Biomedical subjects
Publications and source records attributed to R Stephens.
Endotoxin has been implicated in the processes that can lead to organ failure and death after surgery and critical illness. While there are no currently available commercial therapies directed against endotoxin, many have been tried or are in an experimental stage. In this article we outline past, present and future approaches to anti-endotoxin therapy.
Renal cell carcinoma (RCC) is an angiogenic tumor resistant to standard cytotoxic chemotherapeutic agents. Although often responsive to immunomodulatory agents including interleukin 2 and IFN-alpha, the overall results in randomized Phase III studies are disappointing with only modest improvements in overall survival. This Phase II study evaluated the efficacy and tolerability of razoxane, an antiangiogenic topoisomerase II inhibitor, in 40 patients (32 men, 8 women; age: range, 31-76 years; median, 58 years) with inoperable RCC. Twenty patients received razoxane 125 mg p.o., twice a day for 5 days each week for 8 weeks (one cycle). This was repeated in patients with stable disease (StD), but was discontinued after 16 weeks if there was no evidence of an objective response. Because minimal toxicity was seen, subsequent patients (n = 20) were treated until progressive disease (PD) was documented. Of 38 evaluable patients, 11 (29%) had StD for a minimum of 4 months, and the remainder had PD. Median overall survival was 7.3 months. Duration of survival was significantly better in patients with StD compared with those with PD (P = 0.003). The effect of treatment on six potential surrogate serum/plasma (vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), urokinase plasminogen activator soluble receptor (uPAsr), E-selectin, vascular cell adhesion molecule-1 (VCAM-1) and von Willebrand's factor (vWF) and two urinary (VEGF and bFGF) markers of angiogenesis was evaluated before and after 1 cycle of treatment. Pretreatment serum VEGF and E-selectin levels above the median value were associated with a poor prognosis. Serum VCAM-1 levels and urinary VEGF levels rose significantly after one cycle in patients with PD but not in those with StD. Serum VEGF, bFGF, VCAM-1 and vWF, plasma uPAsr and urinary bFGF levels were significantly higher in PD patients compared with StD patients before and/or after 1 cycle of treatment. In conclusion, razoxane is an antiangiogenic agent that has minimal toxicity and that requires further evaluation in combination with other active agents in the treatment of RCC. Surrogate serum and urinary markers of angiogenesis may have a role to play in predicting disease response and overall survival in RCC.
We have mapped and sequenced the region immediately centromeric of the human major histocompatibility complex (MHC). A cluster of 13 genes/pseudogenes was identified in a 175 kb PAC linking the TAPASIN locus with the class II region. It includes two novel human genes (BING4 and SACM2L) and a thus far unnoticed human leucocyte antigen (HLA) class II pseudogene, termed HLA-DPA3. Analysis of the G+C content revealed an isochore boundary which, together with the previously reported telomeric boundary, defines the MHC class II region as one of the first completely sequenced isochores in the human genome. Comparison of the sequence with limited sequence from other cell lines shows that the high sequence variation found within the classical class II region extends beyond the identified isochore boundary leading us to propose the concept of an "extended MHC". By comparative analysis, we have precisely identified the mouse/human synteny breakpoint at the centromeric end of the extended MHC class II region between the genes HSET and PHF1.
A novel human gene RED, and the murine homologue, MuRED, were cloned. These genes were named after the extensive stretch of alternating arginine (R) and glutamic acid (E) or aspartic acid (D) residues that they contain. We term this the 'RED' repeat. The genes of both species were expressed in a wide range of tissues and we have mapped the human gene to chromosome 5q22-24. MuRED and RED shared 98% sequence identity at the amino acid level. The open reading frame of both genes encodes a 557 amino acid protein. RED fused to a fluorescent tag was expressed in nuclei of transfected cells and localised to nuclear dots. Co-localisation studies showed that these nuclear dots did not contain either PML or Coilin, which are commonly found in the POD or coiled body nuclear compartments. Deletion of the amino terminal 265 amino acids resulted in a failure to sort efficiently to the nucleus, though nuclear dots were formed. Deletion of a further 50 amino acids from the amino terminus generates a protein that can sort to the nucleus but is unable to generate nuclear dots. Neither construct localised to the nucleolus. The characteristics of RED and its nuclear localisation implicate it as a regulatory protein, possibly involved in transcription.
OBJECTIVE: To assess serum beta2-microglobulin levels in human immunodeficiency virus (HIV)-infected and uninfected pregnant women, variations of serum beta2-microglobulin levels during pregnancy and postpartum, factors that might influence beta2-microglobulin levels in pregnant women, and the association between beta2-microglobulin and perinatal HIV-1 transmission. METHODS: We assayed 374 stored (-70C) serum samples from pregnant women enrolled in the Newark perinatal HIV-1-transmission study and 18 nonpregnant women for beta2-microglobulin using a microparticulate enzyme immunoassay. The Student t test, Wilcoxon rank test, binomial test, and Spearman correlation coefficient were used for statistical analysis, with P < .05 considered statistically significant. A linear regression model was used to assess the effect of independent variables on serum beta2-microglobulin levels. RESULTS: There were no significant differences (P = .16) in serum beta2-microglobulin levels between pregnant and nonpregnant HIV-negative women (1.07+/-0.35 versus 0.99+/-0.18 mg/L). Beta2-Microglobulin levels did not vary throughout pregnancy and postpartum, irrespective of HIV serostatus. Substance abuse did not alter beta2-microglobulin levels. Human immunodeficiency virus infection caused significant increases of this surrogate marker, but it could not discriminate among disease stages. Beta2-Microglobulin levels at delivery were lower among women who delivered HIV-infected infants. CONCLUSION: Human immunodeficiency virus infection was associated with increased serum beta2-microglobulin levels in pregnant women and was the most significant correlate of increases of that marker. Pregnancy and substance use during pregnancy did not influence levels of serum beta2-microglobulin significantly.
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BACKGROUND: Cheilitis is a common problem, the cause of which is often obscure. OBJECTIVE: Data on 75 cases of recalcitrant cheilitis were analyzed. These had been referred to a tertiary care center. METHODS: Each of the 75 patients had undergone a detailed history, physical examination, and patch tests. RESULTS: Of the patients, 53 were female (67%), and the age range was 9 to 79 years. Of the cases, 36% included irritant contact dermatitis (ICD), 25% included allergic contact dermatitis (ACD), 19% were attributed to atopic eczema, and in 9% the dermatitis was of unknown cause. Nine percent were noneczematous. The materials causing ACD were medicaments applied to the lips, lipstick ingredients, sunscreen agents, toothpaste ingredients, colophony in dental floss and toothpicks, nail varnish, cosmetics, and nickel in the mouthpiece of a flute. CONCLUSION: The most common cause of cheilitis was irritation, frequently caused by liplicking. About one quarter was caused by ACD. Medicaments, lipsticks, sunscreens, and toothpaste were the most common allergens. Atopic eczema is a commonly overlooked cause of cheilitis. However, there is a troublesome group of patients, 9% in this series, who are often severely affected, but the cause of their cheilitis remains obscure.
We have studied the actions of helper T lymphocyte-1 and -2 (Th1 and Th2) cells in an acute model of eosinophilic airway inflammation by infusing chicken ovalbumin-specific (OVA-specific) Th1 cells, Th2 cells, or both into unsensitized mice and challenging the mice with an OVA aerosol. OVA challenge after infusion of Th1 cells alone resulted in airway inflammation with lymphocytes and monocytes. Challenge after the infusion of Th2 cells alone resulted in minimal inflammation. In contrast, when Th1 and Th2 cells were transferred together, they cooperated to promote a robust eosinophil-predominant inflammatory response. Th1 cells alone were readily recruited to the airways after challenge, but in the absence of Th1 cells, Th2 cells did not accumulate in the airways. When transferred together, both Th1 and Th2 cells, as well as endogenous eosinophils, were effectively recruited. This recruitment was correlated with increased VCAM-1 expression in the medium- and large-sized vessels of the lung and could be inhibited by treating the mice with neutralizing antibodies to TNF-alpha or VCAM-1. These data indicate that Th2 cells require signals in addition to antigen for their effective recruitment to the airways. Th1 cells can provide these signals.
Ascites and serum of patients with ovarian carcinoma contain a soluble form of urokinase-type plasminogen activator receptor (uPAR). We now report that pro-uPA-Sepharose-purified uPAR from ascites of patients with ovarian carcinoma is the full-length molecule missing the glycosyl-phosphatidylinositol anchor, as determined by its amino acid composition. We next examined the significance of determining serum soluble uPAR (suPAR) levels in ovarian cancer patients using a specific ELISA and compared the results with serum concentrations of CA-125, an established diagnostic marker. Serum from pre- and postoperative ovarian cancer patients was assayed for suPAR and CA-125. The majority of the patients with ovarian cancer had enhanced preoperative serum levels of suPAR compared with healthy controls, but suPAR concentrations decreased after operation. Although uPAR was associated with most ovarian carcinomas, it appeared to be a less specific indicator for ovarian cancer than CA-125. On the other hand, suPAR was more specific for other types of solid tumors. Moreover, we have observed some cases of ovarian cancer that showed increase of suPAR but not of CA-125. The prognostic significance of serum suPAR assay for survival of ovarian carcinoma patients was evaluated using Cox's proportional hazards analysis. Our preliminary data show that high preoperative levels of suPAR were associated with worse survival of the patients, whereas CA-125 had no prognostic implications. This is the first report evaluating the assay of serum suPAR levels in ovarian cancer and analyzing its value as a tumor or prognostic marker.
Psychological performance tests have been used since the mid-1960s in occupational and environmental health toxicology. The interpretation of significantly different test scores in neurobehavioural studies is not straightforward in the regulation of chemicals. This paper sets out some issues which emerged from discussions at an international workshop, organised by the United Kingdom Health and Safety Executive (HSE), to discuss differences in interpretation of human neurobehavioural test data in regulatory risk assessments. The difficulties encountered by regulators confronted with neurobehavioural studies seem to be twofold; some studies lack scientific rigor; other studies, although scientifically sound, are problematic because it is not clear what interpretation to place on the results. Issues relating to each of these points are discussed. Next, scenarios within which to consider the outcomes of neurobehavioural studies are presented. Finally, conclusions and recommendations for further work are put forward.
The human genes encoding the "ovalbumin" subgroup of closely related serine proteinase inhibitors (serpins) are located at 18q21.3 and 6p25. Those at 6p25 include proteinase inhibitor 6 (PI-6; gene symbol PI6), proteinase inhibitor 9 (PI-9; gene symbol PI9) and monocyte neutrophil elastase inhibitor (M/NEI; gene symbol ELANH2). Here we describe the fine mapping of these genes to a 200-kb region of chromosome 6 that includes the markers WI-8835 and D6S1338, and the establishment of the gene order: tel-PI6-PI9-ELANH2-cen. PI6 and ELANH2 are transcribed towards the telomere, and structural analysis shows that PI6 and PI9 are organized identically, having seven exons and six introns. PI6 and PI9 are almost identical in structure to the ovalbumin serpin genes at 18q21.3. The 18q21.3 genes have an extra exon and intron, otherwise all the other exon/intron boundaries are conserved between the two groups. These results represent the first detailed map of the chromosome 6 serpin gene cluster, and demonstrate that although they are very closely related, the 6p25 and 18q21-->q23 ovalbumin serpin genes form two structurally distinct groups. These findings do not support a previously proposed model for evolution of the clusters which invoked an inter-chromosomal duplication of the entire 6p25 group to 18q21.3.
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Many clinical trials groups now routinely consider including Quality of Life (QoL) assessment in trials. Indeed, several have policies stating that QoL should be considered as a potential endpoint in all new trials and that if it is not to be evaluated the applicants should justify not doing so. However, inclusion of QoL in clinical trials presents a number of difficult organisational issues, and serious problems in compliance have frequently been reported. Thus, in multicentre clinical trials many of the expected QoL questionnaires fail to be successfully completed and returned, although a few groups have claimed high success rates. However, it is well recognised that if questionnaires are missing, there may be bias in the interpretation of trial results, and the estimates of treatment differences and the overall level of QoL may be inaccurate and misleading. Hence it is important to seek methods of improving compliance, at the level of both the participating institution and the patient. We describe a number of methods for addressing these issues, which we suggest should be considered by all those writing clinical trial protocols involving QoL assessment. These are based upon over a decade of experience with assessing QoL in Medical Research Council (MRC) cancer clinical trials. In particular, we provide a checklist for points that should be covered in protocols. Examples are given from a range of current MRC Cancer Trials Office protocols, which it is proposed might act as templates when writing new protocols.
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