The microsomal epoxide hydrolase Tyr113His polymorphism: Association with risk of ovarian cancer

Functional significance has been demonstrated in vitro for the exon 3 T-->C Tyr113His amino acid substitution polymorphism of the microsomal epoxide hydrolase (EPHX) gene. The higher activity or fast TT genotype was previously reported to be associated with an increased risk of ovarian cancer, and this association may reflect enhanced activation of endogenous or exogenous substrates to more reactive and mutagenic derivatives. Components of cigarette smoke are examples of exogenous substrates subject to such bioactivation, and smoking exposure may thus modify the risk associated with the EPHX polymorphism. We examined 545 cases of epithelial ovarian cancer and 287 unaffected controls for this EPHXT-C genetic variant to investigate whether, in the Australian population, the TT genotype was associated with (i) specific ovarian tumor characteristics; (ii) risk of ovarian cancer, overall or for specific subgroups; and (iii) risk of ovarian cancer in smokers specifically. Genotyping was carried out using the Perkin-Elmer ABI Prism 7700 Sequence Detection System for fluorogenic polymerase chain reaction allelic discrimination. Stratification of the ovarian cancer cases according to tumor behavior (low malignant potential or invasive), grade, stage, and p53 immunohistochemical status failed to show any heterogeneity with respect to the genotype defined by the EPHX polymorphism. There was a suggestion of heterogeneity with respect to histologic subtype (P= 0.03), largely due to a decreased frequency of the TT genotype in endometrioid tumors. EPHX genotype distribution did not differ significantly between unaffected controls and ovarian cancer cases (overall, low malignant potential, or invasive) either overall or after stratification by smoking status. However, the TT genotype was associated with a decreased risk of invasive ovarian cancer of the endometrioid subtype specifically (age-adjusted odds ratio = 0.38, 95% confidence interval=0.17-0.87). The results suggest that the proposed EPHX-mediated bioactivation of components of cigarette smoke to mutagenic forms is unlikely to be involved in the etiology of ovarian cancer in general but that a greater rate of EPHX-mediated detoxification may decrease the risk of endometrioid ovarian cancer. (C) 2001 Wiley-Liss, Inc.

Polymorphisms at the glutathione S-transferase GSTM1, GSTT1 and GSTP1 loci: risk of ovarian cancer by histological subtype

The phase II glutathione S-transferases (GSTs) GSTT1, GSTM1 and GSTP1 catalyse glutathione-mediated reduction of exogenous and endogenous electrophiles. These GSTs have broad and overlapping substrate specificities and it has been hypothesized that allelic variants associated with less effective detoxification of potential carcinogens may confer an increased susceptibility to cancer. To assess the role of GST gene variants in ovarian cancer development, we screened 285 epithelial ovarian cancer cases and 299 unaffected controls for the GSTT1 deletion (null) variant, the GSTM1 deletion (null) variant and the GSTP1 codon 104 A-->G Ile-->Val amino acid substitution variant, The frequencies of the GSTT1, GSTM1 and GSTP1 polymorphic variants did not vary with tumour behaviour (low malignant potential or invasive) or p53 immunohistochemical status. There was a suggestion that ovarian cancers of the endometrioid or clear cell histological subtype had a higher frequency of the GSTT1 and GSTM1 deletion genotype than other histological subgroups. The GSTT1, GSTM1 and GSTP1 genotype distributions did not differ significantly between unaffected controls and ovarian cancer cases (overall or invasive cancers only). However, the GSTM1 null genotype was associated with increased risk of endometrioid/clear cell invasive cancer [age-adjusted OR (95% CI) = 2.04 (1.01-4.09), P = 0.05], suggesting that deletion of GSTM1 may increase the risk of ovarian cancer of these histological subtypes specifically. This marginally significant finding will require verification by independent studies.

Status, legitimacy and ingroup bias in the context of an organizational merger

Adopting an intergroup perspective, the research was designed to examine predictors of employee responses to an organizational merger. Data were collected from 120 employees of a newly merged scientific organization. As predicted from social identity theory, the most negative responses to the merger were apparent among the employees of the low status premerger organization. There was also evidence of ingroup bias among both groups of employees involved in the merger—as expected, the bias was most marked on the status-irrelevant dimensions for the employees of the lower status organization, but most marked on the status-relevant dimensions for the employees of the high status organization. Also, in support of social identity theory, the perceived legitimacy of the basis for the status differentiation between the groups was associated with more positive responses to the merger among employees of the low status premerger organization, but with poorer responses among employees of the high status premerger organization. There was consistent evidence that the status by legitimacy interaction was mediated through the extent to which employees of the newly merged organization perceived a common ingroup identity

The status of the Diplosentidae (Acanthocephala : Palaeacanthocephala) and a new family of acanthocephalans from Australian wrasses (Pisces : Labridae)

The status and composition of the Diplosentidae Tubangui et Masilungan, 1937 are reviewed. The type species of the type genus, Diplosentis amphacanthi Tubangui et Masilungan, 1937 from Siganus canaliculatus (Park, 1797) in the Philippines, is concluded to have been described inaccurately,in supposedly possessing, only two cement glands and lemnisci enclosed in a membranous sac. The species is almost certainly very close to species of Neorhadinorhynchus yamaguti, 1939 and Sclerocollum Schmidt of Paperna, 1978 which have also been reported from siganids from the tropical Indo-Pacific. Species of these genera have four cement glands and unexceptional lemnisci. As a result, Diplosentis Tubangui et Masilungan, 1937 is best considered to have affinities with the Cavisomidae Meyer, 1932. The Cavisomidae has priority over the Diplosentidae; thus the Diplosentidae becomes a synonym of the Cavisomidae. Neorhadinorhynchus and Sclerocollum are considered synonyms of Diplosentis. The affinities of the other species and genera formerly included in the Diplosentidae (other species of Diplosentis, Allorhadinorhynchus Yamaguti, 1959, Amapacanthus Salgado-Maldonado et Santos, 2000, Pararhadinorhynchus Johnston et Edmonds, 1947, Golvanorhynchus Noronha, do Fabio et Pinto, 1978 and Slendrorhynchus Amin et Soy, 1996) are discussed. It is concluded that all but Pararhadinorhynchus, two species of Diplosentis and Amapacanthus can be accommodated elsewhere satisfactorily. A new family, Transvenidae, is proposed for a small group of acanthocephalans that genuinely possess only two cement glands. Transvena annulospinosa gen. n., sp. n. is described from the labrids Anampses neoguinaicus Bleeker, 1878 (type host), A. geographicus Valenciennes, 1840, A. caeruleopunctatus Ruppell, 1829, Hemigymnus fasciatus (Bloch, 1792), and H. melapterus (Bloch, 1791) from the Great Barrier Reef, Queensland, Australia. Transvena gen. n. is distinguished from all other acanthocephalan genera by having a combination of a single ring of small spines on its trunk near or at the junction between the neck and trunk, two cement glands, a double-walled proboscis receptacle and hooks which decrease in length from the apex to the base of the proboscis. A second new genus within the Transvenidae, Trajectura, is proposed for T. perinsolens sp. n. from Anampses neoguinaicus, also from the Great Barrier Reef. Trajectura gen. n. is distinguished by the possession of only two cement glands and an anterior conical projection (function unknown) on the females. Diplosentis ikedai Machida, 1992 shares these characters and is recombined as Trajectura ikedai comb. n. Pararhadinorhynchus is transferred to the Transvenidae and Diplosentis manteri Gupta et Fatma, 1979 is recombined as Pararhadinorhynchus manteri comb. n.

Adolescents' perceptions of social status: Development and evaluation of a new indicator

Objective. Eliminating health disparities, including those that are a result of socioeconomic status (SES), is one of the overarching goals of Healthy People 2010. This article reports on the development of a new, adolescent-specific measure of subjective social status (SSS) and on initial exploratory analyses of the relationship of SSS to adolescents' physical and psychological health. Methods. A cross-sectional study of 10 843 adolescents and a subsample of 166 paired adolescent/mother dyads who participated in the Growing Up Today Study was conducted. The newly developed MacArthur Scale of Subjective Social Status (10-point scale) was used to measure SSS. Paternal education was the measure of SES. Indicators of psychological and physical health included depressive symptoms and obesity, respectively. Linear regression analyses determined the association of SSS to depressive symptoms, and logistic regression determined the association of SSS to overweight and obesity, controlling for sociodemographic factors and SES. Results. Mean society ladder ranking, a subjective measure of SES, was 7.2 ± 1.3. Mean community ladder ranking, a measure of perceived placement in the school community, was 7.6 ± 1.7. Reliability of the instrument was excellent: the intraclass correlation coefficient was 0.73 for the society ladder and 0.79 for the community ladder. Adolescents had higher society ladder rankings than their mothers (µteen = 7.2 ± 1.3 vs µmom = 6.8 ± 1.2; P = .002). Older adolescents' perceptions of familial placement in society were more closely correlated with maternal subjective perceptions of placement than those of younger adolescents (Spearman's rhoteens

Standardizing assessment of adverse effects in rheumatology clinical trials. Status of OMERACT Toxicity Working Group March 2000: Towards a common understanding of comparative toxicity/safety profiles for antirheumatic therapies

This paper describes the background and current status of an OMERACT facilitated effort to improve the consistency of adverse event reporting in rheumatology clinical trials, The overall goal is the development of an adverse event assessment tool that would provide a basis for use of common terminology and improve the consistency of reporting severity of side effects within rheumatology clinical trials and during postmarketing surveillance. The resulting Rheumatology Common Toxicity Criteria Index encompassed the following organ systems: allergic/immunologic, cardiac, ENT, gastrointestinal, musculoskeletal, neuropsychiatric, ophthalmologic, pulmonary and skin/integument. Before this tool is widely accepted, its validity, consistency, and feasibility need to be assessed in clinical trials.

Living with osteoarthritis: Patient expenditures, health status, and social impact

Objective. To determine out-of-pocket expenditures related to osteoarthritis (OA) and to explore whether demographic details, health status scores (Medical Outcomes Study 36-item Short Form [SF-36] and Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC]), or perception of social effect were expenditure determinants. Methods. A prospective cohort study of community-dwelling subjects with OA completed 4 consecutive 3-month cost diaries. In addition, subjects completed the SF-36 and WOMAC at baseline and at 12 months. Social impact at baseline was collected. Four groups categorized by age and sex were compared. Patients undergoing joint replacement were excluded. Results. Differences in health status were defined more by age than by sex, especially for physical function. The costs to the patients were high, particularly for women, who spent more on medications and special equipment. Women also reported receiving more assistance from family and friends. Higher disease-related expenditures were associated with greater pain levels, poorer social function and mental health, and longer duration of disease. Significant independent predictors of total patient expenditures related to OA were being female and having joint stiffness. Conclusion. Despite having heavily subsidized health care and access to the Pharmaceutical Benefits Scheme, out-of-pocket costs for patients with OA in Australia are considerable. Higher expenditures for patients with OA are related to more advanced disease, especially for women.

Transactivation-deficient p73 alpha (p73 Delta exon2) inhibits apoptosis and competes with p53

p73 has recently been identified as a structural and functional homolog of the tumor suppressor protein p53. Overexpression of p53 activates transcription of p53 effector genes, causes growth inhibition and induced apoptosis. We describe here the effects of a tumor-derived truncated transcript of p73 alpha (p73 Delta exon2) on p53 function and on cell death. This transcript, which lacks the acidic N-terminus corresponding to the transactivation domain of p53, was initially detected in a neuroblastoma cell line. Overexpression of p73 Delta exon2 partially protects lymphoblastoid cells against apoptosis induced by anti-Fas antibody or cisplatin. By cotransfecting p73 Delta exon2 with wild-type p53 in the p53 null line Saos 2, we found that this truncated transcript reduces the ability of wild-type p53 to promote apoptosis. This anti-apoptotic effect was also observed when p73 Delta exon2 was co-transfected with full-length p73 (p73 alpha). This was further substantiated by suppression of p53 transactivation of the effector gene p21-Waf1 in p73 Delta exon2 transfected cells and by inhibition of expression of a reporter gene under the control of the p53 promoter. Thus, this truncated form of p73 can act as a dominant-negative agent towards transactivation by p53 and p73 alpha, highlighting the potential implications of these findings for p53 signaling pathway. Furthermore, we demonstrate the existence of a p73 Delta exon2 transcript in a very significant proportion (46%) of breast cancer cell lines. However, a large spectrum of normal and malignant tissues need to be surveyed to determine whether this transdominant p73 variant occurs in a tumor-specific manner.

The plant isoflavenoid genistein activates p53 and Chk2 in an ATM-dependent manner

Genistein is an isoflavenoid that is abundant in soy beans. Genistein has been reported to have a wide range of biological activities and to play a role in the diminished incidence of breast cancer in populations that consume a soy-rich diet. Genistein was originally identified as an inhibitor of tyrosine kinases; however, it also inhibits topoisomerase II by stabilizing the covalent DNA cleavage complex, an event predicted to cause DNA damage. The topoisomerase II inhibitor etoposide acts in a similar manner. Here we show that genistein induces the up-regulation of p53 protein, phosphorylation of p53 at serine 15, activation of the sequence-specific DNA binding properties of p53, and phosphorylation of the hCds1/Chk2 protein kinase at threonine 68. Phosphorylation and activation of p53 and phosphorylation of Chk2 were not observed in ATM-deficient cells. In contrast, the topoisomerase II inhibitor etoposide induced phosphorylation of p53 and Chk2 in ATM-positive and ATM-deficient cells. In addition, genistein-treated ATM-deficient cells were significantly more susceptible to genistein-induced killing than were ATM-positive cells. Together our data suggest that ATM is required for activation of a DNA damage-induced pathway that activates p53 and Chk2 in response to genistein.

Urban birth and migrant status as risk factors for psychosis: An Australian case-control study

Background Urban birth and migrant status have been identified as risk factors for psychosis in North American and European studies. The aim of this study was to explore these variables in an Australian case-control study. Method Country of birth of subjects and their parents, and place of birth of Australian-born subjects, were examined in individuals with psychosis drawn from a prevalence study (n = 310) and well controls recruited from the same catchment area (n = 303). Results Migrant status was associated with a significantly decreased odds of having a psychotic disorder. For those born in Australia, neither migrant status of parents nor urban birth was associated with having a psychotic disorder. Conclusions The lack of effect for urban birth and second-generation migrant status may help generate candidate environmental risk factors that operate in Europe but not in Australia.

Rehabilitation outcomes for brain injured patients in Australia: functional status, length of stay and discharge destination

This study describes the rehabilitation length of stay (LOS), discharge destination and discharge functional status of 149 patients admitted with traumatic brain injury (TBI) to an Australian hospital over a 5-year period. Hospital charts of patients admitted between 1993-1998 were reviewed. Average LOS over the 5-year time period was 61.8 days and only decreased nominally over this time. Longer LOS was predicted by lower admission motor FIM scores and presence of comorbidities. Mean admission and discharge motor FIM scores were 58 and 79, which represented a gain of 21 points. Higher discharge motor FIM scores were predicted by higher admission motor FIM scores and younger age. FIM gain was predicted by cognitive status and age. Most patients, 88%, were discharged back to the community, with 30% changing their living setting or situation. Changing living status was predicted by living alone and having poorer functional status on admission.

Ethical practice for biotechnology or defending the status quo

The Queensland, Australia government recently released its Code of Ethical Practice for Biotechnology in Queensland. Hindmarsh and Hulsman question whether this code will serve to help or hinder biotechnology in Queensland and the rest of the world.