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D J Harrison

Publications and source records attributed to D J Harrison.

At least 163 records · Page 9Linked to original sources
PubMed1990

Preferential over-expression of the class alpha rat Ya2 glutathione S-transferase subunit in livers bearing aflatoxin-induced pre-neoplastic nodules. Comparison of the primary structures of Ya1 and Ya2 with cloned class alpha glutathione S-transferase cDNA sequences.

Normal rat liver expresses Ya (Mr 25,500), Yc (Mr 27,500) and Yk (Mr 25,000) Class Alpha glutathione S-transferase (GST) subunits. The Ya-type subunit can be resolved into two separate polypeptides, designated Ya1 and Ya2, by reverse-phase h.p.l.c. In rat livers that possess aflatoxin B1-induced pre-neoplastic nodules, a marked increase is observed in the expression of Ya1, Ya2, Yc and Yk; of these subunits, Ya2 exhibited the greatest increase in concentration. The Ya1 and Ya2 subunits isolated from nodule-bearing livers were cleaved with CNBr, and the purified peptides were subjected to automated amino-acid-sequence analysis. Differences in the primary structures of the two Ya GST subunits were found at positions 31, 34, 107 and 117. These data demonstrate that Ya1 and Ya2 are distinct polypeptides and are the products of separate genes. The amino acid sequences obtained from Ya1 and Ya2 were compared with the cloned cDNAs pGTB 38 [Pickett, Telakowski-Hopkins, Ding, Argenbright & Lu (1984) J. Biol. Chem. 259, 4112-4115] and pGTR 261 [Lai, Li, Weiss, Reddy & Tu (1984) J. Biol. Chem. 259, 5182-5188], which encode rat Ya-type subunits. From these comparisons it appears probable that Ya1 represents the GST subunit encoded by pGTR 261, whereas Ya2 represents the subunit encoded by pGTB 38. It is likely that the over-expression of Ya1 and Ya2 in nodule-bearing livers is of major significance in the acquired resistance of nodules to aflatoxin B1, since previous work [Coles, Meyer, Ketterer, Stanton & Garner (1985) Carcinogenesis 6, 693-697] has shown that the Ya-type GST subunit has high activity towards aflatoxin B1 8,9-epoxide.

Aflatoxins↗
PubMed1990

Glutathione S-transferase detoxication enzymes in cervical neoplasia.

Altered expression of the glutathione S-transferases (GSTs) has been implicated in the progression to tumour after exposure to carcinogens, and GST Pi has been suggested as a possible marker of preneoplasia in the cervix. We have studied expression of the GST isoenzymes in normal cervix, non-dysplastic cervical condylomata, cervical intraepithelial neoplasia (CIN), and invasive squamous carcinoma of the cervix using immunocytochemistry. An increase in GST Pi in CIN as compared with normal cervix was paralleled by a reduction in the expression of microsomal GST. Similar changes were seen in cervical condylomata and immature squamous metaplasia, and thus neither isoenzyme is a marker of dysplasia. Microsomal GST was expressed in only 66 per cent of cases and in 22 per cent showed strong expression in vascular endothelium. These findings are of particular interest in view of the association between cervical carcinoma and cigarette smoking. Differences between individuals in the ability to detoxify environmental carcinogens may influence the likelihood of progression from benign proliferation to invasive malignancy.

Biomarkers, Tumor↗
PubMed1990

Scoliosis in the Rett syndrome: natural history and treatment.

The Rett syndrome (RS) is associated with a neurological form of scoliosis. From 1985 we have instituted a postal survey of families with Rett girls. The prevalence of scoliosis in the survey population is 64%. The age at onset of scoliosis has a normal distribution about a peak age of 8 years, with 72% of cases occurring before age 8. The scoliosis in RS is typically a long thoracolumbar curvature that progresses rapidly in girls over the age of 10 years. Operative treatment is successful in reducing the curvature, preventing curve progression and improving spinal balance for sitting and walking. The 5 girls who walked pre-operatively are still able to do so.

Adolescent↗
PubMed1990

Glutathione S-transferase expression in fetal kidney and Wilms' tumour.

The glutathione S-transferases (GSTs) have been implicated in carcinogenesis and tumour drug-therapy resistance. In this study GST pi was the predominant isoenzyme in the fetal human kidney. It was present in differentiated epithelial structures but never in the primitive mesenchyme. By contrast most cases of Wilms' tumours showed GST pi in both epithelial structures and undifferentiated blastema. The level of expression, as assessed by immunostaining, was no more than moderate, and was generally higher in differentiated elements. In only one case was GST alpha found in Wilms' tumour. This study had demonstrated a difference between fetal kidney and Wilms' tumour blastema in terms of GST expression.

Child↗
PubMed1990

Glutathione S-transferase localization in aflatoxin B1-treated rat livers.

Overexpression of detoxication enzymes is associated with the development of drug-resistant, preneoplastic nodules in the carcinogen-treated rat liver. The most consistent marker of preneoplasia in many experimental models is increased expression of the pi-class glutathione S-transferase (GST) YfYf. We have confirmed by immunostaining that the pi-class GST is overexpressed in aflatoxin B1-induced preneoplastic nodules and liver tumours in rats. However, pi-class GST YfYf has low activity against aflatoxin B1-8,9-epoxide, and most activity against this cytotoxic and genotoxic metabolite is associated with the alpha-class GSTs YaYa, YaYc and YcYc. We have demonstrated that there is also a consistent increase in the alpha-class GSTs in this model. It seems likely that the overexpression of the Ya and Yc subunits, rather than increased levels of the pi-class GST YfYf, is responsible for the acquisition of a drug-resistant phenotype in rat liver preneoplastic nodules and tumours induced by aflatoxin B1.

Aflatoxin B1↗
PubMed1990

Glutathione S-transferases in alcoholic liver disease.

There is already evidence in alcoholic liver disease, mostly from studies of morphology and cytokeratin distribution, that hepatocytes can undergo a variety of phenotypic changes. This study reports findings of immunohistochemistry using antibodies against members of the glutathione S-transferase supergene family of detoxification enzymes. Hepatocytes in severe alcoholic liver disease coexpressed both alpha and pi class glutathione S-transferase. This coexpression has been previously described only in human fetal liver and in chemically-induced preneoplastic foci in rat liver. The use of function associated markers should provide additional information in the investigation of liver disease.

Adult↗
PubMed1990

Idiopathic portal hypertension associated with cytotoxic drugs.

Four patients developed clinically important portal hypertension with histological features of idiopathic portal hypertension while they were receiving cytotoxic drugs for chronic myeloid leukaemia and Hodgkin's disease. Mild sclerosis of some small portal triads was the only abnormality seen at light microscopical examination in three of the four cases. In the remaining case light microscopical findings seemed to be normal. Two cases examined by electron microscopy showed perisinusoidal fibrosis; in one case this was the only abnormality detected. There is an association between idiopathic portal hypertension and the use of chemotherapeutic agents, particularly thioguanine. Adequate histological examination of liver tissue, including electron microscopic studies, is recommended for patients who develop hepatic problems while receiving cytotoxic treatment to elucidate this problem.

Adult↗
PubMed1989

Autoantibodies to neutrophil cytoplasmic antigens in systemic vasculitis have the same target specificity.

Many patients with systemic vasculitis have antibodies to neutrophil cytoplasm antigens (ANCA) detectable by indirect immunofluorescence. We sought to characterize further the nature of these antigens. Western blots of neutrophil protein extracts indicated that nine patients' sera, positive for ANCA by immunofluorescence, all reacted with a 45 kDa and a 27-31 kDa protein. Negative control sera, and sera taken in remission, did not react with either of these antigens. The results suggest that ANCA in vasculitis have the same target specificity and may therefore permit greater accuracy of diagnosis and increase our understanding of the pathogenesis of the conditions.

Antibody Specificity↗
PubMed1989

Novel histopathologic findings in a surviving case of hemolytic uremic syndrome after bone marrow transplantation.

We report novel renal histopathologic features in a patient with hemolytic uremic syndrome after allogeneic bone marrow transplantation who survived with plasma exchange therapy. This distribution of vascular lesions within the kidney differed from previously described cases, which were uniformly fatal, in that there were marked arterial changes in addition to arteriolar and glomerular microangiopathy. A high rate of frequency of apoptotic cells within glomeruli was found. These findings are discussed in terms of their pathogenetic and prognostic relevance.

Adolescent↗
PubMed1989

Opportunistic infection and antineutrophil cytoplasm antibodies in Wegener's granulomatosis.

Antineutrophil cytoplasmic antibodies (ANCA) are of established value in the diagnosis of Wegener's granulomatosis allowing early introduction of therapy. These patients are at risk of opportunistic infection, especially whilst receiving immunosuppressive drugs and this may mimic reactivation of disease. We present three cases of Wegener's granulomatosis complicated by opportunistic infection and assess the value of ANCA detection. Two presented with symptoms compatible with disease reactivation but ANCA were negative. One died with pulmonary infection due to Pneumocystis carinii, Aspergillus fumigatus and Herpes simplex. Transbronchial biopsy in the second case revealed Pneumocystis carinii. A third case had strongly positive serum ANCA at diagnosis but in addition pulmonary infection with Legionella pneumophila. ANCA detection is of value in patients with Wegener's granulomatosis, but the result must be interpreted in the full clinical context.

Autoantibodies↗
PubMed1989

Glutathione S-transferase isoenzymes in human renal carcinoma demonstrated by immunohistochemistry.

Glutathione S-transferase (GST) in man comprise at least four gene families. Three of these families give rise to cytosolic isoenzymes (alpha, mu and pi classes), whilst the remainder is membrane bound and has been called microsomal GST. These enzymes are implicated in tumourogenesis and both pi class GST and alpha class GST have been described in four cases of human renal cell carcinoma. Using specific polyclonal rabbit antisera we have demonstrated by immunohistochemistry that all 12 renal carcinomas studied contained GST pi. Most tumours also contained GST alpha, GST mu and microsomal GST isoenzymes but their distribution was heterogeneous and sometimes very focal. This heterogeneity of GST isoenzyme distribution within tumours has not been well documented previously, but is relevant to our understanding of the functions of GST, and to the interpretation of biochemical quantification experiments using tissue extracts.

Carcinoma, Renal Cell↗
PubMed1989

Cytosolic and microsomal glutathione S-transferase isoenzymes in normal human liver and intestinal epithelium.

Glutathione S-transferases are a group of drug metabolising and detoxification enzymes. We have studied the distribution of four isoenzymes, acidic, basic, neutral, and microsomal GST in human liver, gall bladder, and small and large intestinal epithelium by immunohistochemistry. Antibodies were raised in rabbits to purified GST subunits and several formalin fixed paraffin sections of each human tissue studied using the peroxidase-antiperoxidase method. Staining density was graded from very strong (+++) to negative (-). All four enzymes were identified within the liver, the acidic GST being found almost exclusively within the biliary epithelium. The gall bladder epithelium stained strongly for acidic and basic GST. In the small intestinal epithelium the acidic and neutral GST were readily identified in villi and crypts, whilst basic GST was found only in the villi and microsomal only in the crypts. In the colonic mucosa only acidic GST could consistently be identified. This histological heterogeneity may have functional implications for these enzymes in human hepatobiliary and intestinal tissue.

Cytosol↗
PubMed1989

Distribution of glutathione S-transferase isoenzymes in human kidney: basis for possible markers of renal injury.

To determine whether the tissue distribution of glutathione S-transferase (GST) isoenzymes could define the precise nature of renal injury, 13 adult kidneys were studied, using specific antibodies raised against purified isoenzymes. Basic GST stained strongly proximal convoluted tubules and some medullary tubules; acidic GST stained strongly distal convoluted tubules and medullary tubules; neutral GST stained similarly to acidic GST, but weaker, and microsomal GST stained glomerular and interstitial endothelium and collecting ducts deep in the medulla, although there was considerable variation in staining intensity among cases. It is suggested that the measurement of these isoenzymes in serum and urine may help to elucidate the localisation of tissue damage, which may be particularly valuable in patients with cyclosporine toxicity following renal transplantation.

Glutathione Transferase↗
PubMed1989

Antibodies to neutrophil cytoplasmic antigens in Wegener's granulomatosis and other conditions.

The use of serum antibodies to neutrophil cytoplasmic antigens (ANCA) as a diagnostic marker for Wegener's granulomatosis and other forms of vasculitis has been assessed. Although ANCA have been described by several groups the precise antigenic targets are unknown, and detection of ANCA still relies on an indirect immunofluorescence assay technique. Several different patterns of fluorescence have been produced by using sera from different groups of patients, and insufficient information is available on the frequency of positive results and of the patterns of immunofluorescence obtained when serum from patients with vasculitis as a part of a generalised connective tissue disease is used. A study was carried out on serum from 240 patients, including 23 patients with Wegener's granulomatosis, 12 with microscopic polyarteritis, and 30 with various connective tissue diseases. Three patterns of fluorescence were observed: bright coarsely granular cytoplasmic, bright non-granular cytoplasmic, and weak diffuse cytoplasmic. The bright, coarsely granular pattern was 86% specific for Wegener's granulomatosis in this series and was observed in 18 of 23 cases. Other patterns of fluorescence were found in various conditions and were not of diagnostic value. The technique is simple, inexpensive, rapid, and reproducible.

Adult↗
PubMed1989

Single strand DNA breaks in mitogen stimulated T lymphocytes are religated by a mechanism independent of accessory cells.

The phenomenon of religation of single-strand DNA breaks (nicks) in mitogenically stimulated human T lymphocytes is an event occurring within 8 h of mitogen stimulation. Many later events in lymphocyte activation are known to be dependent on accessory cells, whereas earlier events are often accessory-cell independent. To establish whether nick religation is dependent or independent of accessory-cell function, lymphocytes were stimulated with PHA in the presence of inhibitors thought to act, in part at least, on accessory cells (methylprednisolone and cyclosporine A), or under conditions in which accessory-cell function is limited (low-density culture, adherent-cell depleted populations). In each case DNA synthesis was inhibited but the religation process was retained, indicating that it is independent of accessory-cell function. Inhibition of DNA synthesis in these cells was shown to be readily reversible on addition of conditioned medium containing accessory-cell products, but there was no further change in ligation.

Antigen-Presenting Cells↗