Factors Associated with Return to Sport After Anterior Cruciate Ligament Reconstruction: A Focus on Athletes Who Desire Preinjury Level of Sport.

INTRODUCTION: In most previous studies investigating return to preinjury level of sport (RTPS) after anterior cruciate ligament reconstruction (ACLR), whether patients continue aiming for RTPS not only before but also after ACLR was unclear because environmental and social factors were not considered. Herein, we aimed to evaluate factors associated with RTPS among athletes who desired to achieve RTPS even after ACLR, excluding patients who no longer desire this goal owing to environmental and social factors. METHODS: Ninety-two patients who underwent primary double-bundle ACLR with a minimum 2-year follow-up and desired to achieve RTPS before surgery were retrospectively enrolled. Twelve (13%) patients who no longer desired to achieve RTPS after ACLR owing to environmental and social factors were excluded. Sixty-nine patients were included in the final cohort. At the final follow-up, the patients were split into two groups: those who achieved (R group) or did not achieve (N group) RTPS based on patient self-assessment. The Knee Injury and Osteoarthritis Outcome Score (KOOS) and Lysholm scores were also determined. The anterior tibial translation in the Lachman test and acceleration and external rotational angular velocity (ERAV) in the pivot shift test were measured at the hardware removal operation. RESULTS: Significant differences were observed for preinjury level of sports between the groups (P <.05). The rate of RTPS in competitive athletes was lower than that in recreational athletes (20/46: 43%, 16/22: 73%; P =.037). Lysholm score, KOOS symptom, pain, and quality of life showed higher values in the R than in the N group (P <.050). Acceleration was significantly lower in the R than in the N group (P =.028). CONCLUSION: Competitive level of sports is a risk factor for failure to achieve RTPS. The postoperative functional outcomes in the group that achieved RTPS showed more favorable results. These results provide important information to enable the surgeons to consider the appropriate surgical plan for competitive athletes who desire to achieve RTPS after ACLR.

Anterior Cruciate Ligament-Injured Knees With Meniscal Ramp Lesions Manifest Greater Anteroposterior and Rotatory Instability Compared With Isolated Anterior Cruciate Ligament-Injured Knees.

PURPOSE: To investigate the effects of ramp lesion (RL) and its repair on knee instability in patients with anterior cruciate ligament (ACL) injury by quantitatively assessing anteroposterior and rotational knee instability before and after ACL reconstruction. METHODS: All primary double-bundle ACL reconstructions using hamstring autografts between 2016 and 2021 were evaluated retrospectively. Patients with RLs without other meniscal injuries were included in group R, whereas those with isolated ACL injuries constituted group C. RL was repaired using all-inside devices in all patients in group R. Knee instability, including the amount of anterior tibial translation (ATT), and the acceleration and external rotational angular velocity of the knee joint (ERAV) during the pivot-shift test were assessed at the time of surgery. The pivot-shift test grade was recorded. RESULTS: A total of 73 patients were included in this study. Preoperatively, group R (n = 23) had significantly greater pivot-shift grades (P = .039), ATT (6.0 mm, group R; 4.5 mm, group C, P < .001), acceleration (6.8, 2.8; P = .037), and ERAV (3.9, 2.8; P = .001) than group C (n = 50). Intraoperatively, ATT (-1.0 mm, -1.0 mm; P < .001), acceleration (1.2, 1.1; P < .001), and ERAV (1.4, 1.2; P < .001) were significantly decreased compared with the preoperative values in both groups. No significant differences in these values were observed between groups R and C. CONCLUSIONS: ACL-injured knees accompanied by RLs exhibited significantly greater anteroposterior and rotatory instability than knees with isolated ACL injuries; increased knee instability can be effectively addressed by performing RL repair in conjunction with ACL reconstruction. The quantitative assessments employed-specifically measuring ATT, acceleration, and ERAV during the pivot-shift test-have allowed us to delineate these aspects of knee instability with greater precision. LEVEL OF EVIDENCE: Level Ⅲ, retrospective comparative study.

Constitutional varus knee due to tibial deformity is common and represents a good indication for high tibial osteotomy in Japanese population: Consideration of 1010 knees.

PURPOSE: This study aimed to elucidate the characteristics of varus knee deformities in the Japanese population, prevalence of various around knee osteotomy procedures and influence of femoral and tibial bowing. METHODS: Varus knee deformity was defined as a weight-bearing line ratio of <50%. A total of 1010 varus knees were selected from 1814 varus knees with weight-bearing full-length radiographs, obtained at two facilities, based on exclusion criteria. Various parameters were measured, and around knee osteotomy simulations based on the deformity centre were conducted using digital planning tools. Bowing of the femoral and tibial shafts was measured, with bowing defined as follows: ≤ -0.6° indicating lateral bowing and ≥ 0.6° indicating medial bowing. Statistical analysis was performed to investigate age-related correlations and their impact on surgical techniques. RESULTS: The study revealed that the proximal tibia was the centre of deformity in Japanese varus knees (42.8%), and high tibial osteotomy was frequently indicated (81.6%). Age demonstrated a mild correlation with femoral shaft bowing (r = -0.29), leading to an increase in the mechanical lateral distal femoral angle and to a decrease in the hip-knee-ankle angle and weight-bearing line ratio (r = -0.29, 0.221, 0.219). The tibial shaft bowing was unaffected by age (r = -0.022). CONCLUSION: A significant proportion of Japanese individuals with varus knees exhibit a deformity centre located in the proximal tibia, making them suitable candidates for high tibial osteotomy. No age-related alterations were discerned in tibial morphology, indicating that the occurrence of constitutional varus knees is attributable to tibial deformities in the Japanese patient cohort. LEVEL OF EVIDENCE: Level IV.

Factors Associated With Residual Pivot Shift After ACL Reconstruction: A Quantitative Evaluation of the Pivot-Shift Test Preoperatively and at Minimum 12-Month Follow-up.

Background: Postoperative residual rotatory laxity remains despite improvement in surgical techniques for anterior cruciate ligament (ACL) reconstruction (ACLR). Purpose: To evaluate factors associated with residual pivot shift after ACLR by quantitative measurement of the pivot shift before and after surgery. Study Design: Case-control study; Level of evidence, 3. Methods: A total of 97 patients who underwent primary double-bundle ACLR between June 2016 and March 2021 and underwent surgery to remove staples, with at least 12 months of follow-up evaluation, were enrolled. Quantitative measurements were performed under general anesthesia immediately before ACLR (preoperatively), after temporary fixation of the ACL graft (intraoperatively), and immediately before staple removal (postoperatively). The laxity of pivot shift was assessed using inertial sensors to measure acceleration and external rotational angular velocity (ERAV). Descriptive data were assessed for associations with postoperative acceleration and ERAV in a univariate analysis. A multiple linear regression analysis was performed to identify factors associated with postoperative acceleration and ERAV. Results: Anterior tibial translation, acceleration, and ERAV increased from intra- to postoperatively (P < .05). Factors significantly associated with postoperative acceleration were age (ß = -0.238; P = .021), lateral posterior tibial slope (PTS) (ß = 0.194; P = .048), and preoperative acceleration (ß = 0.261; P = .008). Factors significantly affecting postoperative ERAV were age (ß = -0.222; P = .029), ramp lesions (ß = 0.212; P = .027), and preoperative ERAV (ß = 0.323; P = .001). Conclusion: Greater preoperative laxity in the pivot shift was the factor having the most significant association with residual pivot shift after ACLR using quantitative measurements under general anesthesia. Younger age, higher lateral PTS, and concomitant ramp lesions were significant predictors of residual pivot shift. These findings can help pre- and intraoperative decision-making regarding whether an anterolateral structure augmentation should be added.

Efficacy of all-inside devices in reducing gap and step-off in knee extension for ramp lesion repair: A cadaveric study.

PURPOSE: The aim of this study is to assess the dynamics of the tear site of meniscal ramp lesions, particularly considering knee flexion angles, and validate anchor fixation using an all-inside device. METHODS: Eight Thiel-embalmed paired cadaveric knees with their whole bodies were used in this study. The ramp lesions were created arthroscopically, and ramp lesion dynamics were evaluated by gradually extending the knee from 90° of knee flexion. Changes in the gap and step-off (0: no step-off; 1: cross-sectional overlap exists; and 2: tibial articular surface exposed) were evaluated at 90°, 60°, 30°, and 10° of knee flexion. After dynamic evaluation, all-inside repairs of the ramp lesions using all-inside devices were conducted. Dissection was performed to confirm the position of anchor fixation. RESULTS: As the knee was extended, the gap significantly decreased at all knee flexion angles. Similarly, the step-off grade decreased as the knee was extended, and the step-off completely disappeared in all cases when the knee was extended from 30° to 10°. The average knee flexion angle at which the gap and step-off completely disappeared was 22.5°. After suturing the ramp lesion, arthroscopic evaluation showed that the gap had disappeared and the step-off had been repaired in all cases. Anchor fixation locations were not found within the joint but were fixed to the semimembranosus tendon or its surrounding articular capsule. Overall, 31% (5/16) anchors were fixed to the attachment site of the semimembranosus tendon, whereas the remaining were fixed to the articular capsule, located peripherally to the semimembranosus tendon. CONCLUSION: Suturing with an all-inside device for ramp lesions is a good option, and the repair in knee extension was found to be reasonable, considering the dynamics of ramp lesions in this study. LEVEL OF EVIDENCE: Level IV.

Comparison of Visibility and Risk of Neurovascular Tissue Injury Between Portals in Needle Arthroscopy of the Anterior Ankle Joint: A Cadaveric Study.

Background: For needle arthroscopy with 0° viewing, the visible range of intra-articular structures and the difference between portals remain unknown, as do the risks for neurovascular tissue at each portal. Purpose: To clarify the visibility and safety of needle arthroscopy. Study Design: Descriptive laboratory study. Methods: Ten cadaveric ankle specimens were used. A needle arthroscope with a 1.9-mm diameter was inserted from 4 portals (anteromedial [AM], anterolateral [AL], medial midline [MM], and anterocentral [AC]). Visibility was assessed using a 15-point ankle arthroscopy checklist. In addition, the ankles were dissected to measure the distance between each portal and neurovascular tissues. The visibility of the ankle joint was compared between portals. Results: The success rate of visibility in the deltoid ligament and the tip of the medial malleolus was 100% from the AM, MM, and AC portals and 10% from the AL portal, with significant differences between the portals (P < .01). The visibility success rates in the origin of the anterior talofibular ligament and the tip of the lateral malleolus were 20% for the AM portal, 90% for the MM and AC portals, and 100% for the AL portal, with significant differences between the portals (P < .01). All other points of the ankle joint were visualized from all the portals with a 100% success rate. The AC portal was in contact with the anterior neurovascular bundle in 4 of the 10 specimens. Conclusion: When needle arthroscopy was performed from the AM or AL portal, the site opposite to the portal in the ankle joint was difficult to visualize. Conversely, most points of the ankle joint could be visualized from the MM and AC portals. Care should be taken when creating an AC portal because of its proximity to the anterior neurovascular bundle. Clinical Relevance: The present study provides information regarding which portal should be selected to perform needle arthroscopy in the ankle joint, which will be beneficial for management of ankle injuries.

Macrodomain Mac1 of SARS-CoV-2 Nonstructural Protein 3 Hydrolyzes Diverse ADP-ribosylated Substrates.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for a global pandemic that resulted in more than 6-million deaths worldwide. The virus encodes several non-structural proteins (Nsps) that contain elements capable of disrupting cellular processes. Among these Nsp proteins, Nsp3 contains macrodomains, e.g., Mac1, Mac2, Mac3, with potential effects on host cells. Mac1 has been shown to increase SARS-CoV-2 virulence and disrupt ADP-ribosylation pathways in mammalian cells. ADP-ribosylation results from the transfer of the ADP-ribose moiety of NAD + to various acceptors, e.g., proteins, DNA, RNA, contributing on a cell's biological processes. ADP-ribosylation is the mechanism of action of bacterial toxins, e.g., Pseudomonas toxins, diphtheria toxin that disrupt protein biosynthetic and signaling pathways. On the other hand, some viral macrodomains cleavage ADP-ribose-acceptor bond, generating free ADP-ribose. By this reaction, the macrodomain-containing proteins interfere ADP-ribose homeostasis in host cells. Here, we examined potential hydrolytic activities of SARS-CoV-2 Mac1, 2, and 3 on substrates containing ADP-ribose. Mac1 cleaved α-NAD + , but not ß-NAD + , consistent with stereospecificity at the C-1" bond. In contrast to ARH1 and ARH3, Mac1 did not require Mg 2+ for optimal activity. Mac1 also hydrolyzed O -acetyl-ADP-ribose and ADP-ribose-1"-phosphat, but not Mac2 and Mac3. However, Mac1 did not cleave α-ADP-ribose-(arginine) and ADP-ribose-(serine)-histone H3 peptide, suggesting that Mac1 hydrolyzes ADP-ribose attached to O- and N-linked functional groups, with specificity at the catalytic site in the ADP-ribose moiety. We conclude that SARS-CoV-2 Mac1 may exert anti-viral activity by reversing host-mediated ADP-ribosylation. New insights on Nsp3 activities may shed light on potential SARS-CoV-2 therapeutic targets. IMPORTANCE: SARS-CoV-2, the virus responsible for COVID-19, encodes 3 macrodomain-containing proteins, e.g., Mac1, Mac2, Mac3, within non-structural proteins 3 (Nsp3). Mac1 was shown previously to hydrolyze ADP-ribose-phosphate. Inactivation of Mac1 reduced viral proliferation. Here we report that Mac1, but not Mac2 and Mac3, has multiple activities, i.e., Mac1 hydrolyzed. α-NAD + and O -acetyl-ADP-ribose. However, Mac1 did not hydrolyze ß-NAD + , ADP-ribose-serine on a histone 3 peptide (aa1-21), and ADP-ribose-arginine, exhibiting substrate selectivity. These data suggest that Mac1 may have multi-function as a α-NAD + consumer for viral replication and a disruptor of host-mediated ADP-ribosylation pathways. Understanding Mac1's mechanisms of action is important to provide possible therapeutic targets for COVID-19.

A PARP inhibitor, rucaparib, improves cardiac dysfunction in ADP-ribose-acceptor hydrolase 3 ( Arh3 ) deficiency.

Aims: Patients with ADP-ribose-acceptor hydrolase 3 ( ARH3 ) deficiency exhibit stress-induced childhood-onset neurodegeneration with ataxia and seizures (CONDSIAS). ARH3 degrades protein-linked poly(ADP- ribose) (PAR) synthesized by poly(ADP-ribose)polymerase (PARP)-1 during oxidative stress, leading to cleavage of the ADP-ribose linked to protein. ARH3 deficiency leads to excess accumulation of PAR, resulting in PAR-dependent cell death or parthanatos. Approximately one-third of patients with homozygous mutant ARH3 die from cardiac arrest, which has been described as neurogenic, suggesting that ARH3 may play an important role in maintaining myocardial function. To address this question, cardiac function was monitored in Arh3 -knockout (KO) and - heterozygous (HT) mice. Methods and results: Arh3 -KO male mice displayed cardiac hypertrophy by histopathology and decreased cardiac contractility assessed by MRI. In addition, both genders of Arh3 -KO and -HT mice showed decreased cardiac contractility by dobutamine stress test assessed by echocardiography. A direct role of ARH3 on myocardial function was seen with a Langendorff-perfused isolated heart model . Arh3 -KO male mouse hearts showed decreased post-ischemic rate pressure products, increased size of ischemia-reperfusion (IR) infarcts, and elevated PAR levels. Consistently, in vivo IR injury showed enhanced infarct size in Arh3 -KO mice in both genders. In addition, Arh3 -HT male mice showed increased size of in vivo IR infarcts. Treatment with an FDA-approved PARP inhibitor, rucaparib, improved cardiac contractility during dobutamine-induced stress and exhibited reduced size of in vivo IR infarcts. To understand better the role of ARH3, CRISPR-Cas9 was used to generate different Arh3 genotypes of myoblasts and myotubes. Incubation with H2O2 decreased viability of Arh3 -KO and -HT myoblasts and myotubes, resulting in PAR-dependent cell death that was reduced by PARP inhibitors or by transfection with the Arh3 gene. Conclusion: ARH3 regulates PAR homeostasis in myocardium to preserve function and protect against oxidative stress; PARP inhibitors reduce the myocardial dysfunction seen with Arh3 mutations.

Mono-ADP-ribosyltransferase 1 ( Artc1 )-deficiency decreases tumorigenesis, increases inflammation, decreases cardiac contractility, and reduces survival.

Arginine-specific mono-ADP-ribosylation is a reversible post-translational modification; arginine-specific, cholera toxin-like mono-ADP-ribosyltransferases (ARTCs) transfer ADP-ribose from NAD + to arginine, followed by cleavage of ADP-ribose-(arginine)protein bond by ADP-ribosylarginine hydrolase 1 (ARH1), generating unmodified (arginine)protein. ARTC1 has been shown to enhance tumorigenicity as does Arh1 deficiency. In this study, Artc1 -KO and Artc1/Arh1 -double-KO mice showed decreased spontaneous tumorigenesis and increased age-dependent, multi-organ inflammation with upregulation of pro-inflammatory cytokine TNF- α . In a xenograft model using tumorigenic Arh1 -KO mouse embryonic fibroblasts (MEFs), tumorigenicity was decreased in Artc1 -KO and heterozygous recipient mice, with tumor infiltration by CD8 + T cells and macrophages, leading to necroptosis, suggesting that ARTC1 promotes the tumor microenvironment. Furthermore, Artc1/Arh1 -double-KO MEFs showed decreased tumorigenesis in nude mice, showing that tumor cells as well as tumor microenvironment require ARTC1. By echocardiography and MRI, Artc1 -KO and heterozygous mice showed male-specific, reduced myocardial contractility. Furthermore, Artc1 -KO male hearts exhibited enhanced susceptibility to myocardial ischemia-reperfusion-induced injury with increased receptor-interacting protein kinase 3 (RIP3) protein levels compared to WT mice, suggesting that ARTC1 suppresses necroptosis. Overall survival rate of Artc1 -KO was less than their Artc1 -WT counterparts, primarily due to enhanced immune response and inflammation. Thus, anti-ARTC1 agents may reduce tumorigenesis but may increase multi-organ inflammation and decrease cardiac contractility.

ADP-ribose-acceptor hydrolase 2 ( Arh2 ) deficiency results in cardiac dysfunction, tumorigenesis, inflammation, and decreased survival.

ADP-ribosylation is a reversible reaction with ADP-ribosyltransferases catalyzing the forward reaction and ADP-ribose-acceptor hydrolases (ARHs) hydrolyzing the ADP-ribose acceptor bond. ARH2 is a member of the 39-kDa ARH family (ARH1-3), which is expressed in heart and skeletal muscle. ARH2 failed to exhibit any in vitro enzymatic activity. To determine its possible in vivo activities, Arh2 -knockout (KO) and - heterozygous (Het) mice were generated using CRISPR-Cas9. Arh2 -KO mice exhibited decreased cardiac contractility by MRI, echocardiography and dobutamine stress with cardiomegaly and abnormal motor function. Arh2 -Het mice showed results similar to those seen in Arh2 -KO mice except for cardiomegaly. Arh2 -KO and -Het mice and mouse embryonic fibroblasts (MEFs) developed spontaneous tumors and subcutaneous tumors in nude mice. We identified 13 mutations in Arh2 -Het MEFs and heterozygous tumors, corresponding to human ARH2 mutations in cancers obtained from COSMIC. Of interest, the L116R mutation in Arh2 gene plays a critical role in aggressive tumorigenesis in nude mice, corresponding to human ARH2 mutations in stomach adenocarcinoma. Both genders of Arh2 -KO and -Het mice showed increased unexpectedly deaths and decreased survival rate during a 24-month observation, caused by tumor, inflammation, non-inflammation (e.g., cardiomegaly, dental dysplasia), and congenital diseases. Thus, Arh2 plays a pivotal role in cardiac function, tumorigenesis, inflammation, and overall survival.

An Analysis of the Femoral Drilling Angle to Avoid Tunnel Collision during Double-Bundle Anterior Cruciate Ligament and Anterolateral Ligament Reconstruction on the Knee.

Concomitant anterior cruciate ligament (ACL) and anterolateral ligament (ALL) reconstruction has been reported as an effective technique for providing rotational control of the knee. However, the intraoperative risk of collision with an ACL tunnel during the drilling for the femoral ALL tunnel has been described. The purpose of this study was to investigate the various femoral drilling procedures to avoid tunnel collisions during combined double-bundle ACL and ALL reconstruction. Nine cadaveric knees were used in this study. ACL drilling was performed through the anteromedial portal to footprints of the posterolateral bundle at 120° (PL120) and 135° (PL135) knee flexion and the anteromedial bundle at 120° (AM120) and 135° (AM135) knee flexion. ALL drilling was performed at 0° (Cor0-ALL) and 30° (Cor30-ALL) coronal angles using a Kirschner wire (K-wire). The distance between the ALL footprint and ACL K-wire outlets, axial angles of ALL K-wires colliding with ACL K-wires, and distances from the ALL footprint to the collision point were measured. From these values, the safe zone, defined as the range of axial angles in which no collisions or penetrations occurred, was identified by simulation of tunnels utilized for reconstruction grafts in each drilling procedure. The point-to-point distance from the ALL footprint to the K-wire outlet was significantly greater in the AM120 than the AM135 (13.5 ± 3.1, 10.8 ± 3.2 mm; p = 0.048) and in the PL135 than the PL120 (18.3 ± 5.5, 16.1 ± 6.5 mm; p = 0.005) conditions, respectively. During an ACL drilling combination of PL135/AM120, a safe zone of > 45° in Cor30-ALL was identified. With a narrow safe zone during the PL135/AM120 combination only, the risk of femoral tunnel collisions in combined double-bundle ACL and ALL reconstruction is high. AM drilling at 120° and PL drilling at > 135° knee flexion, combined with ALL drilling at 30° coronal angle and > 45° axial angle, may reduce this risk.

ARH Family of ADP-Ribose-Acceptor Hydrolases.

The ARH family of ADP-ribose-acceptor hydrolases consists of three 39-kDa members (ARH1-3), with similarities in amino acid sequence. ARH1 was identified based on its ability to cleave ADP-ribosyl-arginine synthesized by cholera toxin. Mammalian ADP-ribosyltransferases (ARTCs) mimicked the toxin reaction, with ARTC1 catalyzing the synthesis of ADP-ribosyl-arginine. ADP-ribosylation of arginine was stereospecific, with ß-NAD+ as substrate and, α-anomeric ADP-ribose-arginine the reaction product. ARH1 hydrolyzed α-ADP-ribose-arginine, in addition to α-NAD+ and O-acetyl-ADP-ribose. Thus, ADP-ribose attached to oxygen-containing or nitrogen-containing functional groups was a substrate. Arh1 heterozygous and knockout (KO) mice developed tumors. Arh1-KO mice showed decreased cardiac contractility and developed myocardial fibrosis. In addition to Arh1-KO mice showed increased ADP-ribosylation of tripartite motif-containing protein 72 (TRIM72), a membrane-repair protein. ARH3 cleaved ADP-ribose from ends of the poly(ADP-ribose) (PAR) chain and released the terminal ADP-ribose attached to (serine)protein. ARH3 also hydrolyzed α-NAD+ and O-acetyl-ADP-ribose. Incubation of Arh3-KO cells with H2O2 resulted in activation of poly-ADP-ribose polymerase (PARP)-1, followed by increased nuclear PAR, increased cytoplasmic PAR, leading to release of Apoptosis Inducing Factor (AIF) from mitochondria. AIF, following nuclear translocation, stimulated endonucleases, resulting in cell death by Parthanatos. Human ARH3-deficiency is autosomal recessive, rare, and characterized by neurodegeneration and early death. Arh3-KO mice developed increased brain infarction following ischemia-reperfusion injury, which was reduced by PARP inhibitors. Similarly, PARP inhibitors improved survival of Arh3-KO cells treated with H2O2. ARH2 protein did not show activity in the in vitro assays described above for ARH1 and ARH3. ARH2 has a restricted tissue distribution, with primary involvement of cardiac and skeletal muscle. Overall, the ARH family has unique functions in biological processes and different enzymatic activities.

Ultrasonographic Assessment of Glenohumeral Joint Stability Immediately After Arthroscopic Bankart-Bristow Procedure.

Background: The changes in glenohumeral joint stability after surgery in a clinical setting are yet unknown. Purpose/Hypothesis: This study aimed to compare the anterior humeral head translation between pre- and postsurgical conditions using ultrasonography. It was hypothesized that ultrasonographic assessment would reveal decreased anterior translation. Study Design: Case series; Level of evidence, 4. Methods: A total of 27 patients (24 male, 3 female; mean age, 24.1 ± 9.7 years) with anterior shoulder instability were studied prospectively. All the patients underwent the arthroscopic Bankart-Bristow procedure under general anesthesia, and ultrasonographic evaluation was performed before and immediately after surgery. The forearm was fixed with an arm positioner in the beach-chair position, and the ultrasonographic transducer was located at the posterior part of the shoulder to visualize the humeral head and glenoid rim at the level of interval between the infraspinatus tendon and teres minor tendon. The upper arm was drawn anteriorly with a 40-N force at 0°, 45°, and 90° of shoulder abduction with neutral rotation. The distance from the posterior edge of the glenoid to that of the humeral head was measured using ultrasonography with and without anterior force. Anterior translation was defined by subtracting the distance with anterior force from the distance without anterior force. Results: The humeral head position was translated posteriorly immediately after surgery in all patients. Anterior translation decreased significantly after surgery at 45° (7.7 ± 4.3 vs 5.8 ± 2.0 mm; P = .031) and 90° (8.9 ± 3.4 vs 6.1 ± 2.2 mm; P < .001) of abduction, whereas there was no difference between pre- and postsurgical translation at 0° of abduction (4.9 ± 2.3 vs 4.0 ± 2.1 mm, P = .089). Conclusion: Ultrasonographic assessment immediately after a Bankart-Bristow procedure showed the humeral head was translated posteriorly relative to the glenoid at 0°, 45°, and 90° of abduction. The surgery also decreased anterior translation in response to an anteriorly directed force at 45° and 90° of abduction.

Ultrasound Assessment of Anterior Humeral Head Translation in Patients With Anterior Shoulder Instability: Correlation With Demographic, Radiographic, and Clinical Data.

Background: Ultrasonography can be used to quantitatively assess anterior humeral head translation (AHHT) at different degrees of shoulder abduction. Risk factors for recurrent shoulder instability have been identified. Hypothesis: It was hypothesized that the number of dislocations or glenoid or humeral bone loss would be associated with more AHHT as measured using ultrasound. Study Design: Cross-sectional study; Level of evidence, 3. Methods: A total of 39 patients who underwent surgery for anterior shoulder instability were prospectively studied. Ultrasound assessment of AHHT was performed immediately after general anesthesia was induced. The upper arm was placed at 0°, 45°, and 90° of abduction, and a 40-N anterior force was applied to the proximal third of the arm. The distance from the posterior edge of the glenoid to that of the humeral head was measured at each abduction angle using ultrasound with and without a 40-N anterior force, and the AHHT was calculated. The differences in translation at each shoulder angle were compared. Additionally, the authors investigated the association between AHHT and demographic, radiographic, and clinical data. Results: Compared with the AHHT at 0° of abduction (5.29 mm), translation was significantly larger at 45° of abduction (8.90 mm; P < .01) and 90° of abduction (9.46 mm; P < .01). The mean translation was significantly larger in female patients than in male patients at all degrees of abduction (P ≤ .036 for all). There was no correlation between AHHT at any abduction angle and number of dislocations, clinical data, or radiographic data (including bone loss). Conclusion: Ultrasound assessment of AHHT showed larger amounts of laxity at 45° and 90° than at 0° of abduction. Anterior glenohumeral laxity was greater in female than male patients. Glenoid or humeral bone loss did not correlate with AHHT, thereby clarifying that bone loss has no direct effect on measurements of capsular laxity in neutral rotation.

Poly(ADP-ribose) Polymerase 1 Mediates Rab5 Inactivation after DNA Damage.

Parthanatos is programmed cell death mediated by poly(ADP-ribose) polymerase 1 (PARP1) after DNA damage. PARP1 acts by catalyzing the transfer of poly(ADP-ribose) (PAR) polymers to various nuclear proteins. PAR is subsequently cleaved, generating protein-free PAR polymers, which are translocated to the cytoplasm where they associate with cytoplasmic and mitochondrial proteins, altering their functions and leading to cell death. Proteomic studies revealed that several proteins involved in endocytosis bind PAR after PARP1 activation, suggesting endocytosis may be affected by the parthanatos process. Endocytosis is a mechanism for cellular uptake of membrane-impermeant nutrients. Rab5, a small G-protein, is associated with the plasma membrane and early endosomes. Once activated by binding GTP, Rab5 recruits its effectors to early endosomes and regulates their fusion. Here, we report that after DNA damage, PARP1-generated PAR binds to Rab5, suppressing its activity. As a result, Rab5 is dissociated from endosomal vesicles, inhibiting the uptake of membrane-impermeant nutrients. This PARP1-dependent inhibition of nutrient uptake leads to cell starvation and death. It thus appears that this mechanism may represent a novel parthanatos pathway.

Diagnosis of medial meniscal ramp lesion is difficult by pre-operative magnetic resonance imaging evaluation and needs a methodical arthroscopic exploration.

BACKGROUND: Meniscal ramp lesion (RL) is the peripheral lesion of the posterior horn of the medial meniscus (PHMM) associated with anterior cruciate ligament (ACL) tear. The purpose of this study was to evaluate the accuracy of pre-operative magnetic resonance imaging (MRI) evaluation in diagnosing RL and to identify whether the difficulty in diagnosis differs depending on the location of RL. METHODS: ACL-injured patients undergoing ACL reconstruction from January 2017 to January 2019 were enrolled. A methodical arthroscopic exploration to identify RL was conducted intra-operatively using three steps, namely, the anterior visualization step, the inter-condylar visualization step, and the posteromedial step. The location of the RLs was evaluated and classified into two types as follows: Red-red zone (RR) - a meniscal tear of the red-red zone of the PHMM. Menisco-capsular junction (MCJ) - a lesion at the menisco-capsular junction of the PHMM, which is more peripheral than RR. Furthermore, the accuracy of 1.5-T MRI evaluation to diagnose RL by two testers using sagittal proton-density fat-saturated images was calculated. RESULTS: Of the 81 patients enrolled, 11 had RL: 5 cases each were at the MCJ and RR, and 1 case was at both locations. The sensitivity of MRI for detecting RL was 27.3-45.5%, whereas the specificity was 84.3-95.7% in total. The sensitivity of MRI in detecting RL at the RR and MCJ was 40.0-80.0%, 0-20.0%, respectively. The intra-observer reliability of the MRI evaluation was moderate (κ coefficient: 0.40-0.46), while the inter-observer reliability was fair to moderate (κ coefficient: 0.27-0.41). CONCLUSIONS: A low sensitivity of the MRI in detecting RL at the MCJ was observed, and the reliability of the MRI evaluation for diagnosis of RL was not high. Therefore, methodical arthroscopic exploration is essential to diagnose RL even when it is not suspected on pre-operative MRI.

Anterolateral ligament reconstruction in addition to primary double-bundle anterior cruciate ligament reconstruction for grade 3 pivot shift improves residual knee instability during surgery.

PURPOSE: High-grade pivot shift in the anterior cruciate ligament (ACL) injured knee is a risk factor for postoperative residual pivot shift. Procedures in addition to ACL reconstruction such as anterolateral ligament (ALL) reconstruction have been performed for patients with a high-risk of residual pivot shift. The aim of this study was to investigate the effect of the addition of ALL reconstruction to primary double-bundle ACL reconstruction in patients with preoperative high-grade pivot shift to improve stability as evaluated by quantitative measurement. METHODS: Patients with ACL injuries who showed preoperative grade 3 subjective pivot shift and who underwent primary double-bundle ACL reconstruction combined with ALL reconstructions were retrospectively enrolled. Anterior tibial translation (ATT) in the Lachman test, and acceleration and external rotational angular velocity (ERAV) in the pivot shift were measured as quantitative values. Quantitative values before surgical intervention for ACL-injured knees (ACLD) and uninjured contralateral knees (intact), after temporary fixation of the isolated ACL grafts (ACLR), and subsequently after temporary fixation of both ACL and ALL grafts (ACLR + ALLR) were measured with the patient under general anaesthesia. RESULTS: In total, 18 patients were included. The ATT was lower in ACLR and ACLR + ALLR than in intact (P = .008 and .005), while there was no significant difference between ACLR and ACLR + ALLR (P > .05). The acceleration of ACLR + ALLR was lower than that for ACLR (P = .008), while there was no significant difference between intact and ACLR or ACLR + ALLR (P > .05). The ERAV of ACLR was higher than that of intact (P < .001), while that of ACLR + ALLR was lower than that of ACLR (P < 0.001), and there was no significant difference in ERAV between intact and ACLR + ALLR (P > 0.05). CONCLUSION: According to quantitative assessment of the pivot shift, the addition of ALL reconstruction to primary double-bundle ACL reconstruction improved residual knee instability and restored knee stability during surgery. Combination of ALL reconstruction with primary double-bundle ACL reconstruction was effective for patients with ACL injuries exhibiting a preoperative grade 3 subjective pivot shift. LEVEL OF EVIDENCE: IV.

FK506-Binding Protein 13 Expression Is Upregulated in Interstitial Lung Disease and Correlated with Clinical Severity. A Potentially Protective Role.

Pulmonary fibrosis is a progressive lung disease characterized by myofibroblast accumulation and excessive extracellular matrix deposition. We sought to investigate the role of FKBP13 (13-kD FK506-binding protein), an endoplasmic reticulum-resident molecular chaperone, in various forms of pulmonary fibrosis. We first characterized the gene and protein expression of FKBP13 in lung biopsy specimens from 24 patients with idiopathic pulmonary fibrosis and 17 control subjects. FKBP13 expression was found to be elevated in the fibrotic regions of idiopathic pulmonary fibrosis lung tissues and correlated with declining forced vital capacity and dyspnea severity. FKBP13 expression was also increased in lung biopsy specimens of patients with hypersensitivity pneumonitis, rheumatoid arthritis, and sarcoidosis-associated interstitial lung disease. We next evaluated the role of this protein using FKBP13-/- mice in a bleomycin model of pulmonary fibrosis. Animals were assessed for lung function and histopathology at different stages of lung injury including the inflammatory (Day 7), fibrotic (Day 21), and resolution (Day 50) phases. FKBP13-/- mice showed increased infiltration of inflammatory cells and cytokines at Day 7, increased lung elastance and fibrosis at Day 21, and impaired resolution of fibrosis at Day 50. These changes were associated with an increased number of cells that stained positive for TUNEL and cleaved caspase 3 in the FKBP13-/- lungs, indicating a heightened cellular sensitivity to bleomycin. Our findings suggest that FKBP13 is a potential biomarker for severity of interstitial lung diseases and that it has a biologically relevant role in protecting mice against bleomycin-induced injury, inflammation, and fibrosis.

The 89-kDa PARP1 cleavage fragment serves as a cytoplasmic PAR carrier to induce AIF-mediated apoptosis.

Poly(ADP-ribose) polymerase 1 (PARP1) is a nuclear protein that is activated by binding to DNA lesions and catalyzes poly(ADP-ribosyl)ation of nuclear acceptor proteins, including PARP1 itself, to recruit DNA repair machinery to DNA lesions. When excessive DNA damage occurs, poly(ADP-ribose) (PAR) produced by PARP1 is translocated to the cytoplasm, changing the activity and localization of cytoplasmic proteins, e.g., apoptosis-inducing factor (AIF), hexokinase, and resulting in cell death. This cascade, termed parthanatos, is a caspase-independent programmed cell death distinct from necrosis and apoptosis. In contrast, PARP1 is a substrate of activated caspases 3 and 7 in caspase-dependent apoptosis. Once cleaved, PARP1 loses its activity, thereby suppressing DNA repair. Caspase cleavage of PARP1 occurs within a nuclear localization signal near the DNA-binding domain, resulting in the formation of 24-kDa and 89-kDa fragments. In the present study, we found that caspase activation by staurosporine- and actinomycin D-induced PARP1 autopoly(ADP-ribosyl)ation and fragmentation, generating poly(ADP-ribosyl)ated 89-kDa and 24-kDa PARP1 fragments. The 89-kDa PARP1 fragments with covalently attached PAR polymers were translocated to the cytoplasm, whereas 24-kDa fragments remained associated with DNA lesions. In the cytoplasm, AIF binding to PAR attached to the 89-kDa PARP1 fragment facilitated its translocation to the nucleus. Thus, the 89-kDa PARP1 fragment is a PAR carrier to the cytoplasm, inducing AIF release from mitochondria. Elucidation of the caspase-mediated interaction between apoptosis and parthanatos pathways extend the current knowledge on mechanisms underlying programmed cell death and may lead to new therapeutic targets.