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

Die Analyse kirchlich-administrativer Daten mit Hilfe der EDV

Die Autoren geben einen Überblick über das Quellenmaterial und die Fragestellungen der Historischen Demographie und führen zwei prinzipiell verschiedene Bearbeitungsmethoden vor. Bei der ersten handelt es sich um eine nicht-namentliche Auswertung der Kirchenbücher (anonyme oder aggregative Methode), bei der zweiten um eine nominative Analyse auf der Basis von Familienrekonstitutionen. Bei der nominativen Auswertung ist der EDV-Einsatz unumgänglich; bei der anonymen ist er möglich und bei großen Datenmengen sinnvoll. Die Autoren präsentieren einige Ergebnisse der mit Hilfe dieser Bearbeitungsmethoden durchgeführten Bearbeitungsmethoden und fassen abschließend ihre Erfahrungen der Analyse kirchlich-administrativer Daten mit Hilfe der EDV zusammen. (KS

Quality assessment of a randomly selected sample of Swiss medical expertises : a pilot study

Background: Considerable criticism has lately been raised by the media regarding the quality of Swiss medical expertises. The present investigation was therefore undertaken to assess the professional quality of Swiss medical expertises. The study was part of a market analysis of medical expertises (MGS study). Methods: A sample of 97 anonymised expertises randomly chosen from a total of 3165, collected in the MGS study over a period of 3 months, were evaluated by an international board of medical experts and reviewers, using a stepwise developed questionnaire. Each expertise was independently evaluated by two experts. Data were then tested for plausibility (obvious errors and misunderstandings). The main outcome was the overall quality rating of the expertise that was graded from 1 (very poor) to 6 (excellent) in analogy to the Swiss school grading system. For analysis and interpretation the grades were divided into sufficient (grades >= 4) and insufficient (grades <4). Results: Overall 19.6% (95% confidence interval: 13.1%; 28.3%) of the expertises were rated to be of insufficient quality. The quality was inversely related to the number of involved medical disciplines, the time relapsed since injury and positively related to the difficulty of the expertise. In addition, expertises in the French and Italian languages were rated superior to those in German. Conclusions: Our results confirm recent criticisms that the professional quality of expertises does not suffice. This is hardly acceptable in face of the financial and personal consequences. There is an obvious need for further research using larger samples and for educational programmes on all levels

The provision of out-of-hours care and associated costs in an urban area of Switzerland: a cost description study

BACKGROUND: In Switzerland, General Practitioners (GPs) play an important role for out-of-hours emergency care as one service option beside freely accessible and costly emergency departments of hospitals. The aim of this study was to evaluate the services provided and the economic consequences of a Swiss GP out-of-hours service. METHODS: GPs participating in the out-of-hours service in the city of Zurich collected data on medical problems (ICPC coding), mode of contact, mode of resource use and services provided (time units; diagnostics; treatments). From a health care insurance perspective, we assessed the association between total costs and its two components (basic costs: charges for time units and emergency surcharge; individual costs: charges for clinical examination, diagnostics and treatment in the discretion of the GP). RESULTS: 125 GPs collected data on 685 patient contacts. The most prevalent health problems were of respiratory (24%), musculoskeletal (13%) and digestive origin (12%). Home visits (61%) were the most common contact mode, followed by practice (25%) and telephone contacts (14%). 82% of patients could be treated by ambulatory care. In 20% of patients additional technical diagnostics, most often laboratory tests, were used. The mean total costs for one emergency patient contact were €144 (95%-CI: 137-151). The mode of contact was an important determinant of total costs (mean total costs for home visits: €176 [95%-CI: 168-184]; practice contact: €90 [95%-CI: 84-98]; telephone contact: €48 [95%-CI: 40-55]). Basic costs contributed 83% of total costs for home visits and 70% of total costs for practice contacts. Individual mean costs were similarly low for home visits (€30) and practice contacts (€27). Medical problems had no relevant influence on this cost pattern. CONCLUSIONS: GPs managed most emergency demand in their out-of-hours service by ambulatory care. They applied little diagnostic testing and basic care. Our findings are of relevance for policy makers even from other countries with different pricing policies. Policy makers should be interested in a reimbursement system promoting out-of-hours care run by GPs as one valuable service option

Early Placement of Optional Vena Cava Filter in High-Risk Patients with Traumatic Brain Injury

Objectives:: Patients sustaining severe trauma are at high risk for the development of venous thromboembolic events (VTE). Pharmacologic VTE prophylaxis may be contraindicated early after trauma due to potential bleeding complications. The purpose of this study was to evaluate safety and feasibility of early prophylactic vena cava filter (VCF) placement and subsequent retrieval in multiple injured patients with traumatic brain injury (TBI). Methods:: Analysis of single-institution case series of consecutive patients who received a prophylactic VCF after severe TBI (Abbreviated Injury Scale, AiS ≥ 3) between August 2003 and October 2006. Results:: A total of 34 optional VCF were prophylactically placed with a median delay of 1 day after trauma (range, 0-7 days). All patients had sustained multiple injuries (median Injury Severity Score 41, range, 18-59) with severe TBI (median AiS 4, range 3-5). Median age was 41 years (range, 17-67 years). Two patients had succumbed before potential filter retrieval. Of the remaining patients, 27 (84%) had their filters uneventfully retrieved between 11 and 32 days (median, 18 days) after placement with no retrieval-related morbidity. Five VCF (16%) were left permanently. In one patient (3%) early inferior vena cava occlusion and deep venous thrombosis occurred 14 days after VCF placement. Symptomatic pulmonary embolism was observed in one patient (3%) 5 days after VCF retrieval. Overall trauma-related mortality was 9%. Conclusions:: Early VCF placement may be of benefit for multiple injured patients with TBI when pharmacologic VTE prophylaxis is contraindicated. VCF retrieval is safe and feasible. Filter placement- and retrieval-related morbidity is lo

Early Placement of Optional Vena Cava Filter in High-Risk Patients with Traumatic Brain Injury

Objectives:: Patients sustaining severe trauma are at high risk for the development of venous thromboembolic events (VTE). Pharmacologic VTE prophylaxis may be contraindicated early after trauma due to potential bleeding complications. The purpose of this study was to evaluate safety and feasibility of early prophylactic vena cava filter (VCF) placement and subsequent retrieval in multiple injured patients with traumatic brain injury (TBI). Methods:: Analysis of single-institution case series of consecutive patients who received a prophylactic VCF after severe TBI (Abbreviated Injury Scale, AiS ≥ 3) between August 2003 and October 2006. Results:: A total of 34 optional VCF were prophylactically placed with a median delay of 1 day after trauma (range, 0-7 days). All patients had sustained multiple injuries (median Injury Severity Score 41, range, 18-59) with severe TBI (median AiS 4, range 3-5). Median age was 41 years (range, 17-67 years). Two patients had succumbed before potential filter retrieval. Of the remaining patients, 27 (84%) had their filters uneventfully retrieved between 11 and 32 days (median, 18 days) after placement with no retrieval-related morbidity. Five VCF (16%) were left permanently. In one patient (3%) early inferior vena cava occlusion and deep venous thrombosis occurred 14 days after VCF placement. Symptomatic pulmonary embolism was observed in one patient (3%) 5 days after VCF retrieval. Overall trauma-related mortality was 9%. Conclusions:: Early VCF placement may be of benefit for multiple injured patients with TBI when pharmacologic VTE prophylaxis is contraindicated. VCF retrieval is safe and feasible. Filter placement- and retrieval-related morbidity is lo

Exploring factors associated with family caregivers' preparedness to care for an older family member together with home care nurses : an analysis in a Swiss urban area

Introduction: Home-dwelling older people with chronic diseases often need the support of informal and formal caregivers in order to continue living at home. Family members, however, need to be willing and prepared for caregiving together with home care nurses. Objectives: The purpose of this study was to explore factors associated with family caregivers’ preparedness to care for older home-dwelling adults who also receive home care nursing services. Methods: For this cross-sectional correlational study, a structured questionnaire was sent to family caregivers of adults aged 65 years or older receiving services from a community care agency. A total of 243 participants returned the questionnaire, of which 199 could be analyzed. Results: The stepwise backward regression model explained 29.1% of the variance of family caregivers’ preparedness. Mutuality was the most strongly associated factor with family caregivers’ preparedness whereas professional involvement of family caregiver in care process was important as well. Care intensity showed no significant impact. Conclusion: Nurses should support the whole family emotionally, and appreciate, admire, reinforce, and respect the caregivers’ situation. Home care nurses need to invest in helping families to find solutions, to strengthen their relationships between family members and the older person dwelling at home

Pivotal Role of Tenascin-W (-N) in Postnatal Incisor Growth and Periodontal Ligament Remodeling

The continuously growing mouse incisor provides a fascinating model for studying stem cell regulation and organ renewal. In the incisor, epithelial and mesenchymal stem cells assure lifelong tooth growth. The epithelial stem cells reside in a niche known as the cervical loop. Mesenchymal stem cells are located in the nearby apical neurovascular bundle and in the neural plexus. So far, little is known about extracellular cues that are controlling incisor stem cell renewal and guidance. The extracellular matrix protein tenascin-W, also known as tenascin-N (TNN), is expressed in the mesenchyme of the pulp and of the periodontal ligament of the incisor, and is closely associated with collagen 3 fibers. Here, we report for the first time the phenotype of tenascin-W/TNN deficient mice, which in a C57BL/6N background exhibit a reduced body weight and lifespan. We found major defects in the alveolar bone and periodontal ligament of the growing rodent incisors, whereas molars were not affected. The alveolar bone around the incisor was replaced by a dense scar-like connective tissue, enriched with newly formed nerve fibers likely leading to periodontal pain, less food intake and reduced body weight. Using soft food to reduce mechanical load on the incisor partially rescued the phenotype. In situ hybridization and Gli1 reporter mouse experiments revealed decreased hedgehog signaling in the incisor mesenchymal stem cell compartment, which coordinates the development of mesenchymal stem cell niche. These results indicate that TNN deficiency in mice affects periodontal remodeling and increases nerve fiber branching. Through periodontal pain the food intake is reduced and the incisor renewal and the neurovascular sonic hedgehog secretion rate are reduced. In conclusion, tenascin-W/TNN seems to have a primary function in rapid periodontal tissue remodeling and a secondary function in mechanosensation.Peer reviewe

Synthesis and Structure Elucidation of Glutamyl-Queuosine

Queuosine is one of the most complex hypermodified RNA nucleosides found in the Wobble position of tRNAs. In addition to Queuosine itself, several further modified derivatives are known, where the cyclopentene ring structure is additionally modified by a galactosyl-, a mannosyl-, or a glutamyl-residue. While sugar-modified Queuosine derivatives are found in the tRNAs of vertebrates, glutamylated Queuosine (gluQ) is only known in bacteria. The exact structure of gluQ, particularly with respect to how and where the glutamyl side chain is connected to the Queuosine cyclopentene side chain, is unknown. Here we report the first synthesis of gluQ and, using UHPLC-MS-coinjection and NMR studies, we show that the isolated natural gluQ is the α-allyl-connected gluQ compound