Dealing with damage: Plasma membrane repair mechanisms.

Eukaryotic cells have developed repair mechanisms, which allow them to reseal their membrane in order to prevent the efflux of cytoplasmic constituents and the uncontrolled influx of calcium. After injury, the Ca(2+)-concentration gradient fulfils a dual function: it provides guidance cues for the repair machinery and directly activates the molecules, which have a repair function. Depending on the nature of injury, the morphology of the cell and the severity of injury, the membrane resealing can be effected by lysosomal exocytosis, microvesicle shedding or a combination of both. Likewise, exocytosis is often followed by the endocytic uptake of lesions. Additionally, since plasmalemmal resealing must be attempted, even after extensive injury in order to prevent cell lysis, the restoration of membrane integrity can be achieved by ceramide-driven invagination of the lipid bilayer, during which the cell is prepared for apoptotic disposal. Plasmalemmal injury can be contained by a surfeit of plasma membrane, which serves as a trap for toxic substances: either passively by an abundance of cellular protrusions, or actively by membrane blebbing.

Ca2+-dependent repair of pneumolysin pores: A new paradigm for host cellular defense against bacterial pore-forming toxins

Pneumolysin (PLY), a key virulence factor of Streptococcus pneumoniae, permeabilizes eukaryotic cells by forming large trans-membrane pores. PLY imposes a puzzling multitude of diverse, often mutually excluding actions on eukaryotic cells. Whereas cytotoxicity of PLY can be directly attributed to the pore-mediated effects, mechanisms that are responsible for the PLY-induced activation of host cells are poorly understood. We show that PLY pores can be repaired and thereby PLY-induced cell death can be prevented. Pore-induced Ca2+ entry from the extracellular milieu is of paramount importance for the initiation of plasmalemmal repair. Nevertheless, active Ca2+ sequestration that prevents excessive Ca2+ elevation during the execution phase of plasmalemmal repair is of no less importance. The efficacy of plasmalemmal repair does not only define the fate of targeted cells but also intensity, duration and repetitiveness of PLY-induced Ca2+ signals in cells that were able to survive after PLY attack. Intracellular Ca2+ dynamics evoked by the combined action of pore formation and their elimination mimic the pattern of receptor-mediated Ca2+ signaling, which is responsible for the activation of host immune responses. Therefore, we postulate that plasmalemmal repair of PLY pores might provoke cellular responses that are similar to those currently ascribed to the receptor-mediated PLY effects. Our data provide new insights into the understanding of the complexity of cellular non-immune defense responses to a major pneumococcal toxin that plays a critical role in the establishment and the progression of life-threatening diseases. Therapies boosting plasmalemmal repair of host cells and their metabolic fitness might prove beneficial for the treatment of pneumococcal infections.

Effects of enamel matrix proteins in combination with a bovine-derived natural bone mineral for the repair of bone defects.

OBJECTIVES Previously, the use of enamel matrix derivative (EMD) in combination with a natural bone mineral (NBM) was able to stimulate periodontal ligament cell and osteoblast proliferation and differentiation. Despite widespread use of EMD for periodontal applications, the effects of EMD on bone regeneration are not well understood. The aim of the present study was to test the ability of EMD on bone regeneration in a rat femur defect model in combination with NBM. MATERIALS AND METHODS Twenty-seven rats were treated with either NBM or NBM + EMD and assigned to histological analysis at 2, 4, and 8 weeks. Defect morphology and mineralized bone were assessed by μCT. For descriptive histology, hematoxylin and eosin staining and Safranin O staining were performed. RESULTS Significantly more newly formed trabecular bone was observed at 4 weeks around the NBM particles precoated with EMD when compared with NBM particles alone. The drilled control group, in contrast, achieved minimal bone regeneration at all three time points (P < 0.05). CONCLUSIONS The present results may suggest that EMD has the ability to enhance the speed of new bone formation when combined with NBM particles in rat osseous defects. CLINICAL RELEVANCE These findings may provide additional clinical support for the combination of EMD with bone graft for the repair of osseous and periodontal intrabony defects.

Percutaneous mitral valve edge-to-edge repair: in-hospital results and 1-year follow-up of 628 patients of the 2011-2012 Pilot European Sentinel Registry.

BACKGROUND The use of transcatheter mitral valve repair (TMVR) has gained widespread acceptance in Europe, but data on immediate success, safety, and long-term echocardiographic follow-up in real-world patients are still limited. OBJECTIVES The aim of this multinational registry is to present a real-world overview of TMVR use in Europe. METHODS The Transcatheter Valve Treatment Sentinel Pilot Registry is a prospective, independent, consecutive collection of individual patient data. RESULTS A total of 628 patients (mean age 74.2 ± 9.7 years, 63.1% men) underwent TMVR between January 2011 and December 2012 in 25 centers in 8 European countries. The prevalent pathogenesis was functional mitral regurgitation (FMR) (n = 452 [72.0%]). The majority of patients (85.5%) were highly symptomatic (New York Heart Association functional class III or higher), with a high logistic EuroSCORE (European System for Cardiac Operative Risk Evaluation) (20.4 ± 16.7%). Acute procedural success was high (95.4%) and similar in FMR and degenerative mitral regurgitation (p = 0.662). One clip was implanted in 61.4% of patients. In-hospital mortality was low (2.9%), without significant differences between groups. The estimated 1-year mortality was 15.3%, which was similar for FMR and degenerative mitral regurgitation. The estimated 1-year rate of rehospitalization because of heart failure was 22.8%, significantly higher in the FMR group (25.8% vs. 12.0%, p[log-rank] = 0.009). Paired echocardiographic data from the 1-year follow-up, available for 368 consecutive patients in 15 centers, showed a persistent reduction in the degree of mitral regurgitation at 1 year (6.0% of patients with severe mitral regurgitation). CONCLUSIONS This independent, contemporary registry shows that TMVR is associated with high immediate success, low complication rates, and sustained 1-year reduction of the severity of mitral regurgitation and improvement of clinical symptoms.

Cell therapy for intervertebral disc repair: advancing cell therapy from bench to clinics

Intervertebral disc (IVD) degeneration is a major cause of pain and disability; yet therapeutic options are limited and treatment often remains unsatisfactory. In recent years, research activities have intensified in tissue engineering and regenerative medicine, and pre-clinical studies have demonstrated encouraging results. Nonetheless, the translation of new biological therapies into clinical practice faces substantial barriers. During the symposium "Where Science meets Clinics", sponsored by the AO Foundation and held in Davos, Switzerland, from September 5-7, 2013, hurdles for translation were outlined, and ways to overcome them were discussed. With respect to cell therapy for IVD repair, it is obvious that regenerative treatment is indicated at early stages of disc degeneration, before structural changes have occurred. It is envisaged that in the near future, screening techniques and non-invasive imaging methods will be available to detect early degenerative changes. The promises of cell therapy include a sustained effect on matrix synthesis, inflammation control, and prevention of angio- and neuro-genesis. Discogenic pain, originating from "black discs" or annular injury, prevention of adjacent segment disease, and prevention of post-discectomy syndrome were identified as prospective indications for cell therapy. Before such therapy can safely and effectively be introduced into clinics, the identification of the patient population and proper standardisation of diagnostic parameters and outcome measurements are indispensable. Furthermore, open questions regarding the optimal cell type and delivery method need to be resolved in order to overcome the safety concerns implied with certain procedures. Finally, appropriate large animal models and well-designed clinical studies will be required, particularly addressing safety aspects.

Outcomes after endovascular or open repair for degenerative descending thoracic aortic aneurysm using linked hospital data.

BACKGROUND The population-based effectiveness of thoracic endovascular aortic repair (TEVAR) versus open surgery for descending thoracic aortic aneurysm remains in doubt. METHODS Patients aged over 50 years, without a history of aortic dissection, undergoing repair of a thoracic aortic aneurysm between 2006 and 2011 were assessed using mortality-linked individual patient data from Hospital Episode Statistics (England). The principal outcomes were 30-day operative mortality, long-term survival (5 years) and aortic-related reinterventions. TEVAR and open repair were compared using crude and multivariable models that adjusted for age and sex. RESULTS Overall, 759 patients underwent thoracic aortic aneurysm repair, mainly for intact aneurysms (618, 81·4 per cent). Median ages of TEVAR and open cohorts were 73 and 71 years respectively (P < 0·001), with more men undergoing TEVAR (P = 0·004). For intact aneurysms, the operative mortality rate was similar for TEVAR and open repair (6·5 versus 7·6 per cent; odds ratio 0·79, 95 per cent confidence interval (c.i.) 0·41 to 1·49), but the 5-year survival rate was significantly worse after TEVAR (54·2 versus 65·6 per cent; adjusted hazard ratio 1·45, 95 per cent c.i. 1·08 to 1·94). After 5 years, aortic-related mortality was similar in the two groups, but cardiopulmonary mortality was higher after TEVAR. TEVAR was associated with more aortic-related reinterventions (23·1 versus 14·3 per cent; adjusted HR 1·70, 95 per cent c.i. 1·11 to 2·60). There were 141 procedures for ruptured thoracic aneurysm (97 TEVAR, 44 open), with TEVAR showing no significant advantage in terms of operative mortality. CONCLUSION In England, operative mortality for degenerative descending thoracic aneurysm was similar after either TEVAR or open repair. Patients who had TEVAR appeared to have a higher reintervention rate and worse long-term survival, possibly owing to cardiopulmonary morbidity and other selection bias.

Aorto-bronchial and aorto-pulmonary fistulation after thoracic endovascular aortic repair: an analysis from the European Registry of Endovascular Aortic Repair Complications

OBJECTIVES To learn upon incidence, underlying mechanisms and effectiveness of treatment strategies in patients with central airway and pulmonary parenchymal aorto-bronchial fistulation after thoracic endovascular aortic repair (TEVAR). METHODS Analysis of an international multicentre registry (European Registry of Endovascular Aortic Repair Complications) between 2001 and 2012 with a total caseload of 4680 TEVAR procedures (14 centres). RESULTS Twenty-six patients with a median age of 70 years (interquartile range: 60-77) (35% female) were identified. The incidence of either central airway (aorto-bronchial) or pulmonary parenchymal (aorto-pulmonary) fistulation (ABPF) in the entire cohort after TEVAR in the study period was 0.56% (central airway 58%, peripheral parenchymal 42%). Atherosclerotic aneurysm formation was the leading indication for TEVAR in 15 patients (58%). The incidence of primary endoleaks after initial TEVAR was n = 10 (38%), of these 80% were either type I or type III endoleaks. Fourteen patients (54%) developed central left bronchial tree lesions, 11 patients (42%) pulmonary parenchymal lesions and 1 patient (4%) developed a tracheal lesion. The recognized mechanism of ABPF was external compression of the bronchial tree in 13 patients (50%), the majority being due to endoleak formation, further ischaemia due to extensive coverage of bronchial feeding arteries in 3 patients (12%). Inflammation and graft erosion accounted for 4 patients (30%) each. Cumulative survival during the entire study period was 39%. Among deaths, 71% were attributed to ABPF. There was no difference in survival in patients having either central airway or pulmonary parenchymal ABPF (33 vs 45%, log-rank P = 0.55). Survival with a radical surgical approach was significantly better when compared with any other treatment strategy in terms of overall survival (63 vs 32% and 63 vs 21% at 1 and 2 years, respectively), as well as in terms of fistula-related survival (63 vs 43% and 63 vs 43% at 1 and 2 years, respectively). CONCLUSIONS ABPF is a rare but highly lethal complication after TEVAR. The leading mechanism behind ABPF seems to be a continuing external compression of either the bronchial tree or left upper lobe parenchyma. In this setting, persisting or newly developing endoleak formation seems to play a crucial role. Prognosis does not differ in patients with central airway or pulmonary parenchymal fistulation. Radical bronchial or pulmonary parenchymal repair in combination with stent graft removal and aortic reconstruction seems to be the most durable treatment strategy.

An educational review of cartilage repair: precepts & practice - myths & misconceptions - progress & prospects.

OBJECTIVE The repair of cartilaginous lesions within synovial joints is still an unresolved and weighty clinical problem. Although research activity in this area has been indefatigably sustained, no significant progress has been made during the past decade. The aim of this educational review is to heighten the awareness amongst students and scientists of the basic issues that must be tackled and resolved before we can hope to escape from the whirlpool of stagnation into which we have fallen: cartilage repair redivivus! DESIGN Articular-cartilage lesions may be induced traumatically (e.g., by sports injuries and occupational accidents) or pathologically during the course of a degenerative disease (e.g., osteoarthritis). This review addresses the biological basis of cartilage repair and surveys current trends in treatment strategies, focussing on those that are most widely adopted by orthopaedic surgeons [viz., abrasive chondroplasty, microfracturing/microdrilling, osteochondral grafting and autologous-chondrocyte implantation (ACI)]. Also described are current research activities in the field of cartilage-tissue engineering, which, as a therapeutic principle, holds more promise for success than any other experimental approach. RESULTS AND CONCLUSIONS Tissue engineering aims to reconstitute a tissue both structurally and functionally. This process can be conducted entirely in vitro, initially in vitro and then in vivo (in situ), or entirely in vivo. Three key constituents usually form the building blocks of such an approach: a matrix scaffold, cells, and signalling molecules. Of the proposed approaches, none have yet advanced beyond the phase of experimental development to the level of clinical induction. The hurdles that need to be surmounted for ultimate success are discussed.

Retinal layer measurements after successful macula-off retinal detachment repair using optical coherence tomography

PURPOSE Optical coherence tomography (OCT) was used to analyze the thickness of various retinal layers of patients following successful macula-off retinal detachment (RD) repair. METHODS Optical coherence tomography scans of patients after successful macula-off RD repair were reanalyzed with a subsegmentation algorithm to measure various retinal layers. Regression analysis was performed to correlate time after surgery with changes in layer thickness. In addition, patients were divided in two groups. Group 1 had a follow-up period after surgery of up to 7 weeks (range, 21-49 days). In group 2, the follow-up period was >8 weeks (range, 60-438 days). Findings were compared to a group of age-matched healthy controls. RESULTS Correlation analysis showed a significant positive correlation between inner nuclear-outer plexiform layer (INL-OPL) thickness and time after surgery (P=0.0212; r2=0.1551). Similar results were found for the ellipsoid zone-retinal pigment epithelium complex (EZ-RPE) thickness (P=0.005; r2=0.2215). Ganglion cell-inner plexiform layer thickness (GCL-IPL) was negatively correlated with time after surgery (P=0.0064; r2=0.2101). For group comparison, the retinal nerve fiber layer in both groups was thicker compared to controls. The GCL-IPL showed significant thinning in group 2. The outer nuclear layer was significantly thinner in groups 1 and 2 compared to controls. The EZ-RPE complex was significantly thinner in groups 1 and 2 compared to controls. In addition, values in group 1 were significantly thinner than in group 2. CONCLUSIONS Optical coherence tomography retinal layer thickness measurements after successful macular-off RD repair revealed time-dependent thickness changes. Inner nuclear-outer plexiform layer thickness and EZ-RPE thickness was positively correlated with time after surgery. Ganglion cell-inner plexiform layer thickness was negatively correlated with time after surgery.

Dynamic intraligamentary stabilization and primary repair: A new concept for the treatment of knee dislocation.

BACKGROUND Traumatic knee dislocation represents a rare but devastating injury. Several controversies persist regarding type of treatment, surgical timing, graft selection, repair versus reconstruction of the medial and lateral structures, surgical techniques and postoperative rehabilitation. A new technique for primary ACL stabilization, dynamic intaligamentary stabilization (DIS) was developed at the authors' institution. The purpose of this study was to analyze the clinical and radiological outcomes of surgically treated traumatic knee dislocations by means of the DIS technique for the ACL, primary suturing for PCL, MCL and LCL. METHODS Between 2009 and 2012, 35 patients treated surgically for traumatic knee dislocation with primary anterior cruciate ligament (ACL) reconstruction with DIS, suturing of the posterior cruciate ligament (PCL) and primary complete repair of collaterals, were evaluated clinically (IKDC score, SF12 health survey, Lysholm score, Tegner score) and radiologically with a mean follow up of 2.2 years (range 1.00-3.50 years) years. Instrumented anterior-posterior translation was measured (KT-2000). RESULTS Anterior/posterior translation (KT-2000) for the healthy and injured limb was 4.8mm (range 3-8mm) and 7.3mm (range 5-10) (89N) respectively. Valgus and varus stress testing in 30° flexion was normal in 26 (75%) and 29 (83%) patients, respectively. The IKDC score was B in 29 (83%) and C in 6 (17%) patients, while the mean Tegner score was 6 (range 4-8). The mean Lysholm score was 90.83 (range 81-95) and mean SF-12 physical and mental scores were 54.1 (range 45-60) and 51.0 (range 39-62) respectively. In 2 patients, a secondary operation was performed. CONCLUSIONS Early, one stage reconstruction with DIS can achieve good functional results and patient satisfaction with overall restoration of sports and working capacity without graft requirements.