Star Formation Feedback and Metal Enrichment History Of The Intergalactic Medium

Using hydrodynamic simulations we compute the metal enrichment history of the intergalactic medium (IGM). We show that galactic superwind (GSW) feedback can transport metals to the IGM and that the properties of simulated metal absorbers match observations. The distance of influence of GSW is typically limited to >0.5Mpc and within regions of overdensity >10. Most CIV and OVI absorbers are located within shocked regions of elevated temperature (T>2x10^4K), overdensity (>10), and metallicity ([-2.5,-0.5]). OVI absorbers have typically higher metallicity, lower density and higher temperature than CIV absorbers. For OVI absorbers collisional ionization dominates over the entire redshift range z=0-6, whereas for CIV absorbers the transition occurs at moderate redshift z~3 from collisionally dominated to photoionization dominated. We find that the observed column density distributions for CIV and OVI in the range log N cm^2=12-15 are reasonably reproduced by the simulations. The evolution of mass densities contained in CIV and OVI lines, Omega_CIV and Omega_OVI, is also in good agreement with observations, which shows a near constancy at low redshifts and an exponential drop beyond redshift z=3-4. For both CIV and OVI, most absorbers are transient and the amount of metals probed by CIV and OVI lines of column log N cm^2=12-15 is only ~2% of total metal density at any epoch. While gravitational shocks from large-scale structure formation dominate the energy budget (80-90%) for turning about 50% of IGM to the warm-hot intergalactic medium (WHIM) by z=0, GSW feedback shocks are energetically dominant over gravitational shocks at z > 1-2. Most of the so-called "missing metals" at z=2-3 are hidden in a warm-hot (T=10^{4.5-7}K) gaseous phase, heated up by GSW feedback shocks. Their mass distribution is broadly peaked at $\delta=1-10$ in the IGM, outside virialized halos.Comment: 52 pages, 26 figures, published in the Astrophysical Journal, 2011, ApJ, 731, 1

Clinical characteristics of a large cohort of patients with narcolepsy candidate for pitolisant: a cross-sectional study from the Italian PASS Wakix® Cohort

Introduction Narcolepsy is a chronic and rare hypersomnia of central origin characterized by excessive daytime sleepiness and a complex array of symptoms as well as by several medical comorbidities. With growing pharmacological options, polytherapy may increase the possibility of a patient-centered management of narcolepsy symptoms. The aims of our study are to describe a large cohort of Italian patients with narcolepsy who were candidates for pitolisant treatment and to compare patients' subgroups based on current drug prescription (drug-naive patients in whom pitolisant was the first-choice treatment, switching to pitolisant from other monotherapy treatments, and adding on in polytherapy). Methods We conducted a cross-sectional survey based on Italian data from the inclusion visits of the Post Authorization Safety Study of pitolisant, a 5-year observational, multicenter, international study. Results One hundred ninety-one patients were enrolled (76.4% with narcolepsy type 1 and 23.6% with narcolepsy type 2). Most patients (63.4%) presented at least one comorbidity, mainly cardiovascular and psychiatric. Pitolisant was prescribed as an add-on treatment in 120/191 patients (62.8%), as switch from other therapies in 42/191 (22.0%), and as a first-line treatment in 29/191 (15.2%). Drug-naive patients presented more severe sleepiness, lower functional status, and a higher incidence of depressive symptoms. Conclusion Our study presents the picture of a large cohort of Italian patients with narcolepsy who were prescribed with pitolisant, suggesting that polytherapy is highly frequent to tailor a patient-centered approach

ALDH1A2 (RALDH2) genetic variation in human congenital heart disease

Abstract\ud \ud \ud \ud Background\ud \ud Signaling by the vitamin A-derived morphogen retinoic acid (RA) is required at multiple steps of cardiac development. Since conversion of retinaldehyde to RA by retinaldehyde dehydrogenase type II (ALDH1A2, a.k.a RALDH2) is critical for cardiac development, we screened patients with congenital heart disease (CHDs) for genetic variation at the ALDH1A2 locus.\ud \ud \ud \ud Methods\ud \ud One-hundred and thirty-three CHD patients were screened for genetic variation at the ALDH1A2 locus through bi-directional sequencing. In addition, six SNPs (rs2704188, rs1441815, rs3784259, rs1530293, rs1899430) at the same locus were studied using a TDT-based association approach in 101 CHD trios. Observed mutations were modeled through molecular mechanics (MM) simulations using the AMBER 9 package, Sander and Pmemd programs. Sequence conservation of observed mutations was evaluated through phylogenetic tree construction from ungapped alignments containing ALDH8 s, ALDH1Ls, ALDH1 s and ALDH2 s. Trees were generated by the Neighbor Joining method. Variations potentially affecting splicing mechanisms were cloned and functional assays were designed to test splicing alterations using the pSPL3 splicing assay.\ud \ud \ud \ud Results\ud \ud We describe in Tetralogy of Fallot (TOF) the mutations Ala151Ser and Ile157Thr that change non-polar to polar residues at exon 4. Exon 4 encodes part of the highly-conserved tetramerization domain, a structural motif required for ALDH oligomerization. Molecular mechanics simulation studies of the two mutations indicate that they hinder tetramerization. We determined that the SNP rs16939660, previously associated with spina bifida and observed in patients with TOF, does not affect splicing. Moreover, association studies performed with classical models and with the transmission disequilibrium test (TDT) design using single marker genotype, or haplotype information do not show differences between cases and controls.\ud \ud \ud \ud Conclusion\ud \ud In summary, our screen indicates that ALDH1A2 genetic variation is present in TOF patients, suggesting a possible causal role for this gene in rare cases of human CHD, but does not support the hypothesis that variation at the ALDH1A2 locus is a significant modifier of the risk for CHD in humans.Work supported by grants from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) 01/000090; 00/030722; 01/142381; 02/113402; 03/099982; 04/116068; 04/157044 and Conselho Nacional de Desenvolvimento Científico e Tecnológico 481872/20078. We would like to thank the careful work and thoughtful suggestions of the two reviewers responsible for the reviewing editorial process.Work supported by grants from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) 01/00009-0; 00/03072-2; 01/14238-1; 02/11340-2; 03/09998-2; 04/11606-8; 04/15704-4 and Conselho Nacional de Desenvolvimento Científico e Tecnológico 481872/2007-8. We would like to thank the careful work and thoughtful suggestions of the two reviewers responsible for the reviewing editorial process