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Featured researches published by Mark L. Wilkinson.


Gastroenterology | 1991

Natural history and prognostic variables in primary sclerosing cholangitis

J.Mark Farrant; Karen M. Hayllar; Mark L. Wilkinson; John Karani; Bernard C. Portmann; David Westaby; Roger Williams

The clinical features at the time of presentation and the outcome in 126 patients with primary sclerosing cholangitis were studied to clarify the natural history and prognosis in symptomatic and asymptomatic individuals. The median age of the patients at the time of presentation was 36 years, 62% were male, and 16% were asymptomatic. The median follow-up from time of presentation was 5.8 years. There were more patients who had liver transplants (21%) than patients who died of liver-related disease (16%); the estimated median survival to these end points was 12 years. Cholangiocarcinoma was found in 8 patients and in 23% of those undergoing liver transplantation. Asymptomatic patients had milder disease than symptomatic patients, but in a univariate analysis the presence of symptoms was not prognostically significant. On multivariate analysis, the following independent prognostic factors were found: hepatomegaly, splenomegaly, serum alkaline phosphatase, histological stage, and age. These features were combined to produce a prognostic model that should be valuable in the stratification of patients in clinical trials and in the timing of liver transplantation, particularly in those patients seen soon after presentation.


Gastroenterology | 1987

Primary Sclerosing Cholangitis in Childhood

Mortada El-Shabrawi; Mark L. Wilkinson; Bernard Portmann; Giorgina Mieli-Vergani; Sonny Chong; Roger Williams; Alex P. Mowat

Thirteen children (8 female) with primary sclerosing cholangitis are described, in whom the diagnosis was confirmed by the presence of characteristic changes on endoscopic retrograde cholangiopancreatography. Nine had clinical features of chronic inflammatory bowel disease 1 mo to 5 yr before the onset of primary sclerosing cholangitis (6 patients) or appearing simultaneously with primary sclerosing cholangitis (3 patients). In 4 patients clinical evidence of chronic inflammatory bowel disease was absent but 1 of the 4 was found to have microscopic colitis in colonoscopic biopsy specimens. Biopsies were not performed in the remaining 3 patients. High immunoglobulin G concentrations and positive antinuclear or smooth muscle antibodies were present in all patients except 1 who had been given immunosuppressants. In 7 patients treated with immunosuppressants and followed up for 9 mo to 10 yr there was modest symptomatic improvement. This improvement was accompanied by a fall in transaminase levels in 6 of the patients and histologic improvement in 3 of 4 patients who had undergone biopsy. Greater use of endoscopic retrograde cholangiopancreatography in the last 6 yr led to the identification of 10 of these 13 cases, suggesting a higher incidence of primary sclerosing cholangitis in childhood than would appear from the literature.


Cancer | 1986

Androgen receptor in human normal and malignant pancreatic tissue and cell lines

Timothy P. Corbishley; M.Jawed Iqbal; Mark L. Wilkinson; Roger Williams

Estrogen and progestogen receptors have been demonstrated in human pancreatic adenocarcinoma tissue. Tumor growth as xenografts in nude mice is promoted by testosterone and retarded by cyproterone acetate but is not influenced by estrogens, progestogens, or their antagonists, although estrogen receptors were demonstrated in xenograft cytosol. A new sensitive microassay technique for sex steroid receptors which relies on affinity chromatography was used in this study. With this assay, androgen receptors were detected in five fresh human pancreatic adenocarcinoma specimens (three male), two pancreatic cancer cell lines (Mia PaCa 2 and Ger), one xenograft tumor which responded to androgens, five specimens of normal adult pancreas (two male), and a pool of fetal pancreatic tissue. The similarity of the androgen receptor in pancreatic carcinoma to that of classical androgen target organs was demonstrated by sedimentation behavior and competitive binding studies. The improved sensitivity of the microassay allowed low levels of estrogen, androgen, and progesterone receptors to be detected in normal adult pancreatic tissue.


European Journal of Cancer and Clinical Oncology | 1987

Response to cyproterone acetate treatment in primary hepatocellular carcinoma is related to fall in free 5α-dihydrotestosterone

Alastair Forbes; Mark L. Wilkinson; M.Jawed Iqbal; P. J. Johnson; Roger Williams

The male preponderance in cirrhotic patients with primary hepatocellular carcinoma (HCC) and the presence of androgen receptors in tumour tissue suggest possible benefit from anti-androgenic therapy. Twenty-five cirrhotic patients with irresectable HCC (23 male) were treated with cyproterone acetate (CPA) 300 mg daily. Hepatic ultrasound, alpha-fetoprotein and total and free sex steroid levels were monitored. Five patients had an objective response to therapy with a median duration of 8 weeks and survival in excess of 29 weeks. Median survival for all patients was 14 weeks. Apart from transient paranoia in two cases, side-effects were minimal. Total androgen levels (measured in 13 patients) had fallen significantly at 10 weeks, but free 5 alpha-dihydrotestosterone (DHT) which had fallen by 4.8 pM (median) in five responders, had risen by 5.05 pM in eight non-responders: P less than 0.025. The apparent correlation of response with reduction in free DHT suggests that hormonal manipulation may be effective in HCC if free DHT is reliably reduced. This has been achieved in other conditions by the combination of CPA with low dose oestrogen or with LHRH agonists.


Archives of Disease in Childhood | 1991

Endoscopic retrograde cholangiopancreatography in infantile cholestasis.

Mark L. Wilkinson; Giorgina Mieli-Vergani; Colin Ball; Bernard Portmann; Alex P. Mowat

The difficulty of distinguishing surgically correctable causes of conjugated hyperbilirubinaemia in infants from other causes means that some infants may undergo laparotomy and intraoperative cholangiography unnecessarily, and others may be referred for surgery too late. In an attempt to improve the diagnostic accuracy in infants with conjugated hyperbilirubinaemia when standard methods produced equivocal results, we have been using prototype paediatric duodenoscopes (PJF 7.5 and XPJF 8.0; Olympus) to perform endoscopic retrograde cholangiopancreatography (ERCP). From 159 infants with conjugated hyperbilirubinaemia, 11 were referred for ERCP, which was performed in nine. In four in whom bile ducts were definitely visualised laparotomy was avoided. Operative cholangiography confirmed patent bile ducts in one in whom visualisation had been uncertain. Three of four in whom bile ducts were not seen had extrahepatic biliary atresia. Visible bile drainage in the fourth excluded atresia. No major complications ensued but there was radiological evidence of gall bladder perforation in one (common hepatic duct block) and overinflation with air was a problem until finer cannulae (Wilson-Cook) were introduced. In appropriately selected patients with conjugated hyperbilirubinaemia, ERCP with paediatric duodenoscopes in experienced hands may provide useful diagnostic information.


Clinica Chimica Acta | 1985

Characterisation of high affinity binding sites of androgens in primary hepatocellular carcinoma

Mark L. Wilkinson; M.Jawed Iqbal; Roger Williams

The reported presence of androgen receptors (AR) in hepatocellular carcinoma (HCC) and foetal liver, but not in normal adult human liver, has been followed by further study of AR employing a new microassay. Tissues examined were: 5 samples of HCC with surrounding normal liver in 3 cases; 5 samples of cirrhotic liver and a single specimen of HCC in a child. High affinity binding of 5 alpha-dihydrotestosterone (DHT) was detected in cytosol (11.5-21 fmol/mg, Kd 1.5 X 10(-10)-3.1 X 10(-11) mol/l) and in nucleosol (8.7-11.4 fmol/mg, 6.7-1.4 X 10(-11) mol/l) of the 5 HCC samples. All other liver samples exhibited non-specific binding only. Competition studies indicated that DHT, testosterone, androstenedione, 5 alpha-androstan-3 beta, 17 beta-diol, androst-5-ene-3 beta,17 beta-diol and cyproterone acetate were acting at the same receptor binding site, relative displacement of 3H-DHT being 100, 85.7, 77.4, 67.8, 34.5 and 60.2 per cent respectively. Presence of 3.5S cytosolic and both 2.8S and 4S nucleosolic receptor patterns were demonstrated in both prostatic and HCC tissue. These studies confirm the presence of a cytosolic and nucleosolic androgen receptor in HCC which possesses similar characteristics to the AR of human prostate.


Journal of Hepatology | 1986

Preponderance of serum and intra-hepatic 5α-dihydrotestosterone in males with hepatocellular carcinoma despite low circulating androgen levels*

M.Jawed Iqbal; Mark L. Wilkinson; Alastair Forbes; Timothy P. Corbishley; Roger Williams

To investigate possible influences of the sex-steroid milieu on hepatocellular carcinoma (HCC) and vice versa, circulating and intra-hepatic sex-steroid levels were investigated and compared with the levels in cirrhosis alone. In cirrhotic men with HCC, serum 17 beta-oestradiol levels were normal, unlike the elevated levels in men with cirrhosis alone. Total and free levels of testosterone and 5 alpha-dihydrotestosterone (DHT) were lower in patients with HCC than in cirrhotic or normal men; the greater decrease in testosterone levels caused an elevated DHT: testosterone ratio. Hypothalamic-pituitary axis dysfunction demonstrated for HCC and cirrhotic groups could not explain the differences in sex-steroids between them. Compared with normal tissue, HCC cytosol had lower testosterone and similar DHT levels; both androgens were higher than in cirrhotic tissue, and the intracellular DHT: testosterone ratio in the tumour was much higher than in control tissue. Results suggest alterations in sex-steroid metabolism in HCC favouring hepatic accumulation of 5 alpha-reduced metabolites aided by the elevated intracellular sex-hormone binding globulin levels shown in HCC tissue.


Analytical Biochemistry | 1985

A microassay for the determination of binding parameters of estrogen and androgen receptors employing affinity immobilization on cibacron blue 3GA-sepharose 6B

M.Jawed Iqbal; Timothy P. Corbishley; Mark L. Wilkinson; Roger Williams

The problems of currently available ligand-binding assays for sex-steroid receptor proteins include the relatively large mass of tissue required, the interference by sex hormone-binding globulin (SHBG), and use in the androgen receptor (AR) assay of the unstable synthetic ligand methyltrienolone. To overcome these difficulties the stabilizing effect of the dye Cibacron blue 3GA on AR and estrogen receptor (ER) proteins, and its ability to bind to these proteins, was utilized in developing an assay system for each receptor that could be applied to small samples. Use of the affinity gel Cibacron blue 3GA-Sepharose 6B (Blue gel) for the immobilization of AR, ER, and the steroid ligands bound to these receptors in the standard two-tier column assay system enabled the use of a 1:100 (original tissue weight:volume) concentration, making possible full (5-7 point) Scatchard analysis on tissue specimens of a mass as low as 15-20 mg. Significant stabilization of AR and ER was observed and association constants for these receptors were of a similar order of magnitude to those obtained either by Sephadex LH-20 gel filtration or the dextran-coated charcoal adsorption technique. Inactivation by dilution was shown to be largely prevented based on results obtained with cytosol concentrations from 1:5 to 1:100 (original tissue weight:volume). Because Blue gel does not bind SHBG, the natural steroid 5 alpha-androstan-17 beta-ol-3-one (DHT) may be employed as a ligand in the AR assay.(ABSTRACT TRUNCATED AT 250 WORDS)


Steroids | 1985

An enzyme-linked immunosorbent assay for fetal steroid binding protein of human serum

M.Jawed Iqbal; Alastair Forbes; Timothy P. Corbishley; Mark L. Wilkinson; Roger Williams

The binding characteristics and quantitation of the recently reported fetal steroid binding protein (FSBP) cannot be determined on unpurified samples; an immunoassay was therefore desirable. The protein was purified to homogeneity in order to raise a highly specific polyclonal antibody. An enzyme-linked immunosorbent assay applicable to unpurified samples was developed. Intra- and inter-assay coefficients of variation are 8.0% and 9.2% respectively; there is a sensitivity of 30 fmol FSBP per well, and there is no cross-reactivity with other binding proteins. Results obtained with the assay correlate with the more complex ligand binding assay (r = 0.85; p less than 0.02). Measurement of sera showed that FSBP levels are higher in women than in men (51.2 +/- 10.62 nM; 41.2 +/- 13.65 respectively; p less than 0.05) and are elevated in cirrhotic women (66.4 +/- 18.67; p less than 0.05) and in males with hepatocellular carcinoma (62.2 +/- 13.05; p less than 0.002). Use of the enzyme-linked immunosorbent assay confirmed the identity of FSBP separate from sex hormone binding globulin.


Clinica Chimica Acta | 1987

Interactions of foetal steroid binding protein with other binding proteins in human serum.

Alastair Forbes; Mark L. Wilkinson; M J Iqbal; Roger Williams

Foetal steroid binding protein (FSBP) which is present in normal human serum sometimes exhibits unusual sex-steroid binding; its effects on steroid action are uncertain but potentially important in view of the different levels seen in populations at different risk of breast cancer. Studies of the binding of 5 alpha-dihydrotestosterone to FSBP were conducted at varying concentrations of human serum albumin (HSA) and sex hormone binding globulin (SHBG). The saturable, specific binding of purified FSBP (Ka approximately equal to 5 X 10(8) l/mol), was transformed to a rising, plateau pattern by the addition of HSA. In equilibrium dialysis, FSBP competed with HSA or SHBG in a strictly proportional way when the third protein was absent. In the presence of HSA an initial sharp shift of ligand from SHBG to FSBP was observed with increasing FSBP concentration, but this was reversed as higher levels were reached. Steroid binding by FSBP in vivo may be determined predominantly by its interactions with other binding proteins.

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Alastair Forbes

University of East Anglia

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