Is multiple SNP testing in BRCA2 and BRCA1 female carriers ready for use in clinical practice? Results from a large Genetic Centre in the UK

BRCA1 and BRCA2 are major breast cancer susceptibility genes. Nineteen single nucleotide polymorphisms (SNPs) at 18 loci have been associated with breast cancer. We aimed to determine whether these predict breast cancer incidence in women with BRCA1/BRCA2 mutations. BRCA1/2 mutation carriers identified through the Manchester genetics centre between 1996 and 2011 were included. Using published odds ratios (OR) and risk allele frequencies, we calculated an overall breast cancer risk SNP score (OBRS) for each woman. The relationship between OBRS and age at breast cancer onset was investigated using the Cox proportional hazards model, and predictive ability assessed using Harrell's C concordance statistic. In BRCA1 mutation carriers we found no association between OBRS and age at breast cancer onset: OR for the lowest risk quintile compared to the highest was 1.20 (95% CI 0.82–1.75, Harrell's C = 0.54), but in BRCA2 mutation carriers the association was significant (OR for the lowest risk quintile relative to the highest was 0.47 (95% CI 0.33–0.69, Harrell's C = 0.59). The 18 validated breast cancer SNPs differentiate breast cancer risks between women with BRCA2 mutations, but not BRCA1. It may now be appropriate to use these SNPs to help women with BRCA2 mutations make maximally informed decisions about management options.     

Where do we look when we walk on stairs? Gaze behaviour on stairs,transitions, and handrails

Stair walking is a challenging locomotor task, and visual information about the steps is considered critical to safely walk up and down. Despite the importance of such visual inputs, there remains relatively little information on where gaze is directed during stair walking. The present study investigated the role of vision during stair walking with a specific focus on gaze behaviour relative to (1) detection of transition steps between ground level and stairs, (2) detection of handrails, and (3) the first attempt to climb an unfamiliar set of stairs. Healthy young adults (n = 11) walked up and down a set of stairs with 7 steps (transitions were defined as the two top and bottom steps). Gaze behaviour was recorded using an eye tracker. Although participants spent most part of the time looking at the steps, gaze fixations on stair features covered less than 20% of the stair walking time. There was no difference in the overall number of fixations and fixation time directed towards transitions compared to the middle steps of the stairs. However, as participants approached and walked on the stairs, gaze was within 4 steps ahead of their location. The handrail was rarely the target of gaze fixation. It is noteworthy that these observations were similar even in the very first attempt to walk on the stairs. These results revealed the specific role of gaze behaviour in guiding immediate action and that stair transitions did not demand increased gaze behaviour in comparison with middle steps. These findings may also indicate that individuals may rely on a spatial representation built from previous experience and/or visual information other than gaze fixations (e.g. dynamic gaze sampling, peripheral visual field) to extract information from the surrounding environment.     

Physical activity for people with a disability: a conceptual model

The promotion of a physically active lifestyle has become an important issue in health policy in first-world countries. A physically active lifestyle is accompanied by several fitness and health benefits. Individuals with a disability can particularly benefit from an active lifestyle: not only does it reduce the risk for secondary health problems, but all levels of functioning can be influenced positively. The objective of this article is to propose a conceptual model that describes the relationships between physical activity behaviour, its determinants and functioning of people with a disability. The literature was systematically searched for articles considering physical activity and disability, and models relating both topics were looked for in particular. No models were found relating physical activity behaviour, its determinants and functioning in people with a disability. Consequently, a new model, the Physical Activity for people with a Disability (PAD) model, was constructed based on existing models of disability and models of determinants of physical activity behaviour. The starting point was the new WHO Model of Functioning and Disability, part of the International Classification of Functioning, Disability and Health (ICF), which describes the multidimensional aspects of functioning and disability. Physical activity behaviour and its determinants were integrated into the ICF model. The factors determining physical activity were based mainly on those used in the Attitude, Social influence and self-Efficacy (ASE) model. The proposed model can be used as a theoretical framework for future interventions and research on physical activity promotion in the population of people with a disability. The model currently forms the theoretical basis for a large physical activity promotion trial in ten Dutch rehabilitation centres.     

Mesoatrial shunts for Budd-Chiari syndrome and inferior vena cava thrombosis: angiographic and hemodynamic evaluations

When inferior vena caval obstruction complicates the Budd-Chiari syndrome, conventional portosystemic shunts are not possible. The mesoatrial shunt has been devised to enable portal and sinusoidal decompression in these patients. Findings in 12 patients with Budd-Chiari syndrome and inferior vena caval obstruction in whom a mesoatrial shunt was performed are reported. Preoperative inferior vena cavography with pressure measurements is essential to determine the appropriate shunt procedure. Postoperatively, shunt patency is assessed with superior mesenteric arterial portography. Where possible, transvenous catheterization of the shunt is performed to confirm patency and assess hemodynamic function.     

Digital radiography of subtle pulmonary abnormalities: an ROC study of the effect of pixel size on observer performance

Forty conventional radiographs with examples of mild interstitial infiltrates and subtle pneumothoraces and 40 normal studies of the chest were selected and digitized, with pixel sizes of 1.0, 0.5, 0.2, and 0.1 mm. Observer performance tests were carried out using receiver operating characteristic analysis. Conventional radiographs and digitized images were compared. The results indicate that, in such cases, diagnostic accuracy increases significantly as the pixel size is reduced, at least to the 0.1-mm level. We conclude that, for digital systems using screen-film or similar image receptors, use of a pixel size substantially larger than 0.1 mm may result in some loss of diagnostic accuracy.     

In situ saphenous vein bypass grafts: angiographic evaluation and interventional repair of complications

In situ saphenous vein grafts are being used with increasing frequency for bypass procedures involving the femoral and popliteal arteries. Complications of these procedures include anastomotic stenoses and persistent arteriovenous fistulae that may result in failure of the graft. Balloon angioplasty and embolotherapy with detachable balloons were employed successfully in three or four recent cases of patients with complications from in situ grafts. Tailored angiography is essential for evaluating in situ grafts, and interventional techniques are extremely useful for managing complications.     

Genetic diversity and ecogeographical differentiation among ribosomal DNA alleles in wild and cultivated barley.

DNA from 267 accessions of wild barley from ecologically diverse habitats in Israel and Iran and from 92 accessions of cultivated barley from throughout the world were assayed for the 20 ribosomal DNA (rDNA) spacer-length variants that have been identified in the barley species. These 20 spacer-length variants, which are detectable by Southern blot hybridization, serve as markers of rDNA alleles of two Mendelian loci, Rrn1 and Rrn2. All of the populations of wild barley studied were polymorphic for both loci. In wild barley allele 112 (Rrn1) and allele 107 (Rrn2) behaved as widely adapted wild-type alleles; in our sample of cultivated barley allele 112 also behaved as a wild-type allele but allele 104 was somewhat more frequent than allele 107 in Rrn2. A few other alleles were locally frequent in wild barley. However, most of the 20 alleles were infrequent or rare and such alleles were often associated as "hitchhikers" with one of the wild-type alleles in compound two-component alleles. Allelic and genotypic frequencies differed widely in different habitats in correlation with eight of nine factors of the physical environment. Discrete log-linear multivariate analyses revealed statistically significant associations among alleles of Rrn1 and Rrn2. It was concluded that natural selection acting differentially on various rDNA alleles plays a major role in the development and maintenance of observed patterns of molecular and genetic organization of rDNA variability.     

Increased ischemic injury but decreased hypoxic injury in hypertrophied rat hearts

The purpose of this study was to compare the degree of ischemic and hypoxic injury in normal versus hypertrophied rat hearts to investigate basic mechanisms responsible for irreversible myocardial ischemic injury. Hearts from rats with bands placed on the aortic arch at 23 days of age (BAND) and sham-operated rats (SHAM, 8 weeks postoperative) were isolated, perfused with Krebs buffer, and had a left ventricular balloon to measure developed pressure. Hearts were made globally ischemic until they developed peak ischemic contracture and were reperfused for 30 minutes. Additional hearts were perfused for 15 minutes with glucose-free hypoxic buffer followed by 20 minutes of oxygenated perfusion. There was an 87% increase in heart weight of BAND compared with SHAM (p less than 0.01). During ischemia, lactate levels increased faster in BAND compared with SHAM, ischemic contracture occurred earlier in BAND than in SHAM despite no difference in ATP levels, and postischemic recovery of left ventricular pressure was less in BAND (26.8 +/- 5.6% of control left ventricular pressure, mean +/- SEM) compared with SHAM (40 +/- 4.6%, p less than 0.05). During hypoxic perfusion, lactate release was greater in BAND than in SHAM (48.8 +/- 1.2 versus 26.6 +/- 0.97 mumols/g, p less than 0.01), and with reoxygenation, lactate dehydrogenase release was less in BAND than in SHAM (13.2 +/- 0.7 versus 19.5 +/- 0.2 IU/g, p less than 0.01). After hypoxia and reoxygenation, left ventricular pressure recovery was greater in BAND than in SHAM (93 +/- 8.4% versus 66 +/- 5.3%, p less than 0.01). Thus, this study suggests that hypertrophied hearts have a greater potential for glycolytic metabolism, resulting in an increased rate of by-product accumulation during ischemia, which may be responsible for the increased susceptibility of hypertrophied hearts to ischemic injury.     

Hospitalization of peritoneal dialysis patients: the impact of peritonitis episodes on the hospitalization rate

Peritonitis is still a frequent complication in peritoneal dialysis patients. Medical guidelines have been established to manage this infection. These guidelines do not provide any information regarding the requirement for hospitalization. The main objective of this study was to evaluate the impact of peritonitis episode on the hospitalization rate and on the hospitalization duration in a centre where peritoneal dialysis patients were hospitalized in case of peritonitis. This was a retrospective study of incident peritoneal patients over a six years period. Among 101 peritoneal dialysis patients 65% were hospitalized. Two hundred and twenty hospital stays were registered. The total duration of hospital stays was 2091 days. The hospitalization rate was 2 per patient and per year, the hospital duration was 19 days per patient per year. Of the 220 hospital stays, 67 (30%) were due to a peritoneal infection. Peritonitis episodes represent 581/2091 (28%) days of hospitalization. The mean duration of hospitalization for peritonitis was 8.7+/-7 days. Among the patients hospitalized for a peritonitis episode, 57% were assisted by a nurse at home to perform their peritoneal dialysis exchanges. Of the 67 peritonitis episodes, 91% were discharged from the hospital without any complication. This study emphases the fact that peritonitis has an important impact on the hospitalization rate and on the hospitalization duration in peritoneal dialysis patients. In an attempt to decrease the rate of hospitalization, educational programs are clearly needed in order to treat more peritonitis without any hospitalization requirement.