Plate-associated localized osteitis in mini-pig by biofilm-forming Methicillin-resistant Staphylococcus aureus (MRSA): establishment of a novel experimental model.

PURPOSE: The increasing number of implant-associated infections during trauma and orthopedic surgery caused by biofilm-forming Staphylococcus aureus in combination with an increasing resistance of conventional antibiotics requires new therapeutic strategies. One possibility could be testing for different therapeutic strategies with differently coated plates. Therefore, a clinically realistic model is required. The pig offers the best comparability to the human situation, thus it was chosen for this model. The present study characterizes a novel model of a standardized low-grade acute osteitis with bone defect in the femur in mini-pigs, which is stabilized by a titanium locking plate to enable further studies with various coatings. METHODS: A bone defect was performed on the femur of 7 Aachen mini-pigs and infected with Methicillin-resistant S. aureus (MRSA ATCC 33592). The defect zone was stabilized with a titanium plate. After 14 days, a plate change, wound debridement and lavage were performed. Finally, after 42 days, the animals were lavaged and debrided again, followed by euthanasia. The fracture healing was evaluated radiologically and histologically. RESULTS: A local osteitis with radiologically visible lysis of the bone could be established. The unchanged high Colony-forming Units (CFU) in lavage, the significant differences in Interleukin (IL)-6 in blood compared to lavage and the lack of increase in Alkaline Phosphates (ALP) in serum over the entire observation period show the constant local infection. CONCLUSION: The study shows the successful induction of local osteitis with lysis of the bone and the lack of enzymatic activity to mineralize the bone. Therefore, this standardized mini-pig model can be used in further clinical studies, to investigate various coated implants, bone healing, biofilm formation and immune response in implant-associated osteitis.

The MRI posterior drawer test to assess posterior cruciate ligament functionality and knee joint laxity.

Clinical Magnetic Resonance Imaging (MRI) of joints is limited to mere morphologic evaluation and fails to directly visualize joint or ligament function. In this controlled laboratory study, we show that knee joint functionality may be quantified in situ and as a function of graded posterior cruciate ligament (PCL)-deficiency by combining MRI and standardized loading. 11 human knee joints underwent MRI under standardized posterior loading in the unloaded and loaded (147 N) configurations and in the intact, partially, and completely PCL-injured conditions. For each specimen, configuration, and condition, 3D joint models were implemented to analyse joint kinematics based on 3D Euclidean vectors and their projections on the Cartesian planes. Manual 2D measurements served as reference. With increasing PCL deficiency, vector projections increased significantly in the anteroposterior dimension under loading and manual measurements demonstrated similar patterns of change. Consequently, if combined with advanced image post-processing, stress MRI is a powerful diagnostic adjunct to evaluate ligament functionality and joint laxity in multiple dimensions and may have a role in differentiating PCL injury patterns, therapeutic decision-making, and treatment monitoring.

Comprehensive Assessment of Medial Knee Joint Instability by Valgus Stress MRI.

Standard clinical MRI techniques provide morphologic insights into knee joint pathologies, yet do not allow evaluation of ligament functionality or joint instability. We aimed to study valgus stress MRI, combined with sophisticated image post-processing, in a graded model of medial knee joint injury. To this end, eleven human cadaveric knee joint specimens were subjected to sequential injuries to the superficial medial collateral ligament (sMCL) and the anterior cruciate ligament (ACL). Specimens were imaged in 30° of flexion in the unloaded and loaded configurations (15 kp) and in the intact, partially sMCL-deficient, completely sMCL-deficient, and sMCL- and ACL-deficient conditions using morphologic sequences and a dedicated pressure-controlled loading device. Based on manual segmentations, sophisticated 3D joint models were generated to compute subchondral cortical distances for each condition and configuration. Statistical analysis included appropriate parametric tests. The medial compartment opened gradually as a function of loading and injury, especially anteriorly. Corresponding manual reference measurements by two readers confirmed these findings. Once validated in clinical trials, valgus stress MRI may comprehensively quantify medial compartment opening as a functional imaging surrogate of medial knee joint instability and qualify as an adjunct diagnostic tool in the differential diagnosis, therapeutic decision-making, and monitoring of treatment outcomes.

Deep Learning-Based Post-Processing of Real-Time MRI to Assess and Quantify Dynamic Wrist Movement in Health and Disease.

While morphologic magnetic resonance imaging (MRI) is the imaging modality of choice for the evaluation of ligamentous wrist injuries, it is merely static and incapable of diagnosing dynamic wrist instability. Based on real-time MRI and algorithm-based image post-processing in terms of convolutional neural networks (CNNs), this study aims to develop and validate an automatic technique to quantify wrist movement. A total of 56 bilateral wrists (28 healthy volunteers) were imaged during continuous and alternating maximum ulnar and radial abduction. Following CNN-based automatic segmentations of carpal bone contours, scapholunate and lunotriquetral gap widths were quantified based on dedicated algorithms and as a function of wrist position. Automatic segmentations were in excellent agreement with manual reference segmentations performed by two radiologists as indicated by Dice similarity coefficients of 0.96 ± 0.02 and consistent and unskewed Bland-Altman plots. Clinical applicability of the framework was assessed in a patient with diagnosed scapholunate ligament injury. Considerable increases in scapholunate gap widths across the range-of-motion were found. In conclusion, the combination of real-time wrist MRI and the present framework provides a powerful diagnostic tool for dynamic assessment of wrist function and, if confirmed in clinical trials, dynamic carpal instability that may elude static assessment using clinical-standard imaging modalities.

Seeing Beyond Morphology-Standardized Stress MRI to Assess Human Knee Joint Instability.

While providing the reference imaging modality for joint pathologies, MRI is focused on morphology and static configurations, thereby not fully exploiting the modality's diagnostic capabilities. This study aimed to assess the diagnostic value of stress MRI combining imaging and loading in differentiating partial versus complete anterior cruciate ligament (ACL)-injury. Ten human cadaveric knee joint specimens were subjected to serial imaging using a 3.0T MRI scanner and a custom-made pressure-controlled loading device. Emulating the anterior-drawer test, joints were imaged before and after arthroscopic partial and complete ACL transection in the unloaded and loaded configurations using morphologic sequences. Following manual segmentations and registration of anatomic landmarks, two 3D vectors were computed between anatomic landmarks and registered coordinates. Loading-induced changes were quantified as vector lengths, angles, and projections on the x-, y-, and z-axis, related to the intact unloaded configuration, and referenced to manual measurements. Vector lengths and projections significantly increased with loading and increasing ACL injury and indicated multidimensional changes. Manual measurements confirmed gradually increasing anterior tibial translation. Beyond imaging of ligament structure and functionality, stress MRI techniques can quantify joint stability to differentiate partial and complete ACL injury and, possibly, compare surgical procedures and monitor treatment outcomes.

Evaluating Lumbar Intervertebral Disc Degeneration on a Compositional Level Using Chemical Exchange Saturation Transfer: Preliminary Results in Patients with Adolescent Idiopathic Scoliosis.

Lumbar intervertebral disc (IVD) degeneration is characterized by structural and compositional changes. This study aimed to assess the glycosaminoglycan (GAG) content of IVDs of patients with adolescent idiopathic scoliosis (AIS) and healthy controls using GAG chemical exchange saturation transfer (gagCEST) imaging. Ten AIS patients (mean age 18.3 ± 8.2 years) and 16 healthy controls (mean age 25.5 ± 1.7 years) were included. Clinical standard morphologic MR images (T1w-, T2w-, and STIR-sequences), to rule out further spinal disorders and assess IVD degeneration using the Pfirrmann score, and compositional gagCEST sequences were acquired on a 3T MRI. In AIS patients, the most distal scoliotic curve was determined on whole-spine conventional radiographs and morphological MRI and IVDs were divided as to whether they were affected by scoliotic deformity, i.e., proximal (affected, aIVDs) or distal (unaffected, uaIVDs) to the stable vertebra of the most distal scoliotic curve. Linear mixed models were used to compare mean gagCEST-values. Over all segments, AIS-patients' IVDs exhibited significantly lower gagCEST-values than the controls: 2.76 [2.32, 3.20]% (AIS), 3.51 [3.16, 3.86]% (Control); p = 0.005. Meanwhile, no significant differences were found for gagCEST values comparing aIVDs with uaIVDs. In conclusion, as a powerful diagnostic adjunct, gagCEST imaging may be prospectively applied to detect early compositional degenerative changes in patients suffering from AIS.

Non-Specific Low Back Pain and Lumbar Radiculopathy: Comparison of Morphologic and Compositional MRI as Assessed by gagCEST Imaging at 3T.

Using glycosaminoglycan Chemical Exchange Saturation Transfer (gagCEST) magnetic resonance imaging (MRI), this study comparatively evaluated the GAG contents of lumbar intervertebral disks (IVDs) of patients with non-specific low back pain (nsLBP), radiculopathy, and asymptomatic volunteers to elucidate the association of clinical manifestation and compositional correlate. A total of 18 patients (mean age 57.5 ± 22.5 years) with radiculopathy, 16 age-matched patients with chronic nsLBP and 20 age-matched volunteers underwent standard morphologic and compositional gagCEST MRI on a 3T scanner. In all cohorts, GAG contents of lumbar IVDs were determined using gagCEST MRI. An assessment of morphologic IVD degeneration based on the Pfirrmann classification and T2-weighted sequences served as a reference. A linear mixed model adjusted for multiple confounders was used for statistical evaluation. IVDs of patients with nsLBP showed lower gagCEST values than those of volunteers (nsLBP: 1.3% [99% confidence intervals (CI): 1.0; 1.6] vs. volunteers: 1.9% [99% CI: 1.6; 2.2]). Yet, IVDs of patients with radiculopathy (1.8% [99% CI: 1.4; 2.1]) were not different from patients with nsLBP or volunteers. In patients with radiculopathy, IVDs directly adjacent to IVD extrusions demonstrated lower gagCEST values than distant IVDs (adjacent: 0.9% [99% CI: 0.3; 1.5], distant: 2.1% [99% CI: 1.7; 2.5]). Advanced GAG depletion in nsLBP and directly adjacent to IVD extrusions in radiculopathy indicates close interrelatedness of clinical pathology and compositional degeneration.

Sodium MRI of human articular cartilage of the wrist: a feasibility study on a clinical 3T MRI scanner.

OBJECTIVE: To measure sodium relaxation times and concentrations in human wrists on a clinical magnetic resonance imaging (MRI) scanner with a density-adapted radial sequence. MATERIALS AND METHODS: Sodium MRI of human wrists was conducted on a 3T MR system using a dual-tuned 1H/23Na surface coil. We performed two studies with 10 volunteers each investigating either sodium T1 (study 1) or sodium T2* (study 2) relaxation times in the radiocarpal joint (RCJ) and midcarpal joint (MCJ). Sodium concentrations of both regions were determined. RESULTS: No differences for transversal of longitudinal relaxation times were found between RCJ and MCJ (T2,s*(RCJ) = (0.9 ± 0.4) ms; T2,s*(MCJ) = (0.9 ± 0.3) ms; T2,l*(RCJ) = (14.9 ± 0.9) ms; T2,l*(MCJ) = (13.9 ± 1.1) ms; T1(RCJ) = (19.0 ± 2.4) ms; T1(MCJ) = (18.5 ± 2.1) ms). Sodium concentrations were (157.7 ± 28.4) mmol/l for study 1 and (159.8 ± 29.1) mmol/l for study 2 in the RCJ, and (172.7 ± 35.6) mmol/l for study 1 and (163.4 ± 26.3) mmol/l for study 2 in the MCJ. CONCLUSION: We successfully determined sodium relaxation times and concentrations of the human wrist on a 3T MRI scanner.

Assessment of Articular Cartilage Disorders After Distal Radius Fracture Using Biochemical and Morphological Nonenhanced Magnetic Resonance Imaging.

PURPOSE: To assess radiocarpal articular cartilage after distal radius fracture, with and without intra-articular extension, compared with healthy controls using multiparametric, nonenhanced magnetic resonance imaging (MRI). METHODS: In this prospective study, multiparametric MRI of the radiocarpal articular cartilage was performed in 26 participants (16 males and 10 females; mean age, 39.5 ± 14.7 years; range, 20-70 years) using 3T MRI. The cohort consisted of 14 patients with a distal radius fracture and 12 healthy volunteers. The radiocarpal articular cartilage was assessed using morphological (Double Echo Steady-State [DESS] and True Fast Imaging With Steady-State Precession [TrueFISP]) and biochemical (T2∗) MRI sequences without an intravenous contrast agent. The modified Outerbridge classification system for morphological analyses and region-of-interest biochemical analysis were applied to assess the degree of articular cartilage damage in each patient. RESULTS: Morphological articular cartilage assessment showed no difference between the DESS sequence and the reference standard, TrueFISP. In the morphological (DESS and TrueFISP) and biochemical (T2∗) assessments, patients with intra-articular fractures did not show articular cartilage damage different from those with extra-articular fractures. Greater articular cartilage degradation was observed after distal radius fracture compared with controls. CONCLUSIONS: Posttraumatic radiocarpal articular cartilage damage did not differ between fractures with intra-articular and extra-articular extension, but patients with fractures had notably higher articular cartilage degradation compared with healthy controls. Magnetic resonance imaging using advanced multiparametric sequences may facilitate accurate, noninvasive assessment of articular cartilage changes after distal radius fracture without the need for a contrast agent. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic IV.

Selenium Pretreatment for Mitigation of Ischemia/Reperfusion Injury in Cardiovascular Surgery: Influence on Acute Organ Damage and Inflammatory Response.

Ischemia/reperfusion injury (IRI) contributes to morbidity and mortality after cardiovascular surgery requiring cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA). Multi-organ damage is associated with substantial decreases of blood selenium (Se) levels in patients undergoing cardiac surgery with CPB. We compared the influence of a dietary surplus of Se and pretreatment with ebselen, a mimic of the selenoenzyme glutathione peroxidase, on IRI-induced tissue damage and inflammation. Male Wistar rats were fed either a Se-adequate diet containing 0.3 ppm Se or supplemented with 1 ppm Se (as sodium selenite) for 5 weeks. Two other groups of Se-adequate rats received intraperitoneal injection of ebselen (30 mg/kg) or DMSO (solvent control) before surgery. The animals were connected to a heart-lung-machine and underwent 45 min of global ischemia during circulatory arrest at 16 °C, followed by re-warming and reperfusion. Selenite and ebselen suppressed IRI-induced leukocytosis and the increase in plasma levels of tissue damage markers (AST, ALT, LDH, troponin) during surgery but did not prevent the induction of proinflammatory cytokines (IL-6, TNF-α). Both Se compounds affected phosphorylation and expression of proteins related to stress response and inflammation: Ebselen increased phosphorylation of STAT3 transcription factor in the heart and decreased phosphorylation of ERK1/2 MAP kinases in the lungs. Selenite decreased ERK1/2 phosphorylation and HSP-70 expression in the heart. Pretreatment with selenite or ebselen protected against acute IRI-induced tissue damage during CPB and DHCA. Potential implications of their different actions with regard to molecular stress markers on the recovery after surgery represent promising targets for further investigation.

A cardiopulmonary bypass with deep hypothermic circulatory arrest rat model for the investigation of the systemic inflammation response and induced organ damage.

BACKGROUND: Cardiopulmonary bypass (CPB) is a commonly used technique in cardiac surgery. CPB is however associated with a strong induction of systemic inflammatory response syndrome (SIRS) which in conjunction with ischemia and reperfusion may lead to multiple organ failure. The aim of the study was to establish and characterize a CPB rat model incorporating deep hypothermic circulatory arrest with a specific focus on the extent of the inflammatory reactions and organ damage as a groundwork for novel therapeutics against SIRS and I/R induced organ injury. MATERIALS AND METHODS: Male Wistar rats (n = 6) were cannulated for CPB, connected to a heart-lung-machine (HLM) and cooled to a temperature of 16°C before they underwent 45 minutes of deep hypothermic circulatory arrest with global ischaemia. Arrest was followed by rewarming and 60 minutes of reperfusion. Haemodynamic and vital parameters were recorded throughout the CPB procedure. Only animals displaying sinus rhythm throughout reperfusion were utilized for analysis. Rats were euthanized and tissue samples were harvested. Blood gas analysis was performed and blood samples were taken. Induction of organ damage was examined by analysis of protein levels and phosphorylation status of kinases and stress proteins. Results were compared to animals (n = 6) which did not undergo CPB. RESULTS: CPB induced leucocytosis and an increase of interleukin-6 and TNF-α plasma values indicating an inflammatory response. Markers of tissue damage and dysfunction, such as troponin T, creatinine and AST were elevated. Phosphorylation of STAT3 was induced in all examined organs. Activation of MAPK and induction of heat shock proteins occurred in an organ-specific manner with most pronounced effects in heart, lungs and kidneys. CONCLUSIONS: The presented CPB rat model shows the induction of SIRS and activation of specific signalling cascades. SIRS seems not to be provoked during DHCA and is elicited mainly during reperfusion. This model might be suitable to test the efficacy of therapeutics applied in major heart surgery with and without DHCA.

The 2N-ary Choice Tree Model for N-Alternative Preferential Choice.

The 2N-ary choice tree model accounts for response times and choice probabilities in multi-alternative preferential choice. It implements pairwise comparison of alternatives on weighted attributes into an information sampling process which, in turn, results in a preference process. The model provides expected choice probabilities and response time distributions in closed form for optional and fixed stopping times. The theoretical background of the 2N-ary choice tree model is explained in detail with focus on the transition probabilities that take into account constituents of human preferences such as expectations, emotions, or socially influenced attention. Then it is shown how the model accounts for several context-effects observed in human preferential choice like similarity, attraction, and compromise effects and how long it takes, on average, for the decision. The model is extended to deal with more than three choice alternatives. A short discussion on how the 2N-ary choice tree model differs from the multi-alternative decision field theory and the leaky competing accumulator model is provided.