Clinical and inflammatory characteristics of the European U-BIOPRED adult severe asthma cohort

U-BIOPRED is a European Union consortium of 20 academic institutions, 11 pharmaceutical companies and six patient organisations with the objective of improving the understanding of asthma disease mechanisms using a systems biology approach.This cross-sectional assessment of adults with severe asthma, mild/moderate asthma and healthy controls from 11 European countries consisted of analyses of patient-reported outcomes, lung function, blood and airway inflammatory measurements.Patients with severe asthma (nonsmokers, n=311; smokers/ex-smokers, n=110) had more symptoms and exacerbations compared to patients with mild/moderate disease (n=88) (2.5 exacerbations versus 0.4 in the preceding 12 months; p<0.001), with worse quality of life, and higher levels of anxiety and depression. They also had a higher incidence of nasal polyps and gastro-oesophageal reflux with lower lung function. Sputum eosinophil count was higher in severe asthma compared to mild/moderate asthma (median count 2.99% versus 1.05%; p=0.004) despite treatment with higher doses of inhaled and/or oral corticosteroids.Consistent with other severe asthma cohorts, U-BIOPRED is characterised by poor symptom control, increased comorbidity and airway inflammation, despite high levels of treatment. It is well suited to identify asthma phenotypes using the array of "omic" datasets that are at the core of this systems medicine approach.

Core outcomes and definitions for pediatric fever and neutropenia research: a consensus statement from an international panel.

BACKGROUND There are no specific recommendations for the design and reporting of studies of children with fever and neutropenia (FN). As a result, there is marked heterogeneity in the variables and outcomes that are reported and new definitions continue to emerge. These inconsistencies hinder the ability of researchers and clinicians to compare, contrast and combine results. The objective was to achieve expert consensus on a core set of variables and outcomes that should be measured and reported, as a minimum, in pediatric FN studies. PROCEDURE The Delphi method was used to achieve consensus among an international group of clinicians, pharmacists, researchers, and patient representatives. Four surveys focusing on (i) the identification of a core set of variables and outcomes; and (ii) definitions of these variables and outcomes, were administered electronically. Consensus was predefined as more than 80% agreement on any statement. RESULTS There were forty-five survey participants and the response rate ranged between 84 and 96%. There was consensus on eight core variables and 10 core outcomes that should be collected and reported in all studies of children with FN. Consensus definitions were identified for all of the core outcomes. CONCLUSION Using the Delphi method, expert consensus on a set of core variables and outcomes, and their corresponding definitions, was achieved. These core sets represent the minimum that should be collected and reported in all studies of children with FN. This will promote collaboration and ensure consistency and comparability between studies.

Phenotype and genotype in 103 patients with tricho-rhino-phalangeal syndrome.

Tricho-rhino-phalangeal syndrome (TRPS) is characterized by craniofacial and skeletal abnormalities, and subdivided in TRPS I, caused by mutations in TRPS1, and TRPS II, caused by a contiguous gene deletion affecting (amongst others) TRPS1 and EXT1. We performed a collaborative international study to delineate phenotype, natural history, variability, and genotype-phenotype correlations in more detail. We gathered information on 103 cytogenetically or molecularly confirmed affected individuals. TRPS I was present in 85 individuals (22 missense mutations, 62 other mutations), TRPS II in 14, and in 5 it remained uncertain whether TRPS1 was partially or completely deleted. Main features defining the facial phenotype include fine and sparse hair, thick and broad eyebrows, especially the medial portion, a broad nasal ridge and tip, underdeveloped nasal alae, and a broad columella. The facial manifestations in patients with TRPS I and TRPS II do not show a significant difference. In the limbs the main findings are short hands and feet, hypermobility, and a tendency for isolated metacarpals and metatarsals to be shortened. Nails of fingers and toes are typically thin and dystrophic. The radiological hallmark are the cone-shaped epiphyses and in TRPS II multiple exostoses. Osteopenia is common in both, as is reduced linear growth, both prenatally and postnatally. Variability for all findings, also within a single family, can be marked. Morbidity mostly concerns joint problems, manifesting in increased or decreased mobility, pain and in a minority an increased fracture rate. The hips can be markedly affected at a (very) young age. Intellectual disability is uncommon in TRPS I and, if present, usually mild. In TRPS II intellectual disability is present in most but not all, and again typically mild to moderate in severity. Missense mutations are located exclusively in exon 6 and 7 of TRPS1. Other mutations are located anywhere in exons 4-7. Whole gene deletions are common but have variable breakpoints. Most of the phenotype in patients with TRPS II is explained by the deletion of TRPS1 and EXT1, but haploinsufficiency of RAD21 is also likely to contribute. Genotype-phenotype studies showed that mutations located in exon 6 may have somewhat more pronounced facial characteristics and more marked shortening of hands and feet compared to mutations located elsewhere in TRPS1, but numbers are too small to allow firm conclusions.

Mutation Update of the CLCN5 Gene Responsible for Dent Disease 1

Dent disease is a rare X-linked tubulopathy characterized by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis and/or nephrolithiasis, progressive renal failure, and variable manifestations of other proximal tubule dysfunctions. It often progresses over a few decades to chronic renal insufficiency, and therefore molecular characterization is important to allow appropriate genetic counseling. Two genetic subtypes have been described to date: Dent disease 1 is caused by mutations of the CLCN5 gene, coding for the chloride/proton exchanger ClC-5; and Dent disease 2 by mutations of the OCRL gene, coding for the inositol polyphosphate 5-phosphatase OCRL-1. Herein, we review previously reported mutations (n = 192) and their associated phenotype in 377 male patients with Dent disease 1 and describe phenotype and novel (n = 42) and recurrent mutations (n = 24) in a large cohort of 117 Dent disease 1 patients belonging to 90 families. The novel missense and in-frame mutations described were mapped onto a three-dimensional homology model of the ClC-5 protein. This analysis suggests that these mutations affect the dimerization process, helix stability, or transport. The phenotype of our cohort patients supports and extends the phenotype that has been reported in smaller studies.

Ist der Name schon Programm? Die GLP-Wählerschaft und ihre grünen und freisinnigen Wurzeln

1. Einleitung 2. Theorie: grün und liberal im politischen Raum 2.1 Der «alte» ökonomische Konflikt 2.2 «Neue» Einstellungskonflikte: Ökologie vs. Ökonomie 2.3 Einstellungen bezüglich Öffnung-Schliessung (Immigration, EU-Integration) 3. Die Wählerbetrachtung: die Merkmale und Einstellungen der GLP-Basis 3.1 Das sozioökonomische Profil der GLP-Wählerschaft 3.2 Das Einstellungsprofil der GLP-Wählerschaft 4. Die Elitenbetrachtung: parteiinterne Positionierung und inhaltliche Schwerpunkte der GLP 5. Die Parteielite und die Wählerschaft der GLP im Vergleich 6. Schlussbetrachtungen

Ist der Name schon Programm? Die GLP-Wählerschaft und ihre grünen und freisinnigen Wurzeln

Negativ ausgedrückt ist die GLP weder richtig grün noch richtig liberal. Positiv ausgedrückt ist sie beides ein bisschen. Zu diesem Schluss kommen die Professorinnen Isabelle Stadelmann-Steffen und Karin Ingold von der Universität Bern, die die Präferenzen der Wählerschaft der GLP untersucht haben.

Effect of calf purchase and other herd-level risk factors on mortality, unwanted early slaughter, and use of antimicrobial group treatments in Swiss veal calf operations.

The objective of this survey was to determine herd level risk factors for mortality, unwanted early slaughter, and metaphylactic application of antimicrobial group therapy in Swiss veal calves in 2013. A questionnaire regarding farm structure, farm management, mortality and antimicrobial use was sent to all farmers registered in a Swiss label program setting requirements for improved animal welfare and sustainability. Risk factors were determined by multivariable logistic regression. A total of 619 veal producers returned a useable questionnaire (response rate=28.5%), of which 40.9% only fattened their own calves (group O), 56.9% their own calves and additional purchased calves (group O&P), and 2.3% only purchased calves for fattening (group P). A total number of 19,077 calves entered the fattening units in 2013, of which 21.7%, 66.7%, and 11.6% belonged to groups O, O&P, and P, respectively. Mortality was 0% in 322 herds (52.0%), between 0% and 3% in 47 herds (7.6%), and ≥3% in 250 herds (40.4%). Significant risk factors for mortality were purchasing calves, herd size, higher incidence of BRD, and access to an outside pen. Metaphylaxis was used on 13.4% of the farms (7.9% only upon arrival, 4.4% only later in the fattening period, 1.1% upon arrival and later), in 3.2% of the herds of group O, 17.9% of those in group O&P, and 92.9% of those of group P. Application of metaphylaxis upon arrival was positively associated with purchase (OR=8.9) and herd size (OR=1.2 per 10 calves). Metaphylaxis later in the production cycle was positively associated with group size (OR=2.9) and risk of respiratory disease (OR=1.2 per 10% higher risk) and negatively with the use of individual antimicrobial treatment (OR=0.3). In many countries, purchase and a large herd size are inherently connected to veal production. The Swiss situation with large commercial but also smaller herds with little or no purchase of calves made it possible to investigate the effect of these factors on mortality and antimicrobial drug use. The results of this study show that a system where small farms raise the calves from their own herds has a substantial potential to improve animal health and reduce antimicrobial drug use.

Expert Opinion on the Perceived Effectiveness and Importance of On-Farm Biosecurity Measures for Cattle and Swine Farms in Switzerland.

Biosecurity is crucial for safeguarding livestock from infectious diseases. Despite the plethora of biosecurity recommendations, published scientific evidence on the effectiveness of individual biosecurity measures is limited. The objective of this study was to assess the perception of Swiss experts about the effectiveness and importance of individual on-farm biosecurity measures for cattle and swine farms (31 and 30 measures, respectively). Using a modified Delphi method, 16 Swiss livestock disease specialists (8 for each species) were interviewed. The experts were asked to rank biosecurity measures that were written on cards, by allocating a score from 0 (lowest) to 5 (highest). Experts ranked biosecurity measures based on their importance related to Swiss legislation, feasibility, as well as the effort required for implementation and the benefit of each biosecurity measure. The experts also ranked biosecurity measures based on their effectiveness in preventing an infectious agent from entering and spreading on a farm, solely based on transmission characteristics of specific pathogens. The pathogens considered by cattle experts were those causing Bluetongue (BT), Bovine Viral Diarrhea (BVD), Foot and Mouth Disease (FMD) and Infectious Bovine Rhinotracheitis (IBR). Swine experts expressed their opinion on the pathogens causing African Swine Fever (ASF), Enzootic Pneumonia (EP), Porcine Reproductive and Respiratory Syndrome (PRRS), as well as FMD. For cattle farms, biosecurity measures that improve disease awareness of farmers were ranked as both most important and most effective. For swine farms, the most important and effective measures identified were those related to animal movements. Among all single measures evaluated, education of farmers was perceived by the experts to be the most important and effective for protecting both Swiss cattle and swine farms from disease. The findings of this study provide an important basis for recommendation to farmers and policy makers.

β2-microglobulin is a systemic pro-aging factor that impairs cognitive function and neurogenesis

Aging drives cognitive and regenerative impairments in the adult brain, increasing susceptibility to neurodegenerative disorders in healthy individuals. Experiments using heterochronic parabiosis, in which the circulatory systems of young and old animals are joined, indicate that circulating pro-aging factors in old blood drive aging phenotypes in the brain. Here we identify β2-microglobulin (B2M), a component of major histocompatibility complex class 1 (MHC I) molecules, as a circulating factor that negatively regulates cognitive and regenerative function in the adult hippocampus in an age-dependent manner. B2M is elevated in the blood of aging humans and mice, and it is increased within the hippocampus of aged mice and young heterochronic parabionts. Exogenous B2M injected systemically, or locally in the hippocampus, impairs hippocampal-dependent cognitive function and neurogenesis in young mice. The negative effects of B2M and heterochronic parabiosis are, in part, mitigated in the hippocampus of young transporter associated with antigen processing 1 (Tap1)-deficient mice with reduced cell surface expression of MHC I. The absence of endogenous B2M expression abrogates age-related cognitive decline and enhances neurogenesis in aged mice. Our data indicate that systemic B2M accumulation in aging blood promotes age-related cognitive dysfunction and impairs neurogenesis, in part via MHC I, suggesting that B2M may be targeted therapeutically in old age.

Wirksamkeit der umfassenden kardiologischen Rehabilitation und Sekundärprävention: klinische und epidemiologische Evidenz

Zusammenfassung Die umfassende kardiologische Rehabilitation ist die Summe von koordinierten Maßnahmen, welche die Folgen von Herzerkrankungen vermindern, die Morbidität und Mortalität reduzieren und die gesundheitsbezogene Lebensqualität einschließlich der psychosozialen Situation der Patienten verbessern sollen. Dazu ist die Bereitstellung strukturierter sekundärpräventiver Strategien besonders wichtig. Schwerpunkte dieser Maßnahmen sind die Trainingstherapie und Aktivitätsberatung sowie Ernährungstherapie und -beratung, Raucherentwöhnung, psychosoziale Intervention und Pharmakotherapie (Ades 2001).

(Table 1) Calcium isotope composition, Mg/Ca, Sr/Ca and U/Ca ratios of calcareous cysts of Thoracosphaera heimii

We investigated the influences of temperature, salinity and pH on the calcium isotope as well as trace and minor element (uranium, strontium, magnesium) to Ca ratios on calcium carbonate cysts of the calcareous dinoflagellate species Thoracosphaera heimii grown in laboratory cultures. The natural habitat of this species is the photic zone (preferentially at the chlorophyll maximum depth) of temperate to tropical oceans, and it is abundant in deep-sea sediments over the entire Cenozoic. In our experiments, temperatures ranged from 12 to 30 °C, salinity from 36.5 to 38.8 and pH from 7.9 to 8.4. The delta44/40Ca of T. heimii cysts resembles that of other marine calcifiers, including coccolithophores, foraminifers and corals. However, its temperature sensitivity is considerably smaller and statistically insignificant, and T. heimii might serve as a recorder of changes in seawater delta44/40Ca over geologic time. The Sr/Ca ratios of T. heimii cysts show a pronounced temperature sensitivity (0.016 mmol/mol °C**-1) and have the potential to serve as a palaeo-sea surface temperature proxy. No clear temperature- and pH-dependences were observed for Mg/Ca. U/Ca seems to be influenced by temperature and pH, but the correlations change sign at 23 °C and pH 8.2, respectively.

Dinoflagellate cyst counts and age model from sediment samples of ODP Hole 175-1085A

Sediment samples from ODP Site 1085 were investigated in order to obtain more information on the initiation and development of the Benguela upwelling system during the middle and upper Miocene. In particular, our intent was to establish the causes of the upwelling as well as the response of the upwelling regime to the development of the Antarctic Circumpolar Current. Based on changes in the calcareous dinoflagellate cyst association, we found an initial increase of the dinoflagellate cyst productivity, probably related to the initiation of upwelling about 11.8 Ma ago. Two distinct increases in cyst productivity in conjunction with temperature decreases of the upper water masses reflect upwelling pulses off Namibia and occur at the end of the Miocene cooling events Mi5 (about 11.5 Ma) and Mi6 (about 10.5 Ma). Both cooling events are associated with an ice volume increase in Antarctica and are thought to have led to an increase in southeasterly winds, possibly causing these two upwelling pulses. We demonstrate a decrease in dinoflagellate cyst productivity and enhanced terrigenous input via the Orange River after the Mi5 event. At about 11.1 Ma, the dinoflagellate cyst productivity increases again. The polar cyst species Caracomia arctica occurs here for the first time. This implies an influence of subantarctic mode water and therefore a change in the quality of the upwelling water which allowed the Benguela upwelling to develop into modern conditions. From about 10.4 Ma, C. arctica forms a permanent part of the association, pointing to an establishment of the upwelling regime.