A novel deletion mutation of the EXT2 gene in a large Chinese pedigree with hereditary multiple exostosis

Hereditary multiple exostoses (EXT) is an autosomal dominant disease characterized by the formation of cartilage-capped prominences (exostoses) that develop from the juxta-epiphyseal regions of the long bones. 3 genes are known to be involved in the formation of exostoses. Among them, EXT1 and EXT2, which encode enzymes that catalyse the biosynthesis of heparan sulfate, an important component of the extracellular matrix, are responsible for over 70% of the EXT cases. A large Chinese family with hereditary multiple exostoses has been analysed and the disease-causing mutation has been found. Blood samples were obtained from 69 family members, including 23 affected individuals. The EXT phenotype was shown to be linked to the EXT2 gene by using 2-point linkage analysis. After polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) analysis and DNA sequencing, a previously unreported deletion of a G in exon 3 of EXT2 gene was observed. This deletion co-segregated with the disease phenotype, suggesting that it is the disease-causing mutation in this family. Furthermore, in at least 4 members chondrosarcoma occurred after either an operation or injury of the exostosis and 3 of them died of the malignance in the family. Whether the operation or injury was responsible for the malignant transformation still needs further study. © 2001 Cancer Research Campaign http://www.bjcancer.co

The pair faction of massive galaxies at 0 ≤ z ≤ 3

Using a mass-selected (M-star >= 10(11) M-circle dot) sample of 198 galaxies at 0 <= z <= 3.0 with Hubble Space Telescope/NICMOS H-160-band images from the COSMOS survey, we find evidence for the evolution of the pair fraction above z similar to 2, an epoch in which massive galaxies are believed to undergo significant structural and mass evolution. We observe that the pair fraction of massive galaxies is 0.15 +/- 0.08 at 1.7 <= z <= 3.0, where galaxy pairs are defined as massive galaxies having a companion of flux ratio from 1:1 to 1:4 within a projected separation of 30 kpc. This is slightly lower but still consistent with the pair fraction measured previously in other studies, and the merger fraction predicted in halo-occupation modeling. The redshift evolution of the pair fraction is described by a power law F(z) = (0.07 +/- 0.04) x (1 + z)(0.6 +/- 0.5). The merger rate is consistent with no redshift evolution; however it is difficult to constrain due to the limited sample size and the high uncertainties in the merging timescale. Based on the merger rate calculation, we estimate that a massive galaxy undergoes on average 1.1 +/- 0.5 major mergers from z = 3 to 0. The observed merger fraction is sufficient to explain the number density evolution of massive galaxies, but insufficient to explain the size evolution. This is a hint that mechanism(s) other than major merging may be required to increase the sizes of the massive, compact quiescent galaxies from z similar to 2 to 0

Sildenafil added to pirfenidone in patients with advanced idiopathic pulmonary fibrosis and risk of pulmonary hypertension: A Phase IIb, randomised, double-blind, placebo-controlled study &#8211; Rationale and study design

Background: Pulmonary hypertension (PH) is commonly observed in patients with advanced idiopathic pulmonary fibrosis (IPF). Despite the availability of therapies for both IPF and PH, none are approved for PH treatment in the context of significant pulmonary disease. This study will investigate the use of sildenafil added to pirfenidone in patients with advanced IPF and risk of PH, who represent a group with a high unmet medical need. Methods: This Phase IIb, randomised, double-blind, placebo-controlled trial is actively enrolling patients and will study the efficacy, safety and tolerability of sildenafil or placebo in patients with advanced IPF and intermediate or high probability of Group 3 PH who are receiving a stable dose of pirfenidone. Patients with advanced IPF (diffusing capacity for carbon monoxide 6440% predicted) and risk of Group 3 PH (defined as mean pulmonary arterial pressure 6520 mm Hg with pulmonary arterial wedge pressure 6415 mm Hg on a previous right-heart catheterisation [RHC], or intermediate/high probability of Group 3 PH as defined by the 2015 European Society of Cardiology/European Respiratory Society guidelines) are eligible. In the absence of a previous RHC, patients with an echocardiogram showing a peak tricuspid valve regurgitation velocity 652.9 m/s can enrol if all other criteria are met. The primary efficacy endpoint is the proportion of patients with disease progression over a 52-week treatment period. Safety will be evaluated descriptively. Discussion: Combination treatment with sildenafil and pirfenidone may warrant investigation of the treatment of patients with advanced IPF and pulmonary vascular involvement leading to PH

Sub-millimeter galaxies as progenitors of compact quiescent galaxies

Three billion years after the big bang (at redshift z=2), half of the most massive galaxies were already old, quiescent systems with little to no residual star formation and extremely compact with stellar mass densities at least an order of magnitude larger than in low redshift ellipticals, their descendants. Little is known about how they formed, but their evolved, dense stellar populations suggest formation within intense, compact starbursts 1-2 Gyr earlier (at 3<z<6). Simulations show that gas-rich major mergers can give rise to such starbursts which produce dense remnants. Sub-millimeter selected galaxies (SMGs) are prime examples of intense, gas-rich, starbursts. With a new, representative spectroscopic sample of compact quiescent galaxies at z=2 and a statistically well-understood sample of SMGs, we show that z=3-6 SMGs are consistent with being the progenitors of z=2 quiescent galaxies, matching their formation redshifts and their distributions of sizes, stellar masses and internal velocities. Assuming an evolutionary connection, their space densities also match if the mean duty cycle of SMG starbursts is 42 (+40/-29) Myr (consistent with independent estimates), which indicates that the bulk of stars in these massive galaxies were formed in a major, early surge of star-formation. These results suggests a coherent picture of the formation history of the most massive galaxies in the universe, from their initial burst of violent star-formation through their appearance as high stellar-density galaxy cores and to their ultimate fate as giant ellipticals.Comment: ApJ (in press

Ultra-deep Spitzer Mid-Infrared Spectroscopy of LIRGs and ULIRGs at z ~ 1-2

We present ultra-deep mid-IR spectra of 48 infrared-luminous galaxies in the GOODS-South field obtained with the InfraRed Spectrograph (IRS) on the Spitzer Space Telescope. These galaxies are selected among faint infrared sources (0.14 - 0.5 mJy at 24 um) in two redshift bins (0.76-1.05 and 1.75-2.4) to sample the major contributors to the cosmic infrared background at the most active epochs. We estimate redshifts for 92% of the sample using PAH and Si absorption features. Only few of these galaxies (5% at z~1 and 12% at z~2) have their total infrared luminosity dominated by emission from AGN. The averaged mid-IR spectra of the z~1 LIRGs and of the z~2 ULIRGs are very similar to the averaged spectrum of local starbursts and HII-like ULIRGs, respectively. We find that 6.2um PAH equivalent widths reach a plateau of ~1 um for L(24 mu) < 1E11 L(sun). At higher luminosities, EW (6.2 mu) anti-correlates with L(24 um). Intriguingly, high-z ULIRGs and SMG lie above the local EW (6.2 um) - L(24 um) relationship suggesting that, at a given luminosity, high-z ULIRGs have AGN contributions to their dust emission lower than those of local counterparts. A quantitative analysis of their morphology shows that most of the luminous IR galaxies have morphologies similar to those of IR-quiet galaxies at the same redshift. All z~2 ULIRGs of our sample are IR-excess BzK galaxies and most of them have L(FIR)/L(1600A) ratios higher than those of starburst galaxies at a given UV slope. The ``IR excess'' (Daddi et al. 2007) is mostly due to strong 7.7 um PAH emission and under-estimation of UV dust extinction. On the basis of the AGN-powered L (6 um) continuum measured directly from the mid-IR spectra, we estimate an average intrinsic X-ray AGN luminosity of L(2-10 keV) = (0.1 +/- 0.6) 1E43 erg/s, a value substantially lower than the prediction by Daddi et al. (2007).Comment: 45 pages, 36 figures, 2 tables, accepted for publication on Ap

DOCK6 Mutations Are Responsible for a Distinct Autosomal-Recessive Variant of Adams-Oliver Syndrome Associated with Brain and Eye Anomalies

Author contacted for file

Structure of Protocluster Galaxies: Accelerated Structural Evolution in Overdense Environments?

We present a high spatial-resolution HST/NICMOS imaging survey in the field of a known protocluster surrounding the powerful radio galaxy MRC1138-262 at z=2.16. Previously, we have shown that this field exhibits a substantial surface overdensity of red J-H galaxies. Here we focus on the stellar masses and galaxy effective radii in an effort to compare and contrast the properties of likely protocluster galaxies with their field counterparts and to look for correlations between galaxy structure and (projected) distance relative to the radio galaxy. We find a hint that quiescent, cluster galaxies are on average less dense than quiescent field galaxies of similar stellar mass and redshift. In fact, we find only two (of nine) quiescent protocluster galaxies are of simliar density to the majority of the massive, quiescent compact galaxies (SEEDs) found in several field surveys. Furthermore, there is some indication that the structural Sersic n parameter is higher (n ~ 3-4) on average for cluster galaxies compared to the field SEEDs (n ~ 1-2) This result may imply that the accelerated galaxy evolution expected (and observed) in overdense regions also extends to structural evolution presuming that massive galaxies began as dense (low n) SEEDs and have already evolved to be more in line with local galaxies of the same stellar mass.Comment: 11 pages, 7 figures, 1 table, Accepted for publication in Ap