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Biomedical subjects

G T Williams

Publications and source records attributed to G T Williams.

At least 109 records · Page 6Linked to original sources
PubMed1994

Familial adenomatous polyposis associated thyroid carcinoma: a distinct type of follicular cell neoplasm.

Thyroid carcinoma has been described as occurring more frequently than expected in association with familial adenomatous polyposis. The histology of these cases has not been described in detail, although the reported cases were usually diagnosed as papillary carcinoma. We now report the pathological features of four cases of thyroid carcinoma associated with familial adenomatous polyposis, and review the findings in the literature. The tumours in these four cases were all of follicular cell origin as shown by thyroglobulin immunohistochemistry. In three they were multifocal. The tumours showed some features of papillary carcinoma--grooved nuclei and papillary architecture, but these were not consistent. They also showed features that were unusual for papillary carcinoma--a cribriform pattern and solid areas with spindle cell component. Commonly the tumours combined both patterns. A review of the reported cases of thyroid cancer associated with familial adenomatous polyposis showed that they also were commonly multifocal and occurred predominantly in young women. When the histology was adequately reported or illustrated it was, in most instances, consistent with the findings in our own cases. We therefore suggest that these thyroid tumours form a distinct type with some unusual features. Clearly it is likely that the APC gene is associated with their pathogenesis, and that other factors contribute to the predominantly female incidence in this as in sporadic tumours. Six of 63 reported cases showed metastasis or died from thyroid carcinoma. In a number of cases the tumours presented before the familial adenomatous polyposis was recognized. The findings of these unusual histological features in a thyroid tumour, and particularly of multicentricity, should alert the pathologist to the possibility of familial adenomatous polyposis with its implications for family screening. The tumours are often well demarcated but, because of the multicentricity, total thyroidectomy should be advocated.

Adenocarcinoma, Follicular↗
PubMed1994

Expression of p53 in early (T1) gastric carcinoma and precancerous adjacent mucosa.

Abnormalities of the tumour suppressor gene p53 have been shown in approximately 60% of advanced gastric adenocarcinomas and it has been suggested that the immunohistochemical finding of increased p53 expression is a prognostic marker in gastric cancer. No studies of early (T1) tumours have been reported. Over expression of p53 protein in 95 early gastric carcinomas and in adjacent mucosa was investigated using immunohistochemistry with antibody CM1. Thirty five per cent of the tumours were positive. The frequency of p53 positivity in tumours of tubular histological type (46%) was significantly higher than that in signet ring tumours (10%) (p = 0.006), and neoplasms that invaded deeply into the submucosa were more frequently positive (45%) than others (30%). Five of eight (62%) T1 tumours with lymph node metastases showed immunoreactive p53. In signet ring tumours, immunopositivity correlated with the frequency of DNA aneuploidy. p53 Over expression was also found in 15% of 26 examples of high grade dysplasia in mucosa adjacent to invasive tumours. No positivity was found in intestinal metaplasia or in normal mucosa. The findings show that immunocytochemically demonstrable over expression of p53 correlates with other morphological markers of aggressiveness in T1 gastric adenocarcinoma. The increasing frequency of p53 immunoreactivity in the sequence of high grade dysplasia-->early gastric cancer-->advanced gastric cancer supports the view that abnormalities of p53 are related to tumour progression in gastric carcinogenesis.

Adenocarcinoma↗
PubMed1994

Effect of nicotine on rectal mucus and mucosal eicosanoids.

Because ulcerative colitis is largely a disease of non-smokers and nicotine may have a beneficial effect on the disease, the effect of nicotine on rectal mucosa in rabbits was examined. Nicotine was given subcutaneously by an Alzet mini-pump in doses of 0.5, 1.25, and 2 mg/kg/day for 14 days to three groups of eight animals and compared with eight controls. Mean (SD) serum nicotine concentrations (ng/ml) were 3.5 (1.1), 8.8 (2.3), and 16.2 (5.2) respectively in the treated groups. The thickness of adherent mucus on rectal mucosa in controls (median 36 microns) was significantly reduced by low dose (22 microns, p = 0.0011), and increased by high dose nicotine (48 microns, p = 0.035). Incorporation of radioactive glucosamine into papain resistant glycoconjugates was unchanged, indicating that mucin synthesis was unaltered. Prostaglandins (PG) were reduced, in some cases significantly (6-keto PGF1 alpha, PGF2 alpha, and hydroxy-eicosatetraenoic acid), by nicotine, which showed an inverse dose dependence--with greatest inhibition in relation to the lowest dose. Nicotine, and possibly smoking, may affect colitis by an action on mucosal eicosanoids and on adherent surface mucus secretion in the rectum and large bowel.

Animals↗
PubMed1994

Thickness of adherent mucus gel on colonic mucosa in humans and its relevance to colitis.

The thickness of adherent mucus gel on the surface of colonic mucosa was measured in surgically resected specimens from 46 'control' patients most of whom had carcinoma of the colon; 12 were from right colon, 17 left colon, and 21 from rectum. In addition specimens were examined from 17 patients with ulcerative colitis and 15 patients with Crohn's disease. In controls a continuous layer of mucus was readily seen on specially prepared sections viewed by phase contrast illumination. Mean values for right and left colon and rectum were 107 (48), 134 (68), and 155 (54) microns respectively with a significant difference between right colon and rectum (p = 0.015). Values in ulcerative colitis showed greater variation and in those areas with acute inflammation mucosa was denuded of the mucus layer. In contrast, values for Crohn's disease were normal or greater than normal in thickness--right colon 190 (83) microns compared with 107 48 microns, p = 0.0093. A series of validation experiments are described for the method used to measure mucus thickness. The possible role of mucus in the pathogenesis of inflammatory bowel disease is discussed.

Adolescent↗
PubMed1994

Adult cystic fibrosis and the general surgeon.

We describe three adult patients who had cystic fibrosis and acute abdominal symptoms. In each case there were difficulties in diagnosis and treatment owing to the unfamiliarity of general surgeons with this disease. Successful management will depend on awareness of the entity of acute distal intestinal obstruction which may occur de novo in adult patients with cystic fibrosis.

Acute Disease↗
PubMed1994

Developmental regulation of bcl-2 expression in the thymus.

An important factor in shaping the T-cell receptor (TcR) repertoire during thymocyte development is the susceptibility of double-positive (CD4+ CD8+) thymocytes to induction of apoptosis (negative selection) when the TcR is engaged by 'self'-antigens. Recent evidence has suggested that this susceptibility to apoptosis may be influenced by the expression of bcl-2, a proto-oncogene known to increase the resistance to apoptosis in various cell systems. Using a semi-quantitative polymerase chain reaction (PCR) technique in conjunction with staged embryonic material and purified thymocyte subpopulations we have investigated patterns of bcl-2 expression during normal T-cell development. Our results show that while bcl-2 alpha gene expression is readily detectable in immature CD3-CD4-CD8- thymocytes and in mature single-positive TcRhi cells, it is drastically reduced in TcR negative double-positive (CD3- CD4+ CD8+) cortical thymocytes of intermediate maturity. Careful mapping of bcl-2 alpha re-expression in relation to the onset of TcR expression within the population of embryonic thymocytes indicates that bcl-2 alpha is up-regulated as soon as TcR molecules are expressed on the surface of CD4+ CD8+ thymocytes. Therefore, thymocytes susceptible to apoptosis on TcR ligation express bcl-2 alpha mRNA suggesting that changing levels of bcl-2 expression are unlikely to be the only determinant regulating susceptibility to apoptosis in the thymus. The possible implications of these changes in bcl-2 expression regarding other facets of thymocyte development will be discussed.

Animals↗
PubMed1993

Human CD4+ cytolytic T cells kill antigen-pulsed target T cells by induction of apoptosis.

Stimulation of human CD4+ T cell clones with appropriate specific peptides or with lectins in the absence of APC induces a substantial degree of cell death. We have investigated the mechanisms of induction of this cell death and show that it occurs by apoptosis, identified by morphology and the characteristic pattern of DNA degradation. We also investigated whether this T cell death was a result of a suicide process activated in the T cell after "inappropriate" recognition of Ag on the surface of another T cell clone (and in the absence of other accessory signals), or was due to a conventional lethal hit delivered by one cytolytic T cell to another "target" T cell. Our results strongly suggest that peptide-induced cell death of human CD4+ CTL is due to active killing of Ag-presenting target T cells by effector T cells of the same clone. The cell death that is induced in the target T cell occurs via apoptosis that requires de novo RNA transcription and translation in the effector T cell.

Apoptosis↗
PubMed1993

Membrane immunoglobulin without sheath or anchor.

The canonical form of the B cell antigen receptor is composed of membrane immunoglobulin sheathed by the alpha/beta heterodimer. Whereas membrane IgM cannot be transported to the cell surface in the absence of alpha/beta, both IgD and IgG2b can be expressed naked (i.e. without alpha/beta) on the surface of myeloma transfectants. In the case of one cell-line, such naked IgD has been shown to be inserted into the membrane by a glycosyl-phosphatidylinositol anchor. Here, however, we show that both IgD and IgG2b (but not IgM) can be expressed on the surface of myeloma transfectants without either sheath or anchor. This distinction between the isotypes is attributable to differences in the region of the transmembrane segment.

Amino Acid Sequence↗
PubMed1993

Granulomatous hidradenitis suppurativa and cutaneous Crohn's disease.

Three patients with concurrent hidradenitis suppurativa and Crohn's disease are presented. The notable histological feature in each hidradenitis resection was the presence of numerous discrete epithelioid granulomas in areas of non-inflamed dermis. The purpose of the study was to determine the incidence of epithelioid granulomas in 101 hidradenitis patients and their significance in relation to systemic granulomatous disease. Discrete epithelioid granulomas were identified in 8% of the resections (10 patients). One patient had Crohn's disease and one other pulmonary sarcoidosis. Seven patients with granulomatous hidradenitis neither had nor developed any other disease during the 3-year follow-up period. Clinical review identified a further two patients with Crohn's disease but associated with non-granulomatous changes in the skin resections. Foreign body type granulomas were identified in 25% of the resections adjacent to ruptured hair follicles, sinus tracts or nearby degenerate sweat glands. The study shows that, although foreign body type granulomas are a common finding in hidradenitis, the presence of discrete epithelioid granulomas in the dermis away from the site of active inflammation is unusual and should alert the pathologist to the possibility of systemic granulomatous disease such as Crohn's disease or sarcoidosis.

Adolescent↗
PubMed1993

The mouse B-cell antigen receptor: definition and assembly of the core receptor of the five immunoglobulin isotypes.

We have shown that the core antigen receptor of all five isotypes is composed of immunoglobulin in association with a common heterodimeric alpha/beta sheath. The stoichiometry of the association is unknown although preliminary evidence points to it being an IgH2L2 [alpha/beta]2 association. Studies with chimaeric molecules indicate that much of the immunoglobulin-sheath interaction must occur through the carboxyterminal end of the molecule with particular importance being given to the linker-transmembrane region. The glycosylation of the alpha chain differs according to the isotype with which it is associated. There are two sites for N-linked glycosylation on the alpha chain (Asn-30 and Asn-40); both sites are used. Mutation of Asn-30 alone decreases but does not abolish surface expression of the antigen receptor complex. Mutation of both sites prevents expression of the surface IgM[alpha/beta] complex but not of a surface IgD[alpha/beta] complex. Moreover, the pattern of alpha glycosylation is considerably affected by changes in the linker region between C mu 4 and the transmembrane, giving further support to the importance of this region in immunoglobulin-sheath interaction. Unlike IgM, IgD and IgG2b do not require alpha/beta for transport to the cell surface and can be expressed on the surface without either sheath or glycosyl phosphatidylinositol anchor. This finding may reflect that the IgD transmembrane region is significantly less hydrophobic than that of IgM; however, it should be noted that is not clear whether naked IgD exists in vivo. In fact, we have found that the alpha/beta sheath is necessary in order to facilitate efficient internalization and presentation of antigen by membrane immunoglobulin. The sheath presumably also plays a major role in potentiating transmembrane signalling. However, mutant receptors that do not associate with the alpha/beta sheath are nevertheless able to trigger phosphorylation of cellular proteins on tyrosine residues following cross-linking. Also, in addition to the alpha/beta sheath, other transmembrane proteins associate with the B-cell antigen receptor although they are not required in order to potentiate surface transport. It may be interaction with one of these other associated transmembrane proteins or, alternatively, interaction between the immunoglobulin cytoplasmic tail and, say, the cytoskeleton, that enables antigen receptors lacking the alpha/beta sheath to give rise to cellular signalling.

Amino Acid Sequence↗
PubMed1993

Activation of the inducible orphan receptor gene nur77 by serum growth factors: dissociation of immediate-early and delayed-early responses.

We have characterized the genetic elements that mediate the transcriptional activation of nur77, a growth factor-inducible gene encoding a member of the steroid/thyroid hormone receptor superfamily. Although initially identified as a serum-inducible immediate-early gene with expression kinetics similar to those of c-fos, we found that transcriptional activation of nur77 by serum growth factors in fibroblasts is in fact composed of two components: an immediate-early component, which can occur in the absence of de novo protein synthesis, and a delayed-early component, which is dependent on de novo protein synthesis. The expression of nur77 following serum stimulation reflects the superimposition of immediate-early and delayed-early expression. Immediate-early and delayed-early expression can be dissociated from one another by deletion or base substitution mutations of the nur77 promoter. Immediate-early expression of nur77 is mediated primarily by sequences located between nucleotides -86 and -126 upstream of the transcription start site. This region includes a sequence that resembles but differs from the CArG element found in other serum-inducible promoters. Upstream of the CArG-like element is a potential binding site for a transcription factor of the Ets family; the presence of this site is required for significant transcriptional induction. Delayed-early expression of nur77 is mediated by multiple AP-1-like and GC-rich elements, which can interact with products of immediate-early genes such as Fos/Jun and Zif268, respectively. Furthermore, we show that Zif268 can activate transcription of the nur77 promoter, suggesting that it may play a role in the delayed-early expression of nur77.

3T3 Cells↗
PubMed1993

DNA ploidy in early gastric carcinoma (T1): a flow cytometric study of 100 European cases.

DNA ploidy of 100 early gastric carcinomas (T1) was analysed by flow cytometry on archival material from five European centres and was correlated to morphological features and clinical behaviour. Tumours were classified according to the macroscopic appearance, histological type, and growth pattern. Aneuploidy was observed in 39% of tumours. Aneuploidy was more frequent in submucosal than in mucosal tumours (p = 0.04), in raised than in flat or ulcerated lesions (p = 0.001), and in the intestinal histological than in the diffuse types (p = 0.016). The presence of lymph node metastasis in 10 cases had no obvious relation to DNA ploidy. Five related deaths occurred during the follow up (6 months--16 years) of 84 patients. These results are similar to those reported in a large Japanese series suggesting no major differences between the two populations. Although follow up data were insufficient to relate DNA ploidy to tumour behaviour in this study, the Japanese experience shows that particular attention should be paid to early direction and complete surgical excision of raised intestinal type T1 carcinomas that have a Pen A growth pattern and are aneuploid.

Adult↗
PubMed1993

Comparison of bismuth citrate and 5-aminosalicylic acid enemas in distal ulcerative colitis: a controlled trial.

An enema that contained a complex of bismuth citrate and polyacrylate was compared with 5-aminosalicylic acid (5-ASA) enemas for treatment of distal ulcerative colitis. The multicentre trial involving 63 patients was randomised and double blind with enemas given over four weeks; clinical, sigmoidoscopic, and histological assessments were made. Improvements were seen in both treatment groups. Clinical remission was seen in 18 of 32 patients treated with 5-ASA and 12 of 31 patients treated with bismuth citrate-carbomer (chi 2 1.94; p = 0.16). Sigmoidoscopic remission occurred in 20 of 32 patients in the 5-ASA group and 15 of 31 patients given bismuth (chi 2 1.27; p = 0.26). Improvement of rectal biopsy histology by at least one grade was seen in 16 of 32 patients in the 5-ASA group and 14 of 31 patients with bismuth (chi 2 0.15; p = 0.70). Analysis of covariance gave no significant difference between groups, although there was a trend favouring 5-ASA. There was no evidence of bismuth accumulation during the trial. Bismuth enemas may offer a new therapeutic option in distal ulcerative colitis.

Adult↗