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Biomedical subjects

G T Williams

Publications and source records attributed to G T Williams.

At least 19 recordsLinked to original sources
PubMed1992

Elevated serum CA 19-9 levels in hepatobiliary cystadenoma with mesenchymal stroma. Two case reports with immunohistochemical confirmation.

Hepatobiliary cystadenomas with mesenchymal stroma (CMS) are rare tumors. Two cases are reported that illustrate many features of CMS, including polypoid involvement of the common hepatic duct in one case. Both tumors were associated with elevated serum levels of the tumor-associated antigen CA 19-9 but normal levels of carcinoembryonic antigen and alpha-fetoprotein. Immunohistochemical analysis confirmed the presence of CA 19-9 in the epithelial component of the tumor. The implications of these findings are discussed, both in relation to the histogenesis of CMS and its preoperative diagnosis. A minimally elevated level of CA 19-9 was found in only one of five patients with hydatid disease of the liver, an important differential diagnosis in clinical management.

Adult↗
PubMed1992

Reduction in apoptosis relative to mitosis in histologically normal epithelium accompanies fibrocystic change and carcinoma of the premenopausal human breast.

The aims of this study in 227 premenopausal women were (a) to determine the mitotic index (MI), the thymidine labelling index (LI), and the apoptotic index (AI) within the epithelial cells of histologically 'normal' human breast biopsy material removed away from the site of either a fibroadenoma or a carcinoma; and (b) to relate differences in the kinetic indices of the 'normal' epithelium to the pathology in the same breast diagnosed as fibroadenoma alone (125 patients), fibroadenoma with accompanying mild fibrocystic change (79 patients), or carcinoma (23 patients). Ratios of the average indices (AI/MI, AI/LI, MI/LI) were also calculated to minimize uncertainties related to the total cell population counted, the denominator in the LI, MI, and AI. All indices and ratios of indices were corrected for age, averaged over the cycle, and expressed as log-transformed values for analysis. Significant (P less than 0.001) reductions in AI and in apoptosis relative to mitosis (reduced AI/MI) were found in 'normal' epithelium from breasts having fibrocystic change (AI = 0.17 +/- 0.02; AI/MI = 1.01 +/- 0.18) and carcinoma (AI = 0.19 +/- 0.04; AI/MI = 0.88 +/- 0.29), compared with breast with fibroadenoma alone (AI = 0.27 +/- 0.03; AI/MI = 1.29 +/- 0.39). In the absence of significant differences in MI and LI between the 'normal' tissue groups, this finding raises the possibility that reduced epithelial cell apoptosis might be causally associated with the development of fibrocystic change and with an increased risk of development of carcinoma.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenofibroma↗
PubMed1992

Apoptosis in the development of the immune system: growth factors, clonal selection and bcl-2.

The mammalian immune system is essential for surviving challenge infections with a great range of potential pathogens. The protective effect produced is dependent on many different types of cells which require flexible and independent production and regulation. In particular, many important responses are carried out by lymphocytes, which recognise foreign antigen through exquisitely specific receptors: i.e. surface immunoglobulin (sIg) on B lymphocytes and the T cell receptor (TCR) on T lymphocytes. Each lymphocyte displays receptors with a single specificity, allowing cells with particular specificities to be regulated independently. Since millions of different Igs and TCRs are expressed, the precise selection and regulation of each T and B cell population to produce a useful self-tolerant repertoire is a very complex process. Control of cell populations can, in theory, be exercised at a number of levels, including modulation of active cell death by apoptosis. Recent research has demonstrated that regulation of apoptosis is indeed a crucial element in the control of the immune system in general, and in the development of the TCR and Ig repertoires in particular. The molecular analysis of apoptosis now takes a high priority and the proto-oncogene bcl-2 appears to be responsible for specific suppression of apoptosis in several important situations. It is also clear that malfunctions affecting apoptosis, and in particular bcl-2, can result in significant progression towards malignancy.

Animals↗
PubMed1992

Molecular pathology of gastric carcinoma: progress and prospects.

Gastric carcinoma is the fourth most common malignancy in Western Europe and a major cause of cancer morbidity and mortality worldwide, particularly in the Far East and in areas of South America. The natural history of the disease is not fully established, and there is a need to elucidate the molecular mechanisms of gastric carcinogenesis in order to understand its pathogenesis and to develop molecular markers for clinical diagnostic use. Molecular analysis of colonic carcinogenesis has increased our understanding of its pathogenesis and has demonstrated multistage carcinogenesis in a human cancer. Research in gastric carcinoma has not achieved such significant progress, although a start has been made. We analyze some of the interpretation problems in molecular pathology affecting progress that are of interest to the histopathologist and review recent studies on the molecular biology of gastric carcinoma involving flow cytometry, cytogenetics, allele loss analysis, and transfection. We also summarize current knowledge about each of the major oncogenes and suppressor genes, attempting, in particular, to correlate gene abnormalities with morphologic appearances. The expanding field of cell proliferation and growth factors is outlined, gastric and colon carcinomas are compared, and gastric carcinoma is considered as a model system for the study of differentiation. This report concludes by suggesting directions for future research.

Biomarkers, Tumor↗
PubMed1992

A comparison of upper gastrointestinal mucosal damage by standard and delayed-release indomethacin.

Forty-five patients taking long-term indomethacin and with endoscopic erosions or superficial ulcers in the oesophagus, stomach or duodenal bulb were randomized in a double-blind study to continue with standard indomethacin or receive a 'delayed-release' formulation. This consisted of microgranules of indomethacin coated with an acrylic resin, Eudragit L, which releases drug in the small intestine. Endoscopy was repeated after 8 weeks and biopsies taken on both occasions. Changes in endoscopic lesions and histological appearances were similar in both groups, although mucosal erythema was less in those given Eudragit L indomethacin. Systemic, rather than topical, effects of indomethacin may therefore be responsible for persistence of gastro-duodenal mucosal lesions in these patients. There is reason to question the clinical practice of using expensive, delayed-release preparations.

Adult↗
PubMed1992

Can Crohn's disease be diagnosed at laparotomy?

The typical macroscopic features of Crohn's disease have been well described and are widely regarded as sufficient to diagnose the disease at laparotomy. We report six patients undergoing laparotomy for symptomatic Crohn's disease, shown radiologically, who were found to have macroscopically normal small bowel despite careful examination of the bowel by an experienced surgeon. In four cases resection was deferred, but all subsequently deteriorated and required further surgery. Minor abnormalities found by balloon examination of the terminal ileum prompted resection in two further patients. Histology showed an unusually superficial distribution of inflammation, which could explain the negative findings at laparotomy. We conclude that normal laparotomy findings alone do not exclude a diagnosis of clinically important small bowel Crohn's disease. Crohn's disease should be considered in patients with persisting symptoms after negative laparotomy.

Adolescent↗
PubMed1992

Incidence of ulcerative colitis in Cardiff over 20 years: 1968-87.

The annual incidence of ulcerative colitis in the city of Cardiff was examined over a 20 year period. In the decade 1968-77, the mean annual incidence was 6.4 per 10(5) of the population compared with 6.3 for the period 1978-87. There was no difference in the distribution or extent of the disease between decades or between sexes. This contrasts with the increased incidence of Crohn's disease during the same period. The study included a survey of family practitioners which identified a further 19 patients (11% of the total).

Adolescent↗
PubMed1992

Determination of a critical level of tissue oxygenation in acute intestinal ischaemia.

Tissue oxygen tension (PtO2) was measured using a miniaturised polarographic oxygen electrode in 134 segments of rat small intestine of varying degrees of ischaemia. Without knowledge of the PtO2 levels, the viability of each segment was scored using clinical parameters and tissue damage scored by independent histological examination. Histologically non-viable bowel had significantly impaired tissue oxygenation when compared with viable bowel (t test, p less than 0.001). Marked degrees of tissue hypoxia were frequently tolerated before major histological damage became apparent, a critical PtO2 level of 1.9 mmHg being identified. The overall accuracy rate of PtO2 measurement in the operative prediction of intestinal viability was 92.5%, which contrasts with a rate of only 57.7% for clinical criteria alone.

Animals↗
PubMed1992

Risk of ulceration with long-term indomethacin: endoscopic and histological changes in upper gastro-intestinal mucosa.

Twenty patients taking long-term indomethacin were chosen for the study because all had a normal endoscopic examination; biopsies, however, from the oesophagus, gastric antrum and duodenal bulb revealed histological inflammation in all patients in at least one site. After 8 weeks during which indomethacin therapy was continued, a further endoscopy revealed lesions in 5 patients--peptic ulcer in 3 and erosions in 2--but only 1 of these had any change in gastro-intestinal symptoms. Irrespective of whether mucosal lesions are seen on endoscopy in patients established on non-steroidal anti-inflammatory drug therapy, they remain in danger of developing both ulcers and erosions which are likely to be asymptomatic. At no time can one justifiably feel this patient group is not at risk of peptic ulceration.

Arthritis, Rheumatoid↗
PubMed1992

A stem cell niche theory of intestinal crypt maintenance based on a study of somatic mutation in colonic mucosa.

In both large and small intestine, mutagen administration leads to the occurrence of isolated crypts that are completely populated by a mutated phenotype; therefore, it has been proposed that crypts are maintained by a single stem cell. We show in mice that a single dose of mutagen leads to an early transient increase in frequency of colonic crypts that show a partial mutated phenotype and a later increase in frequency of crypts that show a complete mutated phenotype. This increase reaches a plateau at about the same time as the disappearance of partially mutated crypts. The same is true in the small intestine, but the time course is much slower. We propose an explanation based on multiple crypt stem cells that occupy a "stem cell niche," with random cell loss after stem cell division. A small difference in the number of crypt stem cells that occupy the niche provides a simple explanation for the surprisingly large difference in the time course of phenotypic changes in the large and small intestines after administration of a single dose of mutagen.

Animals↗
PubMed1992

Delay in presentation and misdiagnosis of strangulated hernia: prospective study.

The purpose of this study was to examine the presentation and management of strangulated hernia. The clinical course of 54 patients was recorded. Twenty-one patients (39%) presented after 48 h from the onset of symptoms. Fifteen (28%) had a bowel resection and two (4%) died. Twenty (37%) patients had previously consulted their general practitioner about the hernia, but only seven had been referred for surgery. Five (25%) had been warned of the risk of strangulation. In the 32 (59%) patients previously aware of a hernia, delayed presentation was related to ignorance of the risk of strangulation (P less than 0.01). The strangulated hernia was misdiagnosed by the general practitioner in 17 (33%) patients (necessitating a second visit) and by the hospital registrar in eight (15%). We conclude that strangulated hernia is too often misdiagnosed and all patients who present with a hernia must be referred to a surgeon and warned about strangulation.

Adult↗
PubMed1991

Functional significance of an overlapping consensus binding motif for Sp1 and Zif268 in the murine adenosine deaminase gene promoter.

The murine adenosine deaminase (ADA) gene has a (G + C)-rich promoter that can support diverse tissue-specific gene expression. By using deletion and mutation analyses, we have identified a cis-acting "repressor" element located immediately upstream of the proximal Sp1 binding site in the ADA gene promoter. This repressor element was localized to a binding site for the immediate-early, serum-responsive, DNA binding factor Zif268. This Zif268 binding site partially overlaps a binding site for the general transcription activator Sp1. Disruption of the Zif268 binding site without disturbing the Sp1 binding motif abolished Zif268 binding and resulted in significantly elevated promoter function. Conversely, disruption of the proximal consensus Sp1 binding motif without disturbing the Zif268 binding site resulted in a loss of Sp1 binding at that region and greatly reduced promoter activity. Our results suggest that one function of Zif268 may be to down-regulate this type of mammalian gene promoter by competing with Sp1 for binding to the overlapping binding motif.

Adenosine Deaminase↗
PubMed1991

The B-cell antigen receptor of the five immunoglobulin classes.

Several proteins associate with surface IgM to form the antigen receptor. We show that just two, the alpha and beta associated chains, are sufficient to reconstitute an IgM surface receptor in fibroblasts. Contrary to expectation, a common alpha chain associates with all five immunoglobulin classes. We propose that B-cell antigen receptors consist of a common alpha/beta heterodimer associated with each immunoglobulin class. But the classes differ both in the glycosylation of their associated alpha chain and in their dependence on alpha/beta for surface transport.

Amino Acid Sequence↗
PubMed1991

Activation of Epstein-Barr virus latent genes protects human B cells from death by apoptosis.

Epstein-Barr virus (EBV), a human herpesvirus, establishes a persistent asymptomatic infection of the circulating B-lymphocyte pool. The mechanism of virus persistence is not understood but, given the limited lifespan of most B cells in vivo, it seems most likely that EBV-infected cells must gain access to the long-lived memory B-cell pool. Here we show in an in vitro system that EBV, through expression of the full set of eight virus-coded 'latent' proteins, can protect human B cells from programmed cell death (apoptosis), the deletion mechanism which normally restricts entry into memory. We have found that EBV-positive Burkitt's lymphoma (BL) cell clones retaining the original tumour cell phenotype and expressing only one of the virus latent proteins, the nuclear antigen EBNA 1, are extremely sensitive to apoptosis; in this respect they resemble the tumour's normal cell of origin found in the germinal centres of lymphoid tissue. By contrast, isogenic BL cell clones which have activated expression of all eight EBV latent proteins are resistant to the induction of apoptosis. The EBV latent proteins should therefore be seen not just as activators of B-cell proliferation but, perhaps more importantly, as mediators of enhanced B-cell survival.

Antigens, Differentiation, B-Lymphocyte↗
PubMed1991

The mouse IgH 3'-enhancer.

A lymphoid-specific transcription enhancer element has recently been identified at the far 3' end of the rat immunoglobulin heavy chain (IgH) locus. Sequence analysis presented here reveals that this enhancer is flanked by a 350-bp invert repeat, giving a structure reminiscent of a transposable element. We therefore screened for the equivalent enhancer in the mouse to determine whether its presence was conserved during evolution. A mouse homologue was indeed identified and is located 16 kb downstream of the C alpha 1 exon. It is also flanked by invert repeats and these are not repeated throughout the genome. The mouse and rat enhancers retain high sequence homology. As regard activity, the IgH 3'-enhancer is lymphoid specific. However, this activity was detected in two plasmacytoma lines tested but not in two B cell lymphomas nor in HeLa cells suggesting that the enhancer may only play a stage-specific role during lymphocyte differentiation. As regards function within the IgH locus, we found that inclusion of the mouse IgH 3'-enhancer (in addition to the intron-enhancer) on mu gene expression plasmids effected a small increase in mu mRNA levels in stable plasmacytoma transfectants.

Animals↗
PubMed1991

Differentiation and limited proliferation of isolated Leishmania mexicana amastigotes at 27 degrees C.

We have demonstrated here that while many amastigotes of both Leishmania mexicana amazonensis and Leishmania mexicana mexicana differentiate to promastigotes when placed in culture at 27 degrees C, many others remain as amastigotes in their proliferative cycle. We have used this system to examine the effects of the anti-leishmanial compounds amphotericin B, 4-pentenoate and sodium stibogluconate (Pentostam) on the proliferation and differentiation of isolated extracellular amastigotes. Amphotericin B and 4-pentenoate showed little preferential effect on amastigote proliferation over promastigote proliferation although Leishmania mexicana mexicana (strain M379) was generally more resistant to these compounds than Leishmania mexicana amazonensis (strain LV78). This relative resistance was also observed in axenic cultures of proliferating promastigotes. L.m. mexicana amastigote differentiation was inhibited by amphotericin B and 4-pentenoate. Pentostam displayed a greater effect on amastigote differentiation than proliferation in both sub-species although again, a higher concentration was required to produce the same effect in L.m. mexicana.

Amphotericin B↗