Determinants of outcome in operatively and non-operatively treated Weber-B ankle fractures

Introduction: Treatment of ankle fractures is often based on fracture type and surgeon's individual judgment. Literature concerning the treatment options and outcome are dated and frequently contradicting. The aim of this study was to determine the clinical and functional outcome after AO-Weber B-type ankle fractures in operatively and conservatively treated patients and to determine which factors influenced outcome. Patients and methods: A retrospective cohort study in patients with a AO-Weber B-type ankle fracture. Patient, fracture and treatment characteristics were recorded. Clinical and functional outcome was measured using the Olerud-Molander Ankle Score (OMAS), the American Orthopaedic Foot and Ankle Society ankle-hindfoot score (AOFAS) and a Visual Analog Score (VAS) for overall satisfaction (range 0-10). Results: Eighty-two patients were treated conservatively and 103 underwent operative treatment. The majority was female. Most conservatively treated fractures were AO-Weber B1.1 type fractures. Fractures with fibular displacement (mainly AO type B1.2 and Lauge-Hansen type SER-4) were predominantly treated operatively. The outcome scores in the non-operative group were OMAS 93, AOFAS 98, and VAS 8. Outcome in this group was independently negatively affected by age, affected side, BMI, fibular displacement, and duration of plaster immobilization. In the surgically treated group, the OMAS, AOFAS, and VAS scores were 90, 97, and 8, respectively, with outcome negatively influenced by duration of plaster immobilization. Conclusion: Treatment selection based upon stability and surgeon's judgment led to overall good clinical outcome in both treatment groups. Reducing the cast immobilization period may further improve outcome

Modulation of activity in medial frontal and motor cortices during error observation

Contains fulltext : 64780.pdf (publisher's version ) (Closed access)We used measures of the human event-related brain potential to investigate the neural mechanisms underlying error processing during action observation. Participants took part in two conditions, a task execution condition and a task observation condition. We found that activity in both the medial frontal cortex and in the motor cortices, as measured via the error-related negativity and the lateralized readiness potential respectively, was modulated by the correctness of observed behavior. These data suggest that similar neural mechanisms are involved in monitoring one's own actions and the actions of others

A Minimal Physiologically Based Pharmacokinetic Model with a Nested Endosome Compartment for Novel Engineered Antibodies

We proposed here a minimal physiologically based pharmacokinetic (mPBPK) model for a group of novel engineered antibodies in mice and humans. These antibodies are designed with altered binding properties of their Fc domain with neonatal Fc receptor (FcRn) or the Fab domain with their cognate targets (recycling antibodies) in acidic endosomes. To enable simulations of such binding features in the change of antibody pharmacokinetics and its target suppression, we nested an endothelial endosome compartment in parallel with plasma compartment based on our previously established mPBPK model. The fluid-phase pinocytosis rate from plasma to endothelial endosomes was reflected by the clearance of antibodies in FcRn dysfunctional humans or FcRn-knockout mice. The endosomal recycling rate of FcRn-bound antibodies was calculated based on the reported endosomal transit time. The nonspecific catabolism in endosomes was fitted using pharmacokinetic data of a human wild-type IgG1 adalimumab in humans and B21M in human FcRn (hFcRn) transgenic mice. The developed model adequately predicted the pharmacokinetics of infliximab, motavizumab, and an Fc variant of motavizumab in humans and the pharmacokinetics of bevacizumab, an Fc variant of bevacizumab, and a recycling antibody PH-IgG1 and its non-pH dependent counterpart NPH-IgG1 in hFcRn transgenic mice. Our proposed model provides a platform for evaluation of the pharmacokinetics and disposition behaviors of Fc-engineered antibodies and recycling antibodies

Small molecules that inhibit TNF signalling by stabilising an asymmetric form of the trimer

Tumour necrosis factor (TNF) is a cytokine belonging to a family of trimeric proteins; it has been shown to be a key mediator in autoimmune diseases such as rheumatoid arthritis and Crohn\u27s disease. While TNF is the target of several successful biologic drugs, attempts to design small molecule therapies directed to this cytokine have not led to approved products. Here we report the discovery of potent small molecule inhibitors of TNF that stabilise an asymmetrical form of the soluble TNF trimer, compromising signalling and inhibiting the functions of TNF in vitro and in vivo. This discovery paves the way for a class of small molecule drugs capable of modulating TNF function by stabilising a naturally sampled, receptor-incompetent conformation of TNF. Furthermore, this approach may prove to be a more general mechanism for inhibiting protein-protein interactions