Biomedical subjects
Publications and source records attributed to R J Steele.
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The DEAD box RNA helicase, p68, is upregulated in exponentially growing cells and shows cell cycle-dependent changes in nuclear localization. Although some other DEAD box proteins have been implicated in cancer, there have been no reports of any link between p68 status and carcinogenesis. In the present study we have analysed specimens from 50 patients with colorectal adenocarcinomas, including cases in which an adenomatous polyp was also present, by immunohistochemistry and Western blotting. Our data indicate that p68 protein is consistently overexpressed in tumours as compared with matched normal tissue. Examination of the levels of p68 mRNA from both normal and tumour tissue showed no obvious specific increase in p68 mRNA levels in tumours nor any evidence of underlying mutations in the p68 coding region. Interestingly, however, the accumulated p68 appears to be poly-ubiquitylated, suggesting a possible defect in proteasome-mediated degradation in these tumours. This overexpression/ubiquitylation is observed in both pre-invasive and invasive lesions suggesting that the dysregulation of p68 expression occurs early during tumour development. Finally, we demonstrate that ubiquitylation of p68 occurs in cultured cells, thereby providing a model for the molecular analysis of this process and its potential role in tumorigenesis.
BACKGROUND: Little is known of how the quality of life of patients with rectal cancer changes after surgery, and whether or not quality of life is associated with and predictive of survival. The aims of this study were to address these issues. METHODS: The Medical Outcomes Study Short Form 36 (SF-36), and the European Organization for the Research and Treatment of Cancer QLQ-C30 and QLQ-CR38 quality of life questionnaires were administered to patients before surgery for rectal cancer, on discharge home and at 3-month intervals after operation for up to 1 year. Survival was measured in days from the time of surgery to death. RESULTS: Sixty-five patients with a median age of 67 years participated. Most quality of life scores dropped significantly below baseline in the early postoperative period. From the third month onwards some scores, such as the global quality of life score and emotional function score on the QLQ-C30, improved. Other scores, including role function, fatigue and pain on the QLQ-C30, were similar to baseline values after 3-6 months and remained unchanged. However, scores such as sexual enjoyment and male sexual problems on the QLQ-CR38 were worse than baseline in the early postoperative period and remained poor thereafter. Stepwise regression analyses showed that preoperative quality of life dimension scores for physical function, nausea/vomiting and sexual enjoyment, together with age, predicted postoperative 1-year survival with an accuracy of 76.8 per cent. CONCLUSION: The findings of this study confirm that quality of life after rectal cancer surgery changes with time. It is generally worst in the early postoperative period. Preoperative quality of life is a good predictor of survival at 1 year.
AIMS: To determine, in patients operated upon for rectal cancer, the impact that tumour recurrence has on quality of life. METHODS: Twenty-five patients, who had curative surgery for rectal cancer from 1992 to 1997, and who subsequently developed tumour recurrence, participated. Each patient was individually matched with two patients who also had rectal cancer surgery during the same period of time but were considered to be free of cancer. The patients were matched for age, gender, type of operation and socioeconomic status. They answered the European Organization for the Research and Treatment of Cancer (EORTC) QLQ-C30 and CR38 quality of life questionnaires, as well as the SF36 II questionnaire, at least 1 year after surgery. RESULTS: Patients with recurrent rectal cancer had significantly lower quality of life scores than cured patients in most dimensions, as measured by the three questionnaires. A significant difference was also seen in the global quality of life score on the QLQ-C30 (median scores 50 vs 75, z = 4.015, P = 0.0001). CONCLUSION: Recurrence of rectal cancer has a profound effect on quality of life, affecting most measurable dimensions. Treatment of recurrent cancer should not only be directed at the physical aspect of the disease, but also at its psychological and social aspects.
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A panproctocolectomy and permanent ileostomy improves the quality of life of those suffering from ulcerative colitis. However, it is not known how the quality of life of patients who had this operation compares with that of the general population. The aim of this study was to measure the quality of life of these patients using a reliable and validated instrument, and to determine whether these patients enjoy a similar quality of life to the general population. Forty-nine consecutive patients (31 males and 18 females, median age 49 years), who had a panproctocolectomy with a permanent ileostomy for ulcerative colitis in one of three hospitals in Tayside, UK from 1992-1997, participated in the study. The median number of months (range) post-surgery was 29 (12-72). Participants answered a well-validated generic questionnaire on health-related quality of life: the new SF-36 version 2.0 (SF-36II). The results were then compared with population norms of similar age and gender, derived from the Third Oxford Healthy Lifestyle Survey and published by the Health Services Research Unit of the University of Oxford. The mean score difference between patient and population SF-36II scores (95% confidence intervals) were as follows: physical functioning (PF): -3.9 (-9.4, 1.6); role-physical (RP): -4.1 (-9.9, 1.7); role-emotional (RE): -0.1 (-5.6, 5.4); energy-vitality (EV): 8.2 (2.8-13.6); body pain (BP): 6.6 (0.3, 12.9); social functioning (SF): 3.7 (-2.7, 10.1); mental health (MH): 2.5 (-2.5, 7.5); general health perception (GHP): -1.8 (-7.6, 4.0). Despite the fact that these patients underwent major surgery and have a permanent stoma, their quality of life as measured by the SF-36II was very similar to that of the general population.
The nose is becoming a common route of drug administration, however, little is known about the pH of the human nasal cavity. Local pH may have a direct effect on the rate and extent of absorption of ionizable compounds and hence this study was performed to investigate normal pH values and whether pH could be manipulated by various buffers. Twelve healthy volunteers participated in a study to measure pH in the anterior and posterior sites of the nasal cavity. Miniature pH electrodes were placed 3 cm apart in the nasal cavity and a baseline was recorded for 30 min once the pH had stabilized. One hundred microlitres of isotonic solution was sprayed into the nostril and the pH was measured for 4 h post-dose. The following five formulations were tested: formulation A--sodium chloride (0.9%) at pH 7.2; formulation B--sodium chloride (0.9%) at pH 5.8; formulation C--Sorensens phosphate buffer (0.06 M) at pH 5. 8; formulation D--Sorensens phosphate buffer (0.13 M) at pH 5.8 and formulation E--formulation as (c) but adjusted to pH 5.0. Each formulation also contained saccharin sodium (0.5%) as a taste marker for nasal clearance. The time at which each subject detected the taste of saccharin was noted. The 30-minute baseline recording prior to administration of the nasal spray formulation demonstrates that there was both considerable intersubject and intrasubject variation in nasal pH. The average pH in the anterior of the nose was 6.40 (+0. 11, -0.15 S.D.) when calculated from H(+) values. The pH in the posterior of the nasal cavity was 6.27 (+0.13, -0.18 S.D.). The overall range in pH was 5.17-8.13 for anterior pH and 5.20-8.00 for posterior pH. Formulation A caused the pH in the anterior part of the nasal cavity to reach a maximum of 7.06 in 11.25 min from the baseline of pH 6.14 (P<0.05). The mean baseline pH was 6.5 for the posterior part of the nose which did not change over the recording period. Formulation B caused the anterior pH to increase from pH 6. 60 to 7.25 within the first minute. This fell back to a mean pH of 7.07 over the first hour which was still significantly above the baseline. It remained at this value for the remainder of the recording period. The initial average posterior pH was 6.32 and again this did not significantly change over the recording period. Formulation C produced a sustained increase in anterior nasal pH from a baseline pH of 6.57-7.12. A small transient decrease was observed in the pH in the posterior of the nose but baseline pH of 6. 6 was re-established within 15 min post dose. Formulation D significantly reduced anterior nasal pH from 6.30 to 5.87 by 30 min reaching a pH of 5.95 by 90 min where it remained for the remainder of the recording period. The posterior baseline pH was 6.3 and introduction of the pH 5.8 buffer caused a slow increase over 90 min to pH 6.6. Formulation E increased anterior pH from 6.1 to 6.7 for the remainder of the recording period. It had an insignificant effect on posterior nasal pH. The mean (+/-S.D.) time to taste saccharin for formulations A to E was 13.42+/-10.21, 14.67+/-8.37, 11.67+/-8.08, 10.08+/-7.6, 9.80+/-6.73 min, respectively. There was no significant difference between the clearance times for the different formulations. In conclusion, average baseline human nasal pH is approximately 6.3. Nasal anterior pH can be decreased when buffers of 0.13 M and above are used. Mildly acidic solutions produce an increase in pH presumably due to reflux bicarbonate secretion. Posterior nasal pH was not altered by administration of any buffer except the 0.13 M buffer at pH 5.8. This produced a rise in posterior pH.
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BACKGROUND: Owing to decreased hours of work and duration of training, there is a need to refashion the training of surgical specialist registrars (SpRs) in the United Kingdom. This requires more guidance for trainers, but consensus regarding good trainer attributes does not exist. This study describes the training practices of Tayside general surgical trainers working with SpRs and highlights good training practice involving technical and patient management skills. METHODS: 1) Semi-structured interviews carried out with eighteen consultant trainers and twelve SpRs, 2) Action inquiry (i.e. observations and dialogue with participants) during ward, theatre, outpatient clinic and other hospital-based settings with eleven consultant and SpRs pairs. RESULTS AND CONCLUSION: Participants reflected on multiple training episodes and evaluated their impact. Relatively positive or negative impacts on their skill learning, self-esteem and relationship with the trainee or trainer were described. These are presented and discussed in terms of their implications for equipping trainers with techniques for training registrars and those factors which have hindered the adoption of successful strategies.
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We investigated the role of NMDA receptors in memory encoding and retrieval. A delayed matching-to-place (DMP) paradigm in the watermaze was used to examine 1-trial spatial memory in rats. Over periods of up to 21 days, 4 daily trials were given to an escape platform hidden in a new location each day, with the memory interval (ITI) varying from 15 sec to 2 hours between trials 1 and 2, but always at 15 sec for the remaining ITIs. Using chronic i.c.v. infusions of D-AP5, acute intrahippocampal infusions, ibotenate hippocampus + dentate lesions and relevant aCSF or sham surgery control groups, we established: (1) the DMP task is hippocampal-dependent; (2) D-AP5 causes a delay-dependent impairment of memory in which the Groups x Delay interaction was significant on two separate measures of performance; (3) this memory impairment also occurs with acute intrahippocampal infusions; (4) the impairment occurs irrespective of whether the animals stay in or are removed from the training context during the memory delay interval; and (5) D-AP5 affects neither the retrieval of information about the spatial layout of the environment, nor memory of where the escape platform had been located on the last day before the start of chronic D-AP5 infusion. LTP in vivo in the dentate gyrus was blocked in the chronically-infused D-AP5 rats and HPLC measurements at sacrifice revealed appropriate intrahippocampal levels. Acute intrahippocampal infusion of radiolabelled D-AP5 revealed relatively restricted diffusion and was used to estimate whole-tissue hippocampal drug concentrations. These results indicate that (1) short-term memory for spatial information is independent of NMDA receptors; (2) the rapid consolidation of spatial information into long-term memory requires activation of hippocampal NMDA receptors; (3) NMDA receptors are not involved in memory retrieval; and (4) the delay-related effects of NMDA receptor antagonists on performance of this task cannot be explained in terms of sensorimotor disturbances. The findings relate to the idea that hippocampal synaptic plasticity is involved in event-memory (Morris and Frey, Phil Trans R Soc Lond B 1997;352:1489-1503) and to a computational model of one-trial DMP performance of Foster et al. (unpublished data).
In two species of birds, food-storing marsh tits, P. palustris, and non-storing blue tits, P. caeruleus, quantitative receptor autoradiography was used to localize NMDA (N-methyl-D-aspartate)-sensitive [3H]glutamate, [3H]MK801, and [3H]AMPA binding sites, in six regions of the forebrain: hippocampus and parahippocampus, hyperstriatum accessorium (vision) and ventrale (sensory integration), neostriatum (auditory), and lobus parolfactorius (basal ganglia). In both species high levels of labelling to both NMDA and AMPA receptors were observed throughout the forebrain. However, a marked difference in receptor labelling was apparent between the two species, with levels of binding to NMDA ion channel sites being significantly lower (20%) in both the hippocampus and parahippocampus, in food storers compared to non-food storers. The levels of binding to other forebrain regions were remarkably similar in the two species. No differences were seen in the binding to AMPA receptors in forebrain regions of either species.
The aim of this study was to evaluate the safety and tolerability of 4 weeks administration of marimastat, and to seek evidence of biological activity as observed by changes in the endoscopic appearance of the gastric tumours. 35 patients with advanced, inoperable gastric or gastro-oesophageal tumours were recruited. The dose of marimastat was reduced from the starting dose of 50 mg twice daily (6 patients) to 25 mg once daily (29 patients). 31 completed the 28 day study period. Marimastat was generally well tolerated, with the principal treatment-related toxicity being pain and stiffness of the musculoskeletal system. These symptoms occurred more frequently at the higher-dose, and increased to involve a total of 13 patients (37%) with longer-term treatment. The events were usually rapidly reversible on drug discontinuation. 3 patients receiving prolonged treatment experienced more severe symptoms, with the development of skin thickening and contractures in the hands. At endoscopy, 10 patients showed an increased fibrotic cover of the tumour, 8 had decreased haemorrhagic appearance, and in at least 2 cases where comparative tumour histology was assessable, there was evidence of increased stromal fibrotic tissue.
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AIMS: To assess and compare knowledge and awareness of colorectal cancer and breast cancer in a sample of the general population. METHODS: Eleven hundred visitors to six different outpatient clinics, in a University Hospital, were given a study-specific questionnaire, based on educational material from the British Association of Cancer United Patients (CancerBACUP). The questionnaire consisted of 12 statements on the incidence, presentation, detection, treatment and prognosis of colorectal and breast cancer. RESULTS: One thousand and sixty-eight individuals returned the questionnaire. One thousand and four completed questionnaires were analysed. The mean age (SD) of respondents was 50.1 (17.2) years, and the male to female ratio was 2:3. Respondents had read more about breast than about colorectal cancer (60.3%vs 32.4%, P<0.0001, McNemar's test). The proportion of correct answers for each statement on breast cancer was higher than for answers to corresponding items on colorectal cancer. Mean overall scores (95% CI) for breast and colorectal cancer were 88.1 (86.9, 89.2) and 64.4 (62.5, 66.3) respectively, the mean difference (95% CI) being 23.7 (22.0, 25.5). Scores were higher for breast cancer irrespective of age or gender. CONCLUSION: There is a low level of understanding of colorectal cancer in the general population when compared to breast cancer. This highlights the importance of public education in this common cancer.
BACKGROUND AND STUDY AIMS: One reason why many surgeons do not attempt laparoscopic cholangiography is that it is considered to be technically difficult and to produce poor-quality images. PATIENTS AND METHODS: A retrospective comparison was made of twenty randomly selected intraoperative cholangiograms taken during laparoscopic cholecystectomy for each year from 1991 to 1994 (n = 80) by assigning a score (0-4) on the basis of anatomical parameters and radiographic quality. Twenty randomly selected intraoperative cholangiograms taken during open cholecystectomy (OC) were used as controls. RESULTS: The average score for the laparoscopic cholangiograms (LCs) was significantly lower than the average for OC cholangiograms (2.3 vs. 3.4, P< 0.001). In addition, a learning curve was demonstrated, which showed significant improvement in the quality of LCs over the years. Analysis showed that in LCs, only 34 % succeeded in demonstrating the entire biliary tree and only 49% managed to show the extrahepatic duct system. Choledocholithiasis could only be ruled out in 53 % of LC films, compared with 80 % of controls. CONCLUSIONS: Despite an improvement in the quality of laparoscopic cholangiography, it remains inferior to cholangiography during open cholecystectomy. Recommendations are made regarding ways in which improvements could be achieved.
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