The ultimate challenge of cloacal exstrophy.

Purpose: Our review addresses the various system abnormalities associated with cloacal exstrophy and revisits the question of gender assignment. Gender assignment decisions and psychological aspects of gender issues have become the "ultimate challenge." Exploration of gender identity, gender role behavior and sexual orientation has just begun.

Mechanisms of hormonal carcinogenesis in the p53+/- hemizygous knockout mouse: studies with diethylstilbestrol.

The 2-year rodent bioassay has long had a central role in determining whether a compound is carcinogenic. It has recently been suggested that the use of 6-month studies in transgenic mice could reduce costs and animal numbers, without impairing the validity of cancer risk assessment. The p53+/- hemizygous knockout mouse model is phenotypically stable and develops tumors during the 6-month study period only in response to chemical and physical stimuli, showing a high concordance with genotoxic rodent carcinogens.

Non-specialist management of acute renal failure.

In a 12-month prospective study of the initial management of patients with acute renal failure (ARF) in East Kent (population 593 000), we evaluated the initial management of ARF and assessed what proportion of ARF may have been preventable. Patients were seen and assessed on a daily basis, and were followed until discharge from hospital or death; survivors were subsequently followed for 3 years. Overall, 288 patients developed ARF (486 per million population/year).

Tamoxifen and the female genital tract.

Ugwumadu AHN, Carmichael P, Neven P. Tamoxifen and the female genital tract. Int J Gynecol Cancer 1998; 8: 6-15.

An appraisal of telomerase activity in benign prostatic hyperplasia.

Background: Prostate cancer is one of the commonest neoplasms in elderly males in developed countries. It is not clear which individuals are at high risk of developing aggressive adenocarcinoma of the prostate. Biomarkers are therefore urgently needed to identify such individuals.

Modulation of endometrial transforming growth factor beta (TGFbeta) by tamoxifen.

Transforming growth factor beta (TGFbeta) immunoreactivity was determined in endometria from non-drug-therapy and tamoxifen-treated patients. Sections were scored for pathology and quantity image analysis performed to determine levels of glandular- or fibrosis-associated TGFbeta1. Tamoxifen-treated patients displayed greater levels of endometrial dysplasia and glandular hyperplasia, in addition to a statistically significant (P<0.

Assessment of quality of life in a single centre dialysis population using the KDQOL-SF questionnaire.

Health-related quality of life (HRQOL) is a valid marker of outcome for chronic dialysis therapy. A wide range of questionnaires are now available which assess different aspects of an individual's health. Appreciation of those factors that contribute to explaining HRQOL items remains poorly defined.

Atherosclerotic renal artery stenosis: from diagnosis to treatment.

Renovascular hypertension represents a form of correctable hypertension and preventable renal failure. Such patients need to be identified early so that specific therapy can be instigated. Patient identification requires a high index of suspicion in patients with certain clinical features.

N-demethylation accompanies alpha-hydroxylation in the metabolic activation of tamoxifen in rat liver cells.

Previous work has shown that a major route of activation of tamoxifen to DNA-binding products in rat liver cells is via alpha-hydroxylation leading to modification of the N(2)-position of guanine in DNA and to a lesser extent the N(6)-position of adenine. Improved resolution by HPLC has now identified two major adducts in rat liver DNA, one of them the aforementioned tamoxifen-N(2)-guanine adduct and the other the equivalent adduct in which the tamoxifen moiety has lost a methyl group. Treatment of rats or rat hepatocytes with N-desmethyltamoxifen gave rise to the second adduct, whereas treatment with tamoxifen or alpha-hydroxytamoxifen gave rise to both.

Biased T-cell receptor usage is associated with allelic variation in the MHC class II peptide binding groove.

A comprehensive analysis was carried out of the tri-molecular complex of peptide, major histocompatibility class II molecule, and T-cell receptor (TcR) involved in the recognition of the promiscuous HA (306-318) peptide, restricted by one of two closely related HLA-DR alleles, HLA-DRB1*0101 and HLA-DRB1*0103. These two DR molecules differ by only three amino acids at positions 67, 70, and 71, in the third variable region of the DRB1 chain. None of the HA (306-318)-specific T-cell clones restricted by these two DR molecules tolerated amino acid substitution at the peptide-binding position 71, despite the fact that the substitution did not interfere with peptide binding.

Lack of evidence from HPLC 32P-post-labelling for tamoxifen-DNA adducts in the human endometrium.

Tamoxifen is associated with an increased incidence of endometrial cancer in women. It is also a potent carcinogen in rat liver and forms covalent DNA adducts in this tissue. A previous study exploring DNA adducts in human endometria, utilizing thin layer chromatography 32P-postlabelling, found no evidence for adducts in tamoxifen-treated women [Carmichael,P.

DNA adducts in human breast tissue: association with N-acetyltransferase-2 (NAT2) and NAT1 genotypes.

The etiology of human breast cancer is poorly understood, but circumstantial evidence points toward exogenous genotoxins as causative agents; they are believed to exert their carcinogenic action by binding to DNA. Because this binding is often preceded by metabolic activation, it is dependent on the expression and activities of metabolic enzymes of the host. Human mammary tissue samples from 42 women undergoing surgery for breast cancer or reduction mammoplasty were analyzed for DNA adducts by 32P-postlabeling analysis.

Comparison of the formation of 8-hydroxy-2'-deoxyguanosine and single- and double-strand breaks in DNA mediated by fenton reactions.

The formation of 8-hydroxydeoxyguanosine (8-OHdG) and both single- and double-strand breaks in DNA by Fenton-type reactions has been investigated. Salmon sperm DNA was exposed to hydrogen peroxide (50 mM) and one of nine different transition-metal ions (25 microM-1 mM). Modified DNA was isolated and subjected to analysis by liquid chromatography coupled to an electrochemical detection system (LC-ECD), to evaluate the formation of 8-OHdG.

Lipid peroxidation-induced etheno-DNA adducts in the liver of patients with the genetic metal storage disorders Wilson's disease and primary hemochromatosis.

To assess DNA damage caused by lipid peroxidation due to copper and iron storage disorders in the human liver, the formation of the etheno adducts 1,N6-ethenodeoxyadenosine (epsilon dA) and 3,N4-ethenodeoxycytine (epsilon dC) was measured in liver DNA from normal subjects and from patients with Wilson's disease (WD) and primary hemochromatosis. The mean epsilon dA and epsilon dC levels per 10(9) parent nucleotides in normal liver were 19.3 +/- 4.

Interferon-gamma-treated renal tubular epithelial cells induce allospecific tolerance.

Following organ transplantation, tissue parenchymal cells commonly express major histocompatibility complex (MHC) class II molecules as a result of local cytokine release, and thus acquire the capacity to present donor MHC alloantigens to alloreactive CD4+ T cells. The consequences of such a presentation are likely to be relevant in the induction of tolerance to the transplanted tissues, and this has been reported in animal models of transplantation and in humans. In this study, the consequences of antigen presentation by interferon-gamma (IFN-gamma)-treated human renal tubular epithelial cells (RTEC) to resting and activated CD4+ T cells were investigated.

Anergic T cells effect linked suppression.

Although the phenomenon of T cell-mediated suppression is well established, particularly in experimental models of transplantation, the mechanisms involved in this form of immunoregulation remain controversial. We have recently demonstrated, using an in vitro system, that anergic T cells can act as suppressor cells by competing for the membrane of the antigen-presenting cell (APC) and for locally produced interleukin-2. In the experiments described here we have explored the ability of anergic T cells to effect linked suppression in antigen-specific and allospecific responses.

DNA damage in breast epithelial cells: detection by the single-cell gel (comet) assay and induction by human mammary lipid extracts.

The presence of DNA damage in primary cultures of human mammary epithelial cells (HMECs), and the ability of extracts of human mammary lipid to cause such damage, has been investigated. Lipid extracts, prepared by a solid-phase procedure, and HMECs were obtained from breast tissue removed from healthy women (ages 18-50 years) who were resident in the UK and undergoing elective reduction mammoplasties. DNA single strand breaks (SSBs) were detected using the single-cell gel assay (comet assay) with alkaline electrophoresis (pH 12.

Detection of telomerase activity in human prostate: a diagnostic marker for prostatic cancer?

Objective: To assess the role of telomerase activity as a marker for the development of prostate cancer in men with existing benign prostatic hyperplasia (BPH), a known risk factor for prostatic carcinoma.

Materials And Methods: Telomerase activity was assayed, using a highly sensitive polymerase-chain reaction-based assay, in nine biopsies from patients with prostatic cancer, 16 from patients clinically diagnosed with BPH and 11 from patients with no evidence of prostatic disease.

Results: Telomerase activity was detectable in eight of the nine prostate cancer biopsies, in none of the normal prostates and in six of the 16 BPH biopsies.

Allele-specific variation in the degeneracy of major histocompatibility complex (MHC) restriction.

The role of peptides in determining immune responses for both allorecognition and antigen-specific recognition has been clearly documented. The importance of different regions of the major histocompatibility complex (MHC) class II molecule in contributing to recognition has been demonstrated by studies involving site-directed mutagenesis and exon shuffling. These studies have indicated that the N-terminal region of the MHC class II molecule has a role to play in contributing to the T-cell receptor (TCR)-MHC-peptide interaction.

Dissociation of T cell anergy from apoptosis by blockade of Fas/Apo-1 (CD95) signaling.

Induction of anergy and deletion due to apoptosis are two of the mechanisms involved in peripheral tolerance. To clarify the relationship between these two phenomena we have used an in vitro system of T cell Ag presentation. The recognition of Ag displayed by MHC class II-expressing T cells (T-APC) induces partial signals in Ag-specific T cell clones.