A randomized controlled trial of a decision aid for women at increased risk of ovarian cancer.

PURPOSE: To carry out a randomized controlled trial of a decision aid for women at increased risk of developing ovarian cancer to facilitate decision making regarding risk management options. METHODS: This randomized trial, conducted through 6 familial cancer centers, compared the efficacy of tailored decision aid to that of a general educational pamphlet in preparing women for decision making. PARTICIPANTS: 131 women with a family history of breast and/or ovarian cancer or of hereditary nonpolyposis colorectal cancer. OUTCOME MEASURES: Decisional conflict, knowledge about ovarian cancer risk management options, and psychological adjustment were reassessed at 3 time points. RESULTS: Compared to those who received the pamphlet (control), women who received the decision aid (intervention) were significantly more likely to report a high degree of acceptability of the educational material at both follow-up assessment time points. Findings indicate neither group experienced significant increases in psychological distress at either follow-up assessment time points relative to baseline. Two weeks postintervention, the intervention group demonstrated a significant decrease in decisional conflict compared to the control group (t = 2.4, P < 0.025) and a trend for a greater increase in knowledge about risk management options (t = 2.1, P = 0.037). No significant differences were found 6 months postintervention. CONCLUSION: This form of educational material is successful in increasing knowledge about risk management options and in reducing decisional conflict in the shorter term. The decision aid is an effective and acceptable strategy for patient education to facilitate an inclusive and informed decision-making process about managing ovarian cancer risk.

Knowledge of risk management strategies, and information and risk management preferences of women at increased risk for ovarian cancer.

Little research is available on the level of knowledge about ovarian cancer risk management options in women at increased risk for this disease. The study objectives were to evaluate this together with the information and ovarian cancer risk management preferences of high-risk women. One hundred and twenty-nine women were assessed after their attendance at one of six familial cancer clinics in relation to knowledge of surveillance and/or preventative strategies for reduction of ovarian cancer risk, preferences for particular strategies, and information preferences. Screening was selected by 57 (44%) women as the preferred risk management option. One hundred and five women (82%) indicated a wish for as much information as possible about ovarian cancer, including both good and bad outcomes and 114 (89%) reported a preference for sharing treatment decisions with their health professional. Participants' knowledge about ovarian cancer risk management options was significantly associated with educational levels (Z = -3.2, p=0.001) and whether or not ovarian cancer was included in the family history (Z = -2.3, p = 0.018). Findings from this present study indicate that women at increased risk of ovarian cancer who attend familial cancer clinics want as much information as possible about this disease and they want to be involved in the decision-making process. Women who reported a lower level of education (no post-school qualifications) may be most likely to benefit from additional educational strategies designed to supplement genetic counseling to improve their knowledge levels.

A decision aid for women at increased risk for ovarian cancer.

This paper reviews changes that have occurred within and without the medical profession that have fostered an increasing demand for decision aids as adjuncts to practitioners' counseling to prepare patients for decision making. In the absence of data on the efficacy of ovarian cancer screening and prophylactic strategies, decisions about optimal care are difficult for both women and their doctors. Because surveillance and preventive options are an area of great uncertainty, a decision aid has been developed specifically aimed at facilitating decisions involving ovarian cancer risk management options. This was achieved by reviewing and integrating the available literature on models of medical decision making, patient preferences for information and involvement in decision making, the utility of decision aids, and management options for ovarian cancer risk. Findings indicate that patients wish to be informed participants in the decision-making process and that decision aids are an acceptable and effective method of providing quality information in a format that facilitates an inclusive model of shared decision making. A decision aid designed for women at increased risk of ovarian cancer that facilitates informed decision making may be a valuable addition to patient support. A randomized controlled trial of this type of educational material will provide timely and much needed evidence on its acceptability and efficacy.

Psychological impact of prophylactic oophorectomy in women at increased risk of developing ovarian cancer: a prospective study.

OBJECTIVES: The objectives of this study were twofold: to prospectively assess whether expressed intention to undergo prophylactic oophorectomy translated into uptake and to evaluate the psychological impact of the procedure in a sample of unaffected women with a strong family history of breast/ovarian cancer. METHODS: Ninety-five women, initially assessed at the time of their first attendance at a familial cancer clinic, were followed-up 3 years later. A total of 22 women (23.2%) in this study had undergone a prophylactic oophorectomy. Ten women (10.5%) who had undergone a prophylactic oophorectomy during the 3-year follow-up period were compared to 73 women (76.9%) who did not have a prophylactic oophorectomy. Twelve women (12.6%) who had the procedure prior to study entry were also assessed for psychological adjustment and associated information needs. RESULTS: Age emerged as a significant predictor of uptake of prophylactic oophorectomy (chi(2) = 7.13, P = 0.009). Among those who had the procedure after study entry, a significant reduction in ovarian cancer anxiety was observed (Z = -2.19, P = 0.029). Of the 22 women who had undergone a prophylactic oophorectomy in total (both before and after study entry), 86.4% reported a high degree of satisfaction with their decision to have the procedure. A low level of screening uptake was also reported by women who did not have a prophylactic oophorectomy but for whom screening was recommended. CONCLUSION: Findings demonstrate that prophylactic oophorectomy is successful in reducing anxiety about ovarian cancer. The results also suggest that women perceive that the benefit of anxiety reduction may outweigh the potentially adverse effects of the procedure, given that women expressed a high level of satisfaction with their decision.

Airway and respiratory tissue mechanics in normal infants.

Low-frequency respiratory impedance (Zrs) was measured by applying a forcing signal, between 0.5 and 21 Hz at a transrespiratory pressure of 20 cm H(2)O, in a cross-sectional study of 37 normal infants. A model containing an airway resistance (Raw) and inertance (Iaw) and a tissue damping (G) and elastance (H) was fitted to the individual Zrs. Forced expiratory volume in 0.5 second (FEV(0.5)) was determined using the raised volume rapid thoracic compression technique. Multivariate regression analysis was used to analyze the relationships between the lung function parameters and length. Both airway and tissue parameters showed a decreasing quadratic relationship with increasing length. FEV(0.5) showed an increasing cubic relationship with length. A family history of asthma was found to have a negative effect on Raw, H, and FEV(0.5).

Psychological impact of prophylactic oophorectomy in women at increased risk for ovarian cancer.

Women with a family history consistent with a hereditary breast/ovarian cancer syndrome are at significantly increased risk for ovarian cancer. Prophylactic oophorectomy is an option for high-risk women. This study explores the psychosexual impact of prophylactic oophorectomy. A qualitative methodology was selected as most appropriate as no previous research has examined this issue. In-depth interviews were conducted with fourteen women, between 4 months and 7 years after prophylactic oophorectomy. Of these, six were pre- and eight were postmenopausal at the time of oophorectomy. Even though individual differences were observed, a majority view was expressed on several issues. All but one participant reported being satisfied with their decision to undergo oophorectomy. Women emphasised that the procedure had decreased their anxiety about developing ovarian cancer. Postmenopausal women reported no negative impact on their libido. Amongst premenopausal women all but one commenced hormone replacement therapy (HRT) following surgery and, in these women, HRT appeared to mitigate the sexual impact of the procedure. Premenopausal women reported unmet information needs both before and after the procedure, including the effects of surgical menopause and the link between HRT and breast cancer. This exploratory study suggests that prophylactic oophorectomy is a psychologically acceptable risk reduction strategy in high-risk women.

Genome-wide linkage analysis using genetic variance components of alcohol dependency-associated censored and continuous traits.

We used variance-components analysis to investigate the additive genetic effects regulating some of the phenotypes included in the GAW11 data set. Variance-components models were fitted using Gibbs sampling methods in BUGS v 0.6. Linkage analyses for both multivariate normal (MvN) traits and right censored survival times (age-of-onset) were based upon standard Haseman-Elston identity-by-descent sib-pair methods applied directly to traits showing evidence of substantial additive genetic determination (residualized for any important covariates) and to the estimated sigma A2 residuals for those traits. Harm avoidance behavior (TPQ subscale) showed evidence of linkage to markers on chromosomes 1, 13, and 18. P300 levels at the Fp1 site showed evidence of linkage to markers on chromosomes 2, 3, 9, 12, 17, 19, and 20. Platelet monoamine oxidase B (MAOB) levels showed evidence of linkage to D4S1651. The age-of-onset for ALDX1 in those over 30 years old showed evidence of linkage to markers on chromosomes 1, 6, 14, and 15. The age-of-onset for the more strictly defined ALDX2 in those over 30 years old showed evidence of linkage to markers on chromosomes 7 and 14. These results are consistent with a complex, multifactorial susceptibility to alcohol dependency.

Respiratory mechanics during sevoflurane anesthesia in children with and without asthma.

UNLABELLED: We studied lung function in children with and without asthma receiving anesthesia with sevoflurane. Fifty-two children had anesthesia induced with sevoflurane (up to 8%) in a mixture of 50% nitrous oxide in oxygen and then maintained at 3% with children breathing spontaneously via face mask and Jackson-Rees modification of the T-piece. Airway opening pressure and flow were then measured. After insertion of an oral endotracheal tube under 5% sevoflurane, measurements were repeated at 3%, as well as after increasing to 4.2%. Respiratory system resistance (Rrs) and compliance during expiration were calculated using multilinear regression analysis of airway opening pressure and flow, assuming a single-compartment model. Data from 44 children were analyzed (22 asthmatics and 22 normal children). The two groups were comparable with respect to age, weight, ventilation variables, and baseline respiratory mechanics. Intubation was associated with a significant increase in Rrs in asthmatics (17% +/- 49%), whereas in normal children, Rrs slightly decreased (-4% +/- 39%). At 4.2%, Rrs decreased slightly in both groups with almost no change in compliance system resistance. We concluded that in children with mild to moderate asthma, endotracheal intubation during sevoflurane anesthesia was associated with increase in Rrs that was not seen in nonasthmatic children. IMPLICATIONS: Tracheal intubation using sevoflurane as sole anesthetic is possible and its frequency is increasing. When comparing children with and without asthma, tracheal intubation under sevoflurane was associated with an increase in respiratory system resistance in asthmatic children. However, no apparent clinical adverse event was observed.

Polymorphisms in the beta2-adrenoreceptor gene are associated with decreased airway responsiveness.

BACKGROUND: There are a number of candidate genes thought to play a role in the development of asthma. Polymorphisms at amino acid positions 16 (arginine to glycine) and 27 (glutamine to glutamic acid) of the beta2-adrenoreceptor (B2AR) gene are known to be functionally relevant and have been associated with more severe forms of asthma, nocturnal asthma and decreased airway responsiveness in asthmatic subjects. OBJECTIVE: To determine if these polymorphisms contribute to the development of asthma by investigating the associations between the polymorphisms at amino acid positions 16 and 27 of the B2AR gene and asthma-related parameters in a large, phenotypically well-characterized population which was unselected for asthma. METHODS: Subjects (n = 332) were characterized using physiological assessments, immuno-logical data and information obtained from questionnaire. PCR was used to generate a 229 base pair fragment spanning the mutations of interest. Genotype was determined using allele-specific oligonucleotide hybridization and confirmed in 10% of the samples by direct sequencing. Multivariate analysis of the association between genotype and phenotype was then undertaken. RESULTS: Homozygotes for Glu27 were significantly less responsive to histamine than Gln27 homozygotes. In addition, Arg16 homozygotes were more likely to 'wheeze during a cold', in comparison with Gly16 homozygotes. However, there was no association between either polymorphism and physician-diagnosed asthma, eczema, skin reactivity to common allergens or total and specific serum IgE levels. The two polymorphisms were found to be in significant linkage disequilibrium. CONCLUSION: The polymorphism at position 27 was associated with decreased airway responsiveness in the study population and the polymorphism at position 16 was associated with increased wheeze during respiratory infection, but neither was associated with physician-diagnosed asthma or any of the other variables considered.

Regulation of T-helper cell responses to inhalant allergen during early childhood.

BACKGROUND: Recent evidence suggests that preschool children manifest patterns of allergen-specific skin prick test (SPT) reactivity and in vitro T-cell cytokine production which are similar to that of either atopic or nonatopic adults. However, published studies on this age group involve small sample sizes and a restricted number of cytokines, usually in response to polyclonal stimuli. OBJECTIVE: To elucidate the relationship between in vivo and in vitro immune responses to a major inhalant allergen house dust mite (HDM) in preschoolers. METHODS: Peripheral blood mononuclear cells (PBMCs) from matched groups of HDM-SPT+ and SPT- 6-year-olds (n = 30 and 29, respectively) tested for PBMC responses to HDM, and cytokine production measured at both the protein and mRNA levels. Immunoglobulin (Ig) E and IgG subclass antibody titres were determined in serum. Interrelationships between in vitro and in vivo HDM responses were examined via multivariate analyses. RESULTS: SPT reactivity to HDM was associated with in vitro production by putative T cells of interleukin (IL) -4, IL-5, IL-9, IL-10, IL-13 and low level IFNgamma, and with production in vivo of IgE and (all) IgG subclass antibodies; HDM responses in the SPT- group were restricted mainly to IL-10 and IFNgamma and very low levels of IL-4; IL-6 production from non-T-cell sources was common. The cytokine most associated with positive SPT responses was IL-9; SPT weal diameter correlated positively with IL-4, IL-5 and IL-13 and negatively with IL-10. CONCLUSION: Detailed analysis of cytokine responses in this very young age group have the potential to uncover subtle relationships between in vivo and in vitro allergen reactivity which may be less clear in adults, in whom T-cell response patterns are modified via chronic stimulation. The present findings which suggest potentially important roles for IL-9 and IL-10 in the early phase of allergic disease, may be one such example.

Genetic variance components analysis for binary phenotypes using generalized linear mixed models (GLMMs) and Gibbs sampling.

The common complex diseases such as asthma are an important focus of genetic research, and studies based on large numbers of simple pedigrees ascertained from population-based sampling frames are becoming commonplace. Many of the genetic and environmental factors causing these diseases are unknown and there is often a strong residual covariance between relatives even after all known determinants are taken into account. This must be modelled correctly whether scientific interest is focused on fixed effects, as in an association analysis, or on the covariances themselves. Analysis is straightforward for multivariate Normal phenotypes, but difficulties arise with other types of trait. Generalized linear mixed models (GLMMs) offer a potentially unifying approach to analysis for many classes of phenotype including multivariate Normal traits, binary traits, and censored survival times. Markov Chain Monte Carlo methods, including Gibbs sampling, provide a convenient framework within which such models may be fitted. In this paper, Bayesian inference Using Gibbs Sampling (a generic Gibbs sampler; BUGS) is used to fit GLMMs for multivariate Normal and binary phenotypes in nuclear families. BUGS is easy to use and readily available. We motivate a suitable model structure for Normal phenotypes and show how the model extends to binary traits. We discuss parameter interpretation and statistical inference and show how to circumvent a number of important theoretical and practical problems that we encountered. Using simulated data we show that model parameters seem consistent and appear unbiased in smaller data sets. We illustrate our methods using data from an ongoing cohort study.

PTK, the chloroplast RNA polymerase-associated protein kinase from mustard (Sinapis alba), mediates redox control of plastid in vitro transcription.

The major RNA polymerase from mustard chloroplasts is a multi-subunit enzyme consisting of core components and associated factors. Among the latter is a heterotrimeric factor named PTK (plastid transcription kinase) because of its serine/threonine-type protein kinase activity. PTK activity itself depends on its phosphorylation state. In addition, we show that it responds to glutathione but not to other redox-reactive reagents that were tested, and both glutathione and phosphorylation act antagonistically. Using a homologous in vitro system, we find that PTK selectively phosphorylates subunit(s) of plastid RNA polymerase and is involved in determining the level of faithful transcription from the chloroplast psbA promoter. Together, these results establish a role for phosphorylation and redox state in the regulation of plastid gene expression.

Association of polymorphisms in the beta2-adrenoreceptor gene with higher levels of parasitic infection.

The diminishing incidence of parasitic infection in westernised societies has been suggested to result in an increased prevalance of asthma. Asthma is a polygenic disease and genome screens have shown that genes on chromosome 5q31-33 are strongly linked to the disease. The gene for the beta2-adrenoreceptor is located in this region and two polymorphisms have been identified that result in amino acid changes at positions 16 (ArgGly) and 27 (GlnGlu). To determine whether these polymorphisms influence asthma and parasitic infection, a genotype/phenotype study has been performed on a cohort of 126 children from Coche Island in Venezuela. There is a high incidence of asthma on the island and intestinal helminthiasis is endemic. Genotyping for both polymorphisms was carried out by using the polymerase chain reaction and allele-specific oligonucleotide hybridisation. Genotype frequencies in this cohort were consistent with other studies and both polymorphisms were in significant linkage disequilibrium. Individuals who were homozygous for Arg16 had significantly higher levels of specific IgE to Ascaris lumbricoides (P=0.002), significantly higher A. lumbricoides egg counts (P<0.001) and significantly larger wheal sizes following skin-prick testing with A. lumbricoides allergen (P=0.008). There was no association between either polymorphism and total serum IgE or asthma in this population. A combination of mast cell degranulation and the lung migratory phase of A. lumbricoides larvae may result in bronchoconstriction in infected individuals. These results suggest that the Gly 16 allele confers resistance to high levels of parasitic infection in this population. An alternative explanation for the association is that it may be the result of linkage disequilibrium with other genes in the chromosome 5q31-33 region.

Factors relating to cervical screening in New South Wales, Australia.

The aims of this paper were to describe the geographical variation in Pap smear screening rates, standardised for age and adjusted for rates of hysterectomies and to assess the sociodemographic and health care factors associated with the variation. The data used in the study were the percentage of women who had had Pap smears between the years 1990 and 1992 based on the records of the Australian Health Insurance Commission (HIC). The best predictors of screening extracted from the model were the Index of Economic Resources and the proportion of women within each region who were born in non-English speaking countries.

Transcription factor phosphorylation by a protein kinase associated with chloroplast RNA polymerase from mustard (Sinapis alba).

The chloroplast transcription machinery involves multiple components with both catalytic and regulatory functions. Here we describe a serine-specific protein kinase activity that is associated with the major chloroplast RNA polymerase and phosphorylates sigma-like transcription factors in vitro. The kinase activity can be assigned to a 54 kDa polypeptide of partially purified RNA polymerase (KPC, kinase polymerase complex). This polypeptide is also present in a smaller complex that contains several putative polymerase subunits and reveals kinase activity but lacks transcription activity (KC, kinase complex). Although the 54 kDa component could not be chromatographically separated from the rest of this complex without loss of activity, it retained residual kinase activity in an electrophoretic blot assay. The polymerase-associated kinase is itself affected by in vitro phosphorylation and dephosphorylation, which raises the possibility that it is part of a signalling cascade that controls chloroplast transcription in vivo by factor phosphorylation.

Increased Soil Salinity Causes Elevated Cadmium Concentrations in Field-Grown Potato Tubers.

Elevated Cd concentrations have been observed in potato (Solatium tuberosum L.) tubers from commercial crops in certain regions of southern Australia. Reasons for enhanced Cd uptake by tubers were investigated by a survey of commercial crops and associated soils. Eighty-nine sites were selected and paired tuber and soil samples taken. Concentration of Cd in tubers was compared to potato variety, tuber elemental composition, and chemical-physical characteristics of topsoil (0-150) and subsoil (150-300 mm). Tuber Cd concentrations were positively related to soil electrical conductivity (EC) and extractable Cl (R2 = 0.62, P < 0.001) in the topsoil, with extractable Cl accounting for more variation than EC. Tuber Cd concentrations were not strongly related (R2 = 0.23, P < 0.05) to potato variety alone. However, inclusion of variety and EDTA-extractable Zn with water-extractable Cl in a multivariate model resulted in a small but significant improvement in the variance accounted for by the model (R2 =0.73, P < 0.001). Tuber Cd was unrelated to tuber concentrations of P or S, but was positively related to concentrations of major cations in the tuber, particularly Na. Soil pH, total C, EDTA-extractable Cd, or particle-size distribution were not correlated to tuber Cd concentrations, either singly or after inclusion in a multivariate model with soil Cl concentrations. As Cl is known to mobilize soil Cd and increase its phytoavailability, elevated Cd concentrations in potato tubers in southern Australia appear to be largely a result of the use of saline irrigation waters.

Phosphorylation and dephosphorylation affect functional characteristics of chloroplast and etioplast transcription systems from mustard (Sinapis alba L.).

Chloroplast and etioplast RNA polymerase preparations each consist of a multi-subunit core and a set of three sigma-like transcription factors, SLF67, SLF52 and SLF29. Despite this structural similarity, the enzymes from either plastid type are functionally distinct, as is reflected by their different promoter usage and the tight core-SLF association in the etioplast but not the chloroplast holoenzyme. We tested whether these differences are related to phosphorylation. Treatment of the chloroplast enzyme with protein kinase converted it to an etioplast-type form and vice versa, treatment of the etioplast enzyme with phosphatase generated chloroplast-type properties. Although both the core enzyme and the SLF polypeptides were phosphorylation targets, only the SLFs seem to confer plastid-type-specific DNA binding characteristics. Methylation interference and DNase I footprint patterns in the psbA promoter region were found to correlate with the phosphorylation state of the chloroplast and etioplast enzymes.