Effectiveness of Gravity and Manual Stress Radiographs and the Use of Lateral Talar Displacement in Determining Ankle Stability of Supination-External Rotation Type Ankle Fractures.

OBJECTIVES: (1) To evaluate adequacy and reproducibility of the gravity and manual stress imaging in the diagnosis of unstable ankle fractures and (2) to evaluate the diagnostic utility of lateral talar displacement ratio (LTDR) derived in relation to the talar body width on ankle stress imaging. DESIGN: Retrospective cohort study. SETTING: Level 1 Trauma Center. PATIENTS: One hundred seventy consecutive patients who presented with supination-external rotation 2 ankle fractures (OTA/AO 44-B2.1) requiring dynamic stress testing. INTERVENTION: Dynamic stress imaging to determine ankle stability. MAIN OUTCOME MEASURE: Ankle instability and subsequent need for surgical fixation as determined by dynamic stress imaging. RESULTS: No statistical significant difference was found between the adequacy of gravity stress radiographs and manual stress images in regards to surgical decision-making (P = 0.595). Using manual and gravity stress images, receiver operating characteristic curves were generated for medial clear space (MCS) (area under the curve = 0.793, 0.901) and LTDR (0.849, 0.850), corresponding to thresholds of 10.5% and 10.2% for manual and gravity, respectively. Seventy-three of 105 patients (69.5%) with MCS > 5 mm and 62 of 75 patients (82.7%) with LTDR > 10% were offered surgical intervention. Sixty-two of the 77 patients (80.5%) offered surgery had both MCS > 5 mm and LTDR > 10%. CONCLUSION: This study shows that manual stress radiographs are just as effective as gravity stress radiographs in making an assessment of ankle fracture stability as there was no difference in diagnostic value between gravity and manual stress imaging in regards to surgical decision-making. Use of additional radiographic measurements such as the LTDR can provide additional information in determining stability when MCS is within a clinical gray area. LEVEL OF EVIDENCE: Diagnostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Synthesis and SAR of novel capsazepine analogs with significant anti-cancer effects in multiple cancer types.

We previously demonstrated that capsazepine (CPZ), a synthetic transient receptor potential Vanilloid subtype 1 (TRPV1) antagonist, has significant anti-cancer effects in vivo. The purpose of this study was to develop more potent analogs based upon CPZ pharmacophore and structure-activity relationships (SAR) across analogs. We generated 30 novel compounds and screened for their anti-proliferative effects in cultured HeLa cervical cancer cells. Cell viability assays identified multiple compounds with IC50s < 15 µM and one compound, 29 with an IC50 < 5 µM; six fold more potent than CPZ. We validated the anti-proliferative efficacy of two lead compounds, 17 and 29, in vivo using HeLa-derived xenografts in athymic nude mice. Both analogs significantly reduced tumor volumes by day 8 compared to control treated animals (p < 0.001) with no observable adverse effects. Calcium imaging determined that compound 17 activates TRPV1 whereas 29 neither activates nor inhibits TRPV1; indicating a unique mechanism-of-action that does not involve TRPV1 signaling. Cell viability assays using a panel of additional tumor types including oral squamous cell carcinoma, non-small cell lung cancer (NSCLC), breast cancer, and prostate cancer cell lines (HSC-3, H460, MDA-231, and PC-3 respectively) demonstrated that both lead compounds were efficacious against every cancer type tested. Compounds 29 displayed IC50s of 1-2.5 µM in HSC-3and PC-3cells. Thus, we propose that these novel CPZ analogs may serve as efficacious therapeutic agents against multiple tumor types that warrant further development for clinical application.