Crystal Structure of an Anti-Ang2 CrossFab Demonstrates Complete Structural and Functional Integrity of the Variable Domain.

Bispecific antibodies are considered as a promising class of future biotherapeutic molecules. They comprise binding specificities for two different antigens, which may provide additive or synergistic modes of action. There is a wide variety of design alternatives for such bispecific antibodies, including the "CrossMab" format. CrossMabs contain a domain crossover in one of the antigen-binding (Fab) parts, together with the "knobs-and-holes" approach, to enforce the correct assembly of four different polypeptide chains into an IgG-like bispecific antibody. We determined the crystal structure of a hAng-2-binding Fab in its crossed and uncrossed form and show that CH1-CL-domain crossover does not induce significant perturbations of the structure and has no detectable influence on target binding

Efficacy and safety of argatroban in patients with acute respiratory distress syndrome and extracorporeal lung support

Background Extracorporeal membrane oxygenation (ECMO) or pumpless extracorporeal lung assist (pECLA) requires effective anticoagulation. Knowledge on the use of argatroban in patients with acute respiratory distress syndrome (ARDS) undergoing ECMO or pECLA is limited. Therefore, this study assessed the feasibility, efficacy and safety of argatroban in critically ill ARDS patients undergoing extracorporeal lung support. Methods This retrospective analysis included ARDS patients on extracorporeal lung support who received argatroban between 2007 and 2014 in a single ARDS referral center. As controls, patients who received heparin were matched for age, sex, body mass index and severity of illness scores. Major and minor bleeding complications, thromboembolic events, administered number of erythrocyte concentrates, thrombocytes and fresh-frozen plasmas were assessed. The number of extracorporeal circuit systems and extracorporeal lung support cannulas needed due to clotting was recorded. Also assessed was the efficacy to reach the targeted activated partial thromboplastin time (aPTT) in the first consecutive 14 days of therapy, and the controllability of aPTT values is within a therapeutic range of 50–75 s. Fisher’s exact test, Mann–Whitney U tests, Friedman tests and multivariate nonparametric analyses for longitudinal data (MANOVA; Brunner’s analysis) were applied where appropriate. Results Of the 535 patients who met the inclusion criteria, 39 receiving argatroban and 39 matched patients receiving heparin (controls) were included. Baseline characteristics were similar between the two groups, including severity of illness and organ failure scores. There were no significant differences in major and minor bleeding complications. Rates of thromboembolic events were generally low and were similar between the two groups, as were the rates of transfusions required and device-associated complications. The controllability of both argatroban and heparin improved over time, with a significantly increasing probability to reach the targeted aPTT corridor over the first days (p < 0.001). Over time, there were significantly fewer aPTT values below the targeted aPTT goal in the argatroban group than in the heparin group (p < 0.05). Both argatroban and heparin reached therapeutic aPTT values for adequate application of extracorporeal lung support. Conclusions Argatroban appears to be a feasible, effective and safe anticoagulant for critically ill ARDS patients undergoing extracorporeal lung support

Decline of Ambient Air Pollution Levels and Improved Respiratory Health in Swiss Children

The causality of observed associations between air pollution and respiratory health in children is still subject to debate. If reduced air pollution exposure resulted in improved respiratory health of children, this would argue in favor of a causal relation. We investigated whether a rather moderate decline of air pollution levels in the 1990s in Switzerland was associated with a reduction in respiratory symptoms and diseases in school children. In nine Swiss communities, 9,591 children participated in cross-sectional health assessments between 1992 and 2001. Their parents completed identical questionnaires on health status and covariates. We assigned to each child an estimate of regional particles with an aerodynamic diameter < 10 μg/m(3) (PM(10)) and determined change in PM(10) since the first survey. Adjusted for socioeconomic, health-related, and indoor factors, declining PM(10) was associated in logistic regression models with declining prevalence of chronic cough [odds ratio (OR) per 10-μg/m(3) decline = 0.65, 95% confidence interval (CI), 0.54–0.79], bronchitis (OR = 0.66; 95% CI, 0.55–0.80), common cold (OR = 0.78; 95% CI, 0.68–0.89), nocturnal dry cough (OR = 0.70; 95% CI, 0.60–0.83), and conjunctivitis symptoms (OR = 0.81; 95% CI, 0.70–0.95). Changes in prevalence of sneezing during pollen season, asthma, and hay fever were not associated with the PM(10) reduction. Our findings show that the reduction of air pollution exposures contributes to improved respiratory health in children. No threshold of adverse effects of PM(10) was apparent because we observed the beneficial effects for relatively small changes of rather moderate air pollution levels. Current air pollution levels in Switzerland still exceed limit values of the Swiss Clean Air Act; thus, children’s health can be improved further

Gastric lactobezoar - a rare disorder?

Gastric lactobezoar, a pathological conglomeration of milk and mucus in the stomach of milk-fed infants often causing gastric outlet obstruction, is a rarely reported disorder (96 cases since its first description in 1959). While most patients were described 1975-1985 only 26 children have been published since 1986. Clinically, gastric lactobezoars frequently manifest as acute abdomen with abdominal distension (61.0% of 96 patients), vomiting (54.2%), diarrhea (21.9%), and/or a palpable abdominal mass (19.8%). Respiratory (23.0%) and cardiocirculatory (16.7%) symptoms are not uncommon. The pathogenesis of lactobezoar formation is multifactorial: exogenous influences such as high casein content (54.2%), medium chain triglycerides (54.2%) or enhanced caloric density (65.6%) of infant milk as well as endogenous factors including immature gastrointestinal functions (66.0%), dehydration (27.5%) and many other mechanisms have been suggested. Diagnosis is easy if the potential presence of a gastric lactobezoar is thought of, and is based on a history of inappropriate milk feeding, signs of acute abdomen and characteristic features of diagnostic imaging. Previously, plain and/or air-, clear fluid- or opaque contrast medium radiography techniques were used to demonstrate a mass free-floating in the lumen of the stomach. This feature differentiates a gastric lactobezoar from intussusception or an abdominal neoplasm. Currently, abdominal ultrasound, showing highly echogenic intrabezoaric air trapping, is the diagnostic method of choice. However, identifying a gastric lactobezoar requires an investigator experienced in gastrointestinal problems of infancy as can be appreciated from the results of our review which show that in not even a single patient gastric lactobezoar was initially considered as a possible differential diagnosis. Furthermore, in over 30% of plain radiographs reported, diagnosis was initially missed although a lactobezoar was clearly demonstrable on repeat evaluation of the same X-ray films. Enhanced diagnostic sensitivity would be most rewarding since management consisting of cessation of oral feedings combined with administration of intravenous fluids and gastric lavage is easy and resolves over 85% of gastric lactobezoars. In conclusion, gastric lactobezoar is a disorder of unknown prevalence and is nowadays very rarely published, possibly because of inadequate diagnostic sensitivity and/or not yet identified but beneficial modifications of patient management

Oxidative Protein Folding Is Driven by the Electron Transport System

AbstractDisulfide bond formation is catalyzed in vivo by DsbA and DsbB. Here we reconstitute this oxidative folding system using purified components. We have found the sources of oxidative power for protein folding and show how disulfide bond formation is linked to cellular metabolism. We find that disulfide bond formation and the electron transport chain are directly coupled. DsbB uses quinones as electron acceptors, allowing various choices for electron transport to support disulfide bond formation. Electrons flow via cytochrome bo oxidase to oxygen under aerobic conditions or via cytochrome bd oxidase under partially anaerobic conditions. Under truly anaerobic conditions, menaquinone shuttles electrons to alternate final electron acceptors such as fumarate. This flexibility reflects the vital nature of the disulfide catalytic system

Sturmian morphisms, the braid group B_4, Christoffel words and bases of F_2

We give a presentation by generators and relations of a certain monoid generating a subgroup of index two in the group Aut(F_2) of automorphisms of the rank two free group F_2 and show that it can be realized as a monoid in the group B_4 of braids on four strings. In the second part we use Christoffel words to construct an explicit basis of F_2 lifting any given basis of the free abelian group Z^2. We further give an algorithm allowing to decide whether two elements of F_2 form a basis or not. We also show that, under suitable conditions, a basis has a unique conjugate consisting of two palindromes.Comment: 25 pages, 4 figure

Forward pi^0 Production and Associated Transverse Energy Flow in Deep-Inelastic Scattering at HERA

Deep-inelastic positron-proton interactions at low values of Bjorken-x down to x \approx 4.10^-5 which give rise to high transverse momentum pi^0 mesons are studied with the H1 experiment at HERA. The inclusive cross section for pi^0 mesons produced at small angles with respect to the proton remnant (the forward region) is presented as a function of the transverse momentum and energy of the pi^0 and of the four-momentum transfer Q^2 and Bjorken-x. Measurements are also presented of the transverse energy flow in events containing a forward pi^0 meson. Hadronic final state calculations based on QCD models implementing different parton evolution schemes are confronted with the data.Comment: 27 pages, 8 figures and 3 table

Measurement of Leading Proton and Neutron Production in Deep Inelastic Scattering at HERA

Deep--inelastic scattering events with a leading baryon have been detected by the H1 experiment at HERA using a forward proton spectrometer and a forward neutron calorimeter. Semi--inclusive cross sections have been measured in the kinematic region 2 <= Q^2 <= 50 GeV^2, 6.10^-5 <= x <= 6.10^-3 and baryon p_T <= MeV, for events with a final state proton with energy 580 <= E' <= 740 GeV, or a neutron with energy E' >= 160 GeV. The measurements are used to test production models and factorization hypotheses. A Regge model of leading baryon production which consists of pion, pomeron and secondary reggeon exchanges gives an acceptable description of both semi-inclusive cross sections in the region 0.7 <= E'/E_p <= 0.9, where E_p is the proton beam energy. The leading neutron data are used to estimate for the first time the structure function of the pion at small Bjorken--x.Comment: 30 pages, 9 figures, 2 tables, submitted to Eur. Phys.