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Biomedical subjects

G T Williams

Publications and source records attributed to G T Williams.

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

The British Society of Gastroenterology early gastric cancer/dysplasia survey: an interim report.

This presentation describes interim findings in a series of 319 patients referred from 41 hospitals on the basis of histopathological findings of 'early gastric cancer', 'dysplasia', or 'worrying mucosal appearances'. Data were recorded using a predefined proforma, and histopathological material circulated amongst a 'panel' of three further pathologists. After this process, 132 patients were classified as having early gastric cancer and 63 as dysplasia. There was good agreement between pathologists as to whether the cases had cancer or dysplasia - but 39 cases said by referring pathologists to have early gastric cancer were classified by the panel as having more extensive disease. Most early gastric cancer cases were diagnosed only after histopathological examination. Cancer or 'possible cancer' was only mentioned after 36% of the radiological investigations and 40.5% of the endoscopies. Computer aided analysis of the patients' symptoms placed 91.3% of the early gastric cancer cases into a 'high risk' group - but was unable to distinguish between early gastric cancer and dysplasia. The five year survival rate of the cases agreed to be early gastric cancer by the panel was well over 90%, but the four year survival rate of cases registered as 'early gastric cancer' but said by the panel to have more advanced disease was under 75%. These findings may account for some of the differences between series, and emphasise the need for precise, widely agreed criteria for the diagnosis of early gastric cancer and gastric dysplasia.

Follow-Up Studies↗
PubMed1990

Porphyria cutanea tarda and haemochromatosis: a family study.

A female patient aged 73 presented with a history of general malaise and hyperpigmentation. Iron studies in the patient and immediate family members indicated that the proband was homozygous for haemochromatosis, but subsequent investigations revealed that porphyria cutanea tarda was responsible for her signs and symptoms. Venesection of four units of blood brought her symptoms under control. The interplay between porphyria cutanea tarda and excess iron deposition is discussed as is the role of extending investigations to first and second degree relatives when either haemochromatosis or porphyria cutanea tarda is suspected.

Aged↗
PubMed1990

Construction, function and immunogenicity of recombinant monoclonal antibodies.

Much of the interest in chimaeric antibodies stems from their presumed lack of immunogenicity in humans. We have tested this assumption using mouse models and have concluded that whilst chimaerisation can certainly lead to a reduction in the total anti-antibody response, a substantial anti-variable region response can nevertheless remain. As it therefore seems likely that determinants within the variable region lead to this anti-antibody response, we have initiated experiments to test whether it might be possible to use transgenic mice that carry human immunoglobulin gene segments in their germline configuration as a means of making a repertoire of entirely human antibodies.

Animals↗
PubMed1989

Isotype exclusion and transgene down-regulation in immunoglobulin-lambda transgenic mice.

A given B lymphocyte makes an antibody containing either kappa- or lambda-light chains, but not both. This isotype exclusion is effected at the level of the rearrangement of the immunoglobulin gene segments, although by an unknown mechanism. An attractive possibility is that, following productive rearrangement of one of the light-chain loci, the newly synthesized light-chain polypeptide inhibits DNA rearrangement for the other isotype. To test such feedback regulation, we have created transgenic mice carrying a rearranged lambda 1-gene. By contrast with the B cells in normal newborn mice which are mainly kappa+lambda-, the B cells in the newborn transgenic mice express lambda- but not kappa-chains. We propose that the synthesis of any light chain, be it kappa or lambda, that allows expression of IgM on the cell surface results in a cessation of all V-J joining. Interestingly, the limited light-chain repertoire of the transgenic mice does not persist and most adult B cells express endogenous kappa-rearrangements and down-regulate the transgene.

Animals↗
PubMed1989

Apoptosis.

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Animals↗
PubMed1989

Antibodies to CD3/T-cell receptor complex induce death by apoptosis in immature T cells in thymic cultures.

The receptors found on most T lymphocytes bind to antigen presented on major histocompatibility complex proteins and consist of dimers of alpha- and beta-polypeptides associated with the invariant CD3 complex. A fully competent immune system requires a diverse array of T-cell antigen receptors (TCRs) with different specificities. This diversity is generated by rearrangement of TCR alpha- and beta-chain gene segments within the thymus where the receptors are first expressed. Any cells carrying self-reactive receptors must be eliminated, suppressed or inactivated so that destructive autoimmunity is avoided. Recently, compelling evidence has shown that one process involved in producing such self-tolerance is clonal deletion of autoreactive cells within the thymus by an as-yet-undefined mechanism. Here we show that engaging the CD3/TCR complex of immature mouse thymocytes with anti-CD3 antibodies produces DNA degradation and cell death through the endogenous pathway of apoptosis. Activation of this process in immature T cells by the binding of the TCR to self-antigens may therefore be the mechanism which produces clonal deletion and consequently self-tolerance.

Animals↗
PubMed1989

Antigen-induced apoptosis in developing T cells: a mechanism for negative selection of the T cell receptor repertoire.

Herein we have investigated the ability of antigen to induce thymocyte death by apoptosis on the basis that this may be the mechanism for the deletion of autoreactive cells during T cell development. We show that the ability of the bacterial "superantigen" staphylococcal enterotoxin B to cause specific depletion of V beta 8+ cells when added to thymus organ cultures is accompanied by DNA degradation into oligonucleosomal fragments, indicating that depletion involves apoptosis. Our results provide the first direct evidence that antigen-induced apoptosis can be triggered in developing T cells.

Animals↗
PubMed1989

The histology of anal skin tags in Crohn's disease: an aid to confirmation of the diagnosis.

We have investigated excision biopsy of anal skin tags as an adjunct to rectal biopsy in the diagnosis of Crohn's disease. Twenty-six patients with proven Crohn's disease of the large and/or small bowel were studied. All had perianal skin tags removed under local anaesthesia as outpatients, when rectal biopsies were also obtained. Three sections from each skin tag and three from each rectal biopsy were examined for granulomas. The rectal biopsies were also examined for changes 'suggestive' of Crohn's disease. Anal skin tags from 26 patients without Crohn's disease acted as controls. Of the patients with Crohn's disease, granulomas were found in both anal skin tags and rectal biopsies in five patients, in anal skin tags only in four, and in rectal biopsies only in three. When present, granulomas were more plentiful in anal skin tags than in rectal biopsies, being seen in all 3 sections in 7 of 9 'positive' tags (i.e.: in 31% of 78 sections), compared to only 1 of 8 'positive' rectal biopsies (i.e.: in 13% of 78 sections). No granulomas were seen in control anal skin tags. The procedure provides a simple technique which is complementary to rectal biopsy, by which histological confirmation of Crohn's disease may be obtained.

Adult↗
PubMed1989

A repertoire of monoclonal antibodies with human heavy chains from transgenic mice.

The introduction of human immunoglobulin gene segments in their unrearranged configuration into the germ line of mice might allow the production of a repertoire of human antibodies. Such transgenic mice could be used for the production of human monoclonal antibodies against human antigens. To test the feasibility of this approach, mice were created that carry a human heavy-chain minilocus comprising unrearranged immunoglobulin variable, diversity, and joining elements linked to a human mu-chain gene. The gene segments of this minilocus are rearranged in a large proportion of cells in thymus and spleen but not in nonlymphoid tissue. Some 4% of the B lymphocytes synthesize human mu chains resulting in a serum titer of about 50 micrograms of transgenic IgM antibody per ml. Hybridomas were established from the transgenic mice that stably secreted several micrograms of antibodies containing human mu heavy chains per milliliter.

Animals↗
PubMed1989

Primary malignant lymphoma of the large intestine complicating chronic inflammatory bowel disease.

Ten cases of malignant lymphoma of the colon and rectum complicating chronic inflammatory bowel disease are presented. Seven patients had chronic ulcerative colitis with a history varying from 6 to 20 years. There was extensive colitis in six of these patients and left-sided colitis in one. All seven lymphomas showed the pathological and immunohistological features of primary B-cell tumours of the gastrointestinal tract with a predominance of high-grade tumours. Three patients had Crohn's disease of the large intestine complicated by malignant lymphoma of the sigmoid colon or rectum. The history of Crohn's disease varied from 30 months to 20 years and in each case there was fissuring and fistulae. There was extensive anal involvement in two cases. Histologically the three lymphomas were heterogeneous: one was of 'granulomatous' T-cell type and the other two were markedly polymorphic and of equivocal phenotype. They were also characterized by numerous multinucleate tumour giant cells. Primary colorectal malignant lymphoma should be regarded as a rare, but significant, complication of ulcerative colitis. Immunosuppression may be an additional factor in the genesis of intestinal lymphoma in Crohn's disease. The prognosis appears to be dependent on factors already known to be of prognostic significance in primary gut lymphomas: a predominance of high-grade tumours suggests that the outlook is generally worse than that for idiopathic primary large intestinal lymphoma.

Adult↗
PubMed1989

E1a transactivation of the human HSP70 promoter is mediated through the basal transcriptional complex.

We have examined the promoter sequence requirements for E1a transactivation of the human HSP70 gene by using a transient cotransfection assay. A 5' deletion study has defined a basal transcription unit extending to -74 relative to the transcription initiation site which was fully E1a responsive. Further deletion, abolishing a CCAAT element at -67, drastically reduced basal and E1a-induced expression. A linker-scanner analysis has identified four functional elements within the basal transcription unit which may interact with CTF, SP1, TFIID, and an ATF/AP1-like factor. Sequences between -100 and -188 can partially compensate for mutations in these elements. No mutation specifically abolished E1a inducibility. Any reduction in absolute E1a-induced levels was accompanied by a corresponding reduction in absolute basal levels, thereby maintaining a constant relative fold induction. We conclude that E1a transactivation of the human HSP70 promoter does not require any single basal transcription element. We also examined an HSP70 promoter fragment, containing the CCAAT element at -67 and the purine-rich element at -54, out of its normal context by fusing it upstream of a transcriptionally inactive herpes simplex virus thymidine kinase deletion construct containing only the TATA box. The resulting chimeric promoter was fully E1a responsive. Mutagenesis of this promoter fusion demonstrated that the CCAAT element was essential for detectable basal and E1a-induced expression. Mutations in the purine-rich element resulted in an approximately 10-fold elevation in basal levels and rendered the promoter nonresponsive to E1a.

Adenovirus Early Proteins↗
PubMed1989

Hemin-induced transcriptional activation of the HSP70 gene during erythroid maturation in K562 cells is due to a heat shock factor-mediated stress response.

Hemin-induced differentiation of the human erythroleukemia cell line K562 results in the expression and accumulation of erythroid-specific gene products such as embryonic and fetal hemoglobins and the elevated synthesis of the major heat shock protein HSP70. This activity was suggested to represent activation of a heat shock gene during erythroid maturation independent of stress induction. In this study, we demonstrate that hemin induces the transcription of two members of the human HSP70 gene family, HSP70 and GRP78 (BiP). However, the induction of HSP70 by hemin showed characteristics consistent with the molecular events associated with a heat shock or stress response. The increase in HSP70 gene transcription was accompanied by induction of the stress-induced form of the heat shock transcription factor. Moreover, a heat shock element was required for the hemin responsiveness of chimeric heat shock promoter-chloramphenicol acetyltransferase genes transiently expressed in transfected K562 cells.

Carrier Proteins↗
PubMed1989

Unusual and intraoperative epicardial echocardiographic features of a papillary tumour of the aortic valve.

A mass with a diameter of 0.8 cm was detected in the aortic root of a 53 year old woman during routine preoperative cross sectional echocardiographic assessment of a secundum atrial septal defect. Intraoperative epicardial echocardiography showed that the mass was attached by a slender stalk to the tip of the left coronary cusp of the aortic valve, and histological examination showed that it was a papillary tumour. Intraoperative epicardial echocardiography can help in planning the excision of papillary tumours, and excision is advised even when there are no symptoms.

Aortic Valve↗
PubMed1989

Effect of ranitidine on gastroduodenal mucosal damage in patients on long-term non-steroidal anti-inflammatory drugs.

Twenty-four patients taking long-term non-steroidal anti-inflammatory drugs (NSAIDs) were followed in a double-blind placebo-controlled trial to assess the effect of ranitidine 300 and 600 mg daily on upper gastrointestinal mucosal damage and to assess methods of monitoring mucosal damage. Sixteen were given ranitidine and 8 had placebo throughout the study. Comparisons suggested that ranitidine reduced symptoms and endoscopic evidence of mucosal damage. Histological evidence of gastritis was present in only half of those on ranitidine but in all receiving placebo. Erosions and blood loss occurred intermittently during the study but faecal blood losses using 51Cr-labelled red cells failed to identify any difference between groups. Endoscopic observation of erosions and serial biopsies may provide simple, reliable measurements for future studies to assess the effect of therapy in reducing mucosal damage from long-term NSAIDs.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1989

Abdominal lymphoma--the place for surgery.

Gastrointestinal lymphoma (GIL) is rare but may be cured by surgery and chemotherapy. Because symptoms frequently mimic common abdominal conditions, presentation is often to a surgeon. Fifty-five patients with GIL were treated between 1975 and 1984: all underwent operations before the correct diagnosis was made, 22 (40%) as emergencies. Misdiagnosis in 23 (42%) led to a delay in correct treatment of greater than or equal to 6 months from the start of symptoms: in 17 (31%) the delay was greater than or equal to one year. Endoscopy and radiology were inaccurate and suggested peptic ulceration, Crohn's disease or irritable bowel syndrome. The site of disease was usually stomach and duodenum (26, 47%) or ileum and jejunum (29, 53%). The extent of surgical resection was associated with survival at greater than or equal to 3 years-in 16 (29%) who underwent 'complete resection' 14 survived, but only one of 28 survived when the operation was limited to diagnostic biopsy (P less than 0.0001). Most deaths occurred within one year of operation, commonly from perforation or haematemesis from residual mural disease during chemotherapy. In 5 of 11 patients who had biopsy only, CT scans suggested localized disease, and 'complete resection' was achieved at a second laparotomy. Complete resection should be attempted wherever possible before chemotherapy. The place for surgeons with experience is clearly central to the management of this disease.

Adult↗