Altering relative metal-binding affinities in multifunctional Metallochaperones for mutant p53 reactivation.

The p53 protein plays a major role in cancer prevention, and over 50% of cancer diagnoses can be attributed to p53 malfunction. p53 incorporates a structural Zn site that is required for proper protein folding and function, and in many cases point mutations can result in loss of the Zn2+ ion, destabilization of the tertiary structure, and eventual amyloid aggregation. Herein, we report a series of compounds designed to act as small molecule stabilizers of mutant p53, and feature Zn-binding fragments to chaperone Zn2+ to the metal depleted site and restore wild-type (WT) function. Many Zn metallochaperones (ZMCs) have been shown to generate intracellular reactive oxygen species (ROS), likely by chelating redox-active metals such as Fe2+/3+ and Cu+/2+ and undergoing associated Fenton chemistry. High levels of ROS can result in off-target effects and general toxicity, and thus, careful tuning of ligand Zn2+ affinity, in comparison to the affinity for other endogenous metals, is important for selective mutant p53 targeting. In this work we show that by using carboxylate donors in place of pyridine we can change the relative Zn2+/Cu2+ binding ability in a series of ligands, and we investigate the impact of donor group changes on metallochaperone activity and overall cytotoxicity in two mutant p53 cancer cell lines (NUGC3 and SKGT2).

Creating musical features using multi-faceted, multi-task encoders based on transformers.

Computational machine intelligence approaches have enabled a variety of music-centric technologies in support of creating, sharing and interacting with music content. A strong performance on specific downstream application tasks, such as music genre detection and music emotion recognition, is paramount to ensuring broad capabilities for computational music understanding and Music Information Retrieval. Traditional approaches have relied on supervised learning to train models to support these music-related tasks. However, such approaches require copious annotated data and still may only provide insight into one view of music-namely, that related to the specific task at hand. We present a new model for generating audio-musical features that support music understanding, leveraging self-supervision and cross-domain learning. After pre-training using masked reconstruction of musical input features using self-attention bidirectional transformers, output representations are fine-tuned using several downstream music understanding tasks. Results show that the features generated by our multi-faceted, multi-task, music transformer model, which we call M3BERT, tend to outperform other audio and music embeddings on several diverse music-related tasks, indicating the potential of self-supervised and semi-supervised learning approaches toward a more generalized and robust computational approach to modeling music. Our work can offer a starting point for many music-related modeling tasks, with potential applications in learning deep representations and enabling robust technology applications.

Synthesis and biological evaluation of salophen nickel(II) and cobalt(III) complexes as potential anticancer compounds.

Recent in vitro investigations of N,N'-bis(salicylidene)-1,2-phenylenediamine (SAP) iron(III) complexes substituted with alkyl (ethyl, propyl, butyl) carboxylates at position 4 in tumor and leukemia cells revealed strong cytotoxic activity. In continuation of this study, analogous nickel(II) and cobalt(III) complexes were synthesized and tested in HL-60 leukemia, and cisplatin-sensitive and -resistant A2780 ovarian cancer cell lines. The biological activity depended on the extent of cellular uptake and the formation of reactive oxygen species (ROS). Inactive [(Ni(II)SAP] complexes (1-3) only marginally accumulated in tumor cells and did not induce ROS. The cellular uptake of [Co(III)SAP]Cl complexes (4-6) into the cells depended on the length of the ester alkyl chain (ethyl, 4 < propyl, 5 < butyl, 6). The cytotoxicity correlated with the presence of ROS. The low cytotoxic complex 4 induced only few ROS, while 5 and 6 caused a good to outstanding antiproliferative activity, exerted high ROS generation, and induced cell death after 48 h. Necrostatin-1 prevented the biological effects, proving necroptosis as part of the mode of action. Interestingly, the effects of 5 and 6 were not reversed by Ferrostatin-1, but even enhanced upon simultaneous application to the tumor cells.

Shear strain and inflammation-induced fixed charge density loss in the knee joint cartilage following ACL injury and reconstruction: A computational study.

Excessive tissue deformation near cartilage lesions and acute inflammation within the knee joint after anterior cruciate ligament (ACL) rupture and reconstruction surgery accelerate the loss of fixed charge density (FCD) and subsequent cartilage tissue degeneration. Here, we show how biomechanical and biochemical degradation pathways can predict FCD loss using a patient-specific finite element model of an ACL reconstructed knee joint exhibiting a chondral lesion. Biomechanical degradation was based on the excessive maximum shear strains that may result in cell apoptosis, while biochemical degradation was driven by the diffusion of pro-inflammatory cytokines. We found that the biomechanical model was able to predict substantial localized FCD loss near the lesion and on the medial areas of the lateral tibial cartilage. In turn, the biochemical model predicted FCD loss all around the lesion and at intact areas; the highest FCD loss was at the cartilage-synovial fluid-interface and decreased toward the deeper zones. Interestingly, simulating a downturn of an acute inflammatory response by reducing the cytokine concentration exponentially over time in synovial fluid led to a partial recovery of FCD content in the cartilage. Our novel numerical approach suggests that in vivo FCD loss can be estimated in injured cartilage following ACL injury and reconstruction. Our novel modeling platform can benefit the prediction of PTOA progression and the development of treatment interventions such as disease-modifying drug testing and rehabilitation strategies.

A computational lens into how music characterizes genre in film.

Film music varies tremendously across genre in order to bring about different responses in an audience. For instance, composers may evoke passion in a romantic scene with lush string passages or inspire fear throughout horror films with inharmonious drones. This study investigates such phenomena through a quantitative evaluation of music that is associated with different film genres. We construct supervised neural network models with various pooling mechanisms to predict a film's genre from its soundtrack. We use these models to compare handcrafted music information retrieval (MIR) features against VGGish audio embedding features, finding similar performance with the top-performing architectures. We examine the best-performing MIR feature model through permutation feature importance (PFI), determining that mel-frequency cepstral coefficient (MFCC) and tonal features are most indicative of musical differences between genres. We investigate the interaction between musical and visual features with a cross-modal analysis, and do not find compelling evidence that music characteristic of a certain genre implies low-level visual features associated with that genre. Furthermore, we provide software code to replicate this study at https://github.com/usc-sail/mica-music-in-media. This work adds to our understanding of music's use in multi-modal contexts and offers the potential for future inquiry into human affective experiences.

Prediction of local fixed charge density loss in cartilage following ACL injury and reconstruction: A computational proof-of-concept study with MRI follow-up.

The purpose of this proof-of-concept study was to develop three-dimensional patient-specific mechanobiological knee joint models to simulate alterations in the fixed charged density (FCD) around cartilage lesions during the stance phase of the walking gait. Two patients with anterior cruciate ligament (ACL) reconstructed knees were imaged at 1 and 3 years after surgery. The magnetic resonance imaging (MRI) data were used for segmenting the knee geometries, including the cartilage lesions. Based on these geometries, finite element (FE) models were developed. The gait of the patients was obtained using a motion capture system. Musculoskeletal modeling was utilized to calculate knee joint contact and lower extremity muscle forces for the FE models. Finally, a cartilage adaptation algorithm was implemented in both FE models. In the algorithm, it was assumed that excessive maximum shear and deviatoric strains (calculated as the combination of principal strains), and fluid velocity, are responsible for the FCD loss. Changes in the longitudinal T1ρ and T2 relaxation times were postulated to be related to changes in the cartilage composition and were compared with the numerical predictions. In patient 1 model, both the excessive fluid velocity and strain caused the FCD loss primarily near the cartilage lesion. T1ρ and T2 relaxation times increased during the follow-up in the same location. In contrast, in patient 2 model, only the excessive fluid velocity led to a slight FCD loss near the lesion, where MRI parameters did not show evidence of alterations. Significance: This novel proof-of-concept study suggests mechanisms through which a local FCD loss might occur near cartilage lesions. In order to obtain statistical evidence for these findings, the method should be investigated with a larger cohort of subjects.

Patellar Malalignment Is Associated With Patellofemoral Lesions and Cartilage Relaxation Times After Hamstring Autograft Anterior Cruciate Ligament Reconstruction.

BACKGROUND: There is growing evidence suggesting a link between patellofemoral joint (PFJ) osteoarthritis in anterior cruciate ligament (ACL)-reconstructed knees and altered joint alignment. PURPOSE: To determine whether patellar alignment differs between participants with and without ACL reconstruction (ACLR) and to identify possible associations between patellar alignment and PFJ osteoarthritis features over 3 years. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: A total of 37 participants with ACLR (sex, 23 male; mean ± SD age, 28.1 ± 7.4 years) and 20 healthy controls (13 male; 30.4 ± 4.8 years) participated. Patients underwent magnetic resonance imaging: (1) sagittal T2-weighted fat-saturated fast spin echo images to calculate patellar alignment, (2) sagittal 3-dimensional intermediate-weighted fast spin echo Cube sequence for clinical morphological grading (modified Whole-Organ Magnetic Resonance Imaging Score [WORMS]), and (3) sagittal combined T1ρ/T2 mapping sequence for performing voxel-based relaxometry. Patellar alignment of the ACLR knees were assessed at 6 months (baseline). One-way analysis of variance was used to compare patellar alignment among the ACLR (at 6 months), contralateral, and control knees. Within the ACLR group, a logistic regression model was used to identify if patellar alignment measures at baseline were risk factors for worsening of PFJ structural changes over 3 years. Statistical parametric mapping was used to evaluate the longitudinal associations between patellar alignment and cartilage relaxation times at 3 years. RESULTS: When compared with control knees, ACLR knees exhibited a laterally and anteriorly displaced patella (P = .045 and P = .041), less flexion (P = .031), and less lateral spin (P = .012). Furthermore, excessive lateral displacement was a significant predictor of worsening of WORMS (P = .050). Lateral displacement was positively correlated with increased T1ρ and T2 in the patellar and trochlear cartilage at 3 years. Patellar lateral spin revealed similar negative findings. CONCLUSION: Participants with ACLR exhibited a laterally and anteriorly displaced patella, less flexion, and less lateral spin when compared with healthy controls. Excessive patellar lateral displacement was the strongest predictor to the development of PFJ osteoarthritis features longitudinally.

Amide and ester derivatives of chlorido[4-carboxy-1,2-disalicylideneaminobenzene]iron(iii) as necroptosis and ferroptosis inducers.

In continuation of the structure-activity study about 4-substituted chlorido[N,N'-disalicylidene-1,2-phenylenediamine]iron(iii) complexes as necroptosis and ferroptosis inducers, we introduced a 4-COOH group at the 1,2-phenylenediamine moiety of the lead ([Fe(iii)salopheneCl]) and derived the resulting complex 15 to the respective ethyl, propyl, or butyl amides (16-18) and esters (19-21). The compounds 16-21 exerted concentration-dependent antiproliferative and antimetabolic effects against HL-60 cells. The esters were more active than the analogous amides. Elongation of the alkyl chain enhanced the activity of the amides, while that of the esters decreased. The complexes 16-21 induced necroptosis and/or ferroptosis but not apoptosis. Studies on protein binding and uptake into HL-60 cells indicated that the complexes mainly accumulated by passive transport. The high binding tendency of all complexes to apo-Transferrin, however, points to participation of a carrier-mediated transport into the cells, too.

Identification of locations susceptible to osteoarthritis in patients with anterior cruciate ligament reconstruction: Combining knee joint computational modelling with follow-up T1ρ and T2 imaging.

BACKGROUND: Finite element modelling can be used to evaluate altered loading conditions and failure locations in knee joint tissues. One limitation of this modelling approach has been experimental comparison. The aims of this proof-of-concept study were: 1) identify areas susceptible to osteoarthritis progression in anterior cruciate ligament reconstructed patients using finite element modelling; 2) compare the identified areas against changes in T2 and T1ρ values between 1-year and 3-year follow-up timepoints. METHODS: Two patient-specific finite element models of knee joints with anterior cruciate ligament reconstruction were created. The knee geometry was based on clinical magnetic resonance imaging and joint loading was obtained via motion capture. We evaluated biomechanical parameters linked with cartilage degeneration and compared the identified risk areas against T2 and T1ρ maps. FINDINGS: The risk areas identified by the finite element models matched the follow-up magnetic resonance imaging findings. For Patient 1, excessive values of maximum principal stresses and shear strains were observed in the posterior side of the lateral tibial and femoral cartilage. For Patient 2, high values of maximum principal stresses and shear strains of cartilage were observed in the posterior side of the medial joint compartment. For both patients, increased T2 and T1ρ values between the follow-up times were observed in the same areas. INTERPRETATION: Finite element models with patient-specific geometries and motions and relatively simple material models of tissues were able to identify areas susceptible to post-traumatic knee osteoarthritis. We suggest that the methodology presented here may be applied in large cohort studies.

A New Approach in Cancer Treatment: Discovery of Chlorido[N,N'-disalicylidene-1,2-phenylenediamine]iron(III) Complexes as Ferroptosis Inducers.

Chlorido[N,N'-disalicylidene-1,2-phenylenediamine]iron(III) complexes generate lipid-based ROS and induce ferroptosis in leukemia and neuroblastoma cell lines. The extent of ferroptosis on the mode of action is regulated by simple modifications of the substituents at the 1,2-phenylenediamine moiety. In HL-60 cells, the unsubstituted lead exclusively caused ferroptosis. For instance, a 4-F substituent shifted the mode of action toward both ferroptosis and necroptosis, while the analogously chlorinated derivative exerted only necroptosis. Remarkably, cell-death in NB1 neuroblastoma cells was solely induced by ferroptosis, independent of the used substituents. The effects were higher than that of the therapeutically applied drug cisplatin. These data clearly demonstrate for the first time that not only iron ions but also iron salophene complexes are potent ferroptosis inducers, which can be optimized as antitumor agents.

Functional workspace and patient-reported outcomes improve after reverse and total shoulder arthroplasty.

BACKGROUND: Low-cost motion analysis systems (LCMASs) have emerged as easy and practical methods to measure the functional workspace (FWS). Thus, we ventured to apply an LCMAS, the Kinect2 gaming camera, to evaluate the FWS in patients with shoulder osteoarthritis (OA) and patients who underwent total shoulder arthroplasty (TSA) or reverse total shoulder arthroplasty (RTSA). METHODS: A cross-sectional study of participants with OA (n = 53), TSA (n = 70), and RTSA (n = 34) was performed. The FWS as measured by an LCMAS, the American Shoulder and Elbow Surgeons (ASES) Standardized Shoulder Assessment Form score, and the Patient-Reported Outcomes Measurement Information System (PROMIS) score were collected. For participants who underwent TSA or RTSA, the FWS was evaluated at 6, 12, and 24 months postoperatively. The correlation of the FWS with the ASES score and PROMIS score was determined. Significance was set at P < .05. RESULTS: Patients who underwent TSA or RTSA had a significantly higher FWS than patients with shoulder OA at almost all time points. Patients who underwent TSA had a significantly higher FWS than patients who underwent RTSA at 24 months after surgery. PROMIS and ASES scores showed strong correlations with the FWS in patients who underwent TSA (R = 0.75 [P < .001] and R = 0.83 [P < .001], respectively) and RTSA (R = 0.84 [P < .001] and R = 0.73 [P < .001], respectively). CONCLUSION: The FWS measured by an LCMAS is an easy and low-cost method to quantify the reachable space of the hand in patients and shows strong correlations with patient-reported outcome measures. This may be a useful tool to assess upper-extremity range of motion before and after shoulder arthroplasty.

Cyclops lesions detected by MRI are frequent findings after ACL surgical reconstruction but do not impact clinical outcome over 2 years.

OBJECTIVES: To assess the impact of cyclops lesions with MRI in patients treated for anterior cruciate ligament (ACL) tears on clinical outcome. METHODS: In 113 patients (age 29.8 ± 10.5y; 55 females; BMI 24.8 ± 3.7 kg/m2) with complete ACL tear, 3 T-MRI scans were obtained before, 6-months, 1-year (n = 75) and 2-years (n = 33) after ACL reconstruction. Presence and volume of cyclops lesions were assessed. Clinical outcomes were measured using the Knee injury and Osteoarthritis Outcome Score (KOOS) and differences between time points (∆KOOS) were calculated. Changes of KOOS subscales were compared between patients with and without cyclops lesion. KOOS was also correlated with lesion volume. RESULTS: Cyclops lesions were found in 25% (28/113), 27% (20/75) and 33% (11/33) of patients after 6-months, 1- and 2-years, respectively. The lesion volume did not change significantly (P > 0.05) between time points, measuring 0.65 ± 0.59, 0.81 ± 0.70 and 0.72.9 ± 0.96 cm3, respectively. Clinical outcomes based on KOOS subscales were not significantly different in patients with cyclops lesions compared to those without cyclops lesions (each comparison P > 0.05), and no significant associations of clinical outcomes with lesion volume were found (P > 0.05). CONCLUSIONS: Neither presence nor size of cyclops lesions within the first 2-years after ACL surgery were associated with inferior clinical outcome. KEY POINTS: • Cyclops lesions had a prevalence of 25% in patients after ACL reconstruction. • Subjects with cyclops lesions did not have an inferior clinical outcome. • Cyclops lesions developed within the first 6 months after surgery. • The size of cyclops lesions did not significantly change over a period of 2 years.

Evolution of Intrameniscal Signal-Intensity Alterations Detected on MRI Over 24 Months in Patients With Traumatic Anterior Cruciate Ligament Tear.

OBJECTIVE: The objective of our study was to assess the prevalence and evolution of intrameniscal signal-intensity alteration in subjects with an anterior cruciate ligament (ACL) tear over 24 months and compare clinical outcome and changes of cartilage between subjects with and those without this meniscal abnormality. MATERIALS AND METHODS: Fifty-seven subjects with an ACL tear were screened for intrameniscal signal-intensity alteration. Morphologic and compositional MRI was performed before ACL reconstruction and 12 and 24 months after ACL reconstruction. Twelve subjects with an intrameniscal signal-intensity alteration and 12 subjects without any meniscal abnormality on MRI were identified. Clinical outcome was measured using the Knee Injury and Osteoarthritis Outcome Score (KOOS), and T1ρ and T2 maps of the cartilage were obtained. RESULTS: In 10 of 12 subjects (83%) the meniscal signal-intensity abnormality identified on baseline MRI was located at the posterior horn of the medial meniscus. None of these subjects presented with a meniscal tear over 24 months of follow-up. At 12 months after the ACL tear, the intrameniscal signal-intensity alteration detected on baseline MRI had completely resolved in seven of 12 subjects (58%), showed a signal-intensity decrease in four (33%), and remained stable in one subject (8%). Of the 10 subjects who underwent MRI at 24 months, the meniscal signal-intensity alteration had completely resolved in eight (80%), and the signal intensity had decreased in the other two subjects. Changes in the KOOS and cartilage T1ρ and T2 values from baseline and 24 months did not differ significantly between subjects with and those without intrameniscal signal-intensity alteration (p > 0.05). CONCLUSION: High intrameniscal signal-intensity alterations are a common finding in subjects with an ACL tear and have a benign course over 24 months after surgical repair of the ACL tear.

Analysis of the articular cartilage T1ρ and T2 relaxation times changes after ACL reconstruction in injured and contralateral knees and relationships with bone shape.

The objectives of this study were twofold: (1) to evaluate the longitudinal change in cartilage T1ρ and T2 6- and 12-months after ACL reconstruction (ACLR) in both reconstructed and intact contralateral knees with the aim of validating the role of the contralateral knee as an internal control in longitudinal studies; (2) to explore relationships between bone shape at the time of injury and the progression of T1ρ and T2 over 12-months after ACLR. T1ρ and T2 cartilage relaxation times and 3D MRI-based statistical shape modeling (SSM) of tibia and femur were computed for both knees of forty ACL-injured patients and 15 healthy controls. ACL subjects were scanned 8.4 ± 6.4 weeks after injury (2.4 ± 3.7 weeks prior to ACLR), 6- and 12-months after ACLR. Longitudinal changes in T1ρ and T2 values were assessed using linear mixed model, and partial correlation coefficients were calculated between bone shape and longitudinal changes in T1ρ and T2 values. Significant longitudinal increases in T1ρ and T2 values were observed in reconstructed and contralateral knees 6-months after ACLR. Tibial bone shape features, associated with the medial plateau height and width, were observed to be correlated with cartilage T1ρ and T2 progression in reconstructed knees. Our results suggest that caution should be used in considering contralateral knee as internal controls in longitudinal ACL studies and 3D MRI-based-SSM might serve as an imaging biomarker for the early stratification of patients at risk for developing post-traumatic accelerated cartilage degeneration and potentially osteoarthritis after ACL tear. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:707-717, 2017.

Synthesis and In Vitro Evaluation of Thiolated Carrageenan.

The aim of this study was to generate and characterize a thiolated carrageenan. Thiolated carrageenan (carrageenan-SH) was synthesized from kappa (κ)- and iota (ι)-carrageenan by bromine replacement of the hydroxyl moieties followed by substitution to thiol groups using thiourea. Thiolated κ- and ι-carrageenan exhibited 176.57 ± 20.11 and 109.51 ± 18.26 µmol thiol groups per gram polymer, respectively. The resazurin test in Caco-2 cells revealed no toxic effect of both thiolated carrageenans at a concentration below 0.1% (w/v). Regarding efflux pump inhibitory effect, cellular accumulation of multidrug-resistance protein 2 substrate, sulforhodamine 101, was 1.38- and 1.35-fold increased in cells treated with thiolated κ- and ι-carrageenan, respectively. Modification of κ- and ι-carrageenan led to 3.9- and 2.0-fold increase in dynamic viscosity of mucus-thiolated carrageenan mixture within 4 h. Furthermore, residence time of κ- and ι-carrageenan-SH on porcine intestinal mucosa was 6.4- and 1.8-fold prolonged, respectively, as demonstrated by rotating cylinder method, indicating improved mucoadhesive properties. Hence, thiolation of carrageenans led to novel pharmaceutical excipients for various applications.

MR imaging characteristics and clinical symptoms related to displaced meniscal flap tears.

OBJECTIVES: The purpose of our study was (1) to analyze the flap tear location, direction of displacement and size on magnetic resonance (MR) imaging, (2) to describe associated knee abnormalities including presence of effusion, synovitis, bone marrow edema pattern or ligamentous tear, and (3) to assess clinical findings found with flap tears, including the pain score, and determine differences between operative and nonoperative groups. MATERIALS AND METHODS: A retrospective radiology database search over the last 3 years identified 238 patients with flap tears, of which ultimately 58 with isolated flap tears were included after exclusion of patients with other significant knee internal derangement, severe degenerative change or prior surgery. MR studies of the knee were analyzed by two radiologists. Imaging characteristics were correlated with associated knee abnormalities and clinical findings. Statistical analysis employed linear and logistic regression models. Inter- and intrareader reliability was calculated. RESULTS: The medial meniscus was the most common site of flap tears (52/60, 87 %), with inferior displacement (47/60, 78 %). The degree of tibial cartilage loss had a positive correlation with the visual analog pain scale (p = 0.03). Patients who underwent arthroscopy were younger than those who did not (p = 0.01) and more likely to have a positive clinical McMurray test (p = 0.01). CONCLUSION: Medially and inferiorly displaced flap tears are the most common tear pattern. Those undergoing arthroscopy are more likely to have positive meniscal signs on clinical examination. A greater degree of cartilage loss involving the tibia on MR imaging was associated with increasing visual analog pain scores.

Lesser tuberosity avulsions in adolescents.

BACKGROUND: Subscapularis tendon avulsions of the lesser tuberosity are relatively rare and often missed acutely and their characteristic appearance is frequently not recognized or is misinterpreted for an osteochondroma or a neoplastic process. QUESTIONS/PURPOSES: This report reviews our experience with six adolescents who had subscapularis tendon avulsions of the lesser tuberosity. METHODS: Six male adolescents (12-15 years) presented with shoulder pain following history of trauma during amateur sport. Clinical notes including range of motion, strength tests, and pain assessment were reviewed along with imaging studies pre- and post treatment. Treatment consisted of either surgical or conservative measures. RESULTS: Two of the six patients had a large avulsion that simulated an exostosis of the proximal humerus that was misdiagnosed as an osteochondroma at two different outside institutions. All six cases were diagnosed with subscapularis tendon avulsion of the lesser tuberosity following clinical and imaging evaluation at our institution. Five of the patients underwent surgical repair and fixation of the tendon and the lesser tuberosity with suture anchors. One patient was treated conservatively. All patients had a good outcome with recovery of full shoulder strength and motion upon follow-up. CONCLUSION: Clinicians should have a high index of suspicion of lesser tuberosity avulsions in adolescents who present with loss of internal rotation and anterior shoulder pain following traumatic injuries. In addition, an osseous fragment or exostosis along the inferomedial humeral head should suggest a subscapularis tendon avulsion and also should not be confused with an osteochondroma or a neoplastic process.

MR T(1)ρ quantification of cartilage focal lesions in acutely injured knees: correlation with arthroscopic evaluation.

OBJECTIVE: Quantitative T1ρ MRI has been suggested as a promising tool to detect changes in cartilage composition that are characteristic of cartilage damage and degeneration. The objective of this study was to evaluate the capability of MR T1ρ to detect cartilage lesions as evaluated by arthroscopy in acutely ACL-injured knees and to compare with the Whole-Organ Magnetic Resonance Imaging Score (WORMS) using clinical standard MRI. METHOD: Ten healthy controls (mean age 35) with no ACL injury or history of osteoarthritis (OA) and 10 patients with acute ACL injuries (mean age 39) were scanned at 3 Tesla (3T). ACL patients underwent ACL reconstruction, where focal lesions were graded according to an Outerbridge grading system during arthroscopic evaluation. Normalized MR T1ρ values (T1ρ z-scores normalized to control values in matched regions) in full thickness, and superficial and deep layers of cartilage were compared between defined sub-compartments with and without focal lesions. Intraclass (ICC) correlation and the root mean square coefficient of variation (RMS-CV) were performed to evaluate the inter-observer reproducibility of T1ρ quantification. Sub-compartments of cartilage were also evaluated using WORMS scoring and compared to their Outerbridge score respectively. RESULTS: The inter-observer ICC and the RMS-CV of the sub-compartment T1ρ quantification were 0.961 and 3.9%, respectively. The average T1ρ z-scores were significantly increased in sub-compartments with focal lesions compared to those without focal lesions and to the control cohort (p<0.05). CONCLUSION: Our results indicate that T1ρ provided a better diagnostic capability than clinical standard MRI grading in detecting focal cartilage abnormalities after acute injuries. Quantitative MRI may have great potential in detecting cartilage abnormalities and degeneration non-invasively, which are occult with standard morphological MRI.

The duration of symptoms does not correlate with rotator cuff tear severity or other patient-related features: a cross-sectional study of patients with atraumatic, full-thickness rotator cuff tears.

HYPOTHESIS: The purpose of this cross-sectional study is to determine whether the duration of symptoms influences the features seen in patients with atraumatic, full-thickness rotator cuff tears. Our hypothesis is that an increasing duration of symptoms will correlate with more advanced findings of rotator cuff tear severity on magnetic resonance imaging, worse shoulder outcome scores, more pain, decreased range of motion, and less strength. METHODS: We enrolled 450 patients with full-thickness rotator cuff tears in a prospective cohort study to assess the effectiveness of nonoperative treatment and factors predictive of success. The duration of patient symptoms was divided into 4 groups: 3 months or less, 4 to 6 months, 7 to 12 months, and greater than 12 months. Data collected at patient entry into the study included (1) demographic data, (2) history and physical examination data, (3) radiographic imaging data, and (4) validated patient-reported measures of shoulder status. Statistical analysis included a univariate analysis with the Kruskal-Wallis test and Pearson test to identify statistically significant differences in these features for different durations of symptoms. RESULTS: A longer duration of symptoms does not correlate with more severe rotator cuff disease. The duration of symptoms was not related to weakness, limited range of motion, tear size, fatty atrophy, or validated patient-reported outcome measures. CONCLUSIONS: There is only a weak relationship between the duration of symptoms and features associated with rotator cuff disease.

OATP1B1-related drug-drug and drug-gene interactions as potential risk factors for cerivastatin-induced rhabdomyolysis.

OBJECTIVE: Genetic variation in drug metabolizing enzymes and membrane transporters as well as concomitant drug therapy can modulate the beneficial and the deleterious effects of drugs. We investigated whether patients exhibiting rhabdomyolysis who were taking cerivastatin possess functional genetic variants in SLCO1B1 and whether they were on concomitant medications that inhibit OATP1B1, resulting in accumulation of cerivastatin. METHODS: This study had three components: (a) resequencing the SLCO1B1 gene in 122 patients who developed rhabdomyolysis while on cerivastatin; (b) functional evaluation of the identified SLCO1B1 nonsynonymous variants and haplotypes in in-vitro HEK293/FRT cells stably transfected with pcDNA5/FRT empty vector, SLCO1B1 reference, variants, and haplotypes; and (c) in-vitro screening of 15 drugs commonly used among the rhabdomyolysis cases for inhibition of OATP1B1-mediated uptake of cerivastatin in HEK293/FRT cells stably transfected with reference SLCO1B1. RESULTS: The resequencing of the SLCO1B1 gene identified 54 variants. In-vitro functional analysis of SLCO1B1 nonsynonymous variants and haplotypes showed that the V174A, R57Q, and P155T variants, a novel frameshift insertion, OATP1B1*14 and OATP1B1*15 haplotype were associated with a significant reduction (P<0.001) in cerivastatin uptake (32, 18, 72, 3.4, 2.1 and 5.7% of reference, respectively). Furthermore, clopidogrel and seven other drugs were shown to inhibit OATP1B1-mediated uptake of cerivastatin. CONCLUSION: Reduced function of OATP1B1 related to genetic variation and drug-drug interactions likely contributed to cerivastatin-induced rhabdomyolysis. Although cerivastatin is no longer in clinical use, these findings may translate to related statins and other substrates of OATP1B1.