PRO-FIT-CARE study: the feasibility assessment of a pilot online exercise intervention for persons living with obesity and female infertility.

Introduction: Moderate-to-high physical activity participation is associated with a reduced risk of infertility. Yet, exercise interventions that target cardiorespiratory fitness, independent of weight loss, are lacking in obesity and female fertility research. Purpose: The primary objective of the PRO-FIT-CARE (PROmoting FITness for CArdiometabolic & REproductive Health) study was to assess the feasibility of a moderate-to-high-intensity online exercise program for persons with obesity and female infertility. Methods: Feasibility, safety, acceptability, and efficacy were assessed by examining: (1) recruitment and consent rate, (2) study retention, (3) adverse events, (4) participant satisfaction, (5) adherence, and (6) cardiorespiratory fitness. Results: Eleven of thirty-two women contacted agreed to participate in the program (34.4% consent rate). Eight participants (72.7%) completed the study. One musculoskeletal injury was reported. There was a 30% adherence rate based on prescribed exercise intensity (60%-80% of heart rate maximum). One of eleven participants attended 80% of the exercise intervention. Based on a weekly satisfaction survey, the program had an overall high level of satisfaction. Compared to sex and age normative data, post-intervention, two of eight participants improved their cardiorespiratory fitness percentile rank. Conclusion: The study highlights challenges with adherence to an online exercise program. While the program was safe and participants reported high levels of program satisfaction, approaches to improve adherence must be incorporated.

Management of parapharyngeal space cavernous sinus haemangioma using transoral robotic surgery.

Cavernous haemangiomas are a very rare occurrence in the parapharyngeal space (PPS). Here, we present a case of a 58-year-old woman with an incidentally identified left PPS mass thought to be a pleomorphic adenoma that underwent excision by transoral robotic surgery (TORS). Intraoperative findings demonstrated no solid mass present and histological assessment of resected tissue confirmed a cavernous haemangioma. We discuss our experience in the management of a radiological and surgical mismatch of a PPS mass in what we believe to be the first cavernous haemangioma to be excised by TORS in this region.

Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS): a new autosomal dominant syndrome.

OBJECTIVE: The purpose of this study was the clinical and pathological characterisation of a new autosomal dominant gastric polyposis syndrome, gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS). METHODS: Case series were examined, documenting GAPPS in three families from Australia, the USA and Canada. The affected families were identified through referral to centralised clinical genetics centres. RESULTS: The report identifies the clinical and pathological features of this syndrome, including the predominant dysplastic fundic gland polyp histology, the exclusive involvement of the gastric body and fundus, the apparent inverse association with current Helicobacter pylori infection and the autosomal dominant mode of inheritance. CONCLUSIONS: GAPPS is a unique gastric polyposis syndrome with a significant risk of gastric adenocarcinoma. It is characterised by the autosomal dominant transmission of fundic gland polyposis, including areas of dysplasia or intestinal-type gastric adenocarcinoma, restricted to the proximal stomach, and with no evidence of colorectal or duodenal polyposis or other heritable gastrointestinal cancer syndromes.

Evaluation of a candidate breast cancer associated SNP in ERCC4 as a risk modifier in BRCA1 and BRCA2 mutation carriers. Results from the Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA).

BACKGROUND: In this study we aimed to evaluate the role of a SNP in intron 1 of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers. METHODS: We have genotyped rs744154 in 9408 BRCA1 and 5632 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and assessed its association with breast cancer risk using a retrospective weighted cohort approach. RESULTS: We found no evidence of association with breast cancer risk for BRCA1 (per-allele HR: 0.98, 95% CI: 0.93-1.04, P = 0.5) or BRCA2 (per-allele HR: 0.97, 95% CI: 0.89-1.06, P = 0.5) mutation carriers. CONCLUSION: This SNP is not a significant modifier of breast cancer risk for mutation carriers, though weak associations cannot be ruled out.

The TP53 Arg72Pro and MDM2 309G>T polymorphisms are not associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers.

BACKGROUND: The TP53 pathway, in which TP53 and its negative regulator MDM2 are the central elements, has an important role in carcinogenesis, particularly in BRCA1- and BRCA2-mediated carcinogenesis. A single nucleotide polymorphism (SNP) in the promoter region of MDM2 (309T>G, rs2279744) and a coding SNP of TP53 (Arg72Pro, rs1042522) have been shown to be of functional significance. METHODS: To investigate whether these SNPs modify breast cancer risk for BRCA1 and BRCA2 mutation carriers, we pooled genotype data on the TP53 Arg72Pro SNP in 7011 mutation carriers and on the MDM2 309T>G SNP in 2222 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analysed using a Cox proportional hazards model within a retrospective likelihood framework. RESULTS: No association was found between these SNPs and breast cancer risk for BRCA1 (TP53: per-allele hazard ratio (HR)=1.01, 95% confidence interval (CI): 0.93-1.10, P(trend)=0.77; MDM2: HR=0.96, 95%CI: 0.84-1.09, P(trend)=0.54) or for BRCA2 mutation carriers (TP53: HR=0.99, 95%CI: 0.87-1.12, P(trend)=0.83; MDM2: HR=0.98, 95%CI: 0.80-1.21, P(trend)=0.88). We also evaluated the potential combined effects of both SNPs on breast cancer risk, however, none of their combined genotypes showed any evidence of association. CONCLUSION: There was no evidence that TP53 Arg72Pro or MDM2 309T>G, either singly or in combination, influence breast cancer risk in BRCA1 or BRCA2 mutation carriers.

Genetic, functional, and histopathological evaluation of two C-terminal BRCA1 missense variants.

BACKGROUND: The vast majority of BRCA1 missense sequence variants remain uncharacterized for their possible effect on protein expression and function, and therefore are unclassified in terms of their pathogenicity. BRCA1 plays diverse cellular roles and it is unlikely that any single functional assay will accurately reflect the total cellular implications of missense mutations in this gene. OBJECTIVE: To elucidate the effect of two BRCA1 variants, 5236G>C (G1706A) and 5242C>A (A1708E) on BRCA1 function, and to survey the relative usefulness of several assays to direct the characterisation of other unclassified variants in BRCA genes. METHODS AND RESULTS: Data from a range of bioinformatic, genetic, and histopathological analyses, and in vitro functional assays indicated that the 1708E variant was associated with the disruption of different cellular functions of BRCA1. In transient transfection experiments in T47D and 293T cells, the 1708E product was mislocalised to the cytoplasm and induced centrosome amplification in 293T cells. The 1708E variant also failed to transactivate transcription of reporter constructs in mammalian transcriptional transactivation assays. In contrast, the 1706A variant displayed a phenotype comparable to wildtype BRCA1 in these assays. Consistent with functional data, tumours from 1708E carriers showed typical BRCA1 pathology, while tumour material from 1706A carriers displayed few histopathological features associated with BRCA1 related tumours. CONCLUSIONS: A comprehensive range of genetic, bioinformatic, and functional analyses have been combined for the characterisation of BRCA1 unclassified sequence variants. Consistent with the functional analyses, the combined odds of causality calculated for the 1706A variant after multifactorial likelihood analysis (1:142) indicates a definitive classification of this variant as "benign". In contrast, functional assays of the 1708E variant indicate that it is pathogenic, possibly through subcellular mislocalisation. However, the combined odds of 262:1 in favour of causality of this variant does not meet the minimal ratio of 1000:1 for classification as pathogenic, and A1708E remains formally designated as unclassified. Our findings highlight the importance of comprehensive genetic information, together with detailed functional analysis for the definitive categorisation of unclassified sequence variants. This combination of analyses may have direct application to the characterisation of other unclassified variants in BRCA1 and BRCA2.

Prenatal diagnosis of tetrasomy 18p using multiplex fluorescent PCR and comparison with a variety of techniques.

We report genetic characterization of isochromosome 18p using a combination of cytogenetic and molecular genetic methods, including multiplex fluorescent PCR. The patient was referred for chorionic villus sampling (CVS) due to advanced maternal age and maternal anxiety. The placental karyotype was 47,XX,+mar, with the marker having the appearance of a small supernumerary isochromosome. Because differentiating between isochromosomes and other structural rearrangements is normally very difficult, a variety of genetic tests including fluorescence in situ hybridization (FISH), PCR, and multiplex fluorescent PCR were undertaken to determine chromosomal origin and copy number and, thus, allow accurate diagnosis of the corresponding syndrome. FISH determined that the marker chromosome contained chromosome 18 material. PCR of a variety of short tandem repeats (STRs) confirmed that there was at least one extra copy of the maternal 18p material. However, neither FISH nor PCR could accurately determine copy number. Multiplex fluorescent PCR (MF-PCR) of STRs simultaneously determined that: (1) the marker included 18p material; (2) the marker was maternal in origin; (3) allele copy number indicated tetrasomy; and (4) contamination of the sample could be ruled out. Results were also rapid with accurate diagnosis of the syndrome tetrasomy 18p possible within 5 hours.

Unintentional fatal injuries arising from unpaid work at home.

OBJECTIVE: Unpaid work in and around the home is a common and potentially high risk activity, yet there is limited information about the circumstances surrounding resulting injuries. This study aimed to describe circumstances surrounding fatal injuries resulting from home duties activities, in order to identify and prioritise areas for prevention. DESIGN AND SETTING: Coroners' reports on all unintentional deaths in Australia from 1989-92 inclusive were inspected to identify deaths of interest. Rates were calculated using population data and incorporating measures of time engaged in particular home duties activities. RESULTS: There were 296 home duties deaths over the four year period. Most (83%) deaths were of males, and males had 10 times the risk of fatal injury compared with females. The most common activities resulting in fatal injuries were home repairs, gardening, and car care. The highest risk activities (deaths per million persons per year per hour of activity) were home repairs (49), car care (20), home improvements (18), and gardening (16). Being hit by inadequately braced vehicles during car maintenance, falls from inadequately braced ladders, contact with fire and flames while cooking, and contact with electricity during maintenance were the most common injury scenarios. CONCLUSIONS: Fatal injury of persons engaged in unpaid domestic work activities is a significant cause of death. Use of activity specific denominator data allows appropriate assessment of the degree of risk associated with each activity. The recurrence of similar circumstances surrounding many independent fatal incidents indicates areas where preventative interventions might be usefully targeted.

Coverage of work related fatalities in Australia by compensation and occupational health and safety agencies.

AIMS: To determine the levels of coverage of work related traumatic deaths by official occupational health and safety (OHS) and compensation agencies in Australia, to allow better understanding and interpretation of officially available statistics. METHODS: The analysis was part of a much larger study of all work related fatalities that occurred in Australia during the four year period 1989 to 1992 inclusive and which was based on information from coroners' files. For the current study, State, Territory, and Commonwealth OHS and compensation agencies were asked to supply unit record information for all deaths identified by the jurisdictions as being due to non-suicide traumatic causes and which were identified by them as being work related, using whatever definitions the agencies were using at the relevant time. This information was matched to cases identified during the main study. RESULTS: The percentage of working deaths not covered by any agency was 34%. Only 35% of working deaths were covered by an OHS agency, while 57% were covered by a compensation agency. The OHS agencies had minimal coverage of work related deaths that occurred on the road (to workers (8%) or commuters (3%)), whereas the compensation system covered these deaths better than those of workers in incidents that occurred in a workplace (65% versus 53%). There was virtually no coverage of bystanders (less than 8%) by either type of agency. There was marked variation in the level of coverage depending on the industry, occupation, and employment status of the workers, and the type of injury event involved in the incident. CONCLUSIONS: When using data from official sources, the significant limitations in coverage identified in this paper need to be taken into account. Future surveillance, arising from a computerised National Coroners Information System, should result in improved coverage of work related traumatic deaths in Australia.

Oncogenic human papillomavirus infection and cervical lesions in aboriginal women of Nunavut, Canada.

BACKGROUND: The high rate of cervical cancer among aboriginal women of northern Canada has prompted the search for more aggressive methods to augment Papanicolaou (Pap) screening in this population. Nearly all cervical cancers result from oncogenic human papillomavirus (HPV) infections. This has generated interest for incorporating HPV testing into the current screening program. GOALS: To determine the prevalence of oncogenic HPVs in Nunavut, and to assess the association between HPV and squamous intraepithelial lesions (SIL). STUDY DESIGN: A cross-sectional study was conducted on the Pap-screened populations in 19 communities of Nunavut, Canada. Liquid-based cytology was used to screen for SIL. HPV testing was performed using the Hybrid Capture II assay. Correlates of HPV infection and SIL were assessed by logistic regression with control for potential confounders. RESULTS: In 1290 women ages 13 to 79 years, the prevalence rate was 26% for oncogenic HPV and 6.9% for SIL. The odds ratio for the association between HPV and SIL was 37.9 (95% CI, 17.7-80.8) after multivariate adjustment. This association increased markedly with increasing viral load. More than 90% of the women with squamous intraepithelial lesions had positive test results for HPV. More than 75% of the women who had positive test results for HPV but negative test results for SIL were younger than 30 years. CONCLUSION: The results of this study form the basis for further evaluation of the role that liquid-based cytology and HPV testing plays and will contribute to the strategy for cervical cancer prevention in Nunavut.

Height discordance in monozygotic females is not attributable to discordant inactivation of X-linked stature determining genes.

We tested the hypothesis that X-linked genes determining stature which are subject to skewed or non-random X-inactivation can account for discordance in height in monozygotic female twins. Height discordant female monozygotic adult twins (20 pairs) were identified from the Australian Twin Registry, employing the selection criteria of proven monozygosity and a measured height discordance of at least 5 cm. Differential X-inactivation was examined in genomic DNA extracted from peripheral lymphocytes by estimating differential methylation of alleles at the polymorphic CAG triplet repeat of the Androgen receptor gene (XAR). There were 17/20 MZ pairs heterozygous at this locus and informative for analysis. Of these, 10/17 both had random X-inactivation, 5/17 showed identical X-inactivation patterns of non random inactivation and 2/17 (12%) showed discordant X-inactivation. There was no relationship between inactivation patterns and self-report chorionicity. We conclude that non-random X-inactivation does not appear to be a major contributor to intra-pair height discordance in female MZ twins.

Human twinning is not linked to the region of chromosome 4 syntenic with the sheep twinning gene FecB.

The tendency to dizygotic (DZ) twinning is inherited in both humans and sheep, and a fecundity gene in sheep (FecB) maps to sheep chromosome 6, syntenic with human 4q21-25. Our aim was to see whether a gene predisposing to human DZ twinning mapped to this region. DNA was collected from 169 pairs and 17 sets of 3 sisters (trios) from Australia and New Zealand who had each had spontaneous DZ twins, mostly before the age of 35, and from a replication sample of 111 families (92 affected sister pairs) from The Netherlands. Exclusion mapping was carried out after typing 26 markers on chromosome 4, of which 8 spanned the region likely to contain the human homologue of the sheep FecB gene. We used nonparametric affected sib pair methods for linkage analysis [ASPEX 2.2, Hinds and Risch, 1999]. Complete exclusion of linkage (lod < -2) of a gene conferring a relative risk for sibs as low as 1.5 (lambda(s) > 1.5) was obtained for all but the p terminus region on chromosome 4. Exclusion in the syntenic region was stronger, down to lambda(s) = 1.3. We concluded that if there is a gene influencing DZ twinning on chromosome 4, its effect must be minor.

Spinocerebellar ataxia type 7: a distinctive form of autosomal dominant cerebellar ataxia with retinopathy and marked genetic anticipation.

When a child presents with progressive ataxia, there is a broad differential diagnosis and a very long list of potential investigations. Spinocerebellar ataxia type 7 presenting in infancy is a rare condition where a presumptive diagnosis can be made based on the clinical features alone. These include rapidly progressive ataxia, retinopathy and autosomal dominant inheritance with marked genetic anticipation of paternal origin. The father of the infant may manifest minimal symptoms at a time when the infant is severely affected. Diagnosis is confirmed by the demonstration of an expansion of a CAG repeat in the coding region of the gene on chromosome 3p. We present a case to illustrate the diagnostic difficulties. Antenatal diagnosis was performed in two subsequent pregnancies.

Investigation of a cryptic interstitial duplication involving the Prader-Willi/Angelman syndrome critical region.

A 3-year-old female referred with developmental delay, hypotonia and seizures was found to have a cryptic interstitial duplication of the Prader-Willi/Angelman critical region (PWACR). Her clinical features form part of a common phenotype characteristic of PWACR duplications including developmental delay, behavioural problems and speech difficulties. Microsatellite analysis showed that the duplication had arisen de novo, was maternal in origin and involved the entire 4-Mb PWACR between the common deletion breakpoints. The existence of cryptic rearrangements emphasises the need for molecular tests alongside conventional cytogenetics when investigating abnormalities involving this imprinted region.

Mendelian segregation of normal CAG trinucleotide repeat alleles at three autosomal loci.

Segregation ratio distortion (SRD) with preferential transmission of expanded CAG alleles has been reported in Machado-Joseph disease (MJD/SCA3), spinocerebellar ataxia type I (SCA1), and dentatorubral-pallidoluysian atrophy (DRPLA). We have examined the transmission frequencies of alleles in normal heterozygotes at these disease loci in 377 pairs of twins and their parents and find no evidence for SRD.

A methodological appraisal of the impact of different classification procedures used in three different phases of the australian rheumatoid arthritis twin survey.

AIMS: To compare methodological aspects of the impact of different classification procedures used in three phases of a twin study examining genetic factors in the aetiopathogenesis of rheumatoid arthritis (RA). METHODS: We have previously reported the results of a study of the aetiopathogenesis of RA based on the Australian Twin Registry (ATR). In the original 258 pairs self-reporting a diagnosis of RA in twin, co-twin or both, a very high false positive self-reporting rate for RA was noted (Phase 1). Subsequent diagnostic information obtained by a disease-specific questionnaire, followed by telephone interviews with subjects and review of information obtained by mail and telephone interview from the patient's general practitioner or musculoskeletal specialist, identified 23 'true' RA pairs (Phase 2). Pairwise concordance percentages for RA based on those 20 discordant and 3 concordant pairs were as follows: monozygotic (MZ) 21% (95% confidence interval (CI)=6-44%), dizygotic (DZ) 0% (95% CI=0-25%) (probandwise concordance MZ 35% (8.9-67.3), DZ 0% (0-50.3)). Given the potential effects of misclassification on data interpretation, we have further pursued the accuracy of diagnosis by a systematic clinical, serological and radiographical evaluation of the 23 RA pairs (Phase 3). RESULTS: In only one instance did more intense diagnostic investigation of the 23 pairs result in recategorization. The probandwise concordance percentages were recalculated: MZ=37.5%, DZ=0%. CONCLUSIONS: Our original contention that genetic factors play some part in the aetiopathogenesis of RA, but do not account entirely for its determination, has been substantiated at a higher level of confidence and at almost identical levels of concordance.