Showing papers by "University of Wales published in 1987"

Endothelium-derived relaxing factor inhibits in vitro platelet aggregation.

Abstract: We studied the effects of endothelium-derived relaxing factor (EDRF), bovine retractor penis muscle inhibitory factor and sodium nitroprusside, three stimulants of guanylate cyclase, on the in vitro aggregation of washed human platelets. Platelet aggregation induced either by collagen or by the thromboxane A2 analogue U46619 was inhibited by all three agents. The anti-aggregatory effect of each agent was inhibited by haemoglobin. The anti-aggregatory effect of EDRF was potentiated by superoxide dismutase. These findings are discussed in relation to a potential role for EDRF in haemostasis.

EDRF coordinates the behaviour of vascular resistance vessels.

Abstract: Constriction of vascular smooth muscle in response to the stimulus of raised intravascular pressure—the myogenic response1,2— represents a positive feedback mechanism which, if unopposed, could theoretically lead to instability in the intact circulation3,4. Dilation in response to increased intraluminal flow would provide an opposing feedback mechanism which could confer overall stability4. Flow-dependent dilation in conduit vessels5–7 is mediated by endothelium-derived relaxing factor (EDRF)8–14, but the relationship between flow and EDRF activity has not been studied in resistance vessels in situ. We here demonstrate that EDRF can coordinate the aggregate hydrodynamic properties of an intact network. Under control conditions, EDRF maintains a fourth-power relationship between diameter and flow so that the pressure gradient in each vessel asymptotically approaches a constant value at high flow rates. Basal EDRF release may also maintain a similar spatial distribution of flow at different flow rates, even under conditions of moderate pharmacological constriction.

Twin Concordance for DSM-III Schizophrenia: Scrutinizing the Validity of the Definition

Abstract: DSM-III diagnoses were applied to 26 monozygotic (MZ) and 34 dizygotic (DZ) probands and their co-twins from the Maudsley Hospital (1948 to 1965) schizophrenic series of Gottesman and Shields. DSM-III criteria for schizophrenia were found to be highly reliable and valid, and to have a broad heritability of 0.85, which is comparable with the Research Diagnostic Criteria and Feighner criteria from which they were derived. When the full range of DSM-III diagnoses were considered, both affective disorder and schizophrenia were found in genetically identical individuals. The effect of DSM-III nosology on the twin series was also explored by adding other diagnoses to that of schizophrenia and observing the effect on the MZ/DZ concordance ratio. The addition of affective disorder with mood-incongruent delusions to the schizophrenia spectrum produced the largest increase in the ratio and, by implication, a "more genetic" combination than schizophrenia alone. The maximum MZ/DZ concordance ratio (7.68) was produced by schizophrenia, plus affective disorder with mood-incongruent delusions, plus schizotypal personality disorder, plus atypical psychosis. The effect of adding paranoid disorder (paranoia) and all other affective categories was a reduction in the ratio.

Denture stomatitis: a review.

Abstract: Denture stomatitis has been reported in 11-67% of complete denture wearers. It is more common on the palatal mucosa and in female patients. In Newton's type I denture stomatitis, where the inflammation remains focal, trauma seems to be responsible. In Newton's types II and III denture stomatitis, where the denture-bearing mucosa is diffusely involved, most workers assert that the aetiology is multi-factorial. Evidence is presented incriminating Candida albicans colonization of the fitting surface of the prosthesis in many cases of denture stomatitis promoted by continuous denture wearing. Allergic and primary irritant reactions to the denture base material, systemic predisposing factors including dietary deficiency and haematological disorders, also play a part. In most cases of denture stomatitis, elimination of denture faults, control of denture plaque and discontinuous denture wearing are sufficient treatment. The routine use of antiseptic or antimycotic drugs seems unnecessary.

Proliferative index in breast carcinoma determined in situ by Ki67 immunostaining and its relationship to clinical and pathological variables

Abstract: Sixty cases of primary breast carcinoma have been studied using a monoclonal antibody, Ki67, which recognizes an antigen expressed by cells in G1, S, G2, and M phases of the cell cycle but not Go. A Ki67 score (positive cells/total tumour cells) was determined, and possible relationships between this index of cellular proliferation and a number of clinical and pathological parameters were investigated. There was a strong positive correlation between the Ki67 score and mitotic index (p less than 0.001), a weak negative correlation with age (p less than 0.02), and weak positive correlations with histological tumour grade (p less than 0.03), tumour necrosis (p less than 0.01), and cellular reaction (p less than 0.01). No relationship was noted between the Ki67 score and tumour size, nodal status, tumour oestrogen receptor levels, or menopausal status. The Ki67 score may prove to be an objective indicator of biological behaviour and thus be of clinical significance, particularly since it is not strongly related to other clinical and pathological parameters used in predicting outcome in breast carcinoma.

Common pathogenetic mechanism for three tumor types in bilateral acoustic neurofibromatosis

Abstract: Bilateral acoustic neurofibromatosis (BANF) is a genetic defect associated with multiple tumors of neural crest origin. Specific loss of alleles from chromosome 22 was detected with polymorphic DNA markers in two acoustic neuromas, two neurofibromas, and one meningioma from BANF patients. This indicates a common pathogenetic mechanism for all three tumor types. The two neurofibromas were among three taken from the same patient, and both showed loss of identical alleles demonstrating that the same chromosome suffered deletion in both tumors. The third neurofibroma from this patient showed no detectable loss of heterozygosity, which suggests the possibility of a more subtle mutational event that affects chromosome 22. In the two acoustic neuromas, only a portion of chromosome 22 was deleted, narrowing the possible chromosomal location of the gene that causes BANF to the region distal to the D22S9 locus in band 22q11. The identification of progressively smaller deletions on chromosome 22 in these tumor types may well provide a means to clone and characterize the defect.

Clinical aspects of X-linked hypohidrotic ectodermal dysplasia.

Abstract: Boys with X-linked hypohidrotic ectodermal dysplasia and their families were studied Many suffered severe illness in early childhood and nearly 30% died; many had feeding problems, severe fever, atopic disease, and recurrent respiratory infections Some infants failed to thrive We found no consistent common endocrine or immunological abnormality, although, most had abnormal immunoglobulin production This may be related to the abnormal mucosa of the gastrointestinal and respiratory tracts which exacerbates the chronic obstructive airways disease found later in life in those who smoke Mental handicap was not a feature, although convulsions sometimes occurred during fever Early diagnosis is important to avoid attacks of severe fever and so that rational management may be planned for other problems that arise Dental advice should be sought before school age and genetic counselling may also be required Many female carriers may be recognised at clinical examination: their affected sons can then be diagnosed more readily

Circulating intact parathyroid hormone measured by a two-site immunochemiluminometric assay.

Abstract: A direct immunoassay for circulating intact human PTH (hPTH) is described. The method relies on the formation of an immune complex of labeled antiamino-terminal PTH antibody, intact hPTH, and solid phase antimidregion PTH antibody. A chemiluminescent aryl acridinium ester is used as label. Serum samples (100 microL) are incubated with labeled antibody, and subsequently the bound fraction is separated by the addition of solid phase antibody. The bound luminescence is quantitated in an automatic luminometer. Luminescence intensity is directly proportional to the amount of intact PTH present in the sample. Only intact PTH was found to react in this system; there was no significant interference from PTH fragments. The assay detection limit of 0.8 pmol/L hPTH-(1-84) allowed detection of intact PTH in the serum of all normal subjects tested. A clear distinction was found between hypercalcemic individuals subsequently proven to have primary hyperparathyroidism and those with malignancies. The assay offers several advantages over previously described PTH immunoassays with regard to specificity, rapidity, and reagent stability. It, thus, provides a valuable means of investigating parathyroid physiology and clinical disorders of extracellular calcium metabolism.

Age related reactivation of an X-linked gene

Abstract: We have investigated age-related reactivation of the X chromosome by devising a model in which reactivation of a single gene in one cell among many can be identified. We have used mice with an X-autosomal translocation giving consistent non-random inactivation of the normal X (as judged by biochemical and cytogenetic techniques), that also carry a defective form of a histochemically demonstrable X-linked enzyme. When the gene for the normal enzyme was located on the inactivated normal X a uniformly negative histochemical picture would be predicted in doubly heterozygous animals. A very small proportion of enzyme-positive cells was found in young animals. This proportion increased very significantly with age, but the patch size did not change, showing that the result was not due to preferential division of enzyme-positive cells, but was instead due to the conversion of previously enzyme-negative to enzyme-positive cells. These observations provide the first evidence with a true X-linked gene for an age-related decrease in the stability of the X-inactivation mechanism.

Tumour cell killing by tumour necrosis factor: inhibition by anaerobic conditions, free-radical scavengers and inhibitors of arachidonate metabolism.

Abstract: Previous work on the mechanism of tumour-cell killing by the macrophage product tumour necrosis factor (TNF) is consistent with a free radical-induced process. In this study, free-radical involvement was sought by (i) investigating the effects on TNF cytolysis of anaerobic conditions, free-radical scavengers and inhibitors of two potential pathways of free-radical generation (oxidative phosphorylation and arachidonate metabolism) and (ii) looking for increased malonyldialdehyde (MDA) production in TNF-treated cells (MDA is a free radical-induced lipid peroxidation product). Although TNF cytolysis of L929 cells was inhibited by anaerobic conditions, only limited effects were seen with free-radical scavengers. Suppression of arachidonate metabolism by steroids effectively inhibited TNF cytolysis but the mitochondrial poison rotenone did not. There was a marked, but late, increase in MDA production in TNF-treated cells. Overall, these results indicate that if free radicals are involved it is at a late stage in the cytolytic process. However the most striking observation in this study is that arachidonate metabolism is an essential link in the cytolytic process.

The ordination and classification of macroinvertebrate assemblages in the catchment of the River Wye in relation to environmental factors

Abstract: SUMMARY. 1. Macroinvertebrates were sampled from three habitats at forty-five sites in the catchment of the Welsh River Wye. Species assemblages were ordinated by DECORANA. classified by TWIN-SPAN and related to physico-chemical factors using correlation and multiple discriminant analysis respectively. 2. DECORANA axis 1 was correlated with pH or total hardness, whilst axis 2 correlated with slope or distance from source. TWINSPAN groupings were also related to hardness and, to a lesser extent, slope. Assemblages at soft-water sites ( 10 m km−1), the fauna was dominated numerically by Ephemerop-tera, net-spinning Trichoptera, Mollusca and Crustacea. 3. We suggest that our data do not support the River Continuum Concept unless there are modifications to allow for multiple gradients.

Clinical Genetics as Clues to the "Real" Genetics of Schizophrenia: (A Decade of Modest Gains While Playing for Time).

Abstract: Although a decade has passed since the genetics of schizophrenia was examined for the Schizophrenia Bulletin, the epigenetic puzzle of schizophrenia has not yielded its secrets to any scientific break-through. In this article we review a sample of the highlights relevant to enlightened genetic thinking, i.e., a broad diathesis-stressor framework with multifactorial causation assumed and with provision for the epigenetic interaction of psychosocial as well as neurobiological factors. The clinical genetic epidemiologist needs to know the lifetime morbid risks generated by different definitions of schizophrenia, as well as the consequences for the familial risks generated by the various family, twin, and adoption strategies. Schizophrenia appears to occur through an interaction of a genetic susceptibility with some kind of environmental stress; the stress need not be an environment containing a person with a diagnosis in the schizophrenia spectrum; the genetic factors in schizophrenia have specificity as they do not increase the risk for major affective disorders or delusional disorder. Clearly, schizophrenia is clinically or phenotypically heterogeneous, but whether this variety is paralleled by etiological heterogeneity or to what extent is problematic. Once the existence of an important genetic predisposition to developing schizophrenia has been established, it becomes important to provide a theory (or theories) to account for its mode (modes) of transmission. Psychiatric geneticists have not yet solved the problem, in part because of the difficulty of specifying the appropriate phenotype to analyze and also because of the unknown degree of heterogeneity. Genetic markers are a special category of biological markers. In addition to conventional markers, the advent of "the new genetics" of recombinant DNA has meant that many more genetic markers (probes) are now available and that the day is not far off when the human genome will be extensively mapped. Considerable optimism exists about the future usefulness of genetic markers in detecting major gene effects and resolving problems of heterogeneity in schizophrenia.

Short‐term experimental acidification of a Welsh stream: comparing the biological effects of hydrogen ions and aluminium

Abstract: SUMMARY. 1. A soft-water stream iti upland Wales was dosed with sulphuric acid and aluminiutn sulphate at two successive points to create sitnultaneous episodes of low pH, and low pH with increased aluminiutn. Chemical atid biological responses were measured before, during and after the episode and were compared with a reference zone. 2. The pH fell frotn ∼7.0 to 4.28 (±0.18 SD) and 5.02 (±0.10) respectively in the acid and aluminium zones. Corresponding aluminium concentrations during the episode were 0.052 g Al m−3 (±0.008) and 0.347 g Al nr3 (±0.047), the former not differing significantly from the reference zone. The concentration of cadmium rose to 0.002- 0.011 g Cd m−3in both treated areas, but the concentrations of other metals were unchanged. 3. In situ toxicity tests were performed with macroinvertebrates and fish. Chironomus riparius. Hydropsyche angustipennis and Dinocras cephalotes suffered no mortality. Ecdyonurus venosus, Baetis rhodani and Gammarus pulex showed up to 25% mortality in both treatment zones and further mortalities occurred after the episode. Brown trout Salmo trutta and salmon Valmo salar s howed 7–10% mortality in the acid zone, but 50–87% in the aluminium zone, where salmon had a significantly shorter LT50than trout. 4. The drift of Simuliidae increased during treatment in both acid and aluminium zones. Drift densities of Dixa puherula, Protonemura meyeri, Ephemeralla ignita and Dicranota sp. increased in the aluminium zone. The most pronounced response was by Baetis rhodani in the aluminium zone where drift density increased by ×8.4 during the episode. 5. Baetis rhodani was the only taxon to show a significant decline in benthic density during the treatment, and then only in the aluminium zone. Drift could account for most of the losses. 6. The depth distribution of invertebrates in the substratum differed between zones following treatment. More individuals were present at the surface of the reference zone (1287 m−2±747) than at the surface of the other zones (<400 m−2); however, densities at greater depths were similar. These patterns probably reflected differences prior to the treatments.

Cell proliferation studies in the rat prostate: II. The effects of castration and androgen‐induced regeneration upon basal and secretory cell proliferation

Abstract: The changes over short and prolonged periods (up to three months) after castration on the proliferative activity of basal and secretory epithelial cells in the rat prostate were studied. Although castration induced widespread apoptosis of the secretory cells, no compensatory hyperplasia of the basal cells in response to this was noted. Instead, observations of the cell kinetics and ultrastructure suggested that both the basal and secretory cells entered a quiescent state as a result of castration. The proliferative potential of secretory cells was not diminished up to three months after castration. During androgen-induced regeneration of the prostate the pattern of basal and secretory cell proliferation was found to be similar to that observed during normal growth, although it was more rapid and of shorter duration.

Plasmid transfer between strains of Pseudomonas aeruginosa on membrane filters attached to river stones.

Abstract: SUMMARY: A naturally occurring mercury-resistance, conjugative plasmid, designated pQM1, was isolated from a bacterial population on the surface of stones from a river using Pseudomonas aeruginosa as a recipient. This was a narrow-host-range plasmid [IncP-13; 165 MDa; Tra+, Hgr, fluorescein mercuric acetater, merbrominr, Phi(E79), UVr] confined to some Pseudomonas spp. It was used to demonstrate transfer between bacteria on stones in laboratory microcosm experiments and in situ. Transfer occurred (3·3 × 10-1 to 6·8 × 10-9 per recipient) at all the temperatures used (6-20°C), although frequencies were lower in the cold. Nutrient status also affected transfer frequency, rich conditions promoting transfer. The presence of competing bacteria in the natural epilithon lowered transfer frequencies, but when unscrubbed stones were heat treated, transfer was enhanced, perhaps because of nutrient release from the heated epilithon.

Transdermal drug delivery and cutaneous metabolism.

Abstract: 1. The delivery of drugs via the skin to achieve systemic therapeutic effect is currently under intense investigation.2. The skin offers unique advantages and limitations for drug input into the bo...

Rapid small scale preparation of bacterial genomic DNA, suitable for cloning and hybridization analysis

Abstract: We describe a rapid procedure for extracting purified chromosomal DNA from Pseudomonas putida, and some minor modifications needed for use in other organisms, including Gram-positive strains. The technique is rapid and generally produces between 1 and 5 μg of DNA from 1 ml of liquid culture. The DNA is highly purified and can be readily cut with small quantities of restriction endo-nucleases, cloned into plasmid vectors and used as a substrate for hybridization with labelled DNA probes. Genetical analysis and cloning of genomic DNA from environmentally important organisms like Ps. putida has become increasingly important. Bacterial chromosomal DNA is usually prepared from large volumes of liquid culture, and involves time-consuming steps necessary to purify the DNA sufficiently for use in cloning experiments (e. g. Marmur 1961). We have developed a method for preparing small quantities of genomic DNA, which involves whole cell lysis and purification by precipitation and centrifugation. Loss of DNA occurs by shearing, but the yield of DNA is sufficient, and the quality is high. The method has been used to prepare DNA from a variety of organisms and is particularly applicable where the preparation and analysis of DNA from a large number of isolates is required.

Eyes or patients? Traps for the unwary in the statistical analysis of ophthalmological studies

Abstract: In reports on ophthalmological research the results of measurements on the eye are often expressed as mean and standard deviation based on m patients, n eyes (n greater than m). This approach leads to t tests that are invalid because the measurements on the two eyes of one subject are usually related, not independent. In a simulation study involving intraocular pressure data analysed in this way, the null hypothesis of no difference between groups was rejected at a nominal alpha = 0.05 level in 39 out of 200 simulations; thus the true alpha was nearly 0.2. This approach is excessively prone to produce false positive results.

Towards a reduction in publication bias.

Abstract: Current practice results in the publication of many research studies in medical and related disciplines which may be criticised on the grounds of inadequate sample size and statistical power. Small studies continue to be carried out with little more than a blind hope of showing the desired effect. Nevertheless, papers based on such work are submitted for publication, especially if the results turn out to be statistically significant. There is confusion about what makes a result suitable for publication. Often there is a preference for statistically significant results at the peer review stage. Consequently published reports of small studies tend to contain too many false positive results and to exaggerate the true effects. The use of a criterion of a posteriori power does not eliminate the bias; a priori power is the criterion of choice. This could be implemented by peer review of study protocols at the planning stage by funding bodies and journals.

Duodenal carcinoid tumours, phaeochromocytoma and neurofibromatosis: islet cell tumour, phaeochromocytoma and the von Hippel-Lindau complex: two distinctive neuroendocrine syndromes.

Abstract: To clarify neuroendocrine syndromes we have reviewed the association of neurofibromatosis with carcinoid tumours and of neurofibromatosis, phaeochromocytoma or von Hippel-Lindau complex with either carcinoid or islet cell tumours. In nine cases of neurofibromatosis with a carcinoid tumour studied all carcinoid tumours were in the duodenum, were distinctive histo-logically and had widespread somatostatin immunoreactivity. The duodenum was the primary site in 18 of 20 further published cases of carcinoid tumour and neurofibromatosis. Phaeochromocytoma was also present in six of these 27 cases with neurofibromatosis and duodenal carcinoid tumour. Six patients have been reported with Von Hippel-Lindau complex, phaeochromocytoma and islet cell tumour. A further 11 patients showed phaeochromocytoma and islet cell tumour. No cases of Von Hippel—Lindau complex had a carcinoid tumour, and no cases of neurofibromatosis had an islet cell tumour. We conclude that the association of neurofibromatosis, duodenal carcinoid tumour and phaeochromocytoma forms a distinctive neuroendocrine syndrome, sharply separated from the association of Von Hippel—Lindau complex with islet cell tumour and phaeochromocytoma. This separation is important in pathogenesis, diagnosis and clinical management.

Mesothelioma in Cyprus: the role of tremolite.

Abstract: There is a chrysotile mine in the central mountains of Cyprus but no other appreciable source of industrial asbestos. Hence the island was thought to offer ideal conditions to seek pure chrysotile induced mesothelioma. The first reported case was a village woman whose lung tissue contained amphibole asbestos fibres, which were later identified as tremolite. This began a search for the origin of her exposure to asbestos. Our studies have shown that tremolite is widespread, being found, along with chrysotile, in domestic and environmental dust samples. Other cases of mesothelioma have been diagnosed, and the pattern of their distribution suggests that the mine is not the major source of disease. Exposure to tremolite is equally, if not more, important.