Design and Evaluation of [F]CHDI-650 as a Positron Emission Tomography Ligand to Image Mutant Huntingtin Aggregates.

Therapeutic interventions are being developed for Huntington's disease (HD), a hallmark of which is mutant huntingtin protein (mHTT) aggregates. Following the advancement to human testing of two [C]-PET ligands for aggregated mHTT, attributes for further optimization were identified. We replaced the pyridazinone ring of CHDI-180 with a pyrimidine ring and minimized off-target binding using brain homogenate derived from Alzheimer's disease patients.

Development of a ligand for in vivo imaging of mutant huntingtin in Huntington's disease.

Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG trinucleotide expansion in the huntingtin () gene that encodes the pathologic mutant HTT (mHTT) protein with an expanded polyglutamine (polyQ) tract. Whereas several therapeutic programs targeting mHTT expression have advanced to clinical evaluation, methods to visualize mHTT protein species in the living brain are lacking. Here, we demonstrate the development and characterization of a positron emission tomography (PET) imaging radioligand with high affinity and selectivity for mHTT aggregates.

Angular stable locking in a novel intramedullary nail improves construct stability in a distal tibia fracture model.

Introduction: Intramedullary nails are frequently used for treatment of unstable distal tibia fractures. However, insufficient fixation of the distal fragment could result in delayed healing, malunion or nonunion. Recently, a novel concept for angular stable nailing was developed that maintains the principle of relative stability and introduces improvements expected to reduce nail toggling, screw migration and secondary loss of reduction.

Pharmacological characterization of mutant huntingtin aggregate-directed PET imaging tracer candidates.

Huntington's disease (HD) is caused by a CAG trinucleotide repeat expansion in the first exon of the huntingtin (HTT) gene coding for the huntingtin (HTT) protein. The misfolding and consequential aggregation of CAG-expanded mutant HTT (mHTT) underpin HD pathology. Our interest in the life cycle of HTT led us to consider the development of high-affinity small-molecule binders of HTT oligomerized/amyloid-containing species that could serve as either cellular and in vivo imaging tools or potential therapeutic agents.

[C]CHDI-626, a PET Tracer Candidate for Imaging Mutant Huntingtin Aggregates with Reduced Binding to AD Pathological Proteins.

The expanded polyglutamine-containing mutant huntingtin (mHTT) protein is implicated in neuronal degeneration of medium spiny neurons in Huntington's disease (HD) for which multiple therapeutic approaches are currently being evaluated to eliminate or reduce mHTT. Development of effective and orthogonal biomarkers will ensure accurate assessment of the safety and efficacy of pharmacologic interventions. We have identified and optimized a class of ligands that bind to oligomerized/aggregated mHTT, which is a hallmark in the HD postmortem brain.

[Antegrade and retrograde nailing of humeral shaft fractures].

Objective: Restoring humeral shaft alignment using direct or indirect reduction techniques with subsequent intramedullary stabilisation with an antegrade or retrograde inserted humeral nail. Achieving osseous union and restoration of painfree upper arm function.

Indications: Antegrade: Humerus shaft fractures located in the proximal 2/3 of the humerus.

Evaluation of the reduction, tightening and gripping performance of an innovative set screw technology for instrumented posterior lumbar fusion: A biomechanical study.

Background: Instrumented posterior lumbar fusion with top-loading pedicle screw systems (PSS) requires fully tightened set screws to achieve a secure fixation and symmetric load condition. This assumes a complete reduction of the rod by 90°, which is not always attainable in situ, especially under constraint. The objective of this work is to compare the mechanical performance of different innovative set screw technologies, which should improve the tightening process.

Imaging Mutant Huntingtin Aggregates: Development of a Potential PET Ligand.

Mutant huntingtin (mHTT) protein carrying the elongated N-terminal polyglutamine (polyQ) tract misfolds and forms protein aggregates characteristic of Huntington's disease (HD) pathology. A high-affinity ligand specific for mHTT aggregates could serve as a positron emission tomography (PET) imaging biomarker for HD therapeutic development and disease progression. To identify such compounds with binding affinity for polyQ aggregates, we embarked on systematic structural activity studies; lead optimization of aggregate-binding affinity, unbound fractions in brain, permeability, and low efflux culminated in the discovery of compound , which exhibited target engagement in autoradiography (ARG) studies in brain slices from HD mouse models and postmortem human HD samples.

Safety and efficacy of 2D-fluoroscopy-based iliosacral screw osteosynthesis: results of a retrospective monocentric study.

Introduction: Iliosacral screw osteosynthesis is a well-accepted procedure for stabilization of sacral fractures and iliosacral (fracture) dislocations.

Materials And Methods: In this monocentric study, safety and efficacy of conventional 2D-fluoroscopic-guided iliosacral screw insertion were evaluated.

Results: During a 10-year period (2005-2014), 98 patients between the age of 18 and 65 years received 207 iliosacral screws in 101 procedures.

Suprapatellar nailing of fractures of the tibia.

Objective: Intramedullary nailing of tibia fractures via a suprapatellar, transarticular approach with the knee joint in 20-30° of flexion and the use of specific protection tubes to preserve intra-articular structures.

Indications: Extra-articular fractures of the proximal tibia; simple and comminuted fractures of the tibia diaphysis; segmental diaphyseal fractures of the tibia; extra-articular fractures of the distal tibia and fractures with simple intra-articular distal extension; floating knee injuries.

Contraindications: Gustilo grade 3C open fractures of the tibia; severe soft tissue laceration, contamination or infection in the suprapatellar area; ipsilateral knee joint prosthesis; knee arthrodesis; implants blocking the nail entry point.

Intramedullary Nailing of Metaphyseal Fractures of the Lower Extremity.

Intramedullary nailing is a worldwide accepted technique for stabilization of fractures of long bones. Technique, instruments and implants primarily have been developed for the fixation of short (transverse and oblique) diaphyseal fractures. First generation nails were hollow and slotted, which gave them some elasticity.

Suppressor of Cytokine Signaling 3 in Macrophages Prevents Exacerbated Interleukin-6-Dependent Arginase-1 Activity and Early Permissiveness to Experimental Tuberculosis.

Suppressor of cytokine signaling 3 (SOCS3) is a feedback inhibitor of interleukin (IL)-6 signaling in macrophages. In the absence of this molecule, macrophages become extremely prone to an IL-6-dependent expression of arginase-1 (Arg1) and nitric oxide synthase (NOS)2, the prototype markers for alternative or classical macrophage activation, respectively. Because both enzymes are antipodean macrophage effector molecules in () infection, we assessed the relevance of SOCS3 for macrophage activation during experimental tuberculosis using macrophage-specific SOCS3-deficient (LysMSOCS3) mice.

Efficacy of drugs used in the treatment of IBD and combinations thereof in acute DSS-induced colitis in mice.

Aims: Although acute dextran sodium sulphate (DSS)-induced colitis in mice is frequently used as a preclinical model for testing drugs involved in inflammatory bowel disease (IBD), only limited data is available that compares the efficacy of established drug treatments and combinations employed in IBD. We have therefore compared the efficacy of aminosalicylates (mesalazine, olsalazine), corticosteroids (budesonide), thiopurines (6-thioguanine (6-TG)) and cyclosporine A (CsA) and combinations thereof as well as the EP4 agonist AGN205203 in the acute DSS-colitis model.

Main Methods: Female BALB/c mice were challenged with 4% DSS in drinking water for 7 days to induce colitis and treated daily with different drugs/combinations orally.

Internal fixation of fractures of the proximal humerus with the MultiLoc nail.

Objective: Anatomical reduction of two- to four-part fractures of the proximal humerus using indirect reduction techniques. Intramedullary fixation with a short humerus nail. Restoration of a stable bone-implant construct that enables early functional after-treatment.

Radiation exposure in whole-body computed tomography of multiple trauma patients: bearing devices and patient positioning.

Background: Whole-body computed tomography (WBCT) plays an important role in the management of severely injured patients. We evaluated the radiation exposure of WBCT scans using different positioning boards and arm positions.

Methods: In this retrospective study, the radiation exposure of WBCT using a 16-slice multislice computed tomography scanner was evaluated.

Stabilization of fatigue fractures of the dorsal pelvis with a trans-sacral bar. Operative technique and outcome.

Introduction: Due to ageing of our population the number of fatigue fractures of the pelvic ring is steadily growing. These fractures are often treated with bed rest but may result in a disabling immobility with severe pain. An operative treatment is an option in these cases.

Traumatic damage to the cartilage influences outcome of anatomically reduced acetabular fractures: a medium-term retrospective analysis.

We reviewed 77 patients with an acetabular fracture, treated operatively through a non-extensile approach after an average time of 45 months. The ilioinguinal approach was chosen in 41, the Kocher-Langenbeck approach in 36 patients. Following the Letournel classification, the most frequent lesions were posterior wall (26%), two-column (22.

Radiological analysis, operative management and functional outcome of open book pelvic lesions: a 13-year cohort study.

Unlabelled: We present the clinical and radiological outcome of a 13-year cohort study of 38 open book pelvic lesions. All patients were treated in one Level I Trauma centre. In the posterior pelvis, sacro-iliac diastasis was seen in 31 patients, sacral fracture in 7.

DAP10 contributes to CD8(+) T cell-mediated cytotoxic effector mechanisms during Mycobacterium tuberculosis infection.

The activating C-type lectin-like receptor NKG2D, which is expressed by mouse NK cells and activated CD8 T cells, was previously demonstrated to be involved in tumor rejection and as a defense mechanism against viral and bacterial infections. Because CD8 T cells are important for protective immune responses during chronic Mycobacterium tuberculosis (Mtb) infection and represent a promising target for new vaccine strategies to prevent human pulmonary tuberculosis (TB), we studied the immune response in mice deficient for the NKG2D adapter molecule DAP10 during experimental TB. After aerosol infection, DAP10-defcient mice displayed an unimpaired recruitment, activation and development of antigen-specific CD8 T cells.

Mid- to long-term results after bipolar radial head arthroplasty.

Background: Radial head arthroplasty is considered the treatment of choice for unreconstructable radial head fractures in the acute fracture situation. Although short-term results in the current literature are promising, replacement of the radial head remains controversial as long-term results are still missing. We report our 8.

Outcome in Pelvic Ring Fractures.

Pelvic ring fractures represent a negative prognostic factor for what concerns morbidity and mortality of a polytraumatized patient. The subjective and functional prognosis of a pelvic ring fracture is dependent upon its degree of instability. Associated severe peripelvic soft tissue injuries and neurovascular lesions (complex pelvic trauma) affect outcome negatively.

Management of Acute Hemorrhage in Pelvic Trauma: An Overview.

Pelvic disruption is a combination of fractures or dislocations of the pelvic ring with trauma of the soft tissues on the inside and outside of this ring. Hemodynamic instability is the result of blood loss out of the fracture fragments, the posterior venous plexus, ruptured pelvic organs, or arterial lesions. In the resuscitation phase, different measures are possible to reduce the volume of the disrupted pelvis and to restore mechanical stability.

[Reconstruction of fractures of the anterior wall and the anterior column of the acetabulum using an ilioinguinal approach].

Objective: Restoration of the congruence of the hip joint. Correction of gaps or steps in the articular surface, especially in the main weight-bearing area of the acetabular dome. Correction of femoral head subluxation.

[Patella fracture].

Objective: Reconstruction of the extensor apparatus of the knee joint. Open reduction and stable internal fixation of patella fractures. Exact reconstruction of the articular surface of the patellofemoral joint.