Transcriptional Profiling Uncovers a Network of Cholesterol-Responsive Atherosclerosis Target Genes

Despite the well-documented effects of plasma lipid lowering regimes halting atherosclerosis lesion development and reducing morbidity and mortality of coronary artery disease and stroke, the transcriptional response in the atherosclerotic lesion mediating these beneficial effects has not yet been carefully investigated. We performed transcriptional profiling at 10-week intervals in atherosclerosis-prone mice with human-like hypercholesterolemia and a genetic switch to lower plasma lipoproteins (Ldlr−/−Apo100/100 Mttpflox/flox Mx1-Cre). Atherosclerotic lesions progressed slowly at first, then expanded rapidly, and plateaued after advanced lesions formed. Analysis of lesion expression profiles indicated that accumulation of lipid-poor macrophages reached a point that led to the rapid expansion phase with accelerated foam-cell formation and inflammation, an interpretation supported by lesion histology. Genetic lowering of plasma cholesterol (e.g., lipoproteins) at this point all together prevented the formation of advanced plaques and parallel transcriptional profiling of the atherosclerotic arterial wall identified 37 cholesterol-responsive genes mediating this effect. Validation by siRNA-inhibition in macrophages incubated with acetylated-LDL revealed a network of eight cholesterol-responsive atherosclerosis genes regulating cholesterol-ester accumulation. Taken together, we have identified a network of atherosclerosis genes that in response to plasma cholesterol-lowering prevents the formation of advanced plaques. This network should be of interest for the development of novel atherosclerosis therapies

Restoring tibiofemoral alignment during ACL reconstruction results in better knee biomechanics

"Published online: 24 October 2017"PURPOSE: Anterior cruciate ligament (ACL) reconstruction (ACLR) aims to restore normal knee joint function, stability and biomechanics and in the long term avoid joint degeneration. The purpose of this study is to present the anatomic single bundle (SB) ACLR that emphasizes intraoperative correction of tibiofemoral subluxation that occurs after ACL injury. It was hypothesized that this technique leads to optimal outcomes and better restoration of pathological tibiofemoral joint movement that results from ACL deficiency (ACLD). METHODS: Thirteen men with unilateral ACLD were prospectively evaluated before and at a mean follow-up of 14.9 (SD = 1.8) months after anatomic SB ACLR with bone patellar tendon bone autograft. The anatomic ACLR replicated the native ACL attachment site anatomy and graft orientation. Emphasis was placed on intraoperative correction of tibiofemoral subluxation by reducing anterior tibial translation (ATT) and internal tibial rotation. Function was measured with IKDC, Lysholm and the Tegner activity scale, ATT was measured with the KT-1000 arthrometer and tibial rotation (TR) kinematics were measured with 3Dmotion analysis during a high-demand pivoting task. RESULTS: The results showed significantly higher TR of the ACL-deficient knee when compared to the intact knee prior to surgery (12.2° ± 3.7° and 10.7° ± 2.6° respectively, P = 0.014). Postoperatively, the ACLR knee showed significantly lower TR as compared to the ACL-deficient knee (9.6°±3.1°, P = 0.001) but no difference as compared to the control knee (n.s.). All functional scores were significantly improved and ATT was restored within normal values (P < 0.001). CONCLUSIONS: Intraoperative correction of tibiofemoral subluxation that results after ACL injury is an important step during anatomic SB ACLR. The intraoperative correction of tibiofemoral subluxation along with the replication of native ACL anatomy results in restoration of rotational kinematics of ACLD patients to normal levels that are comparable to the control knee. These results indicate that the reestablishment of tibiofemoral alignment during ACLR may be an important step that facilitates normal knee kinematics postoperatively. LEVEL OF EVIDENCE: Level II, prospective cohort study.The authors gratefully acknowledge the funding support from the Hellenic Association of Orthopaedic Surgery and Traumatology (HAOST-EEXOT)info:eu-repo/semantics/publishedVersio

Assessing activity participation in the ACL injured population: a systematic review of activity rating scale measurement properties

Background: Participation is an important factor in assessing both the requirement for and outcome from anterior cruciate ligament reconstruction. Many patient-reported rating scales exist; however, measurement properties have not been well established. Objective: To provide a systematic review to identify currently available activity rating scales for anterior cruciate ligament injured subjects and to evaluate current knowledge of their measurement properties. Methods: Systematic searches of four databases (Medline, AMED, EMBASE, and CINAHL) without date or language restriction, using terms structured around the PICOS system were completed on 1st March 2011. Citation tracking, reference screening and contact with lead authors of key papers completed the search strategy. Studies using participation rating scales were identified to assess frequency of reporting and cited validation. Studies assessing one or more psychometric properties of the identified rating scales were subject to independent data extraction and critical appraisal by two independent authors using published tools. Results: Thirty-one rating scales were identified from 241 outcome studies. Most scales were inadequately developed or validated prior to use. Only three scales (Tegner, CSAS, and Marx) had psychometric analysis in eight studies of mixed quality. Only the Tegner scale has adequate assessment of reliability, validity, and responsiveness. The use of type, intensity, and frequency variables in the identified scales is discussed. Conclusions: The Tegner scale has been adequately validated; however, other rating scales require further validation. A comprehensive comparative analysis of clinical applicability and psychometric testing of existing scales, including clinically useful statistics, is required

Kinematic predictors of subjective outcome after anterior cruciate ligament reconstruction: An in vivo motion analysis study

Purpose: The purpose of this study was to test whether rotational knee kinematics during dynamic pivoting activities are predictive of subjective functional outcome (IKDC, Lysholm), objective laxity scores (KT max), and activity levels (Tegner) in patients after anterior cruciate ligament reconstruction (ACLR). Methods: Thirty-one patients with single-bundle ACLR were evaluated prospectively with 3D-motion analysis during (1) descending a stairway and pivoting and (2) landing from a jump and pivoting. The side-to-side difference of tibial rotation range of motion (SSDTR) between the ACLR and the contralateral intact knee was calculated for the pivoting phase of each task. Linear regression models were applied with SSDTR, for each task predictors of the subjective IKDC score, Lysholm score, anterior tibial translation, and Tegner activity level. Results: SSDTR for descending and landing were predictive of the IKDC subjective score (R 2 = 0.46, p &lt; 0.001 and R 2 = 0.40, p &lt; 0.001, respectively) with "medium" effect sizes and of the Lysholm score (R 2 = 0.13, p &lt; 0.05 and R 2 = 0.09, n. s.) with "small" to "none" effect sizes. SSDTR was not predictive of anterior translation or Tegner activity level (n. s.). Conclusions: Restoring rotational kinematics during dynamic pivoting activities after ACLR is predictive of functional outcome. The ability of the athlete after ACLR to control tibial rotation during pivoting activities may be predictive of functional outcome. Level of evidence: Case series study. Level IV. © 2012 Springer-Verlag