Biomedical subjects
Publications and source records attributed to R Davies.
Coronary artery bypass surgery (CABS) is a common operation, which is often complicated by neurological sequelae. Disturbances of cerebral blood flow have been reported up to eight days after surgery and pituitary apoplexy has previously been reported. We report a case of hypopituitarism without pituitary apoplexy, which developed after a period of sustained arterial hypotension, during coronary artery bypass surgery.
The canalithiasis hypothesis proposes that benign positional vertigo (BPV) is caused by dislodged otoconia that settle in the posterior semicircular canal (PSC). When head position is changed these particles move within the canal and induce abnormal endolymph flow. To clear the PSC from debris we developed a procedure that consists of a full circle of backward head rotation in the exact plane of the canal. Patients were seated in a three-dimensional motion device that rotated in steps of 110 degrees every 30 seconds. The first part of the study was conducted as an open trial; the second part followed a single-blinded, placebo-controlled design: Forward rotation (placebo) was applied first and backward rotation was applied 1 week later if BPV persisted. All patients were assessed with a symptom diary and, in the controlled trial, also with the Dix-Hallpike maneuver. In the open study 10 of 15 patients became asymptomatic after one treatment session. In the controlled trial all 15 patients remained symptomatic after forward rotation while 10 of 14 undergoing backward rotation were relieved from positional vertigo immediately (p = 0.004). The presence of secondary nystagmus during the procedure indicated a favorable outcome. Our findings provide evidence for the efficacy of canal-clearing procedures that validate the canalithiasis hypothesis of BPV.
Interleukin-6 (IL-6) is a cytokine released by thyrocytes and is involved in disease processes such as autoimmune thyroid disease. The secretion of IL-6 can be stimulated by interleukin-1 (IL-1), tumour necrosis factor-alpha (TNF), serum, TSH and agents which increase intracellular cyclic AMP levels. Antithyroid drugs such as methimazole inhibit IL-6 production by thyrocytes but the effects of glucocorticoids and oestrogen have not been investigated. The effects of dexamethasone and 17 beta-oestradiol on IL-1-, TNF-, TSH-, forskolin- and phorbol 12-myristate 13-acetate (PMA)-stimulated IL-6 release in serum-free conditions were studied in human thyrocytes derived from patients with Graves' disease and toxic multinodular goitres, and in the immortalised human thyrocyte cell line, HTori3. Dexamethasone inhibited IL-6 production under stimulated conditions. In serum-free conditions, no basal release of IL-6 was assayable. In all but one of the primary thyroid cultures, TSH did not stimulate IL-6 release above the lower detectable limit of the assay. In Graves' and multinodular goitre thyrocytes, inhibition of IL-1 (100 U/ml)-stimulated IL-6 release by dexamethasone (100 nmol/l) was 62.51% +/- 10.43 (S.E.M.), and in HTori3 cells it was 78.35% +/- 3.9. The degree of IL-1 stimulation of IL-6 release and inhibition by dexamethasone was not significantly different in thyrocytes derived from either Graves' or multinodular glands. 17 beta-Oestradiol had no effect on IL-1-stimulated IL-6 release in either primary thyroid cell culture or in HTori3 cells.
The aims of the EVINCE research project included examination of the impact of information on the clinical knowledge and practice of nurses, midwives and health visitors. EVINCE (Establishing the Value of Information to Nursing Continuing Education) was funded by the British Library R&D Department for 1 year, from 1 November 1995 to 31 October 1996. The methods employed (based on those used in the Value project) included a critical incident type study to establish patterns of information need and use among a random sample of nursing professionals. The nature of the impact of information obtained on present and future competencies was assessed from a survey of the searches and requests presented to library and information services. Nurses, midwives and health visitors did value the information (96% of respondents agreed that there was, or would be an effect on future practice through enhanced competence in one or more areas). The impact findings can be used to guide a more precise assessment of information needs.
One of the aims of the EVINCE study (Establishing the Value of Information to Nursing Continuing Education) was to assess the impact of information obtained from information and library services about nursing knowledge, competencies, and practice. Survey methods included a critical incident type survey of the patterns of information need and use among a random sample of more than 200 nursing, midwifery, and health visiting staff at five sites and a survey of 776 searches and requests presented to 13 different information services. Questionnaire surveys were followed by selected interviews. Results indicated that information seeking in practice was often prompted by a combination of purposes, with 41 percent of information-seeking incidents involving patient care purposes combined with informal or formal education. The profile of information requests seen by the information service differed, there being more emphasis on formal education and research. Nursing professionals value highly the information obtained from information and library services, and information that helps in evidence-based practice is a priority. Information skills are varied, suggesting that much support for critical appraisal is necessary.
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Tamoxifen, an important drug in breast cancer treatment, causes liver cancer in rats. The standard range of in vitro tests have failed to show that it causes DNA damage, but 32P-postlabelling and DNA-binding studies have shown that tamoxifen forms DNA adducts in rat liver. In 1995 a transgenic rat (Big Blue; Stratagene, La Jolla, CA) became available which harbours the bacterial lacI gene, thereby allowing the in vivo study of tamoxifen mutagenesis. Recently, we [Styles JA et al. (1996): Toxicologist 30; 161] showed that tamoxifen caused on increase in the mutation frequency at the lacI gene in these transgenic rats. In this study, we report on our preliminary analysis of the mutational spectra of 33 control and 38 tamoxifen-induced mutant lacI genes. Plasmid DNA containing the lacI gene was isolated from the mutant phages and its DNA sequence determined. In the control animal group, 81% of the mutant lacI genes were point mutations, whilst in the tamoxifen-treated group, 62% of the mutant lacI genes were point mutations. Of the tamoxifen-induced mutants, 43% were GC-->TA transversions and 70% of point mutations. In the control group, GC-->TA transversions were 19% of all mutations and 24% of point mutations. Thus, compared with control animals, tamoxifen treatment had significantly increased the proportion of GC-->TA transversions.
Prostate epithelial differentiation is dictated by its surrounding stroma which determines androgen induced growth responsiveness and expression of specific secretory proteins in normal prostate gland. During neoplastic progression, organ specific stroma has been shown to determine the rate of neoplastic progression from androgen-dependent to androgen-independent and metastatic states. Although growth factors and extracellular matrix are recognized as important contributors to prostate epithelial growth, hormonal responsiveness, and neoplastic progression, the exact mechanism of intercellular communication between stromal and epithelial cells remains undefined. In addition to the importance of defining the reciprocal interaction between stromal and epithelial interaction in the prostate, clonal interaction between two dissimilar prostate epithelial cell is also recognized to contribute to disease progression. In this review, we summarized recent advances made in delineating molecular mechanisms underlying stromal epithelial interaction and clonal interaction between androgen-dependent and androgen-independent prostate cancer cells in vivo and in culture. Understanding cellular interaction between prostate epithelium and its surrounding stroma could help us in developing metastatic models of prostate carcinogenesis. This concept will allow us to define epithelial-specific markers, markers induced as the result of stromal-epithelial interaction, and stroma-associated markers. These markers together will assist us in diagnosing, preventing, prognosing and treating prostate cancer more efficaciously in the future.
The potent kinase inhibitor staurosporine and its protein kinase C (PKC)-selective analogue CGP 41251 are known to sensitise cells with the multidrug resistance (MDR) phenotype mediated by P-glycoprotein (P-gp) to cytotoxic agents. Here four PKC-selective staurosporine cogeners, CGP 41251, UCN-01, RO 31 8220 and GF 109203X, were compared with staurosporine in terms of their MDR-reversing properties and their susceptibility towards P-gp-mediated drug efflux from MCF-7/Adr cells. Staurosporine was the most potent and the bisindolylmaleimides RO 31 8220 and GF 109203X the least potent cytostatic agents. When compared with MCF-7 wild-type cells, MCF-7/Adr cells were resistant towards the growth-arresting properties of RO 31 8220 and UCN-01, with resistance ratios of 12.6 and 7.0 respectively. This resistance could be substantially reduced by inclusion of the P-gp inhibitor reserpine. The ratios for GF 109203X, staurosporine and CGP 41251 were 1.2, 2.0 and 2.9 respectively, and they were hardly affected by reserpine. These results suggest that RO 31 8220 and UCN-01 are avidly transported by P-gp but that the other compounds are not. Staurosporine and CGP 41251 at 10 and 20 nM, respectively, decreased efflux of the P-gp probe rhodamine 123 (R123) from MCF-7/Adr cells, whereas RO 31 8220 and GF 109203X at 640 nM were inactive. CGP 41251 was the most effective and GF 109203X the least effective inhibitor of equilibrium binding of [3H]vinblastine to its specific binding sites, probably P-gp, in MCF-7/Adr cells. Overall, the results imply that for this class of compound the structural properties that determine susceptibility towards P-gp-mediated substrate transport are complex. Comparison with ability to inhibit PKC suggests that the kinase inhibitors affect P-gp directly and not via inhibition of PKC. Among these compounds CGP 41251 was a very potent MDR-reversing agent with high affinity for P-gp and least affected by P-gp-mediated resistance, rendering it an attractive drug candidate for clinical development.
The MCF-7 doxorubicin-resistant cell line MCF-7/Dox has been used extensively for studies of the multidrug resistance phenomenon. Using fluorescence-activated cell sorting (FACS), these cells were separated into two populations on the basis of rhodamine 123 (R123) accumulation. We designated these as low P-glycoprotein (LP-gp) and high P-gp (HP-gp) cells on the basis of their P-gp content. Using the reverse transcriptase polymerase chain reaction technique controlled by homologous internal standards, we analysed levels of MDR1 and MDR2 mRNA in each cell type. LP-gp and HP-gp cells had MDR1 mRNA levels of 2.17 +/- 0.17 and 6.65 +/- 2.29 amol ng-1 total RNA respectively, compared with 0.00088 +/- 0.00005 amol ng-1 in wild-type MCF-7 cells (MCF-7/WT). MCF-7/WT cells additionally contained 0.023 +/- 0.016 amol ng-1 of MDR2 mRNA, which was unchanged in LP-gp cells, but lower than in HP-gp cells, which contained 0.42 +/- 0.08 amol ng-1. Both LP-gp and HP-gp cells contained increased copies of the MDR1 gene. However, the degree of gene amplification did not correlate with the changes in MDR1 mRNA levels, indicating further regulatory levels of gene expression. The level of P-gp detected by MRK 16 correlated with R123 accumulation. HP-gp cells expressed a 10-fold higher level of P-gp1 than LP-gp cells. However, there was only a 3-fold increase in MDR1 mRNA level in HP-gp cells compared with LP-gp cells. These data suggest that some regulation of P-gp1 expression also occurred at the post-translational level. Phosphorylation of P-gp by protein kinase C (PKC)-alpha is necessary for its activity. Our analysis of PKC-alpha, 0 and epsilon isozyme levels, and subcellular distribution, shows a co-regulation of expression with P-gp, suggesting a necessary role for PKC in P-gp regulation.
AIMS/BACKGROUND: The purpose of the project was to develop a technique for evaluating screening policies in the treatment of insulin dependent diabetic retinopathy. The study was concerned with patients who contracted the disease, aged under 35 years. Simulation was used to describe the progress of a cohort of patients through disease and treatment. METHOD: Data, derived from a literature survey of European and American population and clinic studies, were used to model as closely as possible the development of retinopathy in all its stages, together with the effects of screening and treatment. The model output was validated against published data. RESULTS: The results showed that where screening sensitivities are high, the frequency of screening makes little difference to the years of sight saved, but it does make a difference if screening sensitivities are close to 50%. CONCLUSIONS: Although annual screening is normally desirable, biannual screening could be considered where patient compliance and screening sensitivities are both high.
Gestational thyrotoxicosis is now widely believed to result from excessive thyroidal stimulation by hCG. Our clinical impression has been that this condition is more frequent in Asian women than in those of European origin. To assess this possibility further, we analyzed thyroid hormone levels in the sera of 294 Asian women, obtained as part of a screening program at 15-16 weeks of pregnancy, and compared these with 292 sera from age- and parity-matched European women at a similar time of gestation. TSH levels were significantly lower in the Asian group (P < 0.001). Suppressed TSH levels (< 0.35 mIU/L) were found in 15.7% of Asian women and 4.8% of European women (P < 0.001). In both groups of women with suppressed TSH values, hCG and hCG beta levels were higher than in the women with normal TSH levels. Free T4 levels in the Asian women were significantly higher in those with suppressed TSH (P < 0.001), but this was not found in the European women. There was also a significant increase in the free T3 index in the Asian women with suppressed TSH compared to that in an age-matched group of Asian women with normal TSH levels (P < 0.02), but this was not observed in European women with suppressed TSH. None of the women with suppressed TSH had thyroid-stimulating antibodies. These results show that Asian women more frequently develop biochemical evidence of thyrotoxicosis at the beginning of the second trimester of pregnancy than those of European origin and are, therefore, likely to be at greater risk of clinically apparent gestational thyrotoxicosis and hyperemesis gravidarum. Genetically determined differences in the production or metabolism of hCG isoforms may account for this increased risk.
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The case of an 80-year-old woman who presented with a 1-year history of a right medial canthal mass and bloody tears and who was found to have a lacrimal sac melanoma is reported. A literature search revealed that only 16 cases of primary lacrimal sac melanoma have been reported. Current therapeutic modalities are discussed.
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