Deletions of the derivative chromosome 9 occur at the time of the Philadelphia translocation and provide a powerful and independent prognostic indicator in chronic myeloid leukemia

Chronic myeloid leukemia (CML) is characterized by formation of the BCR-ABL fusion gene, usually as a consequence of the Philadelphia (Ph) translocation between chromosomes 9 and 22. Large deletions on the derivative chromosome 9 have recently been reported, but it was unclear whether deletions arose during disease progression or at the time of the Ph translocation. Fluorescence in situ hybridization (FISH) analysis was used to assess the deletion status of 253 patients with CML. The strength of deletion status as a prognostic indicator was then compared to the Sokal and Hasford scoring systems. The frequency of deletions was similar at diagnosis and after disease progression but was significantly increased in patients with variant Ph translocations. In patients with a deletion, all Ph+ metaphases carried the deletion. The median survival of patients with and without deletions was 38 months and 88 months, respectively (P = .0001). By contrast the survival difference between Sokal or Hasford high-risk and non-high-risk patients was of only borderline significance (P = .057 and P = .034). The results indicate that deletions occur at the time of the Ph translocation. An apparently simple reciprocal translocation may therefore result in considerable genetic heterogeneity ab initio, a concept that is likely to apply to other malignancies associated with translocations. Deletion status is also a powerful and independent prognostic factor for patients with CML. The prognostic significance of deletion status should now be studied prospectively and, if confirmed, should be incorporated into management decisions and the analysis of clinical trials. (C) 2001 by The American Society of Hematology

The effects of feed restriction, time of day and time since feeding on behavioral and physiological indicators of hunger in broiler breeder hens

Broiler breeder chickens are commercially feed restricted to slow their growth and improve their health and production, however, there is research demonstrating that this leads to chronic hunger resulting in poor welfare. A challenge in these studies is to account for possible daily rhythms or the effects of time since last meal on measures relating hunger. To address this, we used 3 feed treatments: AL (ad libitum fed), Ram (restricted, fed in the morning), and Rpm (restricted, fed in the afternoon) to control for diurnal effects. We then conducted foraging motivation tests and collected home pen behavior and physiological samples at 4 times relative to feeding throughout a 24-h period. The feed treatment had the largest influence on the data, with AL birds weighing more, having lower concentrations of plasma NEFA, and mRNA expression of AGRP and NPY alongside higher expression of POMC in the basal hypothalamus than Ram or Rpm birds (P &lt; 0.001). R birds were more successful at and had a shorter latency to complete the motivation test, and did more walking and less feeding than AL birds in the home pen (P &lt; 0.01). There was little effect of time since last meal on many measures (P &gt; 0.05) but AGRP expression was highest in the basal hypothalamus shortly after a meal (P &lt; 0.05), blood plasma NEFA was higher in R birds just before feeding (P &lt; 0.001) and glucose was higher in Ram birds just after feeding (P &lt; 0.001), and the latency to complete the motivation test was shortest before the next meal (P &lt; 0.05). Time of day effects were mainly found in the difference in activity levels in the home pen when during lights on and lights off periods. In conclusion, many behavioral and physiological hunger measures were not significantly influenced by time of day or time since the last meal. For the measures that do change, future studies should be designed so that sampling is balanced in such a way as to minimize bias due to these effects.</p

Contributions of lean mass and fat mass to bone mineral density: a study in postmenopausal women

<p>Abstract</p> <p>Background</p> <p>The relative contribution of lean and fat to the determination of bone mineral density (BMD) in postmenopausal women is a contentious issue. The present study was undertaken to test the hypothesis that lean mass is a better determinant of BMD than fat mass.</p> <p>Methods</p> <p>This cross-sectional study involved 210 postmenopausal women of Vietnamese background, aged between 50 and 85 years, who were randomly sampled from various districts in Ho Chi Minh City (Vietnam). Whole body scans, femoral neck, and lumbar spine BMD were measured by DXA (QDR 4500, Hologic Inc., Waltham, MA). Lean mass (LM) and fat mass (FM) were derived from the whole body scan. Furthermore, lean mass index (LMi) and fat mass index (FMi) were calculated as ratio of LM or FM to body height in metre squared (m²).</p> <p>Results</p> <p>In multiple linear regression analysis, both LM and FM were independent and significant predictors of BMD at the spine and femoral neck. Age, lean mass and fat mass collectively explained 33% variance of lumbar spine and 38% variance of femoral neck BMD. Replacing LM and FM by LMi and LMi did not alter the result. In both analyses, the influence of LM or LMi was greater than FM and FMi. Simulation analysis suggested that a study with 1000 individuals has a 78% chance of finding the significant effects of both LM and FM, and a 22% chance of finding LM alone significant, and zero chance of finding the effect of fat mass alone.</p> <p>Conclusions</p> <p>These data suggest that both lean mass and fat mass are important determinants of BMD. For a given body size -- measured either by lean mass or height --women with greater fat mass have greater BMD.</p

Light-Dependant Biostabilisation of Sediments by Stromatolite Assemblages

For the first time we have investigated the natural ecosystem engineering capacity of stromatolitic microbial assemblages. Stromatolites are laminated sedimentary structures formed by microbial activity and are considered to have dominated the shallows of the Precambrian oceans. Their fossilised remains are the most ancient unambiguous record of early life on earth. Stromatolites can therefore be considered as the first recognisable ecosystems on the planet. However, while many discussions have taken place over their structure and form, we have very little information on their functional ecology and how such assemblages persisted despite strong eternal forcing from wind and waves. The capture and binding of sediment is clearly a critical feature for the formation and persistence of stromatolite assemblages. Here, we investigated the ecosystem engineering capacity of stromatolitic microbial assemblages with respect to their ability to stabilise sediment using material from one of the few remaining living stromatolite systems (Highborne Cay, Bahamas). It was shown that the most effective assemblages could produce a rapid (12–24 h) and significant increase in sediment stability that continued in a linear fashion over the period of the experimentation (228 h). Importantly, it was also found that light was required for the assemblages to produce this stabilisation effect and that removal of assemblage into darkness could lead to a partial reversal of the stabilisation. This was attributed to the breakdown of extracellular polymeric substances under anaerobic conditions. These data were supported by microelectrode profiling of oxygen and calcium. The structure of the assemblages as they formed was visualised by low-temperature scanning electron microscopy and confocal laser microscopy. These results have implications for the understanding of early stromatolite development and highlight the potential importance of the evolution of photosynthesis in the mat forming process. The evolution of photosynthesis may have provided an important advance for the niche construction activity of microbial systems and the formation and persistence of the stromatolites which came to dominate shallow coastal environments for 80% of the biotic history of the earth

p16 Mutation Spectrum in the Premalignant Condition Barrett's Esophagus

Background: Mutation, promoter hypermethylation and loss of heterozygosity involving the tumor suppressor gene p16 (CDKN2a/INK4a) have been detected in a wide variety of human cancers, but much less is known concerning the frequency and spectrum of p16 mutations in premalignant conditions. Methods and Findings: We have determined the p16 mutation spectrum for a cohort of 304 patients with Barrett’s esophagus, a premalignant condition that predisposes to the development of esophageal adenocarcinoma. Forty seven mutations were detected by sequencing of p16 exon 2 in 44 BE patients (14.5%) with a mutation spectrum consistent with that caused by oxidative damage and chronic inflammation. The percentage of patients with p16 mutations increased with increasing histologic grade. In addition, samples from 3 out of 19 patients (15.8%) who underwent esophagectomy were found to have mutations. Conclusions: The results of this study suggest the environment of the esophagus in BE patients can both generate an

Protocol for stage 1 of the GaP study (Genetic testing acceptability for Paget's disease of bone): an interview study about genetic testing and preventive treatment: would relatives of people with Paget's disease want testing and treatment if they were available?

BACKGROUND: Paget's disease of bone (PDB) is characterised by focal increases in bone turnover, affecting one or more bones throughout the skeleton. This disrupts normal bone architecture and causes pain, deformity, deafness, osteoarthritis, and fractures. Genetic factors are recognised to play a role in PDB and it is now possible to carry out genetic tests for research. In view of this, it is timely to investigate the clinical potential for a programme of genetic testing and preventative treatment for people who have a family history of PDB, to prevent or delay the development of PDB. Evidence from non-genetic conditions, that have effective treatments, demonstrates that patients' beliefs may affect the acceptability and uptake of treatment. Two groups of beliefs (illness and treatment representations) are likely to be influential. Illness representations describe how people see their illness, as outlined in Leventhal's Self-Regulation Model. Treatment representations describe how people perceive potential treatment for their disease. People offered a programme of genetic testing and treatment will develop their own treatment representations based on what is offered, but the beliefs rather than the objective programme of treatment are likely to determine their willingness to participate. The Theory of Planned Behaviour is a theoretical model that predicts behaviours from people's beliefs about the consequences, social pressures and perceived control over the behaviour, including uptake of treatment. METHODS/DESIGN: This study aims to examine the acceptability of genetic testing, followed by preventative treatment, to relatives of people with PDB. We aim to interview people with Paget's disease, and their families, from the UK. Our research questions are: 1. What do individuals with Paget's disease think would influence the involvement of their relatives in a programme of genetic testing and preventative treatment? 2. What do relatives of Paget's disease sufferers think would influence them in accepting an offer of a programme of genetic testing and preventative treatment? DISCUSSION: Our research will be informed by relevant psychological theory: primarily the Self-Regulation Model and the Theory of Planned Behaviour. The results of these interviews will inform the development of a separate questionnaire-based study to explore these research questions in greater detail

Global aspects of the space of 6D N = 1 supergravities

We perform a global analysis of the space of consistent 6D quantum gravity theories with N = 1 supersymmetry, including models with multiple tensor multiplets. We prove that for theories with fewer than T = 9 tensor multiplets, a finite number of distinct gauge groups and matter content are possible. We find infinite families of field combinations satisfying anomaly cancellation and admitting physical gauge kinetic terms for T > 8. We find an integral lattice associated with each apparently-consistent supergravity theory; this lattice is determined by the form of the anomaly polynomial. For models which can be realized in F-theory, this anomaly lattice is related to the intersection form on the base of the F-theory elliptic fibration. The condition that a supergravity model have an F-theory realization imposes constraints which can be expressed in terms of this lattice. The analysis of models which satisfy known low-energy consistency conditions and yet violate F-theory constraints suggests possible novel constraints on low-energy supergravity theories.Comment: 41 pages, 1 figur

The impact of point mutations in the human androgen receptor : classification of mutations on the basis of transcriptional activity

Peer reviewedPublisher PD