Management after acute injury of the anterior cruciate ligament (ACL). Part 3: Recommendation on surgical treatment.

PURPOSE: The aim of this consensus project was to give recommendations regarding surgical treatment of the anterior cruciate ligament (ACL) injured patient. METHODS: For this consensus process, an expert, steering and rating group was formed. In an initial online meeting, the steering group, together with the expert group, formed various key topic complexes for which multiple questions were formulated. For each key topic, a structured literature search was performed by the steering group. The results of the literature review were sent to the rating group with the option to give anonymous comments until a final consensus voting was performed. Sufficient consensus was defined as 80% agreement. RESULTS: During this consensus process, 30 topics regarding the surgical management and technique of ACL reconstruction were identified. The literature search for each key question resulted in 30 final statements. Of these 30 final statements, all achieved consensus. CONCLUSIONS: This consensus process has shown that surgical treatment of ACL injury is a complex process. Various surgical factors influence patient outcomes. The proposed treatment algorithm can be used as a decision aid for the surgeon. LEVEL OF EVIDENCE: Level V.

Management after acute rupture of the anterior cruciate ligament (ACL). Part 1: ACL reconstruction has a protective effect on secondary meniscus and cartilage lesions.

PURPOSE: The aim of this consensus project was to validate which endogenous and exogenous factors contribute to the development of post-traumatic osteoarthritis and to what extent ACL (anterior cruciate ligament) reconstruction can prevent secondary damage to the knee joint. Based on these findings, an algorithm for the management after ACL rupture should be established. METHODS: The consensus project was initiated by the Ligament Injuries Committee of the German Knee Society (Deutsche Kniegesellschaft, DKG). A modified Delphi process was used to answer scientific questions. This process was based on key topic complexes previously formed during an initial face-to-face meeting of the steering group with the expert group. For each key topic, a comprehensive review of available literature was performed by the steering group. The results of the literature review were sent to the rating group with the option to give anonymous comments until a final consensus voting was performed. Consensus was defined a-priori as eighty percent agreement. RESULTS: Of the 17 final statements, 15 achieved consensus, and 2 have not reached consensus. Results of the consensus were summarized in an algorithm for the management after ACL rupture (infographic/Fig. 2). CONCLUSION: This consensus process has shown that the development of post-traumatic osteoarthritis is a complex multifactorial process. Exogenous (primary and secondary meniscus lesions) and endogenous factors (varus deformity) play a decisive role. Due to the complex interplay of these factors, an ACL reconstruction cannot always halt post-traumatic osteoarthritis of the knee. However, there is evidence that ACL reconstruction can prevent secondary joint damage such as meniscus lesions and that the success of meniscus repair is higher with simultaneous ACL reconstruction. Therefore, we recommend ACL reconstruction in case of a combined injury of the ACL and a meniscus lesion which is suitable for repair. LEVEL OF EVIDENCE: Level V.

Management after acute injury of the anterior cruciate ligament (ACL), part 2: management of the ACL-injured patient.

PURPOSE: The aim of this consensus project was to create a treatment algorithm for the management of the ACL-injured patient which can serve as an aid in a shared decision-making process. METHODS: For this consensus process, a steering and a rating group were formed. In an initial face-to-face meeting, the steering group, together with the expert group, formed various key topic complexes for which various questions were formulated. For each key topic, a structured literature search was performed by the steering group. The results of the literature review were sent to the rating group with the option to give anonymous comments until a final consensus voting was performed. Sufficient consensus was defined as 80% agreement. RESULTS: During this consensus process, 15 key questions were identified. The literature search for each key question resulted in 24 final statements. Of these 24 final statements, all achieved consensus. CONCLUSIONS: This consensus process has shown that ACL rupture is a complex injury, and the outcome depends to a large extent on the frequently concomitant injuries (meniscus and/or cartilage damage). These additional injuries as well as various patient-specific factors should play a role in the treatment decision. The present treatment algorithm represents a decision aid within the framework of a shared decision-making process for the ACL-injured patient. LEVEL OF EVIDENCE: Level V.

Treatment of Combined Injuries to the ACL and the MCL Complex: A Consensus Statement of the Ligament Injury Committee of the German Knee Society (DKG).

BACKGROUND: Different indications and treatment options for combined injuries to the anterior cruciate ligament (ACL) and medial collateral ligament complex (MCL) are not clearly defined. PURPOSE: To perform a modified Delphi process with the Committee for Ligament Injuries of the German Knee Society (DKG) in order to structure and optimize the process of treating a combined injury to the ACL and MCL. STUDY DESIGN: Consensus statement. METHODS: Scientific questions and answers were created based on a comprehensive literature review using the central registers for controlled studies of Medline, Scopus, and Cochrane including the terms medial collateral ligament, anterior cruciate ligament, MCL, ACL, and outcome used in various combinations. The obtained statements passed 3 cycles of a modified Delphi process during which each was readjusted and rated according to the available evidence (grades A-E) by the members of the DKG Ligament Injuries Committee and its registered guests. RESULTS: The majority of answers, including several questions with >1 graded answer, were evaluated as grade E (n = 16) or C (n = 10), indicating that a low level of scientific evidence was available for most of the answers. Only 5 answers were graded better than C: 3 answers with a grade of A and 2 answers with a grade of B. Only 1 answer was evaluated as grade D. An agreement of >80% (range, 83%-100%) among committee members was achieved for all statements. CONCLUSION: The results of this modified Delphi process offer a guideline for standardized patient care in cases of combined injuries to the ACL and MCL.

Deficient knee joint biomechanics in bilateral jumping after anterior cruciate ligament reconstruction.

BACKGROUND: The purpose of this study was to analyze sagittal-plane knee biomechanics in individuals with ACL reconstructions in bilateral countermovement jumps. This aimed to determine potential knee compensation strategies during a high-demanding symmetrical movement task from pre to six months post-ACL reconstruction. METHODS: 20 ACL-reconstructed individuals were tested pre-operatively, and then seven weeks, three months, and six months after reconstruction. Additionally, a matched control group was analyzed. Data were sampled with 3D motion capture and two force plates. The following kinematic data were analyzed: peak knee flexion during countermovement, knee angle at toe-off, and knee flexion excursion during landing. The following kinetic data were analyzed: peak knee extension moments during countermovement and landing. FINDINGS: ACL-reconstructed individuals showed significant increases in knee flexion during countermovement and knee flexion excursion during landing from six weeks to six months after reconstruction but they remained significantly below the level of the controls. The reconstructed knee joint showed increased flexion at toe-off compared to the non-injured leg at all test sessions. Knee extension moments during countermovement increased up to six months after reconstruction, but remained deficient in ACL-reconstructed individuals during countermovement and landing compared to the controls. INTERPRETATION: Although ACL-reconstructed individuals showed increases in most kinematic and kinetic variables, they remained below the controls at six months post-ACL reconstruction. The deficits between contralateral legs and compared to the controls show that six months post-ACL reconstruction, knee joint functionality was still not equal between reconstructed and non-injured legs or in comparison to controls.

Diaryl sulfide-based inhibitors of trypanothione reductase: inhibition potency, revised binding mode and antiprotozoal activities.

Trypanothione reductase (TR) is an essential enzyme of trypanosomatids and therefore a promising target for the development of new drugs against African sleeping sickness and Chagas' disease. Diaryl sulfides with a central anilino moiety, decorated with a flexible N-alkyl side chain bearing a terminal ammonium ion, are a known class of inhibitors. Using computer modelling, we revised the binding model for this class of TR inhibitors predicting simultaneous interactions of the ammonium ion-terminated N-alkyl chain with Glu18 as well as Glu465'/Glu466' of the second subunit of the homodimer, whereas the hydrophobic substituent of the aniline ring occupies the "mepacrine binding site" near Trp21 and Met113. Systematic alteration of the carboxylate-binding fragments and the diaryl sulfide core of the inhibitor scaffold provided evidence for the proposed binding mode. In vitro studies showed IC(50) values in the low micromolar to submicromolar range against Trypanosoma brucei rhodesiense as well as the malaria parasite Plasmodium falciparum.

Design and validation of a testing system to assess torsional cancellous bone failure in conjunction with time-lapsed micro-computed tomographic imaging.

When compressed axially, cancellous bone often fails at an oblique angle along well-defined bands, highlighting the importance of cancellous bone shear properties. Torsion testing to determine shear properties of cancellous bone has often been conducted under conditions appropriate only for axis-symmetric specimens comprised of homogeneous and isotropic materials. However, most cancellous bone specimens do not meet these stringent test conditions. Therefore, the aim of this study was to design and validate a uniaxial, incremental torsional testing system for non-homogeneous orthotropic or non-axis-symmetric specimens. Precision and accuracy of the newly designed torsion system was validated by using Plexiglas rods and beams, where obtained material properties were compared to those supplied by the manufacturer. Additionally, the incremental step-wise application of angular displacement and simultaneous time-lapsed microCT imaging capability of the system was validated using whale cancellous bone specimens, with step-wise application of angular displacement yielding similar torsional mechanical properties to continuous application of angular displacement in a conventional torsion study. In conclusion, a novel torsion testing system for non-homogeneous, orthotropic materials using the incremental step-wise application of torsion and simultaneous time-lapsed microCT imaging was designed and validated.

How does functionality proceed in ACL reconstructed subjects? Proceeding of functional performance from pre- to six months post-ACL reconstruction.

This is the first study examining functionality of subjects with anterior cruciate ligament (ACL) tears and a subsequent reconstruction comprehensively by multiple test sessions from pre- to six months post-reconstruction. The purpose was to evaluate if a generally applied rehabilitation program restores functionality to levels of healthy controls. Subjects with unilateral tears of the ACL were compared to matched healthy controls throughout the rehabilitation. 20 recreational athletes were tested: T1 (preoperative), 6 weeks after tear; T2, 6 weeks, T3, 3 months, T4, 6 months post-reconstruction. At all test sessions, subjects self-evaluated their activity level with the Tegner activity score and their knee state with the Knee Injury and Osteoarthritis Outcome Score. Passive range of motion during knee flexion and extension and leg circumference were measured as functional clinical tests. Bilateral countermovement jumps, one-leg jumps for distance and isometric force tests in knee flexion and extension with 90° and 110° knee angle were conducted as functional performance tests. For determination of functionality, leg symmetry indices (LSIs) were calculated by dividing values of the injured by the uninjured leg. In the ACL group most LSIs decreased from T1 to T2, and increased from T2 and T3 to T4. LSIs of ACL subjects remained lower than LSIs of healthy controls at 6 months post-reconstruction in nearly all parameters. Self-evaluation of ACL subjects showed, additionally, that activity level was lower than the pre-injury level at 6 months post-reconstruction. Low LSIs and low self-evaluation indicate that knee joint functionality is not completely restored at 6 months post-reconstruction. The study shows that multiple comprehensive testing throughout the rehabilitation gives detailed images of the functional state. Therefore, the functional state of ACL reconstructed individuals should be evaluated comprehensively and continuously throughout the rehabilitation to detect persisting deficiencies detailed and adapt rehabilitation programs individually depending on the functionality.

Binding to large enzyme pockets: small-molecule inhibitors of trypanothione reductase.

The causative agents of the parasitic disease human African trypanosomiasis belong to the family of trypanosomatids. These parasitic protozoa exhibit a unique thiol redox metabolism that is based on the flavoenzyme trypanothione reductase (TR). TR was identified as a potential drug target and features a large active site that allows a multitude of possible ligand orientations, which renders rational structure-based inhibitor design highly challenging. Herein we describe the synthesis, binding properties, and kinetic analysis of a new series of small-molecule inhibitors of TR. The conjunction of biological activities, mutation studies, and virtual ligand docking simulations led to the prediction of a binding mode that was confirmed by crystal structure analysis. The crystal structures revealed that the ligands bind to the hydrophobic wall of the so-called "mepacrine binding site". The binding conformation and potency of the inhibitors varied for TR from Trypanosoma brucei and T. cruzi.

Improved inhibitors of trypanothione reductase by combination of motifs: synthesis, inhibitory potency, binding mode, and antiprotozoal activities.

Trypanothione reductase (TR) is an essential enzyme in the trypanothione-based redox metabolism of trypanosomatid parasites. This system is absent in humans and, therefore, offers a promising target for the development of selective new drugs against African sleeping sickness and Chagas' disease. Over the past two decades, a variety of nonpeptidic small-molecule ligands of the parasitic enzyme were discovered. A current goal is to decipher the binding mode of these known inhibitors in order to optimize their structures. We analyzed the binding mode of recently reported 1-(1-(benzo[b]thiophen-2-yl)cyclohexyl)piperidine (BTCP) analogues using computer modeling methods. This led us to conclude that the analogues occupy a different region of the active site than the diaryl sulfide-based class of inhibitors. A combination of the two motifs significantly increased affinity for the enzyme compared to the respective parent compounds. The newly synthesized conjugates exhibit K(ic) values for TR as low as 0.51±0.1 µM and high selectivity for the parasitic enzyme over the related human glutathione reductase (hGR), as was predicted by our molecular modeling studies. In vitro studies showed IC(50) values in the low micromolar to submicromolar range against Trypanosoma brucei rhodesiense, often in combination with low cytotoxicity against mammalian cells. Interestingly, even stronger activities were found against Plasmodium falciparum.

Synthesis, inhibition potency, binding mode, and antiprotozoal activities of fluorescent inhibitors of trypanothione reductase based on mepacrine-conjugated diaryl sulfide scaffolds.

Trypanothione reductase (TR) is a flavoenzyme unique to trypanosomatid parasites and a target for lead discovery programs. Various inhibitor scaffolds have emerged in the past, exhibiting moderate affinity for the parasite enzyme. Herein we show that the combination of two structural motifs of known TR inhibitors - diaryl sulfides and mepacrine - enables the simultaneous addressing of two hydrophobic patches in the active site. The binding efficacy of these conjugates is enhanced over that of the respective parent inhibitors. They show K(ic) values for the parasite enzyme down to 0.9+/-0.1 microm and exhibit high selectivity for TR over human glutathione reductase (GR). Despite their considerable molecular mass and in some cases permanent positive charges, in vitro studies revealed IC(50) values in the low micromolar to sub-micromolar range against Trypanosoma brucei rhodesiense and Trypanosoma cruzi, as well as the malaria parasite Plasmodium falciparum, which lack trypanothione metabolism. The inhibitors exhibit strong fluorescence due to their aminoacridine moiety. This feature allows visualization of the drugs in the parasite where high accumulation was observed by fluorescence microscopy even after short exposure times.