The impact of massive stars on the interstellar medium

In this thesis I present results of numerical simulations carried out with a two-dimensional radiation hydrodynamics code in order to study the impact of massive stars on their surrounding interstellar medium. The evolution of the circumstellar gas is examined for two model stars with different evolutionary tracks and stellar parameters: The first star has an inital mass of 60 solar masses and evolves from a main-sequence O star through luminous blue variable and Wolf-Rayet phases, until it ultimately explodes as a supernova of Type II. The second model star, initially having a mass of 35 solar masses, is supposed to undergo the evolution from the main sequence to the red supergiant and finally the Wolf-Rayet phase, until it also explodes as a supernova. In the 60 solar mass case the interaction of the photoionized HII region with the stellar wind bubble forms a variety of interesting structures like shells, clouds, fingers, and spokes. These results demonstrate that complex structures found in HII regions are not necessarily relics from the time before the gas became ionized but may result from dynamical processes during the course of the HII region evolution. In the 35 solar mass case structure formation in the circumstellar gas during the early main-sequence evolution is much less pronounced because of the lower mechanical wind luminosity of the star. On the other hand, since the shell-like structure of the HII region is largely preserved, effects that rely on this symmetry become more important. I have also analyzed the transfer and deposit of the stellar wind and radiation energy into the circumstellar medium. At the end of the stellar lifetime 0.37 % of the energy released by the 60 solar mass star as Lyman continuum radiation and stellar wind has been transferred to the circumstellar gas. From this fraction 35 % is kinetic energy of bulk motion, 40 % is thermal energy, and the remaining 25 % is ionization energy of hydrogen. The respective values in the 35 solar mass case are 10 %, 36 %, and 54 %, for a total energy transfer efficiency of 1 %. The sweeping up of the slow red supergiant wind by the fast Wolf-Rayet wind in the 35 solar mass case produces remarkable morphological structures and emission signatures, which are compared with existing observations of the Wolf-Rayet bubble S308, whose central star has probably evolved in a manner very similar to the model star. My model reproduces the correct order of magnitude of observed X-ray luminosity, the temperature of the emitting plasma, and the limb brightening of the X-ray intensity profile. This is remarkable, because current analytical and numerical models of Wolf-Rayet bubbles fail to consistently explain these features. A key result is that almost the entire X-ray emission in this stage comes from the shell of red supergiant wind swept up by the shocked Wolf-Rayet wind rather than from the shocked Wolf-Rayet wind itself as hitherto assumed and modeled. This offers a possible solution to what is called the "missing wind problem" of Wolf-Rayet bubbles

Screening Questionnaires for Problem Drinking in Adolescents: Performance of AUDIT, AUDIT-C, CRAFFT and POSIT

Background/Aims: Only rather few data on the validity of screening questionnaires to detect problem drinking in adolescents exist. The aim of this study was to compare the performance of the Alcohol Use Disorders Identification Test (AUDIT), its short form AUDIT-C, the Substance Module of the Problem Oriented Screening Instrument for Teenagers (POSIT), and CRAFFT (acronym for car, relax, alone, forget, family, and friends). Methods: The questionnaires were filled in by 9th and 10th graders from two comprehensive schools. All students received an interview using the alcohol section of the Composite International Diagnostic Interview. Alcohol abuse and alcohol dependence according to DSM-IV as well as episodic heavy drinking served as criteria to validate the screening instruments. Results: All 9th and 10th graders (n = 225) of both schools participated. No significant differences were found for areas under the receiver operating characteristic curves ranging from 0.810 to 0.872. Cronbach’s alpha was satisfactory (0.77–0.80) but poor for CRAFFT (0.64). Different cut-offs are discussed. Conclusions: Considering validity as well as reliability, AUDIT, AUDIT-C and POSIT performed well; however, the POSIT is quite lengthy. AUDIT-C showed good psychometric properties and has clear advantages because of its brevity

Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease

The scurfy mutant mouse strain suffers from a fatal lymphoproliferative disease leading to early death within 3–4 wk of age. A frame-shift mutation of the forkhead box transcription factor Foxp3 has been identified as the molecular cause of this multiorgan autoimmune disease. Foxp3 is a central control element in the development and function of regulatory T cells (T reg cells), which are necessary for the maintenance of self-tolerance. However, it is unclear whether dysfunction or a lack of T reg cells is etiologically involved in scurfy pathogenesis and its human correlate, the IPEX syndrome. We describe the generation of bacterial artificial chromosome–transgenic mice termed “depletion of regulatory T cell” (DEREG) mice expressing a diphtheria toxin (DT) receptor–enhanced green fluorescent protein fusion protein under the control of the foxp3 gene locus, allowing selective and efficient depletion of Foxp3+ T reg cells by DT injection. Ablation of Foxp3+ T reg cells in newborn DEREG mice led to the development of scurfy-like symptoms with splenomegaly, lymphadenopathy, insulitis, and severe skin inflammation. Thus, these data provide experimental evidence that the absence of Foxp3+ T reg cells is indeed sufficient to induce a scurfy-like phenotype. Furthermore, DEREG mice will allow a more precise definition of the function of Foxp3+ T reg cells in immune reactions in vivo

Massive stars and the energy balance of the interstellar medium. II. The 35 solar mass star and a solution to the "missing wind problem"

We continue our numerical analysis of the morphological and energetic influence of massive stars on their ambient interstellar medium for a 35 solar mass star that evolves from the main sequence through red supergiant and Wolf-Rayet phases, until it ultimately explodes as a supernova. We find that structure formation in the circumstellar gas during the early main-sequence evolution occurs as in the 60 solar mass case but is much less pronounced because of the lower mechanical wind luminosity of the star. Since on the other hand the shell-like structure of the HII region is largely preserved, effects that rely on this symmetry become more important. At the end of the stellar lifetime 1% of the energy released as Lyman continuum radiation and stellar wind has been transferred to the circumstellar gas. From this fraction 10% is kinetic energy of bulk motion, 36% is thermal energy, and the remaining 54% is ionization energy of hydrogen. The sweeping up of the slow red supergiant wind by the fast Wolf-Rayet wind produces remarkable morphological structures and emission signatures, which are compared with existing observations of the Wolf-Rayet bubble S308. Our model reproduces the correct order of magnitude of observed X-ray luminosity, the temperature of the emitting plasma as well as the limb brightening of the intensity profile. This is remarkable, because current analytical and numerical models of Wolf-Rayet bubbles fail to consistently explain these features. A key result is that almost the entire X-ray emission in this stage comes from the shell of red supergiant wind swept up by the shocked Wolf-Rayet wind rather than from the shocked Wolf-Rayet wind itself as hitherto assumed and modeled. This offers a possible solution to what is called the ``missing wind problem'' of Wolf-Rayet bubbles.Comment: 52 pages, 20 figures, 2 tables, accepted for publication in the Astrophysical Journa

Absence of the Autophagy Adaptor SQSTM1/p62 Causes Childhood-Onset Neurodegeneration with Ataxia, Dystonia, and Gaze Palsy

Peer reviewe

Extra-cellular matrix proteins induce matrix metalloproteinase-1 (MMP-1) activity and increase airway smooth muscle contraction in asthma

Airway remodelling describes the histopathological changes leading to fixed airway obstruction in patients with asthma and includes extra-cellular matrix (ECM) deposition. Matrix metalloproteinase-1 (MMP-1) is present in remodelled airways but its relationship with ECM proteins and the resulting functional consequences are unknown. We used airway smooth muscle cells (ASM) and bronchial biopsies from control donors and patients with asthma to examine the regulation of MMP-1 by ECM in ASM cells and the effect of MMP-1 on ASM contraction. Collagen-I and tenascin-C induced MMP-1 protein expression, which for tenascin-C, was greater in asthma derived ASM cells. Tenascin-C induced MMP-1 expression was dependent on ERK1/2, JNK and p38 MAPK activation and attenuated by function blocking antibodies against the β1 and β3 integrin subunits. Tenascin-C and MMP-1 were not expressed in normal airways but co-localised in the ASM bundles and reticular basement membrane of patients with asthma. Further, ECM from asthma derived ASM cells stimulated MMP-1 expression to a greater degree than ECM from normal ASM. Bradykinin induced contraction of ASM cells seeded in 3D collagen gels was reduced by the MMP inhibitor ilomastat and by siRNA knockdown of MMP-1. In summary, the induction of MMP-1 in ASM cells by tenascin-C occurs in part via integrin mediated MAPK signalling. MMP-1 and tenascin-C are co-localised in the smooth muscle bundles of patients with asthma where this interaction may contribute to enhanced airway contraction. Our findings suggest that ECM changes in airway remodelling via MMP-1 could contribute to an environment promoting greater airway narrowing in response to broncho-constrictor stimuli and worsening asthma symptoms

Implementing Routine HIV Testing: The Role of State Law

In September 2006, the Centers for Disease Control and Prevention (CDC) recommended routine HIV testing for all Americans aged 13–64, which would eliminate requirements for written consent and pretest counseling as previously required. However, this approach may conflict with state requirements concerning pretest counseling and informed consent for HIV testing. Our survey of state HIV testing laws demonstrates that the majority of states have HIV testing requirements that are inconsistent with the CDC's recommendations. Moreover, states that have recently amended their laws have not eased the requirements for pretest counseling and informed consent. The reasons for the persistence of these legal requirements must be understood to effect policy changes to increase HIV testing

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention

Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1

Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 × 10-5) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 × 10-5). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10-10, odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression