Biomedical subjects
J Houghton
Publications and source records attributed to J Houghton.
Wrestling with Watson's theory of caring.
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Fossil fuels, transport, and public health.
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Is clinical breast examination an acceptable alternative to mammographic screening?
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p53 and P-glycoprotein expression are significant prognostic markers in advanced head and neck cancer treated with chemo/radiotherapy.
The development of biological markers of response to chemo- and radiotherapy to judge benefit to risk ratios for toxic treatments is still at an experimental stage. Tumour cell death is largely by apoptosis and the p53 gene has a major influence on this. P-glycoprotein (P-gp) accumulation has been correlated with treatment failure in several types of cancer. p53 and P-gp expression were studied in 111 advanced head and neck cancers treated with radiotherapy and up to four courses of synchronous or sequential chemotherapy. The probability of survival at 5 years for patients in the trial as a whole was 27.7%, while the cohort used for this marker project was 29.4%. Among the subjects used for the marker study at the time of analysis, 13 remained disease-free and 18 were alive. Immunohistochemistry was used to assess p53 and P-gp expression; 27/111 (24%) head and neck cancers demonstrated p53/P-gp expression and 33/111 (30%) were both p53- and P-gp- negative. In univariate analysis, both p53 and P-gp expression were associated with reduced disease-free and overall survival. Multivariate analysis revealed tumour size, p53, and P-gp expression as the most powerful pretreatment prognosticators in the study cohort. Long-term follow-up results suggest that p53 and P-gp co-expression predicts the biological behaviour or the outcome following chemo/radiotherapy in advanced head and neck cancer.
Effect of cholesterol levels on villous histology in colonic adenomas.
To date no studies have examined the relationship between cholesterol levels and the occurrence of specific colonic polyp histologies. Villous histology has a greater predilection for subsequent malignancies than other histologies. Consequently, we examined the effect of cholesterol levels on the occurrence of villous adenomas. Just under one in 10 (9.5%, 15/158) patients had polyps with villous histologies. Cholesterol levels were positively and nonlinearly associated with a greater likelihood of villous histology, suggesting that a threshold exists for the effect of cholesterol level on the likelihood of having polyps with villous histology [odds ratios (OR) for combined two variable quadratic effect: cholesterol OR, 1.18; 95% confidence interval (CI), 1.02-1.37 and cholesterol squared OR, 1.004; 95% CI, 1.00-1.02]. Our data suggest that, in patients with polyps, higher cholesterol levels increase the likelihood of having polyps with villous histology, but that the effect of cholesterol level reaches a threshold.
Practice and policy of measuring quality of life and health economics in cancer clinical trials: a survey among co-operative trial groups.
BACKGROUND: Co-operative groups have played an important role in the advance of health-related quality of life (HRQL) research. However, definitions of the concept, criteria for selection of existing instruments and methods for data collection and interpretation remain poorly defined in the literature. A survey was conducted amongst the major cancer co-operative groups in order to gain a better understanding of their current policy and processes to ensure optimal HRQL data collection within cancer clinical trials. The topic of health economics was similarly addressed. METHODS: A written questionnaire was addressed to 16 major European and North American cancer co-operative groups. Eleven groups responded (response rate: 69%). however, one group could not provide information for the survey, thus ten questionnaires were available for analysis. RESULTS: The results from this survey among co-operative groups show that HRQL (more than health economics) is recognized as an important, although usually secondary, outcome measure in oncology trials. On the whole, co-operative groups have a rather flexible policy towards the inclusion of HRQL (and HE) into their clinical trials, and practice is very much on a case-by-case basis, but use standard practice guidelines and internal procedures is to ensure well-defined study protocols and enhance good quality studies.
Tumor necrosis factor alpha and interleukin 1beta up-regulate gastric mucosal Fas antigen expression in Helicobacter pylori infection.
Fas-mediated gastric mucosal apoptosis is gaining attention as a cause of tissue damage due to Helicobacter pylori infection. We explored the effects of H. pylori directly, and the effects of the inflammatory environment established subsequent to H. pylori infection, on Fas-mediated apoptosis in a nontransformed gastric mucosal cell line (RGM-1). Exposure to H. pylori-activated peripheral blood mononuclear cells (PBMCs), but not H. pylori itself, induced Fas antigen (Fas Ag) expression, indicating a Fas-regulatory role for inflammatory cytokines in this system. Of various inflammatory cytokines tested, only interleukin 1beta and tumor necrosis factor alpha induced Fas Ag expression, and removal of either of these from the conditioned medium abrogated the response. When exposed to Fas ligand, RGM-1 cells treated with PBMC-conditioned medium underwent massive and rapid cell death, interestingly, with a minimal effect on total cell numbers early on. Cell cycle analysis revealed a substantial increase in S phase cells among cells exposed to Fas ligand, suggesting an increase in their proliferative response. Taken together, these data indicate that the immune environment secondary to H. pylori infection plays a critical role in priming gastric mucosal cells to undergo apoptosis or to proliferate based upon their Fas Ag status.
Contribution of randomised controlled trials to understanding and management of early breast cancer.
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Apoptosis in Helicobacter pylori-associated gastric and duodenal ulcer disease is mediated via the Fas antigen pathway.
Increased mucosal apoptosis is seen in H. pylori-infected gastric tissue; however, the precise mechanism by which this organism triggers programmed cell death is poorly understood and is investigated in this study. One pathway for induction of apoptosis is the Fas Ag pathway. Normal gastric and small bowel tissue express low levels of Fas antigen and nondetectable levels of Fas ligand. Consequent to H. pylori infection, there is elevated expression of Fas antigen in mucosal cells concurrent with Fas ligand expressing lymphocytes. This prompted us to investigate the potential role of Fas in mediating H. pylori-related apoptosis. It has been shown that inflammatory cytokines are abundant in H. pylori-infected tissue and that cytokines regulate the expression of Fas Ag in various tissue types. Using cell culture, we examine the role of specific inflammatory cytokines in activating this pathway. This communication presents the first evidence to implicate the Fas pathway in mediating apoptosis in H. pylori-associated gastric and duodenal ulcer disease.
Body mass index, height and cumulative menstrual cycles at the time of diagnosis are not risk factors for poor outcome in breast cancer.
Obesity, height and age at menarche have been shown to be risk factors for the development of primary breast cancer. However, their prognostic influence on breast cancer once it has presented is uncertain. The present study analysed 448 patients with primary breast cancer to determine whether or not body mass index (BMI), height and cumulative menstrual cycles at diagnosis are independent prognostic variables. The effects of all three variables on survival time and disease free interval were estimated. Of the 448 patients after a median follow up of 6 years, 190 (42%) developed recurrence and 162 (36%) had died. Body Mass Index and height could be calculated from available data in 403 patients and cumulative menstrual cycles in 388 patients. There was no evidence of an effect of BMI on survival time (P=0.99; hazard ratio=1.000; 95% Confidence Interval 0.968-1.034) or disease free interval (P=0.92; hazard ratio=1.002; 95% Confidence Interval 0.973-1.031). Similarly, height and cumulative menstrual years did not influence outcome in patients with primary breast cancer. However, nodal status and tumour size were both significant prognostic factors (P<0.001). The present study found no association between Body Mass Index, height and cumulative menstrual years and outcome in patients with primary breast cancer.
Fas receptor up-regulation and membrane localization concurrent with apoptosis in idiopathic esophageal ulceration: toward a better understanding of esophageal injury in AIDS.
Activation of the Fas-mediated apoptotic pathway in the etiology of idiopathic esophageal ulcerations (IEUs) was investigated. Constitutive expression of Fas ligand (Fas L) was found in the basal layer of the normal esophageal mucosa and in IEUs and cytomegalovirus ulcerations. In addition to an altered cytokine environment, there was significant up-regulation of Fas antigen mRNA and membrane localization of the receptor in IEU specimens. Concomitant increase in the basic components of Fas machinery, together with elevated mucosal apoptosis, strongly suggests the potential role of the Fas signaling pathway in the onset of tissue destruction associated with IEUs.
The informed consent process and the use of the exception to informed consent in the clinical trial of diaspirin cross-linked hemoglobin (DCLHb) in severe traumatic hemorrhagic shock. DCLHb Traumatic Hemorrhagic Shock study group.
UNLABELLED: In the clinical trial of diaspirin cross-linked hemoglobin (DCLHb), optimal therapy required the immediate enrollment of patients with severe, uncompensated, traumatic hemorrhagic shock. When it was not feasible to obtain prospective consent, an exception to informed consent was used according to FDA regulation 21 CFR 50.24. OBJECTIVES: To examine the informed consent process and the use of the consent exception and consent to continue (CTC), and to describe the patients for whom this process was used. METHODS: This was a multicenter, randomized, controlled, single-blinded efficacy trial of DCLHb as an adjunct to standard therapy in the treatment of severe, traumatic hemorrhagic shock. Patients with unstable vital signs or a critical base deficit were treated, with a primary study endpoint of 28-day mortality. RESULTS: During the 11-month study period, 112 patients were randomized in 18 U.S. trauma centers, and data from 98 of the infused patients were analyzed. Prospective consent was obtained from two patients, three family members, and one legally authorized representative (LAR) (6%). Consent to continue was requested for 89 patients (89%), and full participation was granted for 87 of these patients (98%). Consent to continue was provided by 54 (98%) of the 55 patients approached. The mean number of days for family/LAR CTC was 1.1 +/-3.8 days, and 50% of the time it was obtained on the day of study enrollment. Patient CTC was obtained in an average of 13 +/- 23 days, with a median of four days. Patients treated in this protocol were more likely to have sustained penetrating trauma than the overall trauma patient population treated in these trauma centers (44% vs 21%, p = 0.002). CONCLUSIONS: Informed consent in this study of an emergent therapy most often involved the use of the consent exception and consent to continue, the latter of which occurred in a timely manner. Nearly all of those who were approached for CTC approved full participation in the study, suggesting acceptance of the process outlined in the new regulations. Patients treated in a hemorrhagic shock clinical trial may differ from the general trauma patient population.
Salmonella osteoarticular infection without predisposing factors.
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Post-traumatic stress responses following liver transplantation in older children.
Eighteen children aged between 7 and 16 years who had undergone a liver transplantation were interviewed using the Child Post-Traumatic Stress Reaction Index (CPTS-RI) to discover if they had post-traumatic stress symptoms. A case control design was used to define which factors were important for the development of post-traumatic stress. Results of a one-way analysis of variance (ANOVA), with post-traumatic stress symptom intensity as measured on the CPTS-RI as the dependent variable, revealed a significant difference between the liver transplantation group compared with children who had a chronic life-threatening illness or had undergone a routine surgical operation. A post hoc (Tukey's HSD test) statistical analysis was performed and significance at the .05 level was found between the liver transplantation group and both the chronic illness group and the routine surgical operation group. Our results indicate that the acute life-threat involved in the liver transplantation contributed to the development of post-traumatic stress. It was thought that dissociation may be important in preventing the resolution of the trauma. Additional investigations are needed with larger numbers in a longitudinal study beginning before the transplant to determine the course of the PTSD symptoms and the appropriate timing of interventions to reduce the harmful effects of these symptoms.
Putting the risk of breast cancer in perspective.
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Suppression of interleukin-5 prevents mortality in BALB/C mice infected with Cowdria ruminantium.
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Differential gene expression in SV40-mediated immortalization of human fibroblasts.
Normal human diploid fibroblasts (HF) have a limited life span, undergo senescence, and rarely, if ever, spontaneously immortalize in culture. Introduction of the gene for T antigen encoded by the DNA virus SV40 extends the life span of HF and increases the frequency of immortalization; however, immortalization requires both T-dependent and T-independent functions. We previously generated independent SV40-transformed non-immortal (pre-immortal) HF cell lines from which we then obtained immortal sublines as part of a multifaceted approach to identify functions responsible for immortalization. In this study we undertook a search for cellular mRNAs which are differentially expressed upon immortalization. A lambda cDNA library was prepared from a pre-immortal SV40-transformed HF (HF-C). We screened the library with a subtracted probe enriched for sequences present in HF-C and reduced in immortal AR5 cells. A more limited screen was also employed for sequences overexpressed in AR5 using a different strategy. Alterations in the level of mRNAs in AR5 encoding functions relevant to signal transduction pathways were identified; however, most cDNAs encoded novel sequences. In an effort to clarify which of the altered mRNAs are most relevant to immortalization, we performed Northern analysis with RNA prepared from three paired sets of independent pre-immortal and immortal (4 cell lines) SV40-transformants using eight cloned cDNAs which show reduced expression in AR5. Three of these were reduced in additional immortal cell lines as well; one, J4-4 (unknown function) is reduced in all the immortal cell lines tested; a second, J4-3 (possible PP2C type phosphatase) is reduced in 2 of the 3 matched sets; and a third, J2-2 (unknown function) is reduced in 2 unrelated immortal cell lines. Although the roles of these genes are as yet unclear, their further analysis should extend our understanding of the molecular bases for immortalization. In particular, the patterns of expression of J4-4 and J4-3 strongly suggest that they are involved in the process of immortalization and/or can serve as target genes for assessing regulators of gene expression in this process.