PubMed Health⌕ Search

Biomedical subjects

E D Williams

Publications and source records attributed to E D Williams.

At least 19 recordsLinked to original sources
PubMed1995

A computer graphic simulation of squamous epithelium.

An epithelium maintains its integrity through the organized growth and orderly differentiation of a transient cell population derived from stem cells. This organization is dependent upon both physical mechanisms such as cell adhesion and attraction and the relationship between differentiation and cell division. The interactions between these processes are complex and difficult to conceptualize from a purely mathematical approach. We have therefore set out to develop a graphic model of an epithelium controlled by rules that can be modified. We have chosen to model epidermis, the most superficial part of skin, with cells differentiating from a stem cell population and being lost from the surface of the model. The model is novel not only in the rules that govern cell behaviour, but also because it does not require a predefined lattice to assign the position of cells. Each cell assumes a position depending upon the balance of adhesive and repulsive forces that it experiences. Chemical factors which affect the differentiation of individual cell types are assumed to be produced both by cells within the model and externally from the underlying connective tissue. These "chemical factors" diffuse through the model with a concentration that declines as an inverse square with distance from the source. The rules allow the model to grow from a single stem cell to reach a steady state. At steady state the pattern and clonal structure is strikingly similar to that seen in a range of normal epithelia. Furthermore, if part of the model is removed it is capable of regenerating itself without additional rules. The model allows the visualization of the effects of introducing new rules and modifying the interaction between chosen rules. This study demonstrates that a set of simple rules can be used to make a dynamic flexible model resembling skin.

Animals↗
PubMed1995

Identification of tumour-specific translocations in archival material.

A reverse transcriptase nested polymerase reaction (RT-nPCR) method has been developed to detect the presence of a tumour-specific translocation in archival formalin-fixed, paraffin-embedded tissue. This technique can be applied to the large numbers of tumours in pathology departments' archives, allowing correlation of translocations with morphological diagnosis, response to therapy, and survival.

Base Sequence↗
PubMed1995

Mechanisms and pathogenesis of thyroid cancer in animals and man.

The transformation of the normal fully differentiated thyroid follicular cell to the rapidly growing undifferentiated anaplastic thyroid carcinoma cell involves a number of stages which have been defined morphologically and are now being related to various growth pathways and to molecular biological defects. The two main factors involved in this transformation are growth stimulation and mutagenesis. Growth stimulation alone, through elevated TSH, can lead to the development of thyroid tumours, usually benign, and retaining TSH dependency in some cases. Mutagens alone, if growth is suppressed, do not produce tumours, the combination of mutagens and increased growth is a potent carcinogenic regime. Non-genotoxic carcinogenesis in the thyroid involves growth, without mutagenesis the agent often causes this through affecting one component of thyroid hormone synthesis or metabolism, leading to a fall in thyroid hormone levels and a rise in TSH. Growth stimulation increases the rate of cell division, and therefore increases the chance of a mutation. Continued growth increases the change of subsequent events, in particular loss of heterozygosity in a tumour suppressor gene. The main oncogenes involved in human thyroid carcinogens are ras in the follicular tumour pathway, and ret in the papillary carcinoma pathway. p53 is involved in the progression of either papillary or follicular adenoma to an undifferentiated carcinoma. In experimental thyroid carcinogenesis, ras is again involved, with a link between the mutagenic agent used and the type of ras gene showing mutation. Analysis of the involvement of different growth factors and oncogenes in thyroid carcinogenesis suggests that genes related to the two receptors concerned with normal TSH stimulated growth, TSH receptor and the IGF1 receptor may be involved in the progression of thyroid tumours of follicular pathology. Several tyrosine kinase receptors with unknown ligands or of uncertain physiological function are linked to papillary carcinoma. The recent large increase in papillary carcinoma of the thyroid in children exposed to fallout from the Chernobyl nuclear accident underlines the importance of understanding the pathobiology of thyroid neoplasia.

Animals↗
PubMed1995

Normal colonic mucosa in hereditary non-polyposis colorectal cancer shows no generalised increase in somatic mutation.

Hereditary non-polyposis colorectal cancer (HNPCC) has recently been linked to germline defects of DNA repair genes. Colorectal tumours in HNPCC frequently show DNA microsatellite instability, but it is not certain whether this mutator phenotype occurs throughout the morphologically normal colonic mucosa. We have previously used the mPAS histochemical technique in human colorectal mucosa to identify a polymorphism for O-acetyltransferase activity that shows monogenic inheritance and to show that crypt-restricted loss of O-acetyltransferase activity in heterozygotes is due to somatic mutation. We have now used this histochemical technique to measure the somatic mutation frequency in the uninvolved colon of 12 heterozygous patients with HNPCC, 15 with ileocaecal Crohn's disease and 16 with sporadic colorectal cancer (CRC). HNPCC patients showed a significant increase in mutation frequency with age (Mann-Whitney U, P = 0.02). In HNPCC patients aged < 49 years the mean stem cell mutation frequency was significantly lower than in the slightly younger group of patients with Crohn's disease (0.8 +/- 0.9 x 10(-4) vs 3.5 +/- 3.3 x 10(-4), P < 0.01), probably reflecting an increased mutation rate relating to chronic mucosal damage in Crohn's disease. Although not statistically significant, the stem cell mutation frequency was slightly less in HNPCC patients > 50 years than in sporadic CRC cases (4.9 +/- 3.4 x 10(-4) vs 5.9 +/- 3.6 x 10(-4), P > 0.5). We conclude that germline defects in HNPCC do not result in a generalised increase in liability to mutation in normal colonic mucosa but that a second, somatic, event is required. We postulate that this second event occurs in crypt stem cells at low frequency, giving rise to scattered individual crypts composed of mutation-prone cells. The cells in these crypts are then at high risk of acquiring the mutations that lead to adenomas, and to rapid progression to carcinoma.

Adult↗
PubMed1995

Childhood thyroid cancer in England and Wales.

A total of 154 cases of thyroid cancer in children under 15 were registered in England and Wales over a period of 30 years, an incidence of about 0.5 per million per year. A total of 4.5 cases per year were registered in 1963-72, 4.9 in 1973-82 and 5.8 in 1983-92. A rapid rise in incidence with age occurred after the age of 5. Malignancy was confirmed in 92% of the cases in which tissue was available. Of these, 68% were papillary carcinomas, 11% follicular carcinomas and 17% medullary carcinomas. There were two spindle cell tumours with mucous cysts and one teratoma. The increased frequency but small size of medullary carcinomas in the second half of the period suggested that this increase was due to the introduction of screening; it accounted for most of the rise in crude incidence rats with time. The sex ratio (F:M) in all registered cases in the differentiated follicular cell carcinoma groups in children aged under 10 was 1.2:1, and 3.6:1 in the older children. Five children with differentiated thyroid cancer of follicular cell origin died up to 17 years after diagnosis. Two of the eight children aged 9 or less with a 20 year follow-up died, compared with three of 28 older children. An unusual group of differentiated carcinomas showed solid or follicular architecture. These tumours were unencapsulated, often widely invasive, contained psammoma bodies but little or no papillary architecture and the nuclei often lacked prominent grooving. This childhood type of papillary carcinoma contrasted with the classical type commonly found in the adult, which was present in one of 13 confirmed papillary carcinomas in children aged less than 10, compared with 20 of 35 older children. These observations show that thyroid carcinoma in very young children has a different spectrum of histological types from both older children and adults. From the age of about 10 well-differentiated papillary carcinomas rapidly increase in frequency in females, so that the other types come to form only a small proportion of the total. These differences, and the lower incidence but poorer prognosis of thyroid carcinoma in men and the poorer prognosis in post- as compared with premenopausal women, are compatible with a major role for sex hormones in thyroid carcinogenesis in females during the reproductive period. This study documents the incidence of childhood thyroid cancer in England and Wales, explains the rise in crude incidence rates, shows differences between carcinomas in children under and over the age of ten which may correlate with puberty, and draws attention to an unusual aggressive type of childhood papillary carcinoma. It illustrates the value to crude registry data of a pathology review.

Adenocarcinoma, Follicular↗
PubMed1995

Evidence for mutual interdependence of epithelium and stromal lymphoid cells in a subset of papillary carcinomas.

We have correlated the morphological features of 30 human thyroid carcinomas with the cellular localisation of insulin-like growth factor 1 (IGF-1) mRNA and IGF-1 receptor peptide using in situ hybridisation with digoxigenin-labelled oligoprobes and immunohistochemistry. Four of the five follicular carcinomas studied showed a consistent, uniform, strong positivity for IGF-1 mRNA in tumour cells compared with weakly positive surrounding normal follicular tissue and negative stroma. The majority of papillary carcinomas showed weak to moderate epithelial positivity for IGF-1 mRNA and negative stroma. Immunohistochemistry for IGF-1 receptor showed moderate positivity confined to the tumour epithelial cells in both follicular and the majority of papillary carcinomas. However, in a subgroup of papillary carcinomas characterised by a diffuse stromal lymphoid infiltration (n = 5), the stromal cells showed a much stronger reactivity for IGF-1 mRNA than the tumour or background thyroid, and the tumour cells showed a uniformly high level of immunoreactivity for IGF-1 receptor. These results are compatible with the growth of the papillary carcinoma in these cases being the result of a symbiotic relationship between the stromal lymphoid cells and the tumour epithelium with the lymphoid cells responding to an antigen produced by the tumour cells and the tumour cells responding to a growth factor produced by the lymphoid infiltrate. We suggest that this mechanism may be important in other tumours regularly associated with a widespread lymphoid infiltrate.

Animals↗
PubMed1994

Site of production of IGF1 in the normal and stimulated mouse thyroid.

Insulin-like growth factor 1 (IGF1) has emerged as an essential factor in the follicular cell growth response in vitro to TSH, although its source within the thyroid in vivo is not clear. We have studied the localisation of IGF1 mRNA by in situ hybridization using digoxigenin labelled oligoprobes in tissue sections of mouse thyroid. Our results show that in the thyroid IGF1 mRNA is predominantly present in follicular cells and C cells rather than the stroma. Follicular cell levels are higher during postnatal thyroid growth and during the growth response to goitrogen administration, but decrease in the mature animal. This decrease in production is limited to the follicular cells, as IGF1 mRNA is still easily demonstrable in C cells and in the parathyroid. Immunocytochemistry for IGF1 peptide shows a weak and variable follicular cell content in both juvenile and mature mice, but a more uniform distribution during growth in response to a goitrogenic stimulus. These studies show that the follicular cells are the main source of IGF1 in the thyroid, and suggest that the role of IGF1 in follicular cell growth is as an autocrine factor.

Aging↗
PubMed1994

Racial variation in the O-acetylation phenotype of human colonic mucosa.

O-acetylated and non-O-acetylated sialoglycoproteins can be distinguished by the mPAS (mild periodic acid-Schiff) histochemical technique. Individual adults show one of three different patterns of staining of large intestinal mucosa: uniformly mPAS-positive, uniformly mPAS-negative, or mPAS-negative with scattered mPAS-positive crypts. To test our hypothesis that these variations are the result of a single autosomal gene (oat) polymorphism, we have studied the frequency of the three patterns of staining in a total of 435 adult colon specimens from six geographically separate populations: British, South African blacks, Icelanders, Japanese, Hong Kong Chinese, and Bahrainis. The distribution of the three types of staining fell into two groups. In Japanese and Chinese, uniformly mPAS-positive cases were much more frequent than uniformly mPAS-negative cases; this distribution differed significantly (chi 2, P < 0.001) from that in non-Sino-Japanese, where the uniformly mPAS-positive phenotype was much less frequently found than the uniformly mPAS-negative phenotype. In neither of the groups did the frequency of the three phenotypes differ significantly from that predicted for a single gene polymorphism by the Hardy-Weinberg law. The variation in staining patterns between populations is consistent with variation in frequency of a single polymorphic autosomal gene (oat) controlling O-acetylation of sialic acid, probably by an O-acetyl transferase enzyme. Loss of function mutation in the high acetylator gene (oata) in a colonic crypt stem cell in heterozygous individuals would account for the scattered discordant crypts. Gene frequencies for a variety of enzymes differ between the Sino-Japanese and non-Sino-Japanese races.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylation↗
PubMed1994

Human colonic stem cell mutation frequency with and without irradiation.

Mild periodic acid-Schiff (mPAS) staining distinguishes O-acetylated from non-O-acetylated sialoglycoproteins. In human colonic mucosa, individuals possess one of three phenotypes: uniformly mPAS-positive (non-O-acetylated), uniformly mPAS-negative (O-acetylated), and negative with infrequent scattered positive crypts. This is due to a polymorphism in a single autosomal gene (oat). Discordant crypts have not been found in children's colons, suggesting that they result from somatic mutation in heterozygous individuals. We now present evidence to confirm this based on a study of radiation-induced changes. Comparison of mPAS staining of large intestinal mucosa from patients given radiation 4 weeks before surgery for carcinoma of the rectum with matched controls receiving surgery alone showed a similar phenotype distribution, but information irradiated patients showed an increased frequency of discordant crypts (irradiated vs. non-irradiated 14.5 +/- 8.2 x 10(-4) vs. 6.1 +/- 4.2 x 10(-4)). When these were classified as wholly or partially involved by the aberrant phenotype, the increase was most marked in partially involved crypts (7.5 +/- 4.5 x 10(-4) vs. 0.3 +/- 0.5 x 10(-4), Mann-Whitney U, P < 0.005). Two patients receiving radiotherapy many years before colectomy showed a very high total discordant crypt frequency but relatively few partially affected crypts. Studies of somatic mutation in colonic or small intestinal crypts following a single dose of mutagen in mice have shown early partial crypt involvement by the mutated phenotype and later complete crypt involvement.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1994

Expression of the multidrug resistance-associated protein (MRP) gene in human lung tumours and normal tissue as determined by in situ hybridisation.

In a number of cell lines with a multidrug resistant phenotype, there is no overexpression of the putative efflux pump, P-glycoprotein. Some such lines do, however, overexpress the MRP gene which encodes a protein bearing considerable amino acid homology to P-glycoprotein. We have used in situ hybridisation to study expression of the MRP gene in human cell lines, lung tumours (representing all the major histologies) and normal lung tissue. Considerable heterogeneity of expression was seen in parental cell line COR-L23/P whereas relatively uniform high-level expression was seen in the resistant line COR-L23/R. Normal bronchial epithelium was strongly positive, but the major epithelial component of all eight lung tumours studied showed only a negative to weak signal. However, the leading edge of the tumours consistently produced a more intense signal similar to that in normal epithelium. Areas of lymphocytic infiltrate were more strongly positive than the tumour epithelium. These results suggest that expression of the MRP gene may be a significant factor determining response of lung tumours to chemotherapy, but that considerable caution is needed in the interpretation of expression studies carried out on homogenised tissue biopsies.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
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

Thyroid tumorigenesis.

Thyroid tumorigenesis is discussed in the context of the thyroid as a stable tissue, composed of differentiated cells, with a greater dissociation of control of growth from control of differentiation than is found in stem cell tissues. Experimental thyroid carcinogenesis regimes usually use mutagen exposure followed by induced growth. The normal thyroid follicle cell has a limited growth capacity, so loss of one tumour suppressor gene followed by growth-associated loss of heterozygosity would allow escape from this growth limitation, and the formation of a neoplastic clone. In man, there are two pathways of tumour formation, one through follicular adenoma to follicular carcinoma, and one to papillary carcinoma. These two pathways show differing aetiology, and differing oncogene involvement. In the follicular carcinoma pathway TSH-induced growth is relevant as it is in experimental animals. Mutagenesis is important for both papillary and follicular carcinomas. Radiation mutagenesis is of particular current importance because of the occurrence of thyroid carcinoma in children exposed to fallout from Chernobyl. The greater capacity for post-mutagen growth in children than adults is likely to explain the increased radiosensitivity of children, both to external and internal radiation.

Adenocarcinoma, Follicular↗
PubMed1994

Synthesis and storage in rat thyroid C-cells.

Thyroid C-cells have the capacity to produce a variety of peptides, as do C-cell tumors. The cellular content of one such peptide, somatostatin, is restricted to a minority of C-cells in rat and human. We set out to clarify whether the synthesis of somatostatin is equally restricted and to study changes that occur in somatostatin synthesis with age. We used immunocytochemistry to localize somatostatin and calcitonin in conjunction with in situ hybridization, using digoxigenin-labeled oligoprobes to localize somatostatin and calcitonin mRNAs in serial sections of formalin-fixed, paraffin-embedded rat thyroid, and correlated peptide and mRNA content in individual cells. All C-cells synthesize and store calcitonin, and somatostatin synthesis, as shown by mRNA content, is limited to the subset of cells containing immunoreactive somatostatin. The numbers of C-cells in general and of the subset synthesizing somatostatin increase between juvenile and adult animals, but the somatostatin cells remain confined to a small area of the gland. These findings support the proposal that somatostatin production is not facultative, but that C-cells differentiate into two distinct subsets of cells, only one of which synthesizes and stores somatostatin.

Aging↗
PubMed1994

Effect of parathyroid hormone-related protein (PTHrP) on the contractility of the myometrium and localization of PTHrP in the uterus of pregnant rats.

The effect of parathyroid hormone-related protein (PTHrP) on the contractility of uterine segments taken from pregnant rats and the localization of PTHrP in the uterus during pregnancy were investigated. PTHrP(1-34) had a potent inhibitory effect on spontaneous contractions of the longitudinal layer of uterine myometrium taken from rats at day 4 of pregnancy (IC50 1.6 nmol l-1). In low calcium De Jalon's solution, it also decreased base-line tension (IC50 1.5 nmol l-1) in a concentration-dependent manner. The effect of PTHrP(1-34) on uterine motility decreased as pregnancy progressed until day 13, after which PTHrP(1-34) had no measurable effect on uterine contractility. In contrast, PTHrP(1-34) had no effect on the contractions of the circular smooth muscle of the uterus at any stage of pregnancy. PTHrP(50-69) had no effect on the contractility of either muscle layer of the myometrium. A temporal pattern of staining for PTHrP in the uterus of pregnant rats was observed, and the changes in the staining patterns in the endometrium and myometrium were different in each layer. These data suggest that PTHrP may have at least two distinct roles in the uterus, a relaxing action on longitudinal muscle that depends on the hormonal state of the rat and a novel effect either intraluminally or within the endometrial layer.

Animals↗
PubMed1993

Pressure exerted by head bandages used in otological surgery.

The pressure exerted by head bandages at the operation site following ear surgery was measured using a balloon catheter and pressure transducer. The initial pressures achieved, their diminution with time and the relationship of pressure to the induction of headache in the patient were studied. The principal findings were that the standard otological head bandage is rarely tight enough to prevent haematoma formation, bandages have lost their efficacy after the first hour and headaches are associated with a significantly higher initial bandage pressure.

Bandages↗