Inhibition of Vascular Growth by Modulation of the Anandamide/Fatty Acid Amide Hydrolase Axis.

OBJECTIVE: Pathological angiogenesis is a hallmark of various diseases characterized by local hypoxia and inflammation. These disorders can be treated with inhibitors of angiogenesis, but current compounds display a variety of side effects and lose efficacy over time. This makes the identification of novel signaling pathways and pharmacological targets involved in angiogenesis a top priority. Approach and Results: Here, we show that inactivation of FAAH (fatty acid amide hydrolase), the enzyme responsible for degradation of the endocannabinoid anandamide, strongly impairs angiogenesis in vitro and in vivo. Both, the pharmacological FAAH inhibitor URB597 and anandamide induce downregulation of gene sets for cell cycle progression and DNA replication in endothelial cells. This is underscored by cell biological experiments, in which both compounds inhibit proliferation and migration and evoke cell cycle exit of endothelial cells. This prominent antiangiogenic effect is also of pathophysiological relevance in vivo, as laser-induced choroidal neovascularization in the eye of FAAH-/- mice is strongly reduced. CONCLUSIONS: Thus, elevation of endogenous anandamide levels by FAAH inhibition represents a novel antiangiogenic mechanism.

The inter-individual anatomical variation of the trochlear notch as a predisposition for simple elbow dislocation.

PURPOSE: Besides the multi-layered capsule-ligamentous complex of the elbow joint the high bony congruence in the ulnohumeral joint contributes to elbow stability. Therefore, we assume that specific anatomical configurations of the trochlear notch predispose to dislocation. In case of ligamentous elbow dislocation both conservative and surgical treatment is possible without a clear treatment algorithm. Findings of constitutional bony configurations could help deciding for the best treatment option. METHODS: In this retrospective matched-pair analysis we compared MRI imaging from patients sustaining a primary traumatic elbow dislocation (instability group) with patients suffering from chronic lateral epicondylitis (control group), treated between 2009 and 2019. Two independent observers measured different anatomical landmarks of the trochlear notch in a multiplanar reconstructed standardized sagittal trochlear plane (SSTP). Primarily, opening angle and relative depth of the trochlear notch were determined. After adjustment to the proximal ulnar rim in the SSTP, coronoid and olecranon angle, the articular angle as well as the ratio of the tip heights of the trochlear notch were measured. RESULTS: We compared 34 patients in the instability group (age 48 ± 14 years, f/m 19/15) with 34 patients in the control group (age 47 ± 16 years, f/m 19/15). Instability group showed a significantly larger opening angle (94.1° ± 6.9° vs. 88.5° ± 6.9°, p = 0.0002), olecranon angle (60.9° ± 5.3° vs. 56.1° ± 5.1°, p < 0.0001) and articular angle (24.7° ± 6.4° vs. 22.3° ± 5.8°, p = 0.02) compared to the control group. Measuring the height from the coronoid (ch) and olecranon (oh) tip also revealed a significantly larger tip ratio (tr = ch/oh) in the instability group (2.7 ± 0.8 vs. 2.2 ± 0.5, p < 0.0001). The relative depth (61.0% ± 8.3% vs. 62.7% ± 6.0%, p = 0.21) of the trochlear notch as well as the coronoid angle (32.8° ± 4.5° vs. 31.7° ± 5.2°, p = 0.30) showed no significant difference in the instability group compared to the control group. The interrater reliability of all measurements was between 0.83 and 0.94. CONCLUSION: MRI of patients with elbow dislocation show that there seems to be a bony anatomical predisposition. According to the results, it seems reasonable to include predisposing bony factors in the decision-making process when surgical stabilization and conservative treatment is possible. Further biomechanical studies should prove these assumptions to generate critical bony values helping surgeons with decision making. LEVEL OF EVIDENCE: III.

Failure analysis of infection persistence after septic revision surgery: a checklist algorithm for risk factors in knee and hip arthroplasty.

PURPOSE: Several studies describe risk factors for primary periprosthetic joint infection (PJI) and general treatment outcome factors like microbe spectrum or patient-specific risk factors. However, these general and patient dependent findings cannot solely explain all cases of infection persistence after a prior septic revision. This study analyzes possible specific and patient independent reasons for failure after revisions for PJI in knee and hip arthroplasty. METHODS: In a prospective analysis all patients were included that were treated: (1) at our department, (2) with a two-stage exchange, (3) between 2013 and 2017, (4) due to an infection persistence after a previous revision for PJI. Possible reasons for infection persistence were identified using a checklist algorithm, based on international guidelines. RESULTS: 70 patients with infection persistence could be included (44 knee joints, 26 hip joints). The average age was 71 years, the CCI (Charlson Comorbidity Index) 2.8 and the ASA (American Society of Anesthesiologists) score 2.7. In 85% at least one possible reason for patient independent infection persistence could be identified analyzing the previous infection therapy: (1) 50% inadequate therapy concept (n = 35), (2) 33% inadequate surgical debridement (n = 23), (3) 30% inadequate antimicrobial therapy (n = 21), (4) 13% missed external bacterial primary focus (n = 9). After the individual failure analysis, all 70 patients were treated with a two-stage exchange in our department and in 94.9% infection freedom could be achieved (34.3 ± 10.9 months follow-up). CONCLUSIONS: In the majority of failed revisions with subsequent infection persistence at least one possible patient independent failure cause could be identified. The entire previous therapy should be critically reviewed following failing revisions to optimize the outcome of septic revisions. By using a checklist algorithm, high rates of infection freedom were achieved.