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Biomedical subjects

E D Williams

Publications and source records attributed to E D Williams.

At least 37 records · Page 2Linked to original sources
PubMed2002

Patterns of cerebral atrophy in dementia with Lewy bodies using voxel-based morphometry.

Previous cross-sectional MRI studies based on region-of-interest analyses have shown that increased cerebral atrophy is a feature of both Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). Relative preservation of the hippocampus and temporal lobe structures in DLB compared to AD has been reported in region-of-interest-based studies. Recently, image processing techniques such as voxel-based morphometry (VBM) have been developed to provide an unbiased, visually informative, and comprehensive means of studying patterns of cerebral atrophy. We report the first study to use the voxel-based approach to assess patterns of cerebral atrophy in DLB compared to control subjects and AD. Regional gray matter volume loss was observed bilaterally in the temporal and frontal lobes and insular cortex of patients with DLB compared to control subjects. Comparison of dementia groups showed preservation of the medial temporal lobe, hippocampus, and amygdala in DLB relative to AD. Significant gray matter loss was also observed in the thalamus of AD patients compared to DLB.

Aged↗
PubMed2001

Progressive brain atrophy on serial MRI in dementia with Lewy bodies, AD, and vascular dementia.

The authors determined rates of brain atrophy, as assessed by the boundary shift integral on serial MRI, in patients with dementia with Lewy Bodies (DLB, n = 10), AD (n = 9), vascular dementia (VaD, n = 9), and age-matched controls (n = 20). Mean % +/- SD atrophy rates per year were as follows: DLB, 1.4 +/- 1.1; AD, 2.0 +/- 0.9; VaD, 1.9 +/- 1.1; and controls, 0.5 +/- 0.7. Dementia subjects had higher rates than controls (p < 0.001), but there were no significant differences between the three dementia groups. The authors found accelerating atrophy with increasing severity of cognitive impairment, further emphasizing the need for early diagnosis and intervention in dementia.

Aged↗
PubMed2001

Combretastatin-A4 disrupts neovascular development in non-neoplastic tissue.

Combretastatin-A4 phosphate (cis-CA-4) is a tubulin-binding agent currently undergoing clinical trials as an anti-tumour drug. We have investigated whether CA-4 functions as a tumour-specific anti-vascular agent using the hyperplastic thyroid as a novel in vivo model of neovascularization. CA-4 elicited pathological changes in normal tissue, manifested as the induction of multiple, discrete intravascular thrombi. These vascular-damaging effects indicate that CA-4P does not function as a tumour-specific agent but targets neovasculature irrespective of the primary angiogenic stimulus.

Animals↗
PubMed2001

Differences in susceptibility to colonic stem cell somatic mutation in three strains of mice.

Different species and different strains of animals commonly show very different sensitivities to carcinogenic regimes, which are often unexplained. A major possible contributory factor is variation in susceptibility to mutation, but this has not been directly demonstrated. This study therefore quantified the colonic stem cell mutation frequency in three strains of mice using two carcinogens. Stem cell mutations were identified using loss of function of glucose 6-phosphate dehydrogenase (G6PD) in individual crypts, a technique validated by several previous studies. The carcinogens dimethylhydrazine (DMH) and ethyl nitrosurea (ENU) were given to Balb/C, C57BL/6J, and C3H mice. In response to DMH, Balb/C mice were most susceptible, with approximately double the stem cell mutation frequency found in C3H and more than ten-fold that found in C57BL/6J (3.3+/-0.71 vs. 1.5+/-0.52 vs. 0.28+/-0.8x10(-4)). In response to ENU, Balb/C mice and C3H mice were equally susceptible, showing a stem cell mutation frequency approximately twice that of C57BL/6J (3.1+/-0.4 vs. 3.1+/-0.65 vs. 1.63+/-0.28x10(-4)). The observed differences among the strains with respect to somatic mutation following DMH treatment are likely to be due to the previously documented differences in metabolic conversion to the active metabolite. However, as ENU is a directly acting, rapidly inactivated mutagen, strain differences in response to ENU are unlikely to be due to strain-dependent metabolism of the mutagen and are likely to reflect differences in DNA repair efficiency, or possibly in stem cell kinetics among the strains studied. Susceptibility to the induction of colonic stem cell mutation is an important factor in susceptibility to carcinogens, whether due to differences in DNA repair or to other factors. Direct quantification of stem cell mutation frequency allows the separate identification of this component of the carcinogenic cascade and shows that it can make a major contribution to the differing susceptibility of different mouse strains.

1,2-Dimethylhydrazine↗
PubMed2001

New molecular approaches for identifying novel targets, mechanisms, and biomarkers for prostate cancer chemopreventive agents.

Recently developed complementary DNA (cDNA) microarray technology allows simultaneous assessment of expression on many hundreds or thousands of genes simultaneously. This technology holds great promise for providing new insights into prostate carcinogenesis that will reveal new targets for preventive intervention strategies. In addition, this technology will deepen understanding of the means by which putative preventive compounds exert their effects, generating molecular genetic biomarkers of treatment efficacy. Several putative preventive agents are currently under investigation, and development of novel preventive strategies poses significant challenges. High throughput approaches, such as cDNA microarrays, will speed discovery and progress in prostate cancer chemoprevention.

Anticarcinogenic Agents↗
PubMed2001

Measuring extraocular muscle volume using dynamic contours.

The effect of medical treatment on extraocular muscle enlargement in thyroid associated ophthalmopathy (TAO) may be monitored by measuring the change in volume of the extraocular muscles on serial orbital MRI examinations. In theory, 3D image sets offer the opportunity to minimise errors due to poor repositioning and partial volume effects. This study describes an automated technique for estimating extraocular muscle volumes from 3D datasets. Operator input is minimal and the technique is robust. Verification of the technique on both simulated and real datasets is described. For simulated image sets, both automated segmentation and manual outlining produced estimates of volume which were on average 4% less than "true" volume. For real patient data, extraocular muscle volumes measured by the automated technique were 1.6% (SD 13%) less than volumes measured by manual outlining. Coefficient of variation for repeat outlining of the same image dataset for the automated technique was 1.0%, compared with 4% for manual outlining. The manual technique took an experienced operator approximately 20 min to perform, compared to 7 min for the automated technique. The automated method is therefore rapid, reproducible and at least as accurate as other available methods.

Algorithms↗
PubMed2001

Nuclear localization of epidermal growth factor and epidermal growth factor receptors in human thyroid tissues.

Epidermal growth factor (EGF) has widespread growth effects, and in some tissues proliferation is associated with the nuclear localization of EGF and epidermal growth factor receptor (EGFR). In the thyroid, EGF promotes growth but differs from thyrotropin (TSH) in inhibiting rather than stimulating functional parameters. We have therefore studied the occurrence and cellular distribution of EGF and EGFR in normal thyroid, in Graves' disease, where growth is mediated through the thyrotropin receptor (TSHR), and in a variety of human thyroid tumors. In the normal gland the staining was variable, but largely cytoplasmic, for both EGF and EGFR. In Graves' disease there was strong cytoplasmic staining for both EGF and EGFR, with frequent positive nuclei. Nuclear positivity for EGF and particularly for EGFR was also a feature of both follicular adenomas and follicular carcinomas. Interestingly, nuclear staining was almost absent in papillary carcinomas. These findings document for the first time the presence of nuclear EGF and EGFR in thyroid. Their predominant occurrence in tissues with increased growth (Graves' disease, follicular adenoma, and carcinoma) may indicate that nuclear EGF and EGFR play a role in growth regulation in these conditions. The absence of nuclear EGF and EGFR in papillary carcinomas would suggest that the role played by EGF in growth control differs between papillary carcinoma and follicular adenomas/carcinomas of the thyroid.

Adenoma↗
PubMed2001

DNA replication licensing and human cell proliferation.

The convergence point of growth regulatory pathways that control cell proliferation is the initiation of genome replication, the core of which is the assembly of pre-replicative complexes resulting in chromatin being "licensed" for DNA replication in the subsequent S phase. We have analysed regulation of the pre-replicative complex proteins ORC, Cdc6, and MCM in cycling and non-proliferating quiescent, differentiated and replicative senescent human cells. Moreover, a human cell-free DNA replication system has been exploited to study the replicative capacity of nuclei and cytosolic extracts prepared from these cells. These studies demonstrate that downregulation of the Cdc6 and MCM constituents of the replication initiation pathway is a common downstream mechanism for loss of proliferative capacity in human cells. Furthermore, analysis of MCM protein expression in self-renewing, stable and permanent human tissues shows that the three classes of tissue have developed very different growth control strategies with respect to replication licensing. Notably, in breast tissue we found striking differences between the proportion of mammary acinar cells that express MCM proteins and those labelled with conventional proliferation markers, raising the intriguing possibility that progenitor cells of some tissues are held in a prolonged G1 phase or "in-cycle arrest". We conclude that biomarkers for replication-licensed cells detect, in addition to actively proliferating cells, cells with growth potential, a concept that has major implications for developmental and cancer biology.

Animals↗
PubMed2001

Informed consent in genetic research.

History demonstrates that, without adequate informed consent, research participants rights may be violated and their confidence in research as an enterprise undermined. If participants lose confidence in research, they may hesitate to participate in future research protocols. Without human participants to donate biological samples and participate in protocols, research will be difficult, if not impossible to conduct. Thus, appropriate informed consent protects both research participants and the enterprise of research itself. Informed consent principles in genetics not only help ensure the appropriateness of specific research protocols, but they also help support the continuation of all types of research on human participants. Most research involving human participants raises some issues fundamental to the informed consent process, such as whether potential participants truly understand the consequences of their participation in a study, and in which circumstances a person is competent to give consent. Advances in genetics are raising a new set of informed consent issues. The risks that may be involved in genetic research extend far beyond the standard considerations of immediate potential harm to study participants. Genetic information carries with it the possibility of uncovering a future propensity for a given illness. The disclosure of genetic information may lead to problems in obtaining health insurance, employment and/or housing discrimination, and to social and personal problems not only for participants, but also for their family members.

Cross-Cultural Comparison↗
PubMed2000

Gene rearrangement and Chernobyl related thyroid cancers.

The increase in thyroid carcinoma post-Chernobyl has been largely confined to a specific subtype of papillary carcinoma (solid/follicular). This subtype is observed predominantly in children under 10 in unirradiated populations, but maintains a high frequency in those aged 10-15 from those areas exposed to fallout from the Chernobyl accident. The aim of this study was to link morphology with molecular biology. We examined 106 papillary carcinomas from children under the age of 15 at operation. All were examined for rearrangements of the RET oncogene by reverse transcription polymerase chain reaction (RT-PCR); a subset of these cases were also examined for mutations of the three ras oncogenes, exon 10 of the thyroid stimulating hormone receptor, associated more usually with a follicular rather than papillary morphology, and exons 5, 6, 7 and 8 of the p53 gene, commonly involved in undifferentiated thyroid carcinoma. Rearrangements of the REToncogene were found in 44% of papillary carcinomas in which we studied fresh material; none of the tumours examined showed mutation in any of the other genes. The two rearrangements resulting from inversion of part of chromosome 10 (PTC1 and PTC3) accounted for the majority of RET rearrangements identified, with PTC1 being associated with papillary carcinomas of the classic and diffuse sclerosing variants and PTC3 with the solid/follicular variant.

Adolescent↗