Association between family history and mismatch repair in colorectal cancer

BACKGROUND AND AIMS: Germline mutations in mismatch repair (MMR) genes cause a greatly increased risk of cancer of the gastrointestinal and female reproductive tracts (hereditary non-polyposis colorectal cancer (HNPCC)). Loss of MMR expression is common in colorectal cancer (CRC) overall. Such loss is assumed to be acquired predominantly, although a population of CRC cases will include individuals with unrecognised MMR mutations. This study examines the association between MMR gene expression and family history of cancer among the CRC population. METHODS: Individuals with CRC were identified from two well characterised populations: (1) consecutive hospital patients (n = 644) and (2) a population based cases series (n = 249). CRC was examined for expression of hMLH1 and hMSH2 using immunohistochemistry, and expression was related to family history using logistic regression. RESULTS: hMLH1 and hMSH2 expression was assessed in 732 CRCs with 8% showing loss of expression. No association was seen overall for hMLH1 or hMSH2 expression and family history of CRC. Loss of hMSH2 was predicted by family history of extracolonic cancer (odds ratio (OR) 5.78 (95% confidence interval (CI) 0.95–35.18)) and family history suggestive of HNPCC (OR 27.84 (95% CI 4.37–177.56)). Loss of hMLH1 was not predicted by family history of extracolonic cancer or a family history suggestive of HNPCC but was for a family history of at least two affected relatives (OR 4.88 (95% CI 1.25–19.03)). CONCLUSIONS: Individuals with hMSH2 deficient CRC in the general population exhibit a family history and other characteristics suggestive of HNPCC, and may carry germline MMR mutations. Loss of hMLH1 is only associated with a strong family history of extracolonic cancer at older ages, suggesting a novel mechanism of susceptibility

A generic problem with purely metric formulations of MOND

We give a simple argument to show that no purely metric-based, relativistic formulation of Milgrom's Modified Newtonian Dynamics (MOND) whose energy functional is stable (in the sense of being quadratic in perturbations) can be consistent with the observed amount of gravitational lensing from galaxies. An important part of the argument is the fact that reproducing the MOND force law requires any completely stable, metric-based theory of gravity to become conformally invariant in the weak field limit. We discuss the prospects for a formulation with a very weak instability.Comment: 4 pages, revtex4, no figure

Comments on "There is no axiomatic system for the quantum theory"

In a recent paper, Nagata [1] claims to derive inconsistencies from quantum mechanics. In this paper, we show that the inconsistencies do not come from quantum mechanics, but from extra assumptions about the reality of observables

Lense-Thirring Precession in Pleba\'nski-Demia\'nski spacetimes

An exact expression of Lense-Thirring precession rate is derived for non-extremal and extremal Pleba\'nski-Demia\'nski spacetimes. This formula is used to find the exact Lense-Thirring precession rate in various axisymmetric spacetimes, like: Kerr, Kerr-Newman, Kerr-de Sitter etc. We also show, if the Kerr parameter vanishes in Pleba\'nski-Demia\'nski(PD) spacetime, the Lense-Thirring precession does not vanish due to the existence of NUT charge. To derive the LT precession rate in extremal Pleba\'nski-Demia\'nski we first derive the general extremal condition for PD spacetimes. This general result could be applied to get the extremal limit in any stationary and axisymmetric spacetimes.Comment: 9 pages, Some special modifications are mad

Lesbian and bisexual women's human rights, sexual rights and sexual citizenship: negotiating sexual health in England.

Lesbian and bisexual women's sexual health is neglected in much Government policy and practice in England and Wales. This paper examines lesbian and bisexual women's negotiation of sexual health, drawing on findings from a small research project. Themes explored include invisibility and lack of information, influences on decision-making and sexual activities and experiences of services and barriers to sexual healthcare. Key issues of importance in this respect are homophobic and heterosexist social contexts. Drawing on understandings of lesbian, gay and bisexual human rights, sexual rights and sexual citizenship, it is argued that these are useful lenses through which to examine and address lesbian and bisexual women's sexual health and related inequalities

Cartilage-specific ablation of XBP1 signaling in mouse results in a chondrodysplasia characterized by reduced chondrocyte proliferation and delayed cartilage maturation and mineralization

SummaryObjectiveTo investigate the in vivo role of the IRE1/XBP1 unfolded protein response (UPR) signaling pathway in cartilage.DesignXbp1flox/flox.Col2a1-Cre mice (Xbp1CartΔEx2), in which XBP1 activity is ablated specifically from cartilage, were analyzed histomorphometrically by Alizarin red/Alcian blue skeletal preparations and X-rays to examine overall bone growth, histological stains to measure growth plate zone length, chondrocyte organization, and mineralization, and immunofluorescence for collagen II, collagen X, and IHH. Bromodeoxyuridine (BrdU) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) analyses were used to measure chondrocyte proliferation and cell death, respectively. Chondrocyte cultures and microdissected growth plate zones were analyzed for expression profiling of chondrocyte proliferation or endoplasmic reticulum (ER) stress markers by Quantitative PCR (qPCR), and of Xbp1 mRNA splicing by RT-PCR to monitor IRE1 activation.ResultsXbp1CartΔEx2 displayed a chondrodysplasia involving dysregulated chondrocyte proliferation, growth plate hypertrophic zone shortening, and IRE1 hyperactivation in chondrocytes. Deposition of collagens II and X in the Xbp1CartΔEx2 growth plate cartilage indicated that XBP1 is not required for matrix protein deposition or chondrocyte hypertrophy. Analyses of mid-gestation long bones revealed delayed ossification in Xbp1CartΔEx2 embryos. The rate of chondrocyte cell death was not significantly altered, and only minimal alterations in the expression of key markers of chondrocyte proliferation were observed in the Xbp1CartΔEx2 growth plate. IRE1 hyperactivation occurred in Xbp1CartΔEx2 chondrocytes but was not sufficient to induce regulated IRE1-dependent decay (RIDD) or a classical UPR.ConclusionOur work suggests roles for XBP1 in regulating chondrocyte proliferation and the timing of mineralization during endochondral ossification, findings which have implications for both skeletal development and disease

Quantum measurement in a family of hidden-variable theories

The measurement process for hidden-configuration formulations of quantum mechanics is analysed. It is shown how a satisfactory description of quantum measurement can be given in this framework. The unified treatment of hidden-configuration theories, including Bohmian mechanics and Nelson's stochastic mechanics, helps in understanding the true reasons why the problem of quantum measurement can succesfully be solved within such theories.Comment: 16 pages, LaTeX; all special macros are included in the file; a figure is there, but it is processed by LaTe

Misleading signposts along the de Broglie-Bohm road to quantum mechanics

Eighty years after de Broglie's, and a little more than half a century after Bohm's seminal papers, the de Broglie--Bohm theory (a.k.a. Bohmian mechanics), which is presumably the simplest theory which explains the orthodox quantum mechanics formalism, has reached an exemplary state of conceptual clarity and mathematical integrity. No other theory of quantum mechanics comes even close. Yet anyone curious enough to walk this road to quantum mechanics is soon being confused by many misleading signposts that have been put up, and not just by its detractors, but unfortunately enough also by some of its proponents. This paper outlines a road map to help navigate ones way.Comment: Dedicated to Jeffrey Bub on occasion of his 65th birthday. Accepted for publication in Foundations of Physics. A "slip of pen" in the bibliography has been corrected -- thanks go to Oliver Passon for catching it

An automated archival VLA transients survey

In this paper we present the results of a survey for radio transients using data obtained from the Very Large Array archive. We have reduced, using a pipeline procedure, 5037 observations of the most common pointings - i.e. the calibrator fields. These fields typically contain a relatively bright point source and are used to calibrate 'target' observations: they are therefore rarely imaged themselves. The observations used span a time range ˜1984-2008 and consist of eight different pointings, three different frequencies (8.4, 4.8 and 1.4 GHz) and have a total observing time of 435 h. We have searched for transient and variable radio sources within these observations using components from the prototype LOFAR transient detection system. In this paper we present the methodology for reducing large volumes of Very Large Array data; and we also present a brief overview of the prototype LOFAR transient detection algorithms. No radio transients were detected in this survey, therefore we place an upper limit on the snapshot rate of GHz frequency transients >8.0 mJy to ρ≤ 0.032 deg-2 that have typical time-scales 4.3 to 45.3 d. We compare and contrast our upper limit with the snapshot rates - derived from either detections or non-detections of transient and variable radio sources - reported in the literature. When compared with the current Log N-Log S distribution formed from previous surveys, we show that our upper limit is consistent with the observed population. Current and future radio transient surveys will hopefully further constrain these statistics, and potentially discover dominant transient source populations. In this paper we also briefly explore the current transient commissioning observations with LOFAR, and the impact they will make on the field

Bohmian Mechanics at Space-Time Singularities. II. Spacelike Singularities

We develop an extension of Bohmian mechanics by defining Bohm-like trajectories for quantum particles in a curved background space-time containing a spacelike singularity. As an example of such a metric we use the Schwarzschild metric, which contains two spacelike singularities, one in the past and one in the future. Since the particle world lines are everywhere timelike or lightlike, particles can be annihilated but not created at a future spacelike singularity, and created but not annihilated at a past spacelike singularity. It is argued that in the presence of future (past) spacelike singularities, there is a unique natural Bohm-like evolution law directed to the future (past). This law differs from the one in non-singular space-times mainly in two ways: it involves Fock space since the particle number is not conserved, and the wave function is replaced by a density matrix. In particular, we determine the evolution equation for the density matrix, a pure-to-mixed evolution equation of a quasi-Lindblad form. We have to leave open whether a curvature cut-off needs to be introduced for this equation to be well defined.Comment: 42 pages LaTeX, no figures; v2 shortened and minor change