Abdominal aortic aneurysm rupture is not associated with an up-regulation of inflammation within the aneurysm wall.

BACKGROUND: The nature of the inflammatory change within ruptured AAA has not been extensively reported. The aim of this study was to compare the inflammatory response in non-ruptured and ruptured aneurysms with emphasis on the site of rupture. METHODS: Non-rupture site biopsies were taken from the anterior aneurysm sac of non-ruptured (n=31) and ruptured AAA (n=20). In 12 ruptured AAA, a further biopsy was taken from the rupture site. Enzyme-linked immunosorbent assay was used to quantify IL-6, IL-1beta and TNF-alpha. Quantitative immunohistochemistry was undertaken for generic lymphocytes, T-cells, and B-cells. RESULTS: Comparing biopsies in non-ruptured AAA versus a non-rupture site biopsy from ruptured AAA; there was no significant difference in IL-6, IL-1beta, TNF-alpha, generic lymphocytes, T-cell or B-cell content. Comparing ruptured AAA--non-rupture site with rupture site; IL-6 and TNF-alpha were unchanged. By contrast IL-1beta and lymphocytes were lower at the rupture site compared to the non-rupture site (IL-1beta 1.39 ng/mg [0.97-2.29] vs. 1.92 ng/mg [1.46-2.57], p=0.027; generic lymphocytes 2.89% [0.51-5.51] vs. 4.73% [2.27-12.40], p=0.018; T-cells 0.28% [0.04-1.18] vs. 0.82% [0.40-1.36], p=0.027; B-cells 0.16% [0.04-1.14] vs. 1.30% [0.32-5.40], p=0.021). CONCLUSIONS: These findings suggest the biological events leading to AAA rupture may not be dependent on an up-regulation in the inflammatory process.

A fuller understanding of pancreatic neuroendocrine tumours combined with aggressive management improves outcome.

BACKGROUND: Neuroendocrine tumours of the pancreas (PNETs) represent 1-2% of all pancreatic tumours. The terms 'islet cell tumours' and 'carcinoids' of the pancreas should be avoided. The aim of this review is to offer an overview of the history and diagnosis of PNETs followed by a discussion of the available treatment options. METHODS: A search on PubMed using the keywords 'neuroendocrine', 'pancreas' and 'carcinoid' was performed to identify relevant literature over the last 30 years. RESULTS: The introduction of a revised classification of neuroendocrine tumours by the World Health Organisation (WHO) in 2000 significantly changed our understanding of and approach to the management of these tumours. Advances in laboratory and radiological techniques have also led to an increased detection of PNETs. Surgery remains the only treatment that offers a chance of cure with increasing number of non-surgical options serving as beneficial adjuncts. The better understanding of the behaviours of PNETs together with improvements in tumour localisation has resulted in a more aggressive management strategy with a concomitant improvement in symptom palliation and a prolongation of survival. CONCLUSION: Due to their complex nature and the wide range of therapeutic options, the involvement of specialists from all necessary disciplines in a multidisciplinary team setting is vital to provide optimal treatment of this disease.

Online survey of current autopsy practice.

AIMS: The Royal College of Pathologists (RCPath) has for several years published guidance on good autopsy practice. However, pressures such as time, cost and the introduction of the Human Tissue Act have generated suggestions that there is a discrepancy between the published guidelines and what can realistically be achieved in daily practice. The aims of this study were to determine the extent to which practising pathologists agree with this complaint, and what suggestions they might have for its resolution. METHODS: All histopathologists in the UK on the RCPath database (n = 1213) were sent an email invitation to participate in an online questionnaire. RESULTS: 406 pathologists completed the survey, providing numerical data and free-text responses. Results concerning pressures of time, resources and limitations on examination and sampling were in keeping with those expected from recent issues raised. The view that RCPath guidelines are higher than can be achieved in routine coronial autopsy practice was widely supported, but only 45% stated that the RCPath should publish separate guidelines to differentiate between hospital ("consent") autopsies and medico-legal cases. CONCLUSION: The circumstances under which coronial autopsies are conducted in many parts of the UK make it difficult or impossible to comply with current RCPath guidance. Pathologists disagree on whether this situation demands a reduction of RCPath standards, an improvement in autopsy practice in medico-legal cases to current RCPath standards, or the implementation of "double standards". Resolution of this dilemma requires clarification of exactly what a coronial autopsy is trying to achieve.

Obtaining explicit consent for the use of archival tissue samples: practical issues.

BACKGROUND: Over the past few years, research ethics committees have increasingly demanded explicit consent before archival tissue samples can be used in research projects. Current UK guidance in this area requires an assessment of whether it is "practical" to obtain explicit consent. Ethics committees have little experience or evidence to help them to judge what is "practical" in this context. METHODS: We attempted to obtain general consent for research use of surplus tissue from renal transplant biopsies from the entire patient population of the renal transplant unit in Leicester. The nature of this patient population would be expected to facilitate this task. RESULTS: A total of 495 letters were sent. Attempts were made to contact non-responders when they attended the outpatient clinic. One year after the initiation of the project, the opinions of 26% of the patients had still not been ascertained. CONCLUSIONS: The results confirm that the vast majority of patients are happy for "surplus" biopsy material to be used for research; the situation does not parallel the use of autopsy tissue. A requirement to obtain explicit consent for the study of archival tissue is likely, however, to block or at least seriously delay research, which is contrary to the public interest and specifically may harm the interests of the patients concerned. In the UK, the problem of tissue being used against the wishes of the donor has now been largely replaced by the problem of prohibition of tissue use against the wishes of the donor.

Randomized clinical trial of the effect of microemulsion cyclosporin and tacrolimus on renal allograft fibrosis.

BACKGROUND: The aim of this study was to compare the effect of Neoral cyclosporin- and tacrolimus-based therapy on the development of renal allograft fibrosis (chronic allograft nephropathy; CAN) in a prospective randomized trial. METHODS: A total of 102 patients undergoing renal transplantation were randomized to immunosuppression with either microemulsion cyclosporin (Neoral; 15 mg per kg per day adjusted to whole-blood trough concentrations of 200-300 ng/ml) or tacrolimus (0.2 mg per kg per day adjusted to whole-blood trough levels of 8-15 ng/ml) in conjunction with steroids, or at a lower dose (7 mg per kg per day and 0.1 mg per kg per day respectively) with the addition of azathioprine for non-heart-beating renal transplant recipients. Renal transplant interstitial fibrosis was quantified using computerized histomorphometric measurement of picrosirius red-stained 1-year protocol renal transplant biopsies. Levels of interstitial fibrosis were compared in relation to observed efficacy and toxicity profiles of the two drugs. RESULTS: There was a significant increase in allograft interstitial fibrosis in the patients treated with Neoral compared with those given tacrolimus. There was no significant difference in the demographic characteristics between the patient groups or in the incidence of acute rejection (Neoral 36 per cent versus tacrolimus 35 per cent) or steroid-resistant rejection (both 10 per cent) between the two drugs. There was a higher incidence of insulin resistance in the tacrolimus group (post-transplant diabetes mellitus, glucose tolerance testing) but this was not statistically significant. Neoral was associated with a significant increase in total cholesterol (P = 0.030) and low-density lipoprotein (P = 0.021) levels, which persisted throughout the study period. CONCLUSION: Despite equivalent efficacy and pretransplantation risk factors for CAN, Neoral was associated with increased allograft fibrosis and significantly higher serum low-density lipoprotein cholesterol levels compared with tacrolimus.

The development and evaluation of the UK national telepathology network.

AIMS: As technology advances and costs fall, it may be anticipated that soon every histopathologist will expect to be able to exchange electronic images with colleagues. Arguing that the value of a network increases as more people are connected, we sought to install a simple, low-cost telepathology system into any histopathology laboratory which requested it within the UK. METHODS AND RESULTS: We assumed that laboratories had microscopes, computers and internet access. We offered low-cost video cameras, video input cards, software and training to any histopathology department requesting installation, limited only by resources supplied by the UK government. We also established central servers and a website with 'help' files. After 1 year we studied system use and pathologists' opinions by circulating a questionnaire. Installations were completed in 35 laboratories; there are currently 66 registered users of the system, with 16 identified 'experts' covering most organ systems. Serious difficulties were caused by institutional firewalls and reluctance of local information technology (IT) staff to make changes to facilitate the installation or to help resolve subsequent network problems. After installation, many of the telepathology systems remain unused. Concerns were expressed about image quality, though mainly by pathologists who had not used the system for diagnostic work. The system remains available, but the level of use is low. CONCLUSIONS: This project has not achieved its aims. The reasons are complex, but mainly relate to human attitudes. Pathologists with excessive workloads were reluctant to use time to learn new skills which were not directed to reducing workload. IT staff did not perceive the project as part of their routine work. There were also numerous technological problems, but although image quality was cited by many, it was not a complaint of those who actively used the system. These problems have not been encountered by previous projects which involved small groups of committed enthusiasts.

International variation in the interpretation of renal transplant biopsies: report of the CERTPAP Project.

BACKGROUND: The Banff working formulation of renal transplant pathology is intended to have international application. There remains a need to develop methods to harmonize the application of such grading systems between laboratories. Banff grades do not always permit precise management decisions to be made. Alternative schemes have been devised for the diagnosis of acute rejection, but there have been no independent tests of the different approaches. METHODS: Sections from 55 renal transplant biopsies were circulated around the laboratories of 22 major transplant units for the Convergence of European Renal Transplant Pathology Assessment Procedures (CERTPAP) Project. Participating pathologists were asked to grade 32 different histological features, without any clinical information. After each circulation of five cases, feedback was provided to participants. Statistical evidence of improvement in interobserver variation was sought. At the end of the study, correlations with the original clinicopathological diagnosis were sought. RESULTS: Interobserver variation was greater than has previously been reported. For every feature studied, some pathologists consistently under-grade or over-grade. There was relatively little evidence of improvement in interobserver variation as a result of the feedback system. No single feature permitted a reliable diagnosis of acute rejection. Applying the Banff and CCTT schemas to the histological grades showed no clear diagnostic advantage for either system, but a simple computer-based inference network, which combined data from 12 histological features, out performed either approach. Within the "protocol" biopsies studied, long-term survival correlated better with "acute" than with "chronic" histological features. CONCLUSIONS: These results do not undermine the value of the Banff classification, but they demonstrate a need for caution when translating biopsy results between institutions. It is obvious that evaluation of biopsies in multicenter trials must be done in one center. In the management of individual patients, the need to interpret Banff grades in the light of local experience and clinical information is stressed.

Research using human tissues--a crisis of supply?

It is a paradox that the pursuit of ethical practice can sometimes produce distinctly unethical results. Pathologists seek to study diseased human tissues for the benefit of mankind, but in the UK there has been a sudden restriction in the availability of this basic resource, supposedly on ethical grounds. This was triggered by adverse publicity about the inappropriate retention of whole organs at paediatric post-mortem, but the reaction has spread to influence the use of 'surgical waste' left over after routine analysis of therapeutic resections, diagnostic biopsies, and even blood samples. The use of such material for research is being restricted, and its use in teaching and laboratory quality control is being questioned. This has occurred despite the facts that public opinion favours using such 'waste' material for research; that the tissues would otherwise be incinerated; and that until very recently, such tissues were regarded as having been 'abandoned' by the patient. This review attempts to chart how this dramatic change has occurred. It then considers some of the ethical problems in using such 'surplus' tissues and proposes mechanisms by which this valuable resource can remain available for most biomedical research, while maintaining or enhancing the autonomy of individual patients. This crisis has shown a tendency for regulatory authorities to apply very restrictive, oversimplified rules, without due consideration of the character of each project. The motivation is to avoid the possibility of media criticism, even though such rules block ethically sound work which is of value to all, including the individuals whose protection is supposedly being sought. The moral need for logical ethical arguments instead of such 'one size fits all' regulations is emphasized.

Sub-clinical acute rejection detected using protocol biopsies in patients with delayed graft function.

Acute rejection in renal transplants is difficult to diagnose when patients have delayed graft function (DGF) in the early post-transplant period. In this study protocol, renal transplant biopsies were performed in an attempt to detect sub-clinical acute rejection episodes. Eighty-three patients were eligible for the study, of whom 33 had DGE All had protocol renal transplant biopsies performed under ultrasound control at 7 days post-transplant, and those with DGF had further biopsies weekly until the graft functioned. All histologically confirmed acute rejection episodes were treated. Sub-clinical acute rejection was detected in 6/33 (18%) patients with DGF compared to 2/50 (4%) in the other patients (P < 0.05). Borderline rejection was present in 4/33 (12%) and 4/50 (8%) patients, respectively. Because of the high detection rate of sub-clinical acute rejection and the low morbidity of renal transplant biopsies, their use is recommended in patients with DGF.

Differential effects of cyclosporin and tacrolimus on the expression of fibrosis-associated genes in isolated glomeruli from renal transplants.

BACKGROUND: Chronic allograft nephropathy is characterized by an excessive accumulation of extracellular matrix proteins leading to glomerular and interstitial fibrosis. The aim of this study was to determine the effects of two different immunosuppressive agents (cyclosporin and tacrolimus) on the expression of the genes controlling extracellular matrix deposition in renal transplant glomeruli. METHODS: Fifty-one renal transplant recipients were randomized to receive immunosuppression with either microemulsion cyclosporin or tacrolimus. Isolated glomeruli were plucked from protocol transplant biopsies performed 1 week, 3 months and 6 months after transplantation. Expression of the genes for collagen IValpha2, collagen III, matrix metalloproteinase 2, tissue inhibitor of metalloproteinases (TIMP) 1 and TIMP-2, tenascin and transforming growth factor (TGF) beta1 was studied by quantitative reverse transcriptase-polymerase chain reaction. RESULTS: The expression of messenger RNA (mRNA) for collagen III and TIMP-1 was significantly higher in patients receiving cyclosporin therapy than in those having tacrolimus (P < 0.01); this finding was accounted for by differences in the biopsy material at 1 week. A significant difference in collagen III, TIMP-1 and TIMP-2 mRNA expression was also detected between patients depending on the source of renal donor (cadaveric or living). There were no significant differences in the level of glomerular TGF-beta1. CONCLUSION: The data provide new in vivo evidence that tacrolimus may exert a less fibrogenic influence on transplant glomeruli than cyclosporin.

Incidental adult nesidioblastosis after distal pancreatectomy for endocrine microadenoma.

Persistent hyperinsulinaemic hypoglycaemia (nesidioblastosis) presenting with hypoglycaemia is extremely rare in adults. The features are suggestive of an insulinoma with a vague presentation and delayed diagnosis. We describe a report of adult nesidioblastosis in association with a pancreatic endocrine microadenoma.

IgA myeloma presenting as Henoch-Schönlein purpura with nephritis.

IgA nephropathy (IgAN) and Henoch-Schönlein purpura (HSP) are both characterized by IgA-mediated tissue injury, including mesangial proliferative glomerulonephritis. Abnormalities of IgA1 glycosylation are described in IgA nephropathy and HSP nephritis. IgA-antineutrophil cytoplasmic antibodies (ANCA) have been inconsistently described in the serum of patients with HSP. In IgA myeloma, the paraprotein-mediated renal lesion is typically cast nephropathy; IgAN or HSP have only rarely been reported in myeloma even when an IgA paraprotein is circulating in large concentrations. We report the case of a 50-year-old man with IgA myeloma who presented with HSP including nephritis and rapidly progressive renal failure. His IgA1 had altered O-glycosylation in the pattern seen in IgAN and also contained an IgA-ANCA. This case adds further weight to the evidence that IgA1 O-glycosylation abnormalities predispose to mesangial IgA deposition and also that IgA-ANCA may have a pathogenic role in the development of HSP.