Caspase protease manipulation: a novel approach to apoptotic induction in prostate cancer.
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Biomedical subjects
Publications and source records attributed to J M Fitzpatrick.
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BACKGROUND: The mortality rate associated with acute mesenteric ischaemia (AMI) remains high. Diagnosis is frequently confounded by the non-specific history and physical signs, in conjunction with the absence of a reliable biological assay. Glutathione S-transferase (GST) is an enzyme with a crucial role in cellular homoeostasis, the alpha isoenzyme of which is highly specific to small bowel and liver. This study assessed alphaGST as a marker for AMI. METHODS: Twenty-six patients with acute abdominal pain were enrolled. Each patient manifested a diagnostic dilemma, with a potential diagnosis of AMI. Plasma was reserved for alphaGST assay during routine blood testing and stored at -20 degrees C for analysis. A final diagnosis was made by autopsy, laparotomy, a definitive other investigation or a return to full health. RESULTS: Twelve patients had AMI. Plasma alphaGST was significantly increased in patients with AMI (P < 0.0001). Although pH differed and other biochemical changes occurred, only alphaGST accurately predicted AMI. CONCLUSION: A threshold of 4 ng/ml for alphaGST was 100 per cent sensitive and 86 per cent specific for AMI. If these observations can be confirmed, evaluation of alphaGST may reliably predict the presence or absence of AMI.
Previous research investigating shift work and its impact upon the quality of registered nurse performance and outcomes (including biological, psychosocial and organizational) is reviewed. The present study, which involved non-participant observation of staff nurses (n = 34) within their first year of practice (Part 1 or Part 12 of the United Kingdom Professional Register), is described. The findings demonstrated support for earlier research which suggested that 12 1/2 hour shifts are associated with less effective performance. This study, together with previous research, highlights important indicators for the design and management of future empirical work which is required to investigate the influence of shift work upon process as well as outcomes for nurses, service users and the employing organization. This is particularly pertinent in the light of recent changes in work patterns. The well-being and effectiveness of the nursing workforce requires enhancement, and the effective management of shift-work is a key strategy in achieving this.
The primary objective of this study is to perform a blinded evaluation of two groups of retrospective image registration techniques, using as a gold standard a prospective marker-based registration method, and to compare the performance of one group with the other. These techniques have already been evaluated individually [27]. In this paper, however, we find that by grouping the techniques as volume based or surface based, we can make some interesting conclusions which were not visible in the earlier study. In order to ensure blindness, all retrospective registrations were performed by participants who had no knowledge of the gold-standard results until after their results had been submitted. Image volumes of three modalities: X-ray computed tomography (CT), magnetic resonance (MR), and positron emission tomography (PET) were obtained from patients undergoing neurosurgery at Vanderbilt University Medical Center on whom bone-implanted fiducial markers were mounted. These volumes had all traces of the markers removed and were provided via the Internet to project collaborators outside Vanderbilt, who then performed retrospective registrations on the volumes, calculating transformations from CT to MR and/or from PET to MR. These investigators communicated their transformations, again via the Internet, to Vanderbilt, where the accuracy of each registration was evaluated. In this evaluation, the accuracy is measured at multiple volumes of interest (VOI's). Our results indicate that the volume-based techniques in this study tended to give substantially more accurate and reliable results than the surface-based ones for the CT-to-MR registration tasks, and slightly more accurate results for the PET-to-MR tasks. Analysis of these results revealed that the rotational component of error was more pronounced for the surface-based group. It was also apparent that all of the registration techniques we examined have the potential to produce satisfactory results much of the time, but that visual inspection is necessary to guard against large errors.
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PURPOSE: Colonic mucosal metabolism of butyrate may be impaired in ulcerative colitis. In this study we sought to confirm this observation, to determine if a similar change occurs in Crohn's colitis, and to establish whether a panenteric disorder of butyrate metabolism exists in either condition. METHODS: With use of a microculture technique, mucosal metabolic fluxes of 14[C]-labeled butyrate and 14[C]-labeled glutamine were measured as 14[C] carbon dioxide production in mucosal biopsy specimens from the colon and ileum in patients with ulcerative colitis, Crohn's colitis, and healthy bowel. Results were expressed as pmol/microg biopsy DNA/hour. RESULTS: In the colon the mucosal metabolic fluxes of both butyrate and glutamine are reduced in both ulcerative colitis and Crohn's colitis compared with healthy controls. These changes were most marked in the presence of moderate to severe mucosal inflammation, there being no significant difference in mucosal metabolic flux between mildly inflamed mucosa and healthy controls. In the ileum the mucosal metabolic fluxes of butyrate and glutamine did not differ between healthy controls and those with either ulcerative colitis or Crohn's colitis. CONCLUSIONS: Changes in colonic mucosal metabolism of butyrate and glutamine in inflammatory bowel disease occur as a consequence of the inflammatory process and are not peculiar to ulcerative colitis. Ileal mucosal metabolism is unchanged in ulcerative colitis and Crohn's colitis, indicating the absence of a panenteric abnormality of mucosal metabolism in these two conditions.
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PURPOSE: To determine alterations in regional renal blood flow following unilateral nephrectomy using an autoradiographic technique. The role of prostaglandins and the sympathetic nervous system in the mediation of these changes was assessed. MATERIALS AND METHODS: C-14 iodoantipyrine was used as a tracer to measure intrarenal blood flow in anaesthetised rats at multiple time points following nephrectomy. Autoradiographs were produced from tissue sections. C-14 concentrations were measured from standards thus allowing blood flow values to be calculated. RESULTS: Base line values for cortical and medullary blood flow were 806 +/- 63 and 373 +/- 39 ml./100 gm./min. (mean +/- SEM) respectively. At 2 hours post nephrectomy blood flow to both the cortex and medulla increased significantly (1152 +/- 54 and 594 +/- 37; p < 0.05). Blood flow had returned to control levels by 24 hours and was maintained at 5 days post-nephrectomy. Multiple discrete regions of high blood flow within the cortex were observed. Microautoradiography defined the morphological location of these discrete regions of higher blood flow as periglomerular vasculature. Diclofenac administration did not inhibit the augmentation in cortical blood flow post-nephrectomy, while medullary blood flow fell below base line values at both 30 minutes and 2 hours following nephrectomy. Sympathetic denervation did not affect the changes in cortical blood flow seen following nephrectomy, but did ameliorate the changes in medullary blood flow. CONCLUSIONS: Significant, transient changes in regional renal blood flow occur in the residual kidney following unilateral nephrectomy. The interaction between vasoactive mediators and the autonomic nervous system which produces changes in cortical blood flow is complex. It is evident, however, that medullary blood flow is dependent on local prostaglandin production and is also influenced by sympathetic nervous supply.
OBJECTIVE: Advances in imaging resolution have resulted in superior visualization of intracranial anatomy. Because of the inherent complexity of the surgical exposure of these lesions, intraoperative localizing techniques are required. Currently, C-arm fluoroscopy provides only two-dimensional localization for these anatomic structures. The recently described ACUSTAR I system, developed in conjunction with Codman and Shurtleff, Inc. (Randolph, Mass.), is an interactive, image-guided device that allows three-dimensional localization with a degree of accuracy previously unattainable. We assessed the clinical utility of the ACUSTAR I system for intraoperative spatial confirmation during transsphenoidal approaches to pituitary lesions. METHODS: Eight patients underwent transsphenoidal approaches to pituitary lesions with the assistance of the ACUSTAR I system. The spatial relationships were clinically judged intraoperatively by the surgeon and by use of traditional C-arm fluoroscopy and then were compared with the ACUSTAR I system results. RESULTS: In all eight patients, the ACUSTAR I system correctly displayed the surgical orientation and provided localization to within less than 1 mm. In two patients, this facilitated the redirection of an errant approach. No complications were associated with the use of this image-guided device. CONCLUSIONS: The ACUSTAR I system is useful in displaying accurate, three-dimensional anatomic relationships during transsphenoidal approaches to pituitary lesions. This system provides critical information intraoperatively to redirect errant approaches and prevent significant morbidity.
A triangulation design using two simulations, non-participant observation and a semi-structured interview to explore senior student nurse performance in South East England is described. A comparison of student nurse performance (registered general nurse [RGN] programme n = 34; registered nurse Project 2000 diploma programme n = 34; integrated degree programme n = 31) indicated many similarities but also some important differences in outcomes which included: a more systematic approach to information-seeking, better care-planning skills and higher quality nurse performance among integrated degree programme participants; use of a model and the immediate role of the nurse to guide information-seeking and better care-planning skills and weaknesses in clinical nurse performance among RGN programme participants; and weaknesses in the information-seeking, care-planning and clinical nurse performance among Project 2000 diploma participants. There were no significant differences between the clinical performance scores of the RGN and diploma programme participants. The interview data suggested that the integrated degree programme participants had a client focus in contrast to the professional focus of RGN and Project 2000 diploma participants. The findings, however, must be viewed within the context of an exploratory study of limited sample size. The research was funded by the English National Board for Nursing, Midwifery and Health Visiting.
BACKGROUND: Construction of an ileal faecal or urinary reservoir profoundly alters ileal luminal ecology and availability of mucosal metabolic substrates. The aims of this study were to measure mucosal metabolic flux of butyrate and glutamine in histologically normal (control) ileum and to determine the effect of reservoir construction on metabolic fluxes in patients with ileal pouch-anal anastomosis and ileocystoplasty. METHODS: Endoscopic biopsy samples were obtained from normal ileum (n = 10), ileum of patients with ulcerative colitis (n = 10), ileal pouch-anal anastomosis (n = 7), ileocystoplasty (n = 7) and ileal conduit (n = 7). Using a closed microculture technique, biopsy utilization of 14C-labelled butyrate and glutamine was measured as [14C]carbon dioxide production. Biopsy DNA content was measured and [14C]carbon dioxide evolution expressed as picomoles [14C]carbon dioxide per microgram DNA per hour. RESULTS: The metabolic flux of both butyrate and glutamine was reduced in ileal pouch mucosa compared with that of ileal mucosa in patients with ulcerative colitis. In contrast, the metabolic flux of buyrate alone was reduced in ileal mucosa from ileocystoplasty and ileal conduit compared with that in normal ileal mucosa, while the metabolic flux of glutamine remained unchanged. CONCLUSION: Ileal mucosal metabolic fluxes measured in vitro are altered by changing luminal ecology in vivo. These changes may affect the health and mucosal integrity of ileum used to construct these reservoirs.
OBJECTIVE: To assess the public awareness of prostate cancer and willingness to seek medical attention for urinary symptoms, and to determine associated factors. SUBJECTS AND METHODS: A community survey was conducted using a questionnaire administered by the interviewer to 280 randomly selected Irish men aged 40-69 years. RESULTS: A quarter of the men had not heard of prostate cancer; factors associated with having heard were nonmanual social class, living with a female partner and a history of treatment for urinary disease. Eighty per cent said they would be willing to attend a GP if they had urinary symptoms; associated factors were living with a female partner, having heard of prostate cancer and having seen a GP more than once in the preceding year. Just over half deemed attendance to be urgent/important; associated factors were having heard of prostate cancer, living with a female partner and having a relative with cancer. Having a General Medical Services card (a means-tested medical card entitling the holder to free medical services) was negatively associated. Lower social class was negatively associated with routine questioning by a GP about urinary symptoms. CONCLUSIONS: There is a marked social-class gradient in knowledge and willingness to seek medical advice. In the absence of population screening, earlier clinical presentation with prostate cancer is essential if prognosis is to be improved; there is an evident need to improve prostate cancer awareness, particularly in the lower social classes, if this goal is to be achieved.
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OBJECTIVE: Several causes of spatial inaccuracies in image-guided surgery have been carefully studied and documented for several systems. These include error in identifying the external features used for registration, geometrical distortion in the preoperative images, and error in tracking the surgical instruments. Another potentially important source of error is brain deformation between the time of imaging and the time of surgery or during surgery. In this study, we measured the deformation of the dura and brain surfaces between the time of imaging and the start of surgical resection for 21 patients. METHODS: All patients underwent intraoperative functional mapping, allowing us to measure brain surface motion at two times that were separated by nearly an hour after opening the dura but before performing resection. The positions of the dura and brain surfaces were recorded and transformed to the coordinate space of a preoperative magnetic resonance image, using the Acustar surgical navigation system (manufactured by Johnson & Johnson Professional, Inc., Randolph, MA) (the Acustar trademark and associated intellectual property rights are now owned by Picker International, Highland Heights, OH). This system performs image registration with bone-implanted markers and tracks a surgical probe by optical triangulation. RESULTS: The mean displacements of the dura and the first and second brain surfaces were 1.2, 4.4, and 5.6 mm, respectively, with corresponding mean volume reductions under the craniotomy of 6, 22, and 29 cc. The maximum displacement was greater than 10 mm in approximately one-third of the patients for the first brain surface measurement and one-half of the patients for the second. In all cases, the direction of brain shift corresponded to a "sinking" of the brain intraoperatively, compared with its preoperative position. Analysis of the measurement error revealed that its magnitude was approximately 1 to 2 mm. We observed two different patterns of the brain surface deformation field, depending on the inclination of the craniotomy with respect to gravity. Separate measurements of brain deformation within the closed cranium caused by changes in patient head orientation with respect to gravity suggested that less than 1 mm of the brain shift recorded intraoperatively could have resulted from the change in patient orientation between the time of imaging and the time of surgery. CONCLUSION: These results suggest that intraoperative brain deformation is an important source of error that needs to be considered when using surgical navigation systems.
Recent study has increased the understanding of the physiological processes occurring in obstructive uropathy, in particular the role played by vasoactive mediators and cellular mechanisms. There is an emphasis on developing effective and less invasive means of detection and treatment of ureteric obstruction, although it remains to be determined how the techniques currently being assessed will impact on clinical practice.
In a previous study we demonstrated that automatic retrospective registration algorithms can frequently register magnetic resonance (MR) and computed tomography (CT) images of the brain with an accuracy of better than 2 mm, but in that same study we found that such algorithms sometimes fail, leading to errors of 6 mm or more. Before these algorithms can be used routinely in the clinic, methods must be provided for distinguishing between registration solutions that are clinically satisfactory and those that are not. One approach is to rely on a human observer to inspect the registration results and reject images that have been registered with insufficient accuracy. In this paper, we present a methodology for evaluating the efficacy of the visual assessment of registration accuracy. Since the clinical requirements for level of registration accuracy are likely to be application dependent, we have evaluated the accuracy of the observer's estimate relative to six thresholds: 1-6 mm. The performance of the observers was evaluated relative to the registration solution obtained using external fiducial markers that are screwed into the patient's skull and that are visible in both MR and CT images. This fiducial marker system provides the gold standard for our study. Its accuracy is shown to be approximately 0.5 mm. Two experienced, blinded observers viewed five pairs of clinical MR and CT brain images, each of which had each been misregistered with respect to the gold standard solution. Fourteen misregistrations were assessed for each image pair with misregistration errors distributed between 0 and 10 mm with approximate uniformity. For each misregistered image pair each observer estimated the registration error (in millimeters) at each of five locations distributed around the head using each of three assessment methods. These estimated errors were compared with the errors as measured by the gold standard to determine agreement relative to each of the six thresholds, where agreement means that the two errors lie on the same side of the threshold. The effect of error in the gold standard itself is taken into account in the analysis of the assessment methods. The results were analyzed by means of the Kappa statistic, the agreement rate, and the area of receiver-operating-characteristic (ROC) curves. No assessment performed well at 1 mm, but all methods performed well at 2 mm and higher. For these five thresholds, two methods agreed with the standard at least 80% of the time and exhibited mean ROC areas greater than 0.84. One of these same methods exhibited Kappa statistics that indicated good agreement relative to chance (Kappa > 0.6) between the pooled observers and the standard for these same five thresholds. Further analysis demonstrates that the results depend strongly on the choice of the distribution of misregistration errors presented to the observers.
Guidance systems designed for neurosurgery, hip surgery, and spine surgery, and for approaches to other anatomy that is relatively rigid can use rigid-body transformations to accomplish image registration. These systems often rely on point-based registration to determine the transformation, and many such systems use attached fiducial markers to establish accurate fiducial points for the registration, the points being established by some fiducial localization process. Accuracy is important to these systems, as is knowledge of the level of that accuracy. An advantage of marker-based systems, particularly those in which the markers are bone-implanted, is that registration error depends only on the fiducial localization error (FLE) and is thus to a large extent independent of the particular object being registered. Thus, it should be possible to predict the clinical accuracy of marker-based systems on the basis of experimental measurements made with phantoms or previous patients. This paper presents two new expressions for estimating registration accuracy of such systems and points out a danger in using a traditional measure of registration accuracy. The new expressions represent fundamental theoretical results with regard to the relationship between localization error and registration error in rigid-body, point-based registration. Rigid-body, point-based registration is achieved by finding the rigid transformation that minimizes "fiducial registration error" (FRE), which is the root mean square distance between homologous fiducials after registration. Closed form solutions have been known since 1966. The expected value (FRE2) depends on the number N of fiducials and expected squared value of FLE, (FLE-2, but in 1979 it was shown that (FRE2) is approximately independent of the fiducial configuration C. The importance of this surprising result seems not yet to have been appreciated by the registration community: Poor registrations caused by poor fiducial configurations may appear to be good due to a small FRE value. A more critical and direct measure of registration error is the "target registration error" (TRE), which is the distance between homologous points other than the centroids of fiducials. Efforts to characterize its behavior have been made since 1989. Published numerical simulations have shown that (TRE2) is roughly proportional to (FLE2)/N and, unlike (FRE2), does depend in some way on C. Thus, FRE, which is often used as feedback to the surgeon using a point-based guidance system, is in fact an unreliable indicator of registration-accuracy. In this work we derive approximate expressions for (TRE2), and for the expected squared alignment error of an individual fiducial. We validate both approximations through numerical simulations. The former expression can be used to provide reliable feedback to the surgeon during surgery and to guide the placement of markers before surgery, or at least to warn the surgeon of potentially dangerous fiducial placements; the latter expression leads to a surprising conclusion: Expected registration accuracy (TRE) is worst near the fiducials that are most closely aligned! This revelation should be of particular concern to surgeons who may at present be relying on fiducial alignment as an indicator of the accuracy of their point-based guidance systems.