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Biomedical subjects

R Williams

Publications and source records attributed to R Williams.

At least 451 records · Page 25Linked to original sources
PubMed1996

p53 Protein overexpression in cholangiocarcinoma arising in primary sclerosing cholangitis.

The protein encoded by the p53 tumour suppressor gene plays an important part in the regulation of cell growth. Abnormalities of this gene represent one of the most common genetic changes in the development of human cancers. This study investigated the expression of p53 protein in cholangiocarcinoma arising in association with primary sclerosing cholangitis (PSC). Of the 14 patients with cholangiocarcinoma studied, 13 had underlying PSC. The expression of p53 protein was detected immunohistochemically in paraffin wax embedded liver specimens, after microwave pretreatment. The expression of p53 protein was shown in the cholangiocarcinoma tissue of 11 of 14 (78.5%) patients. In five of 10 patients, the accumulation of p53 protein highlighted the presence of neoplastic cells in biliary tissue separate from the main tumour. These cells were mainly located in the septal bile ducts or in the accessory glands, or both, but occasionally also in large portal areas at the periphery of nerves and lymphatics, and in one case in the mucosa of an extrahepatic bile duct. No p53 protein was detectable in liver tissue obtained at the time of transplantation in 15 patients with PSC but not cholangiocarcinoma. These results show that cholangiocarcinoma development in PSC is commonly associated with abnormalities of p53 and that these occur at a late stage in the development of the malignant process. Staining for p53 protein could represent an additional criterion for the diagnosis of cholangiocarcinoma development in patients with PSC.

Adult↗
PubMed1996

Acute liver damage and ecstasy ingestion.

Eight cases of ecstasy related acute liver damage referred to a specialised liver unit are described. Two patients presented after collapse within six hours of ecstasy ingestion with hyperthermia, hypotension, fitting, and subsequently disseminated intravascular coagulation with rhabdomyolysis together with biochemical evidence of severe hepatic damage. One patient recovered and the other with evidence of hyperacute liver failure was transplanted but subsequently died, histological examination showing widespread microvesicular fatty change. Four patients presented with acute liver failure without hyperthermia. All four fulfilled criteria for transplantation, one died before a donor organ became available, and two died within one month post-transplantation of overwhelming sepsis. Histological examination showed submassive lobular collapse. Two patients presented with abdominal pain and jaundice and recovered over a period of three weeks; histological examination showed a lobular hepatitis with cholestasis. Patients developing jaundice or with evidence of hepatic failure particularly encephalopathy and prolongation of the international normalised ratio, or both, whether or not preceded by hyperthermia, should be referred to a specialised liver unit as liver transplantation probably provides the only chance of recovery.

Adolescent↗
PubMed1996

A duodenal mucosal abnormality in the reduction of Fe(III) in patients with genetic haemochromatosis.

BACKGROUND: Previous in vitro studies have shown that the uptake of Fe(III) by freshly isolated duodenal mucosal biopsy specimens is increased in patients with genetic haemochromatosis. Moreover, in the mouse it has recently been found that reduction of Fe(III) to Fe(II) is a prerequisite for iron uptake by the proximal intestine. AIMS/METHODS: This study used the in vitro technique to investigate the rates of reduction and uptake of 59Fe(III) by duodenal mucosal biopsy specimens obtained at endoscopy from treated and untreated patients with genetic haemochromatosis. RESULTS: The rate of reduction of iron in the medium was proportional to the incubation time and was not caused by the release of reducing factors from the tissue fragments. Ferrozine, a specific Fe(II) chelator and ferricyanide, a non-permeable oxidising agent, inhibited uptake of 59Fe showing that reduction of Fe(III) precedes uptake. The rates (all values given as pmol/mg/min) of reduction (152 (49) v 92 (23)) and uptake (8.3 (4.0) v 3.6 (1.3), mean (SD)), were significantly increased in biopsy specimens from the untreated group (n = 6) compared with those from 10 control subjects (p < 0.04). Furthermore, the reduction and uptake rates were still increased in five patients in whom iron stores were normal after venesection treatment. CONCLUSIONS: These results show that there is a persistent abnormality in the reduction and uptake of iron by the intestine in genetic haemochromatosis.

Analysis of Variance↗
PubMed1996

Evaluation of the efficacy and safety of flumazenil in the treatment of portal systemic encephalopathy: a double blind, randomised, placebo controlled multicentre study.

BACKGROUND: Portal systemic encephalopathy (PSE) is a complex neuropsychiatric syndrome associated with hepatic failure. Small scale studies have shown the benzodiazepine receptor antagonist flumazenil to be effective in ameliorating PSE. AIMS: To determine the efficacy of flumazenil in patients with non-comatous mild to moderate PSE (stages I to III) due to severe chronic liver disease. PATIENTS: 49 male and female adults without symptoms of severe bleeding and sepsis and who screened negative for benzodiazepine in both blood and urine, were included in the study. METHODS: Patients were randomised to receive either three sequential bolus injections of flumazenil (0.4, 0.8, and 1 mg) or placebo at one minute intervals, followed by intravenous infusions of either flumazenil (1 mg/h) or placebo for three hours. Clinical PSE grading and vital signs were assessed hourly during baseline and post-treatment periods and half hourly during treatment. The main outcome measures were improvement in group average PSE score and reduction of two points in individual PSE score (clinically relevant improvement). RESULTS: The mean average improvement in the PSE score in the subjects treated with flumazenil was not statistically significantly different from placebo. However, for patients showing clinically relevant improvement, the difference between flumazenil and placebo was statistically significant (seven of 28 v none of 21; p = 0.015). Flumazenil was well tolerated. CONCLUSIONS: A subgroup of patients with PSE resulting from chronic liver disease may benefit from the administration of flumazenil.

Chronic Disease↗
PubMed1996

Liver transplantation for haemophiliacs with hepatitis C cirrhosis.

BACKGROUND: Experience of liver transplantation in haemophiliacs with end stage hepatitis C liver disease is limited and particularly difficult questions are raised when there is also HIV infection. AIMS: This is the first report in Great Britain to describe the operative replacement therapy and initial outcome in four haemophiliacs with end stage HCV cirrhosis. PATIENTS: Two patients had factor VIII, one had factor IX, and one had factor X deficiency. One patient had also contracted HIV infection from factor replacement but had no AIDS defining illnesses. METHODS: Intraoperatively patients were given either factor VIII infusions, factor IX bolus, or fresh frozen plasma, according to formulae devised to calculate exact clotting factor requirements. Baseline preoperative coagulation studies included prothrombin time, activated partial thromboplastin time, fibrinogen concentrations, and factor VIII, IX, and X concentrations. Factor concentrations were then assayed at 12, 24, 48, and 72 hours postoperatively. RESULTS: Postoperatively all patients had coagulation factor concentrations sustained within the normal ranges by 72 hours unsupported (137, 125, 95, 104 IU/dl), representing de novo synthesis by the graft. Transfusion requirements during the operative and immediate post-transplant period were no greater than those of patients without clotting disorders. Two patients had episodes of bleeding postoperatively, one of which was fatal, occurring at the site of a previous untreated subdural bleed. In both instances the bleeding occurred in the presence of normal concentrations of clotting factor. The remaining three patients are at 6, 6, and 12 months post-transplant and remarkably improved clinically with sustained factor concentrations. One patient has evidence of graft dysfunction from HCV recurrence and all have evidence of recurrent viraemia with HCV on polymerase chain reaction studies. CONCLUSIONS: Orthotopic liver transplantation should be considered in haemophiliac patients with end stage liver disease from hepatitis C infection with or without concomitant HIV infection. Their clinical condition is likely to be greatly improved by orthotopic liver transplantation and the haemophilia cured with only a small risk of severe graft dysfunction from recurrent HCV infection.

Adult↗
PubMed1996

Use of specific ELISA for the detection of antibodies directed against p53 protein in patients with hepatocellular carcinoma.

AIMS: To analyse the significance of antibodies to p53 protein as a serological marker for changes in p53 gene expression in patients with hepatocellular carcinoma. METHODS: Thirty eight patients with hepatocellular carcinoma, 19 showing accumulation of p53 protein by immunohistochemistry and 19 having no accumulation, were studied. The presence of anti-p53 was tested using a novel ELISA utilising a recombinant p53 protein as a capture system and verified by western blotting. p53 gene mutations were sought by single strand conformational polymorphism and DNA sequencing analyses. RESULTS: Of 19 patients with p53 protein accumulation in tumour tissue, 10 (52%) had antibodies to p53 in serum by ELISA. Four patients with p53 negative immunohistochemistry also had detectable anti-p53. Western blot analysis confirmed the specificity of the ELISA positive serum samples. The presence of anti-p53 was independent of serum alpha-fetoprotein and was detected in 50% of small tumours while only 8% were alpha-fetoprotein positive. Mutations affecting exons 5 and 6 seem to be more frequently associated with development of anti-p53, than mutations in exons 7 or 8. CONCLUSIONS: The ELISA for anti-p53 is a convenient and specific tet for the detection of humoral response to alterations in p53 gene expression and could be of value in the diagnosis and characterisation of patients with hepatocellular carcinoma.

Antibodies, Neoplasm↗
PubMed1996

Cognitive impairments of alcoholic cirrhotic patients: correlation with endogenous benzodiazepine receptor ligands and increased affinity of platelet receptors.

OBJECTIVES: To determine whether differences in cognitive function between alcoholic and non-alcoholic cirrhotic patients relate to differences in endogenous ligands for the benzodiazepine receptor and/or benzodiazepine binding. METHODS: Seventeen grade-I hepatic encephalopathic patients (nine alcoholic, eight non-alcoholic) were compared with 10 matched controls on plasma concentrations of endogenous ligands for the neuronal benzodiazepine receptor, benzodiazepine binding in platelets, and performance on tests of cognitive function. RESULTS: Both groups of patients were impaired on verbal recall and on reaction time tasks compared with controls; alcoholic patients were also impaired on Reitan's trails test and digit cancellation. Four of the 17 patients had detectable concentrations of endogenous benzodiazepine ligands and they were more impaired than other patients on trails and cancellation tests. The groups did not differ in the density of benzodiazepine platelet receptors, but receptor affinity was higher in alcoholic patients than in controls; furthermore, receptor affinity correlated with the time to complete the cancellation task and with reaction time. CONCLUSION: Alcoholic cirrhotic patients may have enhanced concentrations of ligands for neuronal and peripheral benzodiazepine receptors and these may contribute to cognitive impairments in these patients.

Adult↗
PubMed1996

Tardive dyskinesia and positive and negative symptoms of schizophrenia. A study using instrumental measures.

BACKGROUND: Controversy surrounds the relationship between tardive dyskinesia (TD) and symptoms of schizophrenia. While some studies reported that negative symptoms of schizophrenia may be a risk factor for TD, others reported a relationship between TD and positive symptoms. METHOD: Eighty-four patients were studied, of whom 47 met criteria for TD. Clinical and instrumental procedures were used to increase the sensitivity of our assessments of the presence and severity of TD. Stepwise logistic and linear regression procedures were used to identify demographic variables, psychopathology, and motor parameters associated with the presence and severity of TD. RESULTS: A 3-factor model consisting of age, clinical tremor, and negative symptoms explained 25% of the variance in clinical TD severity. A 6-factor model consisting of female gender, instrumental and clinical measures of parkinsonism, positive, and negative symptoms explained 49% of the variance in severity of instrumentally derived dyskinesia. CONCLUSIONS: These results suggest that the presence of TD may be associated with positive symptoms; that the severity of TD may be related to negative symptoms; and that the relationship between negative symptoms and TD severity may be influenced by the presence of parkinsonism.

Adult↗
PubMed1996

pS2 transfection of murine adenocarcinoma cell line 410.4 enhances dispersed growth pattern in a 3-D collagen gel.

We describe the first model system employing human pS2 gene transfer and expression in a non-pS2-expressing cell line, mouse mammary adenocarcinoma 410.4, in order to analyse the potential effect of human trefoil peptide pS2 in glandular epithelium. Two selected clones, AA4 and AD4, were established and shown to have incorporated the pS2 cDNA sequence into the genome, express pS2 containing transcript and produce the pS2 peptide. When grown in 3-D collagen gels both transfectants show striking morphological changes compared to the vector control clone (VA5). VA5 forms large cohesive spherical aggregates with rare coarse spicular outgrowths, accompanied by prominent hyalinised extracellular matrix deposition. pS2 transfectants form poorly cohesive, stellate colonies with very little or no matrix deposition, radiating long cords composed of single elongated cells, an effect previously observed in other cell lines with hepatocyte growth factor. pS2 transfection had no demonstrable effect on proliferation and this is not a morphogenetic phenomenon, as tubulogenesis is not seen. Motility assays suggest that the pS2 'dispersant' effect in collagen gels is due to an increase in cell motility. There were no measurable alterations in either E-cadherin expression or E-cadherin-dependent cell-cell aggregation. pS2 may play a role in maintenance and restitution of mucosal integrity by accelerating migration/dispersion.

Adenocarcinoma↗
PubMed1996

Effect of ELAD liver support on plasma HGF and TGF-beta 1 in acute liver failure.

The aim of this study was to investigate the effects of treatment with the extracorporeal liver assist device (ELAD) in patients with acute liver failure (ALF) on plasma hepatocyte growth factor (HGF), the most potent growth factor, and transforming growth factor-beta 1 (TGF-beta 1), an inhibitory factor for liver regeneration. Initial plasma HGF, measured by ELISA, was significantly increased in the ALF patients (7.86 +/- SEM 1.76 ng/ml) compared with normal subjects (0.10 +/- 0.02 ng/ml, p < 0.001). After 6 hours of ELAD haemoperfusion, plasma HGF increased further (30.5 +/- 6.19 ng/ml, p < 0.001), with a subsequent decrease towards the initial value by 48 hours. Initial plasma levels of TGF-beta 1 determined by ELISA were significantly increased in the ALF patients (43.4 +/- 5.9 ng/ml) compared with normal subjects (25.1 +/- 2.3 ng/ml, p < 0.01), but there was no change in plasma TGF-beta 1 during the study period in either the ELAD or control ALF group. As HGF is a heparin-binding growth factor and similar changes in HGF were observed during CVVHD, one possible explanation is that heparin administered as anticoagulant for extracorporeal circulation is involved in the effects observed on HGF.

Adolescent↗