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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
PubMed2002

The implementation of guidelines and computerised forms improves the completeness of cancer pathology reporting. The CROPS project: a randomised controlled trial in pathology.

The aim of this study was to determine whether reporting guidelines and computerised form-based reports improve the completeness of histopathological cancer data available for patient management and population cancer registration and to evaluate the acceptability of the intervention. The study was a randomised controlled trial with a split unit design and stratified cluster randomisation. All 16 hospital pathology laboratories in Wales were randomly allocated to report either breast or colorectal resection specimens by computerised form or conventional free text. 1044 reports were analysed in the study arm, 998 in the control arm. Use of pre-defined forms led to a 28.4% (95% confidence interval (CI): 15.7-41.2%) increase in complete reporting of a minimum dataset required for cancer registration and a 24.5% (95% CI: 11.0-38.0%) increase in complete reporting of minimum data required for patient management. Form-based reporting was acceptable to pathologists and preferred by clinicians. In conclusion, guidelines and computerised forms significantly improve the quality of histopathology reporting.

Breast Neoplasms↗
PubMed2002

Commitment to apoptosis induced by tumour necrosis factor-alpha is dependent on caspase activity.

Tumour Necrosis Factor alpha binding at the cell surface induces a complex series of signaling events culminating in the caspase cascade, which is central to apoptosis. However, recent work from several laboratories has questioned caspase involvement in commitment to cell death. We have therefore investigated the involvement of caspases in the crucial commitment stage of tumour necrosis factor-induced apoptosis in human T-leukaemic CEM-C7 cells and breast carcinoma MCF-7 cells, using both peptide-based and viral caspase inhibitors. Our observations converge on the conclusion that commitment to death in these systems is dependent on caspase activity, e.g. baculovirus p35 produces over 50-fold protection of colony-forming ability, the most stringent criterion of cell survival. These observations strongly support the view that the caspase family is of great biological and medical significance, since caspase dysfunction resulting in failure to commit to cell death after treatment with tumour necrosis factor or other stimuli may contribute to cancer development.

Acridine Orange↗
PubMed2002

An insight into the genetic pathway of adenocarcinoma of the small intestine.

BACKGROUND: Although the adenoma to carcinoma pathway in colorectal cancer is well described, the mechanisms of carcinogenesis in the small intestine remain unclear. AIMS: The aim of this study was to investigate candidate genes in the genetic pathway of adenocarcinoma of the small intestine. SUBJECTS AND METHODS: A total of 21 non-familial, non-ampullary adenocarcinomas of the small intestine were analysed. DNA was extracted from formalin fixed paraffin wax embedded tissue using standard techniques. The replication error (RER) status was determined by amplification of BAT26. The mutation cluster region (MCR) of the adenomatous polyposis coli (APC) gene was screened using polymerase chain reaction single strand conformational polymorphism and direct sequencing. Immunohistochemistry was performed on formalin fixed paraffin wax embedded tissue using monoclonal antibodies for hMLH1, hMSH2, beta-catenin, E-cadherin, and p53. RESULTS: Fourteen male and seven female patients with a median age of 64 years (range 21-85) presented with adenocarcinoma of the duodenum (10), jejunum (7), and ileum (4). One cancer (5%) was found to be RER+, and all tumours stained positive for hMLH1 and hMSH2. No mutations were detected in the MCR of the APC gene. beta-Catenin showed increased nuclear expression with loss of membranous staining in 10 cancers (48%). Absent or decreased membrane expression of E-cadherin was found in eight cancers (38%). Strong staining of p53 was found in the nucleus of five cancers (24%). CONCLUSION: We did not detect mutations in the MCR of the APC gene, and this suggests that adenocarcinoma of the small intestine may follow a different genetic pathway to colorectal cancer. Abnormal expression of E-cadherin and beta-catenin was common and reflects an early alternative to APC in this pathway in which mutations may be found in adenocarcinoma of the small intestine.

Adaptor Proteins, Signal Transducing↗
PubMed2001

LUCA-15 suppresses CD95-mediated apoptosis in Jurkat T cells.

The candidate tumour suppressor gene, LUCA-15, maps to the lung cancer tumour suppressor locus 3p21.3. Overexpression of an alternative RNA splice variant of LUCA-15 has been shown to retard human Jurkat T cell proliferation and to accelerate CD95-mediated apoptosis. An antisense cDNA to the 3'-UTR of this splice variant was able to suppress CD95-mediated apoptosis. Here, we report that overexpression of LUCA-15 itself suppresses CD95-mediated apoptosis in Jurkat cells. This suppression occurs prior to the final execution stage of the CD95 signalling pathway, and is associated with up-regulation of the apoptosis inhibitory protein Bcl-2. LUCA-15 overexpression is also able to inhibit apoptosis induced by the protein kinase inhibitor staurosporine, but is not able to significantly suppress apoptosis mediated by the topoisomerase II inhibitor etoposide. These findings suggest that LUCA-15 is a selective inhibitor of cell death, and confirm the importance of the LUCA-15 genetic locus in the control of apoptosis.

Alternative Splicing↗
PubMed2001

In vivo and in vitro studies of immunoglobulin gene somatic hypermutation.

Following antigen encounter, two distinct processes modify immunoglobulin genes. The variable region is diversified by somatic hypermutation while the constant region may be changed by class-switch recombination. Although both genetic events can occur concurrently within germinal centre B cells, there are examples of each occurring independently of the other. Here we compare the contributions of class-switch recombination and somatic hypermutation to the diversification of the serum immunoglobulin repertoire and review evidence that suggests that, despite clear differences, the two processes may share some aspects of their mechanism in common.

Animals↗
PubMed2001

Megacystis-microcolon-intestinal hypoperistalsis syndrome and the absence of the alpha3 nicotinic acetylcholine receptor subunit.

BACKGROUND & AIMS: The megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) is a rare disease of childhood that presents early with intestinal hypoperistalsis, hydronephrosis, and hydroureters. Transgenic mice that lack the alpha3 subunit containing nicotinic acetylcholine (nAChR) have a phenotype similar to that of MMIHS. METHODS: We examined the expression of this subunit in control and MMIHS tissue derived from patients using in situ hybridization (ISH) and immunocytochemistry (ICC). RESULTS: In controls, both techniques showed a wide distribution of alpha3 nAChRs present in ganglion cells, muscle, and epithelium. By contrast, most MMIHS tissue gave negative staining with ISH and variable results with ICC. CONCLUSIONS: These observations are consistent with a lack of alpha3 nAChRs contributing to the pathogenesis of MMIHS.

Abnormalities, Multiple↗
PubMed2001

An operative method for surgical revision of a late failure after endovascular repair of an abdominal aortic aneurysm.

Endoleak is a well-recognized complication of endovascular aortic exclusion stent-grafts. The Vanguard device is anchored into the proximal aorta by an expandable stent surmounted by a circular array of metal hooks. Attempted removal of the whole prosthesis may therefore be technically difficult and result in damage of the aortic wall. Surgery for endoleak may be complicated and carry a mortality rate of 20% to 40%. We describe a simple surgical technique for repair of endoleaks associated with a Vanguard stent-graft, which would be applicable to other such devices. This method involves minimal disruption of the proximal stent and avoids problems that may arise from an attempt to completely remove the endovascular device.

Aged↗
PubMed2001

Malaria-induced apoptosis in mosquito ovaries: a mechanism to control vector egg production.

Many insects are able to adjust their egg production according to physiological conditions such as nutrient supply and mating success. One way in which this is achieved is by resorption of some, or all, of the ovarian follicles at some stage during oogenesis. We have shown that the mosquito Anopheles stephensi responds in this manner when ookinetes of the malaria parasite Plasmodium yoelii nigeriensis first begin to invade the midgut. Little is known about the initiation and regulation of follicle resorption in any insect. Here, we demonstrate that there is a significant positive correlation between follicle resorption and the presence of follicular epithelial cells that are undergoing apoptosis. The parasite causes significantly more follicles to contain apoptotic cells from 16h post-infection onwards. Injection of a caspase inhibitor immediately after feeding on an infective blood meal prevents parasite-induced resorption of follicles and thus demonstrates that apoptosis precedes resorption. Ultrastructural studies show that patches of follicular epithelial cells contain condensed nuclear chromatin, a characteristic of apoptosis, and that no patency develops in these cells. Our work suggests that apoptosis plays a role in malaria-initiated inhibition of mosquito oogenesis and that caspase is central to this process. Follicle resorption is one of the main factors contributing to malaria-induced fecundity reduction in mosquitoes.

Animals↗
PubMed2000

LUCA-15-encoded sequence variants regulate CD95-mediated apoptosis.

Using an expression cloning system to discover novel genes involved in apoptosis, we identified a 326 bp bone marrow cDNA fragment (termed Je2) that suppresses, upon transfection, CD95-mediated apoptosis in Jurkat T cells. Sequence homology revealed that Je2 maps to 3p21.3, to an intronic region of the candidate TSG LUCA-15 locus. It represents, in fact, an antisense transcript to the 3'-UTR of two novel splice variants of this gene. Overexpression of sequence representing one of these splice variants (a 2.6 kb cDNA termed Clone 26), inhibited proliferation of Jurkat cells and sensitized them to CD95-mediated apoptosis. This study therefore implicates the LUCA-15 gene locus in the control of apoptosis.

Alternative Splicing↗
PubMed2000

Zinc has no effect on IL-3-mediated apoptosis of BAF-3 cells but enhances CD95-mediated apoptosis of jurkat cells.

The feasibility of using a zinc-inducible gene expression system for the study of apoptosis-controlling genes in BAF-3 murine B cells and Jurkat human T cells was evaluated. Initially, cell sensitivity to a range of zinc concentrations was examined. It was found that zinc concentrations above 60 microM were toxic to BAF-3 cells and those above 50 microM were toxic to Jurkat cells. Secondly, the zinc concentration required to achieve maximal gene expression was examined. BAF-3 cells transiently transfected with the pMTCB6+/luciferase vector were exposed to zinc concentrations ranging from 0-120 microM, whilst stably transfected Jurkat cells were exposed to 0-70 microM zinc. At zinc concentrations nontoxic to each cell type, the maximum induction achieved was 20-fold (at 60 microM) in BAF-3 cells, and 7.5-fold (at 50 microM) in Jurkat cells. Thirdly, the effect of zinc on apoptosis was examined. It was shown that exposure to nontoxic zinc concentrations had no effect on IL-3 withdrawal-mediated apoptosis of BAF-3 cells. However, in the case of Jurkat cells, pre-exposure to zinc augmented CD95-mediated apoptosis. These results illustrate the importance of characterizing individual cell lines when using zinc-inducible gene expression systems.

Animals↗
PubMed2000

Anal cancer subtype reproducibility study.

For histological subtyping of anal squamous carcinomas the WHO advocates a six-way subdivision, but it has been suspected that the six types cannot be reliably discriminated in practice. We conducted a blinded study involving slides from 103 consecutive cases, each slide being examined by three experts (from Denmark, Australia and UK) on two occasions at least 8 months apart. Agreement on subtypes was low: 72% between rounds within pathologist, 61% between pathologists. Even for the commonest, and most stably diagnosed, type, viz. large-cell keratinising squamous carcinoma, the intra- and interpathologist frequencies of confirmation were only 81% and 71%, respectively. The pathologist marked the picture as typical and his subtype diagnosis as certain 41% of times: even then confirmation frequencies were only 88% and 74%, respectively. Calculations, including kappa analyses, suggest that 26% of the typing variation was noise. The WHO scheme must be even more unreliable in everyday practice. We finally mention a recently demonstrated link between human papilloma virus (HPV) and certain types of anal cancer, which may well provide an additional argument for revising existing subtyping schemes.

Anus Neoplasms↗
PubMed2000

The contribution of somatic hypermutation to the diversity of serum immunoglobulin: dramatic increase with age.

Although somatic mutation contributes to the diversity of only a minor fraction of B cells in mouse spleen or blood, its contribution to the diversity of serum immunoglobulin is unknown. We have devised an immunoassay to monitor mutated antibodies in serum using a monoclonal antibody that recognizes a VK only when mutated at its major intrinsic hot spot. Mutation makes essentially no contribution to the diversity of endogenous serum IgM, IgG, or IgA in young mice. However, in response to environmental antigens, the titer of mutated immunoglobulin in T cell-proficient mice rises strikingly with age, such that the major proportion of serum immunoglobulin in adults is somatically mutated, with the mutation load in IgG being some 10-fold greater than in IgM.

Aging↗
PubMed2000

Nitric oxide mediates a therapeutic effect of nicotine in ulcerative colitis.

BACKGROUND: Ulcerative colitis is a condition of nonsmokers in which nicotine is of therapeutic benefit. AIMS: To examine the in vitro effect of nicotine on colonic smooth muscle activity and the role of nitric oxide (NO) as a mediator. METHODS: Nicotine, 1-10 microM, was administered to strips of circular muscle from the distal sigmoid colon of 9 patients with active ulcerative colitis and 18 with colorectal cancer. The effect of electrical field stimulation (EFS) was examined before nicotine was added. Finally L-NAME, a NO synthetase inhibitor, was added before nicotine was administered again. RESULTS: Muscle strips developed similar spontaneous resting tone. In response to EFS, ulcerative colitis tissue developed lower tensions than the controls. Nicotine significantly reduced the resting tone and peak tension after EFS, with a greater effect in controls. With L-NAME, peak tensions were increased more in ulcerative colitis than controls, and nicotine produced a much smaller reduction. CONCLUSIONS: Nicotine reduces circular muscle activity, predominantly through the release of nitric oxide-this appears to be 'up-regulated' in active ulcerative colitis. These findings may explain some of the therapeutic benefit from nicotine (and smoking) in ulcerative colitis and may account for the colonic motor dysfunction in active disease.

Adult↗
PubMed2000

Dissociation between Fas expression and induction of apoptosis in human islets of Langerhans.

There is increasing evidence that inappropriate induction of apoptosis in pancreatic beta-cells may precede the development of type 1 diabetes in animal models and in man. One mechanism by which this has been proposed to occur involves up-regulation of the death receptor Fas on beta-cells, resulting in apoptosis of the Fas-bearing beta-cells upon ligation of the receptor. We have examined this hypothesis in isolated human islets of Langerhans and show that--in contrast to data obtained with rodent beta-cells--expression of Fas per se is not sufficient to allow induction of apoptosis upon addition of agonistic anti-Fas serum.

Animals↗
PubMed2000

Crohn's disease incidence in Cardiff from 1930: an update for 1991-1995.

OBJECTIVE: To report the incidence of Crohn's disease in the city of Cardiff between 1991 and 1995, in relation to the data of the preceding 65 years. METHODS: The incidence of Crohn's disease was studied by collecting information from clinical records, the department of pathology database and a questionnaire sent to local family practitioners. RESULTS: Eighty-four new patients with Crohn's disease, and resident in Cardiff, were diagnosed between 1991 and 1995. The mean incidence for this quinquennium was 56 cases per 10(6) population per year (95% confidence interval, 44-68). There was a female predominance, particularly in young adults, with an overall male to female ratio of 0.47. Colorectal disease was the most common site of disease at the time of diagnosis. CONCLUSIONS: In relation to the findings of our previous studies, the data suggest that the overall incidence of Crohn's disease is now stable, but that the proportion with colorectal disease continues to increase and there is a marked female preponderance in Crohn's disease presenting in young people.

Adolescent↗
PubMed2000

ACP Best practice no 159. Examination of large intestine resection specimens.

Macroscopic examination of large intestinal resection specimens by the surgical pathologist provides important diagnostic and prognostic information. This review summarises current recommended protocols and evidence based guidelines for gross description, dissection, and histological block selection in both neoplastic and non-neoplastic colorectal disease. Specific lesions discussed include colorectal cancer, polypectomies and polyposis syndromes, and inflammatory bowel disease. Microscopic examination is briefly described, with emphasis on certain pitfalls that might be encountered in routine practice. A section covering special techniques for the investigation of occult bleeding is included.

Clinical Protocols↗