Expression of midkine in the early stage of carcinogenesis in human colorectal cancer

It has been suggested that a heparin-binding growth factor, midkine (MK), plays an important role incarcinogenesis because of its frequent overexpression in various malignant tumours. To clarify whether or not MK contributes to theearly stage of carcinogenesis, we examined the status of MK mRNA in 20 adenomas with moderate- and severe-grade dysplasia, 28carcinomas and 28 corresponding normal tissues, by means of Northern blotting. The MK expression level was significantly moreelevated in adenomas than in normal tissues P< 0.001, unpaired Student's t -test). A difference wasalso observed between carcinomas and the corresponding normal tissues P< 0.04, paired Student's t-test). Moreover, MK immunostaining was positive in the adenomas with moderate- and severe-grade dysplasia and in the carcinomas,but not in mild-grade dysplasia or in normal tissues. These findings were in line with those on Western blotting. In three patientswith both adenomas with moderate- or severe-grade dysplasia and carcinomas, elevated MK expression was observed in the neoplasticlesions. This is the first report of the association of elevated MK expression with the early stage of carcinogenesis in humans. © 1999 Cancer Research Campaig

Gravitational waves from individual supermassive black hole binaries in circular orbits: Limits from the north american nanohertz observatory for gravitational waves

We perform a search for continuous gravitational waves from individual supermassive black hole binaries using robust frequentist and Bayesian techniques. We augment standard pulsar timing models with the addition of time-variable dispersion measure and frequency variable pulse shape terms. We apply our techniques to the Five Year Data Release from the North American Nanohertz Observatory for Gravitational Waves. We find that there is no evidence for the presence of a detectable continuous gravitational wave; however, we can use these data to place the most constraining upper limits to date on the strength of such gravitational waves. Using the full 17 pulsar data set we place a 95% upper limit on the strain amplitude of h 0 ≲ 3.0 × 10-14 at a frequency of 10 nHz. Furthermore, we place 95% sky-averaged lower limits on the luminosity distance to such gravitational wave sources, finding that dL ≳ 425 Mpc for sources at a frequency of 10 nHz and chirp mass 1010 M . We find that for gravitational wave sources near our best timed pulsars in the sky, the sensitivity of the pulsar timing array is increased by a factor of four over the sky-averaged sensitivity. Finally we place limits on the coalescence rate of the most massive supermassive black hole binaries

THE NANOGRAV NINE-YEAR DATA SET: LIMITS ON THE ISOTROPIC STOCHASTIC GRAVITATIONAL WAVE BACKGROUND

We compute upper limits on the nanohertz-frequency isotropic stochastic gravitational wave background (GWB) using the 9 year data set from the North American Nanohertz Observatory for Gravitational Waves (NANOGrav) collaboration. Well-tested Bayesian techniques are used to set upper limits on the dimensionless strain amplitude (at a frequency of 1 yr-1) for a GWB from supermassive black hole binaries of Agw \u3c 1.5 × 10-15. We also parameterize the GWB spectrum with a broken power-law model by placing priors on the strain amplitude derived from simulations of Sesana and McWilliams et al. Using Bayesian model selection we find that the data favor a broken power law to a pure power law with odds ratios of 2.2 and 22 to one for the Sesana and McWilliams prior models, respectively. Using the broken power-law analysis we construct posterior distributions on environmental factors that drive the binary to the GW-driven regime including the stellar mass density for stellar-scattering, mass accretion rate for circumbinary disk interaction, and orbital eccentricity for eccentric binaries, marking the first time that the shape of the GWB spectrum has been used to make astrophysical inferences. Returning to a power-law model, we place stringent limits on the energy density of relic GWs, Ωgw(f)h2 \u3c 4.2 × 10-10. Our limit on the cosmic string GWB, Ωgw(f)h2 \u3c 2.2 × 10-10, translates to a conservative limit on the cosmic string tension with Gμ \u3c 3.3 × 10-8, a factor of four better than the joint Planck and high-l cosmic microwave background data from other experiments

NANOGrav CONSTRAINTS on GRAVITATIONAL WAVE BURSTS with MEMORY

Among efforts to detect gravitational radiation, pulsar timing arrays are uniquely poised to detect \ memory\ signatures, permanent perturbations in spacetime from highly energetic astrophysical events such as mergers of supermassive black hole binaries. The North American Nanohertz Observatory for Gravitational Waves (NANOGrav) observes dozens of the most stable millisecond pulsars using the Arecibo and Green Bank radio telescopes in an effort to study, among other things, gravitational wave memory. We herein present the results of a search for gravitational wave bursts with memory (BWMs) using the first five years of NANOGrav observations. We develop original methods for dramatically speeding up searches for BWM signals. In the directions of the sky where our sensitivity to BWMs is best, we would detect mergers of binaries with reduced masses of 109 M⊙out to distances of 30 Mpc; such massive mergers in the Virgo cluster would be marginally detectable. We find no evidence for BWMs. However, with our non-detection, we set upper limits on the rate at which BWMs of various amplitudes could have occurred during the time spanned by our datae.g., BWMs with amplitudes greater than 10?13 must encounter the Earth at a rate less than 1.5 yr?1

The nanograv nine-year data set: Observations arrival time measurements and analysis of 37 millisecond pulsars

We present high-precision timing observations spanning up to nine years for 37 millisecond pulsars monitored with the Green Bank and Arecibo radio telescopes as part of the North American Nanohertz Observatory for Gravitational Waves (NANOGrav) project. We describe the observational and instrumental setups used to collect the data, and methodology applied for calculating pulse times of arrival; these include novel methods for measuring instrumental offsets and characterizing low signal-to-noise ratio timing results. The time of arrival data are fit to a physical timing model for each source, including terms that characterize time-variable dispersion measure and frequency-dependent pulse shape evolution. In conjunction with the timing model fit, we have performed a Bayesian analysis of a parameterized timing noise model for each source, and detect evidence for excess low-frequency, or \ red,\ timing noise in 10 of the pulsars. For 5 of these cases this is likely due to interstellar medium propagation effects rather than intrisic spin variations. Subsequent papers in this series will present further analysis of this data set aimed at detecting or limiting the presence of nanohertz-frequency gravitational wave signals

The NANOGrav 12.5-Year Data Set: Dispersion Measure Mis-Estimation with Varying Bandwidths

Noise characterization for pulsar-timing applications accounts for interstellar dispersion by assuming a known frequency-dependence of the delay it introduces in the times of arrival (TOAs). However, calculations of this delay suffer from mis-estimations due to other chromatic effects in the observations. The precision in modeling dispersion is dependent on the observed bandwidth. In this work, we calculate the offsets in infinite-frequency TOAs due to mis-estimations in the modeling of dispersion when using varying bandwidths at the Green Bank Telescope. We use a set of broadband observations of PSR J1643-1224, a pulsar with an excess of chromatic noise in its timing residuals. We artificially restricted these observations to a narrowband frequency range, then used both data sets to calculate residuals with a timing model that does not include short-scale dispersion variations. By fitting the resulting residuals to a dispersion model, and comparing the ensuing fitted parameters, we quantify the dispersion mis-estimations. Moreover, by calculating the autocovariance function of the parameters we obtained a characteristic timescale over which the dispersion mis-estimations are correlated. For PSR J1643-1224, which has one of the highest dispersion measures (DM) in the NANOGrav pulsar timing array, we find that the infinite-frequency TOAs suffer from a systematic offset of ~22 microseconds due to DM mis-estimations, with correlations over ~1 month. For lower-DM pulsars, the offset is ~7 microseconds. This error quantification can be used to provide more robust noise modeling in NANOGrav's data, thereby increasing sensitivity and improving parameter estimation in gravitational wave searches.Comment: 15 pages, 7 figure

Valvular regurgitation and surgery associated with fenfluramine use: an analysis of 5743 individuals

<p>Abstract</p> <p>Background</p> <p>Use of fenfluramines for weight loss has been associated with the development of characteristic plaques on cardiac valves causing regurgitation. However, previously published studies of exposure to fenfluramines have been limited by relatively small sample size, short duration of follow-up, and the lack of any estimate of the frequency of subsequent valvular surgery. We performed an observational study of 5743 users of fenfluramines examined by echocardiography between July 1997 and February 2004 in a single large cardiology clinic.</p> <p>Results</p> <p>The prevalence of at least mild aortic regurgitation (AR) or moderate mitral regurgitation (MR) was 19.6% in women and 11.8% in men (<it>p </it>< 0.0001 for gender difference). Duration of use was strongly predictive of mild or greater AR (<it>p </it>< 0.0001 for trend), MR (<it>p </it>= 0.002), and tricuspid regurgitation (TR) (<it>p </it>< 0.0001), as was earlier scan date (<it>p </it>< 0.0001 for those scanned prior to 1 January 2000 versus later). Increasing age was also independently associated with increased risk of AR and MR (both <it>p </it>< 0.0001). With mean follow-up of 30.3 months, AR worsened in 15.2%, remained the same in 63.1%, and improved in 21.7%. Corresponding values for MR were 24.8%, 47.4% and 27.9%. Pulmonary hypertension was strongly associated with MR but not AR. Valve surgery was performed on 38 patients (0.66% of 5743), 25 (0.44%) with clear evidence of fenfluramine-related etiology.</p> <p>Conclusion</p> <p>Regurgitant valvulopathy was common in individuals exposed to fenfluramines, more frequent in females, and associated with duration of use in all valves assessed. Valve surgery was performed as frequently for aortic as mitral valves and some tricuspid valve surgeries were also performed. The incidence of surgery appeared to be substantially increased compared with limited general population data.</p

Evaluation of midkine and anterior gradient 2 in a multimarker panel for the detection of ovarian cancer

The aims of this study were: to characterise and compare plasma concentrations of midkine (MDK) in normal healthy women with concentrations observed in women with ovarian cancer; and to establish and compare the performance of MDK with that of anterior gradient 2 protein (AGR2) and CA125 in the development of multi-analyte classification algorithms for ovarian cancer. Median plasma concentrations of immunoreactive MDK, AGR2 and CA125 were significantly greater in the case cohort (909 pg/ml, 765 pg/ml and 502 U/ml, respectively n = 46) than in the control cohort (383 pg/ml, 188 pg/ml and 13 U/ml, respectively n = 61) (p < 0.001). The area under the receiver operator characteristic curve (AUC) for MDK and AGR2 was not significantly different (0.734 ± 0.046 and 0.784 ± 0.049, respectively, mean ± SE) but were both significantly less than the AUC for CA125 (0.934 ± 0.030, p < 0.003). When subjected to stochastic gradient boosted logistic regression modelling, the AUC of the multi-analyte panel (MDK, AGR2 and CA125, 0.988 ± 0.010) was significantly greater than that of CA125 alone (0.934 ± 0.030, p = 0.035). The sensitivity and specificity of the multi-analyte algorithm were 95.2 and 97.7%, respectively. Within the study cohort, CA125 displayed a sensitivity and specificity of 87.0 and 94.6%, respectively. The data obtained in this study confirm that both MDK and AGR2 individually display utility as biomarkers for ovarian cancer and that in a multi-analyte panel significantly improve the diagnostic utility of CA125 in symptomatic women

An initial psychometric evaluation and exploratory cross-sectional study of the Body Checking Questionnaire among Brazilian women

Body checking is considered an expression of an excessive preoccupation with appearance. The first aim of this study was to evaluate the psychometric properties of a Brazilian Portuguese version of the Body Checking Questionnaire (BCQ). Additionally, we wanted to examine the questionnaire’s associations with body avoidance behaviour, body mass index, dietary habits, and the intensity, frequency, and length of physical exercise. Finally, we also examined the differences between the total BCQ score and the individual BCQ factor scores. Differences between active and sedentary persons and between non-dieters and those on weight-loss diets were also analyzed. For the psychometric study, 546 female public university students from four different courses were surveyed. Two minor samples of university students and eating disorders women were also recruited. In the second part of the study, 403 women were recruited from weight-loss programs, gyms, and a university. All participants were verbally invited to participate in the research and voluntarily took part. Confirmatory factor analysis showed a good fit to the original model of the Brazilian BCQ that retained all 23 items. Satisfactory evidence of construct validity and internal consistency were also generated through analysis of factor loadings, t-values, Cronbach’s alpha, and construct reliability tests. The results also showed associations among body checking and body avoidance, body satisfaction, social anxiety, body mass index, and the frequency and intensity of physical exercise. Significant differences were found between non-dieters and weight-loss dieters for all BCQ factors and the total BCQ score. For physically active and sedentary persons, a significant difference was only observed for idiosyncratic checking behaviour. In conclusion, the BCQ appears to be a valid and reliable scale for Brazilian research, and the associations and differences found in this study suggest that women at gyms and especially in weight-loss programs should be targeted for future body checking studies

The NANOGrav Nine-year Data Set:Limits on the Isotropic Stochastic Gravitational Wave Background

We compute upper limits on the nanohertz-frequency isotropic stochastic gravitational wave background (GWB) using the 9 year data set from the North American Nanohertz Observatory for Gravitational Waves (NANOGrav) collaboration. Well-tested Bayesian techniques are used to set upper limits on the dimensionless strain amplitude (at a frequency of 1 yr(-1)) for a GWB from supermassive black hole binaries of A(gw) <1.5 x 10(-15). We also parameterize the GWB spectrum with a broken power-law model by placing priors on the strain amplitude derived from simulations of Sesana and McWilliams et al. Using Bayesian model selection we find that the data favor a broken power law to a pure power law with odds ratios of 2.2 and 22 to one for the Sesana and McWilliams prior models, respectively. Using the broken power-law analysis we construct posterior distributions on environmental factors that drive the binary to the GW-driven regime including the stellar mass density for stellar-scattering, mass accretion rate for circumbinary disk interaction, and orbital eccentricity for eccentric binaries, marking the first time that the shape of the GWB spectrum has been used to make astrophysical inferences. Returning to a power-law model, we place stringent limits on the energy density of relic GWs, Omega(gw) (f)h(2) <4.2 x 10(-10). Our limit on the cosmic string GWB, Omega(gw) (f)h(2) <2.2 x 10(-10), translates to a conservative limit on the cosmic string tension with G mu <3.3 x 10(-8), a factor of four better than the joint Planck and high-l cosmic microwave background data from other experiments