Accessibility of osteochondral lesion at the capitellum during elbow arthroscopy: an anatomical study.

INTRODUCTION: Osteochondrosis dissecans (OCD) at the capitellum is a common pathology in young patients. Although arthroscopic interventions are commonly used, there is a lack of information about the accessibility of the defects during elbow arthroscopy by using standard portals. MATERIALS AND METHODS: An elbow arthroscopy using the standard portals was performed in seven fresh frozen specimens. At the capitellum, the most posterior and anterior cartilage surface reachable was marked with K-wires. Using a newly described measuring method, we constructed a circular sector around the rotational center of the capitellum. The intersection of K-wire "A" and "B" with the circular sector was marked, and the angles between the K-wires and the Rogers line, alpha angle for K-Wire "A" and beta angle for K-wire "B", and the corridor not accessible during arthroscopy was digitally measured. RESULTS: On average, we found an alpha angle of 53° and a beta angle of 104°. Leaving a sector of 51° which was not accessible via the standard portals during elbow arthroscopy. CONCLUSION: Non-accessible capitellar lesions during elbow arthroscopy should be considered preoperatively, and the informed consent discussion should always include the possibility of open procedures or the use of flexible instruments.

Anatomic evaluation of the triceps tendon insertion at the proximal olecranon regarding placement of fracture fixation devices.

PURPOSE: Olecranon fractures, especially with a small proximal fragment, remain a surgical challenge. Soft tissue irritation and affection of the triceps muscle bear a risk of complications. In order to find an area for a soft-tissue sparing placement of implants in the treatment of olecranon fractures, we aimed to define and measure the segments of the proximal olecranon and evaluate them regarding possible plate placement. METHODS: We investigated 82 elbow joints. Ethical approval was obtained from the local ethics committee, After positioning in an arm holder and a posterior approach we described the morphology of the triceps footprint, evaluated and measured the surface area of the triceps and posterior capsule and correlated the results to easily measurable anatomical landmarks. RESULTS: We found a bipartite insertional footprint with a superficial tendinous triceps insertion of 218.2 mm2 (± 41.2, range 124.7-343.2), a capsular insertion of 159.3 mm2 (± 30.2, range 99.0-232.1) and a deep, muscular triceps insertion area of 138.1 mm2 (± 30.2, range 79.9-227.5). Olecranon height was 26.7 mm (± 2.3, range 20.5-32.2), and olecranon width was 25.3 mm (± 2.4, range 20.9-30.4). Average correlation between the size of the deep insertion and ulnar (r = 0.314) and radial length (r = 0.298) was obtained. CONCLUSIONS: We demonstrated the bipartite morphology of the distal triceps footprint and that the deep muscular triceps insertion area by its measured size could be a possible site for the placement of fracture fixations devices. The size correlates with ulnar and radial length.

Diagnostic Performance of a Panel of miRNAs (OsteomiR) for Osteoporosis in a Cohort of Postmenopausal Women.

A specific signature of 19 circulating miRNAs (osteomiRs) has been reported to be associated with fragility fractures due to postmenopausal osteoporosis. However, it is unknown whether osteoporotic fractures or low BMD phenotypes are independently contributing to changes in osteomiR serum levels. The first aim was to characterize the abundance, sensitivity to hemolysis, and correlation of osteomiR serum levels, the second objective to evaluate the diagnostic accuracy of osteomiRs for osteoporosis according to the WHO criteria and on basis of major osteoporotic fracture history. Fifty postmenopausal women with osteoporosis (with or without fragility fracture) and 50 non-osteoporotic women were included in this cross-sectional study. The diagnostic performance of osteomiRs for osteoporosis based on the WHO definition or fracture history was evaluated using multiple logistic regression and receiver-operator curve (AUC) analysis. The osteomiR® signature is composed of four clusters of miRNAs providing good performance for the diagnosis of osteoporosis in postmenopausal women defined by WHO criteria (AUC = 0.830) and based on history of major osteoporotic fractures (AUC = 0.834). The classification performance for the WHO criteria and for fracture risk is driven by miR-375 and miR-203a, respectively. OsteomiRs, a signature of 19 emerging miRNA bone biomarkers, are measurable in human serum samples. They constitute a panel of independent bone and muscle biomarkers, which in combination could serve as diagnostic biomarkers for osteoporosis in postmenopausal women.

Effectiveness, safety and utilization of vismodegib in locally advanced basal cell carcinoma under real-world conditions in Germany - The non-interventional study NIELS.

BACKGROUND: Basal cell carcinoma (BCC) can arise by the uncontrolled proliferation of cells from multiple epidermal compartments due to aberrant activation of the Hedgehog (Hh) signalling pathway. Vismodegib, a small-molecule inhibitor of this pathway, is approved for treatment of patients with locally advanced (la) BCC inappropriate for surgery or radiotherapy or patients with symptomatic metastatic (m) BCC. OBJECTIVES: The aim of this non-interventional study was to assess effectiveness with a special focus on duration of response (DOR), safety and utilization of vismodegib for treatment of laBCC in daily practice in Germany. METHODS: This non-interventional study (NIS) observed treatment of laBCC with vismodegib according to the German label in clinical practice. All available patients who had received at least one dose of vismodegib between commercial availability of vismodegib in Germany (02 August 2013) and 3 years before end of study (31 March 2016) could be included and were documented retrospectively and/or prospectively for up to 3 years. Primary effectiveness variable was DOR. Assessment of tumour response was carried out by the treating physicians. Exploratory variables included utilization of vismodegib, decision makers for therapy and method of tumour response evaluation. All statistical analyses were descriptive. RESULTS: Between September 2015 and March 2019, 66 patients were observed at 26 German centres. The objective response rate (ORR) was 74.2% and the disease control rate (DCR) was 90.9%. The median DOR was 15.9 months (95% CI: 9.2; 25.7; n = 49 patients with response). The median progression-free survival (PFS) was 19.1 months and the median time to response (TTR) 2.7 months. A total of 340 adverse events were reported in 63 (95.5%) patients; no new safety signals were identified. CONCLUSIONS: The NIS NIELS shows effectiveness and safety of vismodegib in patients with laBCC. It confirms the transferability of the results of the pivotal trial into routine clinical practice.

Overlengthening of the radial column in radial head replacement: a review of the literature and presentation of a classification system.

BACKGROUND: Radial head arthroplasty is a common procedure in elbow surgery. It has been shown to be of benefit for the patients, but there also are relevant complications that should be prevented if possible. One significant complication is overlengthening of the radial head prosthesis. In overlengthening, the head of the prosthesis overextends the physiological level of the native radial head and leads to overcompression in the radiohumeral joint. Rapid erosion and arthritic changes may then impede the clinical outcome. The incidence of overlengthening is not precisely known, but estimations range to up to 20% of all implanted prostheses. METHODS: The present review discusses the available body of literature on overlengthening and lines out a classification system that may be used to guide treatment algorithms. The classification is based on the personal experiences of the author during their clinical practice. RESULTS: In low-grade overlengthening (type I) conservative treatment can be an option. In Types II-IV usually revision surgery is needed. Depending on the state of the capitulum and joint stability, it is possible re-implant a prosthesis, or rely on implant removal alone. DISCUSSION: The present review aimed at shedding light into overlengthening as a complication radial head replacement and to help identify and treat it.

Inducing pilon fractures in human cadaveric specimens depending on the injury mechanism: a fracture simulation.

BACKGROUND: Operative management of pilon fractures, especially high-energy compression injuries, is a challenge. Operative education is of vital importance to handle these entities. Not rarely, it is cut by economics and staff shortage. As public awareness toward operative competence rises, surgical cadaver courses that provide pre-fractured specimens can improve realism of teaching scenarios. The aim of this study is to introduce a realistic pilon fracture simulation setup regarding the injury mechanism. MATERIALS AND METHODS: 8 cadaveric specimens (two left, six right) were fixed onto a custom drop-test bench in dorsiflexion (20°) and light supination (10°). The proximal part of the lower leg was potted, and the specimen was exposed to a high energetic impulse via an axial impactor. CT imaging was performed after fracture simulation to detect the exact fracture patterns and to classify the achieved fractures by two independent trauma surgeons. (AO/OTA recommendations and the Rüedi/Allgöwer). RESULTS: All cadaveric specimens could be successfully fractured: 6 (75%) were identified as a 43-C fracture and 2 (25%) as 43-B fracture type. Regardless of the identical mechanism two different kinds of fracture types were reported. In five cases (62.5%), the fibula was also fractured and in three specimens, a talus fracture was described. There was no statistically significant correlation found regarding Hounsfield Units (HU) and age as well as HU and required kinetic energy. CONCLUSION: A high energetic axial impulse on a fixed ankle specimen in light dorsiflexion (20°) and supination (10°) induced by a custom-made drop-test bench can successfully simulate realistic pilon fractures in cadaveric specimens with intact soft tissue envelope. Although six out of eight fractures (75%) were classified as a 43-C fracture and despite putting a lot of effort into the mechanical setup, we could not achieve an absolute level of precision. Therefore, we suggest that the injury mechanism is most likely a combination of axial loading, shear and rotation. LEVEL OF EVIDENCE: III.

[Radial head fractures : Epidemiology, diagnosis, treatment and outcome]. / Radiuskopffrakturen : Epidemiologie, Diagnose, Behandlung und Outcome.

Radial head fractures account for the majority of bony injuries to the elbow. The usual clinical signs include hemarthrosis, pain and limitations in movement. The standard diagnostic tool is radiological imaging using X­rays and for more complex fractures, computed tomography (CT). Concomitant ligamentous injuries occur more frequently than expected and must be reliably excluded. The classification is based on the modified Mason classification. Mason type I fractures are usually treated conservatively with immobilization and early functional aftercare. Mason type II fractures can be well-addressed by screw osteosynthesis but higher grade fractures (Mason types III-IV) can necessitate a prosthetic radial head replacement. In this case, prosthesis implantation is to be preferred to a radial head resection. The outcome after treatment of radial head fractures can be described as good to very good if all accompanying injuries are adequately addressed.

Peroneal nerve location at the fibular head: an anatomic study using 3D imaging.

INTRODUCTION: Injuries to the peroneal nerve are a common complication in operative treatment of proximal tibial or fibular fractures. To minimize the risk of iatrogenic injury to the nerve, detailed knowledge of the anatomy of the peroneal nerve is essential. Aim of this study was to present a detailed description of the position and branching of the peroneal nerve based on 3D-images to assist preparation for surgical approaches to the fibular head and the tibial plateau. METHODS: The common peroneal nerve, the deep and the superficial peroneal nerve were marked with a radiopaque thread in 18 formalin-embalmed specimens. Three-dimensional X-ray scans were then acquired from the knee and the proximal lower leg in full extension of the knee. In 3D-reconstructions of these scans, distances of the common peroneal nerve and its branches to clearly defined osseous landmarks were measured digitally. Furthermore, the height of the branching of the common peroneal nerve was measured in relation to the landmarks. RESULTS: The mean distance of the common peroneal nerve at the level of the tibial plateau to its posterior osseous limitation was 7.92 ± 2.42 mm, and 1.31 ± 2.63 mm to the lateral osseous limitation of the tibia. In a transversal plane, distance of the common peroneal nerve branching was 27.56 ± 3.98 mm relative to the level of the most proximal osseous extension of fibula and 11.77 ± 6.1 mm relative to the proximal extension of the tibial tuberosity. The deep peroneal nerve crossed the midline of the fibular shaft at a distance of 22.14 mm ± 4.35 distally to the most proximal extension of the fibula, the superficial peroneal nerve at a distance of 33.56 mm ± 6.68. CONCLUSION: As the course of the peroneal nerve is highly variable in between individuals, surgical dissection for operative treatment of proximal posterolateral tibial or fibular fractures has to be done carefully. We defined an area were the peroneal nerve and its branches are unlikely to be found. However, specific safe zones should not be utilized due to the individual anatomic variation.

[Elbow prostheses in rheumatic diseases]. / Ellenbogenprothese bei rheumatischen Erkrankungen.

When the elbow is destroyed due to rheumatic diseases, the joint can be replaced by a prosthesis and total arthroplasty. Improved pharmaceutical treatment for rheumatic diseases has, however, reduced the number of implantations in these patients. Reported 10-year survival rates of the implant currently achieve 81-90%.; however, due to limited long-term survival of the implant and high complication rates, total elbow arthroplasty should still be used with caution. Continuous technical improvements in the available prostheses and in surgical techniques could lead in the future to a decline in complications, such as aseptic loosening and infections.

[Olecranon fractures]. / Olekranonfrakturen.

Olecranon fractures represent a common elbow injury and they are usually treated operatively. Depending on fracture morphology conservative therapy can be considered in geriatric patients. When surgical treatment is performed the anatomical features of the proximal ulna have to be taken into consideration. Tension band wiring is considered a standard procedure for simple fractures and provides good clinical results. Plate osteosynthesis is indicated for more complex fracture patterns. Nowadays, many surgeons prefer plate fixation over tension band wiring even for simple fractures as it leads to a more stable fixation. Both methods frequently require hardware removal for persisting soft tissue irritation. The use of modern low-profile plates could reduce the need for implant removal due to better soft tissue coverage. The available clinical data regarding low-profile plates are promising but limited.

[Total elbow arthroplasty in traumatic and post-traumatic bone defects]. / Ellenbogentotalendoprothetik bei traumatischen und posttraumatischen Knochendefekten.

Total elbow arthroplasty is currently most commonly carried out due to acute trauma or post-traumatic conditions. Bone defects are often present and must be considered in the (pre-)operative workup. The use of semi-constrained prostheses with a systematic cementing technique through a triceps-on approach leads to satisfying clinical results, however, the outcome is worse when compared with rheumatic patients.Primary total elbow arthroplasty for complex distal humerus fractures in the elderly patient or secondary implantation following failed conservative treatment or osteosynthesis represent possible indications for (post­)traumatic joint replacement. The condyles do not have to be reconstructed and the humerus can be shortened by 2-3 cm without sacrificing the functionality of the extensor apparatus. In the case of post-traumatic joint destruction and pronounced chronic instability following complex fractures of the proximal forearm - especially following terrible triad or Monteggia-like injuries - total elbow arthroplasty can be considered as a treatment option. The extensor apparatus must be reconstructed, and the implantation of the prosthesis must thus be combined with plate osteosynthesis of the ulna - if necessary. Chronic deformity should only be corrected as much as needed in order to avoid early aseptic loosening due to increased shearing forces and polyethylene wear.Massive bone loss is problematic and can be compensated with allografts or tumor prostheses. The results of these salvage procedures are less predictable, and complication rates increase significantly.

Functional anatomy of the lateral collateral ligament of the elbow.

INTRODUCTION: The aim of this study was to analyze the functional anatomy of the lateral collateral ligament complex (LCLC) and the surrounding forearm extensors. MATERIALS AND METHODS: Using 81 human cadaveric upper extremities, the anatomy of the forearm extensors-especially the anconeus, supinator and extensor carpi ulnaris (ECU)-was analyzed. After removal of aforementioned extensors the functional anatomy of the LCLC was analyzed. The origin of the LCLC was evaluated for isometry. The insertion types of the lateral ulnar collateral ligament (LUCL) were analyzed and classified. RESULTS: The ECU runs parallel to the RCL to dynamically preserve varus stability. The supinator and anconeus muscle fibers coalesce with the LCLC and lengthen during pronation. The anconeus fibers run parallel to the LUCL in full flexion. The LCLC consists of the annular ligament (AL) and the isometric radial collateral ligament (RCL). During elbow flexion, its posterior branches (LUCL) tighten while the anterior branches loosen. When performing a pivot shift test, the loosened LUCL fibers do not fully tighten in full extension. The LUCL inserts along with the AL at the supinator crest. Three different insertion types could be observed. CONCLUSIONS: The LUCL represents the posterior branch of the RCL rather than a distinct ligament. It is non-isometric and lengthens during elbow flexion. The RCL was found to be of vital importance for neutralization of posterolateral rotatory forces. Pronation of the forearm actively stabilizes the elbow joint as the supinator, anconeus and biceps muscle work in unison to increase posterolateral rotatory stability.

[Chronic ligamentous instability of the elbow]. / Chronische Bandinstabilitäten des Ellenbogengelenks.

BACKGROUND: Chronic ligamentous instability of the elbow is an important pathology as it is accompanied with pronounced dysfunction. Moreover, it represents an established risk factor for the development of osteoarthritis. Posterolateral rotatory instability (PLRI) caused by insufficiency of the lateral collateral ligament (LCL) is the most common type of chronic elbow instability and is usually a sequel of traumatic elbow dislocation. Chronic overload can lead to insufficiency of the ulnar collateral ligament (UCL) with subsequent valgus instability, especially in overhead athletes. DIAGNOSTICS: Subjective instability and recurrent elbow dislocations are not always the main symptoms but elbow instability is instead often characterized by pain and secondary joint stiffness. Many clinical tests are available yet eliciting them can be difficult and inconclusive. A "drop sign" on lateral radiographs as well as the detection of collateral ligament injuries and joint incongruity on MRI scans can support the suspected diagnosis. In some cases, instability can only be verified by diagnostic arthroscopy. TREATMENT: Reconstruction of the lateral ulnar collateral ligament (LUCL) for treatment of PLRI generally leads to good clinical results, yet recurrent instability remains an issue and has been reported in 8 % of cases. UCL reconstruction for chronic valgus instability leads to a return-to-sports rate of about 86 % in the overhead athlete. Ulnar neuropathy, which is seen in approximately 6 % of patients, represents the most common complication. On the rare occasion of multidirectional instability, the box-loop technique can be used for simultaneous reconstruction of the LUCL and UCL with a circumferential graft. 15 cases with promising results have been reported in literature thus far.

[Lateral ulnar collateral ligament reconstruction : A biomechanical analysis of posterolateral rotatory instability of the elbow]. / Laterale ulnare Kollateralbandplastik : Biomechanische Untersuchung zur posterolateralen Rotationsinstabilität des Ellenbogens.

BACKGROUND: Chronic posterolateral rotatory instability (PLRI) of the elbow is the result of an insufficiency of the lateral collateral ligament (LCL). Lateral ulnar collateral ligament (LUCL) reconstruction represents a well-established treatment method for PLRI. However, recurrent instability remains a problem. OBJECTIVES: The goal of this in-vitro study was to evaluate the posterolateral rotatory stability of the intact elbow, after sectioning of the LCL and after LUCL reconstruction with a triceps tendon autograft and double BicepsButton(TM) fixation. MATERIALS AND METHODS: Posterolateral rotatory stability of 6 fresh-frozen elbow specimens at a torque of 3 Nm was analyzed at 0, 45, 90 and 120° of flexion for the intact LCL, after sectioning of the LCL and after LUCL reconstruction. Moreover, cyclic loading (1000 cycles) of the intact specimens and after LUCL reconstruction was performed. RESULTS: The intact LCL and the LUCL reconstruction provided equal primary stability (0.250 ≤ p ≤ 0.888). Sectioning of the LCL significantly increased PLRI (p < 0.001). The stability of the intact specimens and after LUCL reconstruction did not differ after cyclic loading (p = 0.218). During cyclic loading, posterolateral rotation increased significantly more after LUCL reconstruction (3.2 ± 0.8°) when compared to the native LCL (2.0 ± 0.7°, p = 0.020). CONCLUSIONS: LUCL reconstruction with BicepsButton(TM) fixation provides comparable stability to the native LCL. Further clinical results are necessary to evaluate whether this technique can decrease the complication rate.

[The bare area of the proximal ulna : An anatomical study on optimizing olecranon osteotomy]. / Die Bare Area der proximalen Ulna : Eine anatomische Studie zur Optimierung der Olekranonosteotomie.

BACKGROUND: Olecranon osteotomy is an established approach for the treatment of distal humerus fractures. It should be performed through the bare area of the proximal ulna to avoid iatrogenic cartilage lesions. OBJECTIVES: The goal of this study was to analyze the anatomy of the proximal ulna with regard to the bare area and, thereby, to optimize the hitting area of the bare area when performing olecranon osteotomy. MATERIALS AND METHODS: The bare areas of 30 embalmed forearm specimens were marked with a radiopaque wire and visualized three-dimensionally with a mobile C­arm. By means of 3D reconstructions of the data sets, the following measurements were obtained: height of the bare area; span of the bare area-hitting area in transverse osteotomy; ideal angle for olecranon osteotomy to maximize the hitting area of the bare area; distance of the posterior olecranon tip to the entry point of the transverse osteotomy and the ideal osteotomy. RESULTS: The height of the bare area was 4.92 ± 0.81 mm. The hitting area of the transverse osteotomy averaged 3.73 ± 0.89 mm. The "ideal" angle for olecranon osteotomy was 30.7° ± 4.19°. The distance of the posterior olecranon tip to the entry point was 14.08 ± 2.75 mm for the transverse osteotomy and 24.21 ± 3.15 mm for the ideal osteotomy. The hitting area of the bare area in the ideal osteotomy was enhanced significantly when compared to the transverse osteotomy (p < 0.0001). CONCLUSIONS: This study provides guide values for correct osteotomy of the olecranon. Moreover, a 30° angulation of the osteotomy can significantly increase the hitting area of the bare area.

Relative survival of patients with non-malignant central nervous system tumours: a descriptive study by the Austrian Brain Tumour Registry.

BACKGROUND: Unlike malignant primary central nervous system (CNS) tumours outcome data on non-malignant CNS tumours are scarce. For patients diagnosed from 1996 to 2002 5-year relative survival of only 85.0% has been reported. We investigated this rate in a contemporary patient cohort to update information on survival. METHODS: We followed a cohort of 3983 cases within the Austrian Brain Tumour Registry. All patients were newly diagnosed from 2005 to 2010 with a histologically confirmed non-malignant CNS tumour. Vital status, cause of death, and population life tables were obtained by 31 December 2011 to calculate relative survival. RESULTS: Overall 5-year relative survival was 96.1% (95% CI 95.1-97.1%), being significantly lower in tumours of borderline (90.2%, 87.2-92.7%) than benign behaviour (97.4%, 96.3-98.3%). Benign tumour survival ranged from 86.8 for neurofibroma to 99.7% for Schwannoma; for borderline tumours survival rates varied from 83.2 for haemangiopericytoma to 98.4% for myxopapillary ependymoma. Cause of death was directly attributed to the CNS tumour in 39.6%, followed by other cancer (20.4%) and cardiovascular disease (15.8%). CONCLUSION: The overall excess mortality in patients with non-malignant CNS tumours is 5.5%, indicating a significant improvement in survival over the last decade. Still, the remaining adverse impact on survival underpins the importance of systematic registration of these tumours.

Prognostic significance of Ki67 proliferation index, HIF1 alpha index and microvascular density in patients with non-small cell lung cancer brain metastases.

BACKGROUND: Survival upon diagnosis of brain metastases (BM) in patients with non-small cell lung cancer (NSCLC) is highly variable and established prognostic scores do not include tissue-based parameters. METHODS: Patients who underwent neurosurgical resection as first-line therapy for newly diagnosed NSCLC BM were included. Microvascular density (MVD), Ki67 tumor cell proliferation index and hypoxia-inducible factor 1 alpha (HIF-1 alpha) index were determined by immunohistochemistry. RESULTS: NSCLC BM specimens from 230 patients (151 male, 79 female; median age 56 years; 199 nonsquamous histology) and 53/230 (23.0%) matched primary tumor samples were available. Adjuvant whole-brain radiation therapy (WBRT) was given to 153/230 (66.5%) patients after neurosurgical resection. MVD and HIF-1 alpha indices were significantly higher in BM than in matched primary tumors. In patients treated with adjuvant WBRT, low BM HIF-1 alpha expression was associated with favorable overall survival (OS), while among patients not treated with adjuvant WBRT, BM HIF-1 alpha expression did not correlate with OS. Low diagnosis-specific graded prognostic assessment score (DS-GPA), low Ki67 index, high MVD, low HIF-1 alpha index and administration of adjuvant WBRT were independently associated with favorable OS. Incorporation of tissue-based parameters into the commonly used DS-GPA allowed refined discrimination of prognostic subgroups. CONCLUSION: Ki67 index, MVD and HIF-1 alpha index have promising prognostic value in BM and should be validated in further studies.

Necroptosis in immunity and ischemia-reperfusion injury.

Transplantation is invariably associated with ischemia-reperfusion injury (IRI), inflammation and rejection. Resultant cell death has morphological features of necrosis but programmed cell death has been synonymous with apoptosis until pathways of regulated necrosis (RN) have been described. The best-studied RN pathway, necroptosis, is triggered by perturbation of caspase-8-mediated apoptosis and depends on receptor-interacting protein kinases 1 and 3 (RIPK1/RIPK3) as well as mixed linage kinase domain like to form the necroptosome. The release of cytosolic content and cell death-associated molecular patterns (CDAMPs) can trigger innate and promote adaptive immune responses. Thus, the form of cell death can substantially influence alloimmunity and graft survival. Necroptosis is a key element of IRI, and RIPK1 interference by RN-specific inhibitors such as necrostatin-1 protects from IRI in kidney, heart and brain. Necroptosis may be a general mechanism in response to other forms of inflammatory organ injury, and will likely emerge as a promising target in solid organ transplantation. As second-generation RIPK1 and RIPK3 inhibitors become available, clinical trials for the prevention of delayed graft function and attenuation of allograft rejection-mediated injury will emerge. These efforts will accelerate upon further identification of critical necroptosis-triggering receptor(s).

The effect of mycophenolate mofetil on podocytes in nephrotoxic serum nephritis.

Mycophenolate mofetil (MMF) is applied in proteinuric kidney diseases, but the exact mechanism of its effect on podocytes is still unknown. Our previous in vitro experiments suggested that MMF can ameliorate podocyte damage via restoration of the Ca2+-actin cytoskeleton axis. The goal of this study was to characterize podocyte biology during MMF treatment in nephrotoxic serum (NTS) nephritis (NTN). NTN was induced in three-week old wild-type mice. On day 3, half of the mice were treated with MMF (100 mg/kgBW/d p.o.) for one week. On day 10, we performed proteomic analysis of glomeruli as well as super-resolution imaging of the slit diaphragm. For multiphoton imaging of Ca2+ concentration ([Ca2+]i), the experimental design was repeated in mice expressing podocyte-specific Ca2+ sensor. MMF ameliorated the proteinuria and crescent formation induced by NTS. We identified significant changes in the abundance of proteins involved in Ca2+ signaling and actin cytoskeleton regulation, which was further confirmed by direct [Ca2+]i imaging in podocytes showing decreased Ca2+ levels after MMF treatment. This was associated with a tendency to restoration of podocyte foot process structure. Here, we provide evidence that MPA has a substantial direct effect on podocytes. MMF contributes to improvement of [Ca2+]i and amelioration of the disorganized actin cytoskeleton in podocytes. These data extend the knowledge of direct effects of immunosuppressants on podocytes that may contribute to a more effective treatment of proteinuric glomerulopathies with the least possible side effects.