majority of nurses report that they would benefit from further education on the subject to assist in the care of patients.

Adult↗
PubMed2000

The development of a conceptual framework for advancing cancer nursing practice in Europe.

Continued professional development through formal education programmes is essential for improving the quality of care provided to patients with cancer. This paper describes a European Oncology Nursing Society project concerned with advanced cancer nursing education. While the development of an education programme for advanced cancer nursing practice in Europe proves difficult at this time, this project has provided the opportunity to examine some of the key elements of advanced cancer nursing work. In turn, the information gained has enabled the development of a conceptual framework for advancing cancer nursing practice in Europe to be constructed.

Journal Article↗
PubMed2000

Cancer fatigue.

Explore the source record for details and available documents.

Education, Medical, Continuing↗
PubMed1998

Sarcoidosis presenting as palmar erythema.

Sarcoidosis, a multisystem disease of unknown aetiology, is characterized by the formation of non-caseating granulomas which may involve any organ of the body. The commonest sites of predilection are the lungs, skin and lymph nodes. We now report a patient who presented with palmar erythema which on biopsy confirmed the presence of non-caseating granulomas and who responded to systemic corticosteroids. We are unaware of any previous report in the literature of sarcoidosis presenting in this way.

Erythema↗
PubMed1997

A peptide encoding a B-cell epitope from the N-terminus of the capsid protein L2 of bovine papillomavirus-4 prevents disease.

The first 200 N-terminus amino acids of the L2 capsid protein of BPV-4 (designated L2a) are an effective prophylactic vaccine against BPV-4 infection. Vaccination with L2a induces the production of virus neutralizing antibodies, and when L2a antibodies are removed from immune sera, the sera lose their neutralization activity. L2a encodes three dominant B-cell epitopes, defined as epitope 1 (amino acids 101-120), epitope 2 (aa 131-151), and epitope 3 (aa 151-170). To investigate whether any of these epitopes are responsible individually or in combination for protection against viral challenge, synthetic peptides, corresponding to the three epitopes (peptides 11, 14, and 16, respectively) and conjugated to keyhole limpet hemocyanin (KLH) were tested in vaccination challenge experiments. Calves vaccinated with the three peptides together showed no evidence of papillomavirus infection; those vaccinated with peptide 14 alone developed only early lesions which did not progress to proper papillomas and regressed rapidly; those vaccinated with peptide 11 or peptide 16 alone were not protected and proceeded to develop papillomas. Therefore the three B-cell epitopes are not conventionally "neutralizing" when presented individually, but in combination they form a complex neutralization domain, and, in particular, epitope 2, represented by peptide 14, encodes a domain responsible for disease prevention.

Animals↗
PubMed1997

Escape from evolutionary stasis by transposon-mediated deleterious mutations.

Evolution within a rugged fitness landscape is limited by the tendency for organisms to become trapped on local optima resulting in evolutionary stasis. It is presently unclear how founder populations escape from an adaptive peak to found a new species. Insertion sequences, transposons and other mobile DNA elements are found in all species of eukaryotes, bacteria and archaebacteria, where they have been sought and are usually considered to be genomic parasites or selfish genes. However, many transposons and other mobile repetitive DNA are remarkably species or phyla-specific, indicating that infection with transposable elements coincides with speciation events and is involved in promoting evolutionary change. We propose here a model in which transposable elements are involved in speciation events by their ability to produce irreversible deleterious mutations that promote escape from evolutionary stasis. We have constructed a genetic algorithm designed to model both spontaneous and transposon-mediated mutations in populations of asexual digital organisms. We use this model to investigate the effect of transposon-mediated mutations on the rate of evolution of digital organisms as they compete for resources within an artificial adaptive landscape. In the absence of transposon mutations the seed organisms quickly evolve to occupy the nearest adaptive peak but thereafter evolutionary stasis ensues and adjacent empty peaks are left unoccupied. In the presence of transposon mutations, evolution is again dominated by stasis but is punctuated by bursts of rapid evolution in with consecutive unoccupied adaptive peaks are filled with organisms derived from single transposition events. Rapid evolutionary events leading to founding of new biological species, may be similarly initiated by irreversible deleterious mutations induced by transposition.

Adaptation, Physiological↗
PubMed1996

V(D)J recombination activates a p53-dependent DNA damage checkpoint in scid lymphocyte precursors.

Double-stranded DNA breaks (DSBs) trigger p53-mediated cell cycle arrest or apoptosis pathways that limit the oncogenic consequences of exposure to genotoxic agents, but p53-mediated responses to DSB generated by normal physiologic events have not been documented. "Broken" V(D)J coding ends accumulate in scid lymphocyte precursors as a consequence of a mutation in DNA-dependent protein kinase (DNA-PK). The ensuing failure to rearrange efficiently antigen receptors arrests lymphoid development. Here we show that scid thymocytes express high levels of p53 protein, attributable to recombinase activating gene (RAG)-dependent generation of DSB adjacent to V, D, and J gene segments. To examine the functional importance of p53 expression in vivo, we bred p53-/- scid mice. The absence of p53 facilitated production of in-frame V(D)Jbeta coding joints and developmental progression of scid thymocytes, in addition to a dramatic accumulation of pro-B cells. All mice developed disseminated pro-B or immature T cell lymphoma/leukemia by 7-12 weeks of age. We present evidence that p53 deficiency prolongs the survival of scid lymphocyte precursors harboring broken V(D)J coding ends, allowing the accumulation of aneuploid cells. These results demonstrate that a p53-mediated DNA damage checkpoint contributes to the immune deficiency characteristic of the scid mutation and limits the oncogenic potential of DSBs generated during V(D)J recombination.

Animals↗
PubMed1996

CD8/CD4 lineage commitment occurs by an instructional/default process followed by positive selection.

In the present study, we investigated the developmental potential of purified populations of transitional CD4inCD8hi and CD4hiCD8in thymocytes that were further defined according to their differentiation stage by their levels of T cell receptor (TCR) expression into TCRlo, TCRin and TCRhi subpopulations. The differentiation potential of each of these subsets was tested in vitro in a single-cell suspension culture assay that showed that CD4inCD8hiTCRhi are precursors of CD8 single-positive cells, whereas CD4hiCD8inTCRin/hi are precursors of both CD4 and CD8 single-positive thymocytes. The analysis of transitional subsets in mutant mice for either beta 2-microglobulin or major histocompatibility complex (MHC) class II further revealed that lineage commitment to the CD8 lineage requires a TCR-MHC class I engagement, presumably at the immature double-positive stage of thymic development, while CD4 commitment does not require an MHC class II-mediated signal, but rather occurs by default. Using the addition of MHC class I- or class II-expressing cells or the addition of total thymocytes to purified sorted transitional precursors for the duration of the cultures in vitro, we identified an additional stage of differentiation for both CD4 and CD8 lineages that requires a positive selection signal. Examination of protein tyrosine phosphorylation of transitional precursors revealed that CD4inCD8hi transitional cells contain a high level of a 70-kDa phosphorylated protein consistent with a role for ZAP70 in the signal transduction during the positive selection of CD8+ cells.

Animals↗
PubMed1996

Vaccination of cattle with bovine papillomavirus type 4 L2 elicits the production of virus-neutralizing antibodies.

Prophylactic vaccination of cattle with the N terminus (L2a, aa 11-200) of the minor capsid protein L2 completely prevented bovine papillomavirus type 4 (BPV-4) infection of the alimentary canal. To investigate the mechanisms underlying protection from viral infection, sera from vaccinated animals were analysed in neutralization assays both in the nude mouse xenograft system and in cattle. BPV-4 retained its infectivity when incubated with preimmune cattle sera, whereas, when incubated with immune sera from animals vaccinated with either whole L2 or its N terminus L2a, its infectivity was greatly reduced, indicating that the immune sera had neutralizing activity against the virus. This activity could be abrogated by absorbing the immune sera with L2 or L2a, thus indicating that virus neutralization was due to the presence in the immune sera of anti-L2 antibodies.

Animals↗
PubMed1996

Phenotypical characterization of lymphocytes infiltrating regressing papillomas.

Papillomavirus-induced lesions often regress spontaneously in both humans and animals. Papilloma regression is deemed to be due to a cell-mediated immune response, the nature of which is still ill defined, and is accompanied by immune cell infiltrates. To gain further information on the nature and role of the immune cells present in regressing papillomas, we have analyzed biopsies of papillomas induced in the soft palate of cattle by bovine papillomavirus type 4 (BPV-4) and have phenotypically characterized and quantified the lymphocytes present in these lesions. Eleven papilloma biopsies and seven biopsies of noninfected palate were analyzed for the presence of activated CD4+, CD8+, and gamma delta(WC1+) lymphocytes. We found large numbers of lymphocytes in the subepithelial derma of papillomas but not in normal palate tissue; these cellular masses consisted predominantly of CD4+ lymphocytes, with only a few CD8+ and gamma delta(WC1+) lymphocytes, generally positioned at the periphery of these masses. All three subtypes of lymphocytes were found interdigitated with the cells of the basal layer both in papillomas and in normal palate tissue, but while basal layer CD8+ and gamma delta(WC1+) T cells were detected with similar frequencies in papillomas and uninfected palate, basal layer CD4+ T cells were much more frequent in papillomas. CD4+, CD8+, and gamma delta(WC1+) lymphocytes were found in the suprabasal layers of papillomas, but the CD8+ and gamma delta(WC1+) T cells were more numerous and had migrated further into the differentiating keratinocytes of the papilloma fronds than the CD4+ T cells. We conclude that T-cell infiltration is characteristic of regressing BPV-4 papillomas, that CD4+ lymphocytes are specifically and massively recruited into the regressing papillomas, and that although all three lymphocyte subsets can penetrate the papilloma, only the CD8+ and gamma delta(WC1+) lymphocytes are able to migrate into the fronds. These results suggest that all three lymphocyte subsets have an important role to fulfill during natural regression of papillomas.

Animals↗
PubMed1995

Discrimination between major histocompatibility complex class II DQ and DR locus products in cattle.

We have used a panel of anti-major histocompatibility complex (MHC) class II monoclonal antibodies (mAbs) and have assessed their specificity for the products of the individual bovine MHC (BoLA) class II subregions. The mAbs identified two distinct class II molecules by affinity purification and ELISA. Two-dimensional immunoblotting confirmed these data and NH2-terminal sequencing of the purified class II alpha chains of one member of each group identified the subregion specificity of the mAbs. The mAbs VPM36, TH22A and TH81A are specific for BoLA DQ, whereas VPM54, TH14B and J11 are specific for BoLA DR. SW73.2 reacts with both MHC subgroups of all cattle tested.

Amino Acid Sequence↗
PubMed1994

Chemotherapy prolongs survival in inoperable pancreatic carcinoma.

Forty-three patients with irresectable advanced pancreatic cancer were randomized to receive chemotherapy using a combination of 5-fluorouracil, Adriamycin and mitomycin or no chemotherapy. Groups were well matched with regard to age, extent of disease and performance status on entry. Chemotherapy was well tolerated and, although common, side-effects were usually mild. Psychological measurements based on the Hospital Anxiety and Depression score were made in 31 patients. These showed significantly less depression but not anxiety in the treated group immediately after randomization and following 2 months of chemotherapy. Median survival in the treated group was 33 (range 9-80) weeks compared with 15 (range 1-62) weeks in the untreated group (P < 0.002). Chemotherapy should be considered in all patients presenting with advanced inoperable pancreatic cancer.

Adult↗
PubMed1994

Improved discrimination of bovine class II DR beta-chains polymorphisms using immunoblotting.

An immunoblotting technique is reported that reveals electrophoretic variants in the beta-chains of class II antigens of the bovine major histocompatibility complex. One monoclonal antibody, mAb VPM57, reacted on immunoblots with an epitope present in approximately half of the haplotypes investigated. This reagent is especially useful in discriminating electrophoretic variants that have similar isoelectric points.

Animals↗