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Biomedical subjects

E D Williams

Publications and source records attributed to E D Williams.

At least 91 records · Page 5Linked to original sources
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↗
PubMed1993

Demonstration of mRNA using digoxigenin labelled oligonucleotide probes for in situ hybridisation in formamide free conditions.

The value of formamide for use in in situ hybridisation (ISH) for the detection of mRNA, using either single or multi probe cocktails of digoxigenin labelled oligoprobes, was investigated. Three peptides with cell specific localisation in three separate tissues--calcitonin in the thyroid, epidermal growth factor (EGF) in the submaxillary gland, and insulin in the pancreas were studied. In each case localisation was confined to the appropriate cell type, but in the presence of formamide higher concentrations of probe and a longer development time were required. The abolition of formamide from the protocol for ISH makes the technique safer, cheaper, faster and more suitable for routine diagnostic use.

Animals↗
PubMed1993

[Type II multiple endocrine neoplasms (MEN IIB): an unusual cause of constipation. A plea for early thyroidectomy].

We present a 5 year old girl who was diagnosed to have multiple endocrine neoplasia syndrome type IIB (MEN IIB). She presented with serious constipation and had the distinct features of MEN IIB. 100% of the patients with MEN IIB develop medullary thyreoïd carcinoma (MTC). MTC in MEN IIB is known to behave in a very aggressive way. Microscopically MTC was already present in this patient despite of normal calcitonin stimulation tests. Accordingly we plead for a more radical management relating to thyreoïdectomy in MEN IIB.

Child, Preschool↗
PubMed1992

Epithelial--stromal interactions in tumors. A morphologic study of fibroepithelial tumors of the breast.

BACKGROUND AND METHODS: The known spatial interaction between normal breast epithelium and its surrounding stroma prompted an investigation of the spatial relationship between stromal mitoses and the epithelial component of fibroepithelial tumors of the breast. The authors applied a novel computerized morphometric technique to routinely processed histologic sections of 23 fibroepithelial tumors (13 fibroadenomas and 10 phyllodes tumors). The proportional area of epithelium in successive concentric annuli surrounding stromal mitoses was measured, and its distribution was compared with that around suitable control points. RESULTS: The authors found that stromal mitotic activity in these tumors was significantly more likely to occur close to rather than remote from the epithelial component, with a significant excess of epithelium around mitoses compared with control points within a range of 79 microns. Essentially similar findings were obtained when randomly identified fibroblast nuclei were used as control points, thus obviating variations in stromal cell density with distance from epithelium as an explanation for the findings. CONCLUSIONS: These findings support the hypothesis that stromal growth in fibroepithelial tumors depends, to a variable extent, on the epithelial component. An interaction in the opposite direction (i.e., the stroma providing the growth support to the epithelium) also may occur, but this was not investigated. It is suggested that there is an interdependence of growth between the epithelial and stromal components in these tumors that explains their complex morphology and that stromal dependence on epithelium is lost with increasing malignancy of the stromal elements.

Adenofibroma↗
PubMed1992

Dinitrophenyl (DNP) hapten sandwich staining (DHSS) procedure. A 10 year review of its principle reagents and applications.

Over the past 10 years an immunoperoxidase method using dinitrophenyl (DNP) hapten-labelled primary or secondary probes has been devised. Its widely successful application in research and diagnostic work has depended upon the development of certain key reagents. These include a novel non-deleterious DNP labelling compound, a unique multivalent monoclonal bridge antibody, and an efficient DNP hapten substituted or anti-DNP linked marker enzyme. In this article the development of these reagents and various modifications of the basic technique are reviewed in conjunction with the special applications accruing from their use.

Antibodies, Monoclonal↗
PubMed1992

Stepwise transformation of primary thyroid epithelial cells by a mutant Ha-ras oncogene: an in vitro model of tumor progression.

Activating mutations of the ras oncogene family occur at high frequency in all stages of thyroid tumorigenesis, both human and experimental. To test the causal nature of this association, and to investigate the biological role of ras mutation, we introduced a mutant c-Ha-ras gene into normal rat thyroid follicular cells using an ecotropic retroviral vector. The major immediate effect was to greatly extend the proliferative lifespan of these cells in culture from less than 3 to more than 15 doublings, without any observable loss of growth-factor dependence or differentiated functions. This in vitro phenotype strongly supports an initiating role for ras mutation in the genesis of benign thyroid tumors (adenomas) in vivo. Spontaneous transformation was observed at low frequency on continuous culture of mutant ras-expressing cells, giving rise to fully immortalized, growth factor-independent, highly tumorigenic lines. Transformation was associated with (i) loss of responsiveness to the growth inhibitor TGF-beta 1, and (ii) greatly increased nuclear levels of p53 protein, which unexpectedly was not due to point mutation in the conserved regions of the p53-coding sequence. We postulate that these two phenomena are causally related to each other and to the transformed phenotype.

Adenoma↗
PubMed1992

An evaluation of cusum analysis and control charts applied to quantitative gamma-camera uniformity parameters for automated quality control.

Gamma-camera uniformity is often monitored for quality control of performance. Many parameters can be derived from computer analysis of the image of a uniform (flood) source to obtain quantitative measures of uniformity. However, it is not clear which best reflect changes in uniformity, or how action levels should be set. The latter are essential for an automated analysis. To compare the various parameters and assess two techniques used for their analysis, a series of technetium-99m flood images were obtained consecutively. After establishing a baseline from repeated images, uniformity was degraded by offsetting the pulse height analyser (PHA) window by a small amount. Nine non-uniformity parameters were calculated for each flood image, including the Department of Health and Social Security (DHSS) and National Electrical Manufacturers Association (NEMA) integral and differential uniformities, the uniformity index and the percentage of pixels more than 5% from the mean. All parameters were calculated for both central field-of-view (CFOV) and useful field-of-view (UFOV). Eighty such trials were carried out on two gamma-cameras. The PHA offsets ranged from 1-10 keV. The two techniques used for analysis were the control chart and cusum analysis. Decision levels were set for each parameter, as multiples of SD for the control charts or by varying the dimensions of a truncated V-mask for cusum analysis. Receiver operating characteristic (ROC) curves were then used for an objective comparison of the parameters and of the analysis techniques. The area under the ROC curve was used to rank the parameters in order of sensitivity to change in uniformity.(ABSTRACT TRUNCATED AT 250 WORDS)

Gamma Cameras↗
PubMed1992

Detection and partial purification of a potent mitogenic factor for human thyroid follicular cells.

Normal adult human thyroid follicular cells have an extremely limited proliferative capacity in vitro. No previously studied mitogen, including thyrotropin (TSH) or epidermal growth factor (EGF), has in our hands resulted in a significant improvement over the 3-4% nuclear [3H]thymidine pulse-labelling index (LI) obtainable with 10% fetal calf serum. Here we report the detection in the conditioned medium from a sub-clone of NIH3T3 fibroblasts of a mitogenic activity capable of increasing this response up to 10-fold, to an LI of over 20%, together with an even greater relative stimulation of mitotic activity. Preliminary characterisation has excluded EGF and TGF alpha, and demonstrated that the activity is bound reversibly by heparin-Sepharose, thus pointing to a member of the heparin-binding fibroblast- or hepatocyte-growth factor families. This material should have wide practical application in facilitating primary culture of follicular cells, and may reveal new mechanisms of stromal-epithelial interaction regulating normal and neoplastic thyroid growth in vivo.

Cell Division↗
PubMed1992

Cell proliferation and thyroid neoplasia.

The classic experimental model of thyroid neoplasia using radiation as a mutagen followed by long-term goitrogen treatment gives rise to multiple tumours in rats. Radiation alone, with suppression of TSH produces no tumours, TSH-induced growth alone causes a low level of tumorigenesis. Cell proliferation in this model is therefore critical. Epimutation as well as mutation is important. Rodent and human thyroid tumours show a clear stepwise progression, associated with both morphological and oncogene changes. In experimental animals the finding that monoclonal adenomas and carcinomas induced in the presence of long-term high TSH retain TSH dependency suggests that the step in the tumour progression requiring the development of TSH independent growth is bypassed, explaining the frequency of tumour development in this model. Normal thyroid follicular cell growth is limited, and a genotoxic effect before the growth plateau is more effective in carcinogenesis than a genotoxic effect after a period of growth. These observations will be interpreted in relation to the importance of thyroid tumours in regulatory toxicology and the pathobiology of thyroid tumours in man.

Animals↗
PubMed1992

Renal single photon emission computed tomography: should we do it?

Although single photon emission computed tomography (SPECT) imaging has established a place for itself in clinical nuclear medicine for heart and brain studies, its place in renal imaging is not yet clear. Renal SPECT has been subject to limitations imposed by the efficiency of imaging equipment, and has been confined to use with static imaging agents such as technetium-99m (99mTc) dimercaptosuccinate (DMSA). SPECT has been used to investigate space-occupying lesions and anatomical abnormalities, and for quantitative studies of renal uptake and volume. In these areas, it has provided little advantage over conventional imaging, but it has been helpful in individual cases. High-resolution SPECT is a promising new development, which may have applications in detecting and classifying renal scarring. It deserves careful evaluation.

Humans↗