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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.

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.

ObjectivesTo assess the impact of cyclops lesions with MRI in patients treated for anterior cruciate ligament (ACL) tears on clinical outcome.MethodsIn 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.ResultsCyclops 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).ConclusionsNeither 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.

ObjectiveThe 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 methodsFifty-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.ResultsIn 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).ConclusionHigh 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.

ObjectiveQuantitative 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.MethodTen 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.ResultsThe 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

ObjectiveGenetic 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.MethodsThis 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.ResultsThe 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

Membrane transporters play crucial roles in the cellular uptake and efflux of an array of small molecules including nutrients, environmental toxins, and many clinically used drugs. We hypothesized that common genetic variation in the proximal promoter regions of transporter genes contribute to observed variation in drug response. A total of 579 polymorphisms were identified in the proximal promoters (-250 to +50 bp) and flanking 5' sequence of 107 transporters in the ATP Binding Cassette (ABC) and Solute Carrier (SLC) superfamilies in 272 DNA samples from ethnically diverse populations. Many transporter promoters contained multiple common polymorphisms. Using a sliding window analysis, we observed that, on average, nucleotide diversity (pi) was lowest at approximately 300 bp upstream of the transcription start site, suggesting that this region may harbor important functional elements. The proximal promoters of transporters that were highly expressed in the liver had greater nucleotide diversity than those that were highly expressed in the kidney consistent with greater negative selective pressure on the promoters of kidney transporters. Twenty-one promoters were evaluated for activity using reporter assays. Greater nucleotide diversity was observed in promoters with strong activity compared to promoters with weak activity, suggesting that weak promoters are under more negative selective pressure than promoters with high activity. Collectively, these results suggest that the proximal promoter region of membrane transporters is rich in variation and that variants in these regions may play a role in interindividual variation in drug disposition and response.

Background: Six classification systems have been proposed for describing rotator cuff tears designed to help understand their natural history and make treatment decisions. Purpose: To assess the interobserver variation for [...]