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Biomedical subjects

M L Nicholson

Publications and source records attributed to M L Nicholson.

At least 109 records · Page 6Linked to original sources
PubMed2000

Workload generated by a living donor programme for renal transplantation.

BACKGROUND: The ethical and medical implications of live kidney donation result in a comprehensive work-up process. The aim of this study was to determine the magnitude of the workload and the yield of renal transplants generated by a live donor programme. METHODS: Referrals to the Leicester live donor programme over the five-year period 1994-1998 were retrospectively assessed. These were initiated by nephrology referral and subsequently investigated in a stepwise manner. Patients were counselled and baseline tests performed prior to consultant surgeon review and assessment of donor renal function/anatomy. RESULTS: One hundred and fifty referrals consisting of 150 recipients with 269 potential donors were originally made. This resulted in 32/120 (27%) related and 3/30 (10%) unrelated recipients (P=0.06) and 32/220 (15%) related and 3/49 (6%) unrelated donors proceeding to live donor transplantation, with a mean work-up time (+/-SD) of 9 (+/-7) months. One hundred and fifteen recipients (77%) and 234 (87%) donors failed to proceed at various stages of assessment, for a variety of immunological, medical and social reasons. A large number of expensive immunological investigations were required for potential donors, the majority of which did not proceed to transplantation. However as a result of performing these in the early stages of assessment the number of more invasive tests is kept to a minimum. CONCLUSIONS: There is a relatively low yield of transplants from live donor referrals, particularly those between unrelated individuals. The vast majority of referrals fail to proceed for legitimate reasons, but as a result, create a significant workload with notable staffing and financial implications.

Health Care Costs↗
PubMed2000

Analysis of immunoreactivity to a Streptococcus equi subsp. zooepidemicus M-like protein To confirm an outbreak of poststreptococcal glomerulonephritis, and sequences of M-like proteins from isolates obtained from different host species.

The etiologic agent of a large 1998 outbreak of poststreptococcal acute glomerulonephritis (PSGN) in Nova Serrana, Brazil, was found likely to be a specific strain of Streptococcus equi subsp. zooepidemicus from contaminated cheese (S. Balter et al., Lancet 355:1776-1780, 2000). In the present study, we used a serologic screen for a known surface-exposed virulence factor to confirm the epidemiologic findings. Using primers flanking a previously characterized M-like protein gene (J. F. Timoney et al., Infect. Immun. 63:1440-1445, 1995), we amplified and sequenced the M-like protein (designated Szp5058) gene and found it to be identical among four independent acute-phase PSGN patient isolates. Convalescent-phase sera from 33 of 44 patients in the PSGN outbreak were found to contain antibodies highly reactive to a purified Szp5058 fusion protein, compared with 1 of 17 control sera (P < 0. 0001), suggesting that Szp5058 was expressed during infection and further implicating this strain as the cause of the PSGN outbreak. The predicted signal sequence and cell wall association motif of Szp5058 were highly conserved with the corresponding sequence from S. equi subsp. zooepidemicus SzpW60, while the predicted surface-exposed portions differed markedly between these two proteins. The 5' end of the szp5058 gene, including its variable region, was identical to the szp gene from another strain associated with a previous PSGN outbreak in England (M. Barham et al., Lancet i:945-948, 1983), and the corresponding szp sequence found from the Lancefield group C type strain isolated from a guinea pig. In addition, the hypervariable (HV) portion of szp5058 was identical to a previously published HV sequence from a horse isolate (J. A. Walker and J. F. Timoney, Am. J. Vet. Res. 59:1129-1133, 1998). Three other strains of S. equi subsp. zooepidemicus, including another strain previously associated with a PSGN outbreak, were each found to contain a distinct szp gene. Two of these szp genes had HV regions identical to szp regions from isolates recovered from different host species.

Amino Acid Sequence↗
PubMed2000

A modification to aid open tracheostomy.

Open tracheostomy is performed less frequently thereby increasing the likelihood of morbidity, e.g. bleeding. The simple modification described aids the technical process and minimises problems with the procedure.

Humans↗
PubMed1999

Computerized histomorphometric assessment of protocol renal transplant biopsy specimens for surrogate markers of chronic rejection.

BACKGROUND: Chronic transplant rejection has emerged as the commonest cause of long-term renal allograft failure, and early identification of those grafts at risk could allow the targeting of specific therapies aimed at delaying this process. This study explores the usefulness of quantitative immunohistochemistry in defining biopsy-based surrogate markers of allograft damage. METHODS: A consecutive series of 52 renal transplant recipients immunosuppressed with cyclosporine were studied. Needle core transplant biopsies were performed at 1, 3, and 6 months postoperatively. Immunostaining for collagen III, and smooth muscle actin, tenascin, and infiltrating leukocytes was performed using an indirect immunoperoxidase technique. The interstitial area stained (%) was measured using a semiautomatic image analysis system. The results were related to glomerular filtration rates (GFR) measured at 6, 12, and 24 months after transplantation using rank correlation coefficients. RESULTS: The area fraction of immunostained collagen III correlated with 6-month GFR (r=-0.42, P=0.005) and was predictive of 12-month GFR (r=-0.32, P=0.03). An area fraction of immunostained collagen III of >40% at 6 months was associated with a significantly lower GFR at 24 months, compared with a percentage area of < or =40% (31+/-4 versus 45+/-4 ml/min/1.73 m2, P=0.01). Furthermore, a collagen III of >40% at 6 months identified patients who were at risk of progressive deterioration in graft function. CONCLUSIONS: Grafts with poorer long-term function can be predicted using 6-month protocol biopsy specimens immunostained for collagen III. This should prove to be a useful ad interim surrogate marker of allograft damage in studies addressing the effects of new immunosuppressive agents on the development of chronic rejection.

Adolescent↗
PubMed1999

Dual renal transplant from a non-heart beating donor.

In September 1998, a 48 year old male underwent bilateral renal transplantation from a 51 year old non-heart beating donor (NHBD) with ischemic heart disease. The grafts exhibited delayed graft function, otherwise short term results have been good, with a three month serum creatinine of 80 mumol/l, three month GFR of 79 ml/min per 1.73 m2 BSA, and no episodes of acute rejection. We advocate dual transplantation when sub-optimal NHBD kidneys are otherwise in danger of being discarded.

Cadaver↗
PubMed1999

Endogenous renal nitric oxide metabolism following experimental infrarenal aortic cross-clamp-induced ischaemia-reperfusion injury.

BACKGROUND: Abdominal aortic surgery is associated with marked changes in renal haemodynamics. The aim of this study was to investigate the influence of infrarenal cross-clamping on glomerular filtration rate and endogenous renal nitric oxide metabolism. METHODS: Groups of male Wistar rats were subjected to infrarenal aortic cross-clamping followed by reperfusion. Animals were allowed to recover after a left nephrectomy. The glomerular filtration rate of the remaining kidney was measured on the second and seventh day after the procedure before the animal was killed and the remaining kidney harvested. Total nitric oxide synthase (NOS) activity and expression of inducible NOS (iNOS) was determined in renal tissue following 1 h and 7 days of reperfusion. RESULTS: Glomerular filtration rate was impaired on the second and seventh day after operation in all animals subjected to lower torso ischaemia compared with controls (P < 0.05). Renal NOS activity was increased at 1 h and 7 days in animals subjected to infrarenal cross-clamping compared to controls (P < 0.01). iNOS was detected in renal tissue of animals subjected to infrarenal aortic cross-clamping on the seventh day after operation. CONCLUSION: Infrarenal aortic cross-clamping is associated with impairment of renal function in the early postoperative period. There is an increase in endogenous renal nitric oxide metabolism with iNOS expression. Presented in part to the Surgical Research Society, Dublin, Ireland, July 1998

Animals↗
PubMed1999

Biphasic role for nitric oxide in experimental renal warm ischaemia-reperfusion injury.

BACKGROUND: Whilst nitric oxide has a clearly defined role in renal haemostasis, debate continues over its pathophysiology. This study investigated the function of nitric oxide in a model of renal warm ischaemia-reperfusion injury. METHODS: Rats underwent bilateral renal warm ischaemia (45 min) after pretreatment with nitric oxide donors, nitric oxide synthase (NOS) inhibitors or saline (control). Following reperfusion (20 min) a unilateral nephrectomy was performed to measure renal nitric oxide (as nitroxides) and oxidative DNA and protein damage. Renal function was measured on days 2 and 7 before terminal nephrectomy for analysis and morphology. RESULTS: The increase in renal nitric oxide level seen early in reperfusion (20 min) (P < 0.01) was prevented by inhibition of constitutive (cNOS) but not inducible (iNOS) NOS. The increase in oxidative damage (P < 0.01) was exacerbated by nitric oxide donors (P < 0.01) but ameliorated by NOS inhibition (P < 0.01). Control nitric oxide remained increased through to day 7 (P < 0.01) but was reduced by nitric oxide donors and cNOS inhibitors (P < 0.05). Oxidative damage returned towards normal in the control group, whereas both DNA and protein damage persisted following NOS inhibition (P < 0.01). CONCLUSION: Inhibition of the postischaemic increase in the level of nitric oxide was associated with an early decrease in, but eventual exacerbation of, oxidative damage. This suggests the prolonged increase in renal nitric oxide concentration was cytoprotective overall.

Animals↗
PubMed1999

Intragraft expression of transforming growth factor beta1 gene in isolated glomeruli from human renal transplants.

BACKGROUND: Experimental evidence suggests that transforming growth factor (TGF) beta1 is a fibrogenic cytokine. The histopathological changes of chronic renal allograft nephropathy are dominated by fibrotic changes and TGF-beta may have an important aetiological role. This study investigated the relationship between intragraft TGF-beta gene expression and extracellular matrix protein deposition in human renal allografts. METHODS: Sixteen cadaveric renal transplant recipients immunosuppressed with cyclosporin and steroids were studied. Individual glomeruli were isolated from protocol needle-core biopsies and, following messenger RNA extraction, intragraft gene expression was studied by reverse transcriptase-polymerase chain reaction. Collagen III deposition in these renal transplant biopsies was examined by immunohistochemistry and quantified by computerized histomorphometry. RESULTS: There was a positive correlation between renal cortical collagen III immunostaining and the levels of glomerular complementary DNA for TGF-beta1. CONCLUSION: TGF-beta1 is a profibrotic influence in human renal transplants. The methods described should prove of benefit in investigating the mechanisms of chronic renal allograft damage.

Biopsy, Needle↗
PubMed1999

Comparison of the expression of fibrosis-associated genes in glomeruli after renal transplantation between conventional cadaveric and non-heart-beating donors.

BACKGROUND: The main difference between cadaveric heart-beating donors and non-heart-beating donors (NHBDs) is the degree of warm ischaemia to which the kidney is subjected. This study was designed to see if this affected the expression of fibrosis-associated genes in the early period after transplantation. METHODS: A series of 29 cadaveric and 19 NHBD renal transplants was studied. Patients underwent protocol needle-core renal transplant biopsies at 1 week, 3 months and 6 months after transplantation. At least two individual glomeruli were isolated from each biopsy. Messenger RNA was extracted and genes of interest were amplified by reverse transcriptase-polymerase chain reaction, then quantified in an enzyme-linked immunosorbent assay system. RESULTS: Delayed graft function was common in NHBD (17 of 19) compared with cadaveric transplants (six of 29) (P < 0.0001). Acute rejection rates were similar. The level of tissue inhibitor of metalloproteinase 1, an inhibitor of extracellular matrix degradation, was higher in kidneys from NHBDs at 1 week (P = 0.02). There were no other statistically significant differences in the expression of fibrosis-associated genes between the two groups. CONCLUSION: Although the increased ischaemic injury in kidneys retrieved from NHBDs leads to a higher rate of delayed graft function, this does not translate into increased expression of fibrosis-associated genes after the first week.

Adult↗
PubMed1999

Xenotransplantation.

BACKGROUND: Over the past 10 years xenotransplantation has generated much interest in the hope that it will enable us to overcome the current lack of human organ donors. This review examines the evolution and current therapeutic strategies that have been developed to overcome the predominant problem of graft rejection. METHODS: A literature review was undertaken using a Medline search from January 1966 to August 1999. RESULTS AND CONCLUSION: Despite the considerable advances that have been made in molecular biological techniques, xenograft rejection cannot be prevented without significant immunosuppression and toxic side-effects. The problem of delayed rejection, in particular, will probably be very difficult to overcome, although some of the difficulties associated with hyperacute rejection have been resolved. The potential risk of porcine endogenous retrovirus transmission has generated much debate recently, but it is likely that some of the important issues relating to xenotransplantation will never be resolved until carefully regulated clinical trials are allowed to begin.

Animals↗
PubMed1999

A neural network approach to the biopsy diagnosis of early acute renal transplant rejection.

AIMS: To develop and test a neural network to assist in the histological diagnosis of early acute renal allograft rejection. METHODS AND RESULTS: We used three sets of biopsies to train and test the network: 100 'routine' biopsies from Leicester; 21 selected difficult biopsies which had already been evaluated by most of the renal transplant pathologists in the UK, in a study of the Banff classification of allograft pathology and 25 cases which had been classified as 'borderline' according to the Banff classification in a review of transplant biopsies from Oxford. The correct diagnosis for each biopsy was defined by careful retrospective clinical review. Biopsies where this review did not provide a clear diagnosis were excluded. Each biopsy was graded for 12 histological features and the data was entered into a simple single layer perception network, designed using the MATLAB neural network toolbox. Results were compared with logistic regression using the same data, and with 'conventional' histological diagnosis. If the network was trained only with the 100 'routine' cases, its performance with either of the other sets was poor. However, if either of the 'difficult' sets was added to the training group, testing with the other 'difficult' group improved dramatically; 19 of the 21 'Banff' study cases were diagnosed correctly. This was achieved using observations made by a trainee pathologist. The result is better than was achieved by any of the many experienced pathologists who had previously seen these biopsies (maximum 18/21 correct), and is considerably better than that achieved by using logistic regression with the same data. CONCLUSION: A neural network can provide a considerable improvement in the diagnosis of early acute allograft rejection, though further development work will be needed before this becomes a routine diagnostic tool. The selection of cases used to train the network is crucial to the quality of its performance. There is scope to improve the system further by incorporating clinical information. Other related areas where this approach is likely to be of value are discussed.

Acute Disease↗
PubMed1999

Vascularized pancreas allotransplantation--clinical indications and outcome.

AIMS: This review examines the status of vascularized pancreas transplantation as a treatment for Type 1 diabetes mellitus (DM). METHODS: The world literature, with a particular emphasis on data from the International Pancreas Transplant Registry (IPTR), is reviewed and interpreted particularly for clinical indications and outcome. RESULTS: Over 9000 cases of vascularized pancreas transplant (VPT) have been registered, with insulin dependence approaching 82% at 1 year with 94% patient survival. The majority of transplants are simultaneous pancreas and kidney (SPK) transplants, with far fewer pancreas after kidney (PAK) or pancreas transplants alone (PTA). The success rates differ between the procedures but are generally improving as technical advances, improvements in immunosupression and greater experience are gained. The most obvious advantage is an improved quality of life (QoL) but there are risks associated with the procedure and with the immunosuppression. There is some evidence coming to light of a very slow beneficial effect on microvascular complications. CONCLUSIONS: VPT is an attractive option to offer Type 1 DM patients who need or already have a renal allograft. Patients have to decide between the increased surgical risk and the risks of long-term immunosuppression and the benefits of improved QoL. In the absense of end-stage renal failure (ESRF) there is no justification for PTA, except where the diabetes itself poses a greater risk to life than the transplantation procedure.

Diabetes Mellitus, Type 1↗
PubMed1999

Non-cardiogenic pulmonary oedema in vascular surgery.

Non-cardiogenic pulmonary oedema, an early manifestation of the adult respiratory disease syndrome, is a serious complication following major vascular surgery. Hypovolaemia, ischaemia-reperfusion injury, massive blood transfusion, transient sepsis and transient endotoxaemia are insults responsible for initiating the process in vascular surgical patients. Free radicals, cytokines and humoral factors released secondary to the above insults activate neutrophils and facilitate their interaction with the endothelium. Activated neutrophils marginate through the endothelium where they are responsible for tissue injury by the release of free-radicals and proteases. The lungs are a large reservoir of neutrophils and bear a significant part of the injury. Conventional therapy includes treating the underlying condition and providing respiratory support. A better understanding of the pathophysiology of this process has led to new experimental treatment options. Novel therapeutic interventions have included the use of compounds to scavenge free radicals, anti-cytokine antibodies, extracorporeal lung support, nitric oxide and artificial surfactant therapy. The multifactorial nature of this process makes it unlikely that a single "magic bullet" will solve this problem. It is more likely that a combination of preventative, prophylactic and therapeutic modalities may reduce the mortality of this condition.

Humans↗