Mucosal plasma cells are required to protect the upper airway and brain from infection.

While blood antibodies mediate protective immunity in most organs, whether they protect nasal surfaces in the upper airway is unclear. Using multiple viral infection models in mice, we found that blood-borne antibodies could not defend the olfactory epithelium. Despite high serum antibody titers, pathogens infected nasal turbinates, and neurotropic microbes invaded the brain. Using passive antibody transfers and parabiosis, we identified a restrictive blood-endothelial barrier that excluded circulating antibodies from the olfactory mucosa. Plasma cell depletions demonstrated that plasma cells must reside within olfactory tissue to achieve sterilizing immunity. Antibody blockade and genetically deficient models revealed that this local immunity required CD4+ T cells and CXCR3. Many vaccine adjuvants failed to generate olfactory plasma cells, but mucosal immunizations established humoral protection of the olfactory surface. Our identification of a blood-olfactory barrier and the requirement for tissue-derived antibody has implications for vaccinology, respiratory and CNS pathogen transmission, and B cell fate decisions.

RNPS1 inhibits excessive tumor necrosis factor/tumor necrosis factor receptor signaling to support hematopoiesis in mice.

Null mutations of spliceosome components or cofactors are homozygous lethal in eukaryotes, but viable hypomorphic mutations provide an opportunity to understand the physiological impact of individual splicing proteins. We describe a viable missense allele (F181I) of Rnps1 encoding an essential regulator of splicing and nonsense-mediated decay (NMD), identified in a mouse genetic screen for altered immune cell development. Homozygous mice displayed a stem cell­intrinsic defect in hematopoiesis of all lineages due to excessive apoptosis induced by tumor necrosis factor (TNF)­dependent death signaling. Numerous transcript splice variants containing retained introns and skipped exons were detected at elevated frequencies in Rnps1F181I/F181I splenic CD8+ T cells and hematopoietic stem cells (HSCs), but NMD appeared normal. Strikingly, Tnf knockout rescued all hematopoietic cells to normal or near-normal levels in Rnps1F181I/F181I mice and dramatically reduced intron retention in Rnps1F181I/F181I CD8+ T cells and HSCs. Thus, RNPS1 is necessary for accurate splicing, without which disinhibited TNF signaling triggers hematopoietic cell death.

Persistent underloading of patellofemoral joint following hamstring autograft ACL reconstruction is associated with cartilage health.

OBJECTIVE: To determine the longitudinal changes of patellofemoral joint (PFJ) contact pressure following anterior cruciate ligament reconstruction (ACLR). To identify the associations between PFJ contact pressure and cartilage health. DESIGN: Forty-nine subjects with hamstring autograft ACLR (27 males; age 28.8 [standard deviation, 8.3] years) and 19 controls (12 males; 30.7 [4.6] years) participated. A sagittal plane musculoskeletal model was used to estimate PFJ contact pressure. A combined T1ρ/T2 magnetic resonance sequence was obtained. Assessments were performed preoperatively, at 6 months, 1, 2, and 3 years postoperatively in ACLR subjects and once for controls. Repeated Analysis of Variance (ANOVA) was used to compare peak PFJ contact pressure between ACLR and contralateral knees, and t-tests to compare with control knees. Statistical parametric mapping was used to evaluate the associations between PFJ contact pressure and cartilage relaxation concurrently and longitudinally. RESULTS: No changes in peak PFJ contact pressure were found within ACLR knees over 3 years (preoperative to 3 years, 0.36 [CI, -0.08, 0.81] MPa), but decreased over time in the contralateral knees (0.75 [0.32, 1.18] MPa). When compared to the controls, ACLR knees exhibited lower PFJ contact pressure at all time points (at baseline, -0.64 [-1.25, -0.03] MPa). Within ACLR knees, lower PFJ contact pressure at 6 months was associated with elevated T2 times (r = -0.47 to -0.49, p = 0.021-0.025). CONCLUSIONS: Underloading of the PFJ following ACLR persists for up to 3 years and has concurrent and future consequences in cartilage health. The non-surgical knees exhibited normal contact pressure initially but decreased over time achieving limb symmetry.

Mitochondrial Oxidative Phosphorylation Complex Regulates NLRP3 Inflammasome Activation and Predicts Patient Survival in Nasopharyngeal Carcinoma.

We previously reported that tumor inflammasomes play a key role in tumor control and act as favorable prognostic markers in nasopharyngeal carcinoma (NPC). Activated inflammasomes frequently form distinguishable specks and govern the cellular secretion of IL-1ß. However, we know little about the biological and biochemical differences between cells with and without apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) speck formation. In this study, we used proteomic iTRAQ analysis to analyze the proteomes of NPC cells that differ in their ASC speck formation upon cisplatin treatment. We identified proteins that were differentially over-expressed in cells with specks, and found that they fell into two Gene ontology (GO) pathways: mitochondrial oxidative phosphorylation (OxPhos) and ubiquinone metabolism. We observed up-regulation of various components of the OxPhos machinery (including NDUFB3, NDUFB8 and ATP5B), and subsequently found that these changes lead to mitochondrial ROS (mtROS) production, which promotes the formation and activation of NLRP3 inflammasomes and subsequent pyroptosis. In NPC patients, better local recurrence-free survival was significantly associated with high-level expression of NDUFB8 (p = 0.037) and ATP5B (p = 0.029), as examined using immunohistochemistry. However, there were no significant associations between the expression of NDUFB8 and ATP5B with overall survival of NPC patients. Together, our results demonstrate that up-regulated mitochondrial OxPhos components are strongly associated with NLRP3 inflammasome activation in NPC. Our findings further suggest that high-level expression of OxPhos components could be markers for local recurrence and/or promising therapeutic targets in patients with NPC.

Granulocytic MDSC with Deficient CCR5 Alleviates Lipogenesis and Inflammation in Nonalcoholic Fatty Liver Disease.

C-C chemokine receptor type 5 (CCR5) positively contributes to the pathogenesis of nonalcoholic fatty liver disease (NAFLD), a common metabolic liver disease associated with chronic inflammation. CCR5 signaling also facilitates the immunosuppressive activity of a group of immature myeloid cells known as granulocytic myeloid-derived suppressor cells (g-MDSCs). While both hepatocyte and g-MDSC express CCR5, how CCR5 coordinates these two distinct cell types in the hepatic microenvironment remains largely unknown. Here, we used in vivo and ex vivo approaches to define the molecular details of how CCR5 mediates the crosstalk between hepatocytes and g-MDSCs in a mouse model of NAFLD. Global CCR5-deficient mice exhibited more severe steatosis, increased hepatic gene expression of lipogenesis, and exacerbated liver damage in diet-induced obesity. Either NAFLD or CCR5-deficiency per se is causative for the increase of g-MDSCs. Purified g-MDSCs have a higher survival rate in the fatty liver microenvironment, and blockade of CCR5 significantly decreases g-MDSCs' expression of anti-inflammatory factors. On the other hand, the null of CCR5 signaling increases hepatocytes' expression of lipogenic genes in the NAFLD microenvironment. Most importantly, inhibiting g-MDSCs' CCR5 signaling in the fatty liver microenvironment dramatically reduces STAT3 signaling, lipogenic, and pro-inflammatory gene expression in primary hepatocytes. Adoptive cell transfer experiments further demonstrate that CCR5-deficient g-MDSCs mitigate hepatic lipogenic gene expression without facilitating pro-inflammatory cytokine production and liver damage in NAFLD mice. These results suggest that targeting g-MDSCs' CCR5 signaling might serve as a potential therapeutic strategy for NAFLD.

Extracting Voxel-Based Cartilage Relaxometry Features in Hip Osteoarthritis Subjects Using Principal Component Analysis.

BACKGROUND: MRI-based relaxation time measurements provide quantitative assessment of cartilage biochemistry. Identifying distinctive relaxometry features in hip osteoarthritis (OA) might provide important information on regional disease variability. PURPOSE: First, to incorporate fully automatic voxel-based relaxometry (VBR) with principal component analysis (PCA) to extract distinctive relaxometry features in subjects with radiographic hip OA and nondiseased controls. Second, to use the identified features to further distinguish subjects with cartilage compositional abnormalities. STUDY TYPE: Cross-sectional. SUBJECTS: Thirty-three subjects with radiographic hip OA (20 males; age, 50.2 ± 13.3 years) and 55 controls participated (28 males; 41.3 ± 12.0 years). SEQUENCE: A 3.0T scanner using 3D SPGR, combined T1ρ /T2 , and fast spin echo sequences. ASSESSMENT: Pelvic radiographs, patients' self-reported symptoms, physical function, and cartilage morphology were analyzed. Cartilage relaxation times were quantified using traditional regions of interest and VBR approaches. PCA was performed on VBR data to identify distinctive relaxometry features, and were subsequently used to identify a subgroup of subjects from the controls that exhibited compositional abnormalities. STATISTICAL TESTS: Chi-square and independent t-tests were used to compare group characteristics. Logistic regression models were used to identify the possible principal components (PCs) that were able to predict OA vs. control classification. RESULTS: In T1ρ assessment, OA subjects demonstrated higher T1ρ values in the posterior hip region and deep cartilage layer when compared with controls (P = 0.012 and 0.001, respectively). In T2 assessment, OA subjects exhibited higher T2 values in the posterior hip region (P < 0.001). Based on the PC score classification, 16 subjects without radiographic evidence of OA demonstrated relaxometry patterns similar to OA subjects, and exhibited worse physical function (P = 0.003) and cartilage lesions (P = 0.009-0.032) when compared with the remaining controls. DATA CONCLUSION: The study identified distinctive cartilage relaxometry features that were able to discriminate subjects with and without radiographic hip OA effectively. LEVEL OF EVIDENCE: 1 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2020;51:1708-1719.

Runners With Patellofemoral Pain Exhibit Greater Peak Patella Cartilage Stress Compared With Pain-Free Runners.

The primary purpose of this study is to determine whether recreational runners with patellofemoral pain (PFP) exhibit greater peak patella cartilage stress compared with pain-free runners. A secondary purpose was to determine the kinematic and/or kinetic predictors of peak patella cartilage stress during running. A total of 22 female recreational runners (12 with PFP and 10 pain-free controls) participated in this study. Patella cartilage stress profiles were quantified using subject-specific finite element models simulating the maximum knee flexion angle during the stance phase of running. Input parameters to the finite element model included subject-specific patellofemoral joint geometry, quadriceps muscle forces, and lower-extremity kinematics in the frontal and transverse planes. Tibiofemoral joint kinematics and kinetics were quantified to determine the best predictor of stress using stepwise regression analysis. Compared with the pain-free runners, those with PFP exhibited greater peak hydrostatic pressure (PFP vs control: 21.2 [5.6] MPa vs 16.5 [4.6] MPa) and maximum shear stress (PFP vs control: 11.3 [4.6] MPa vs 8.7 [2.3] MPa). Knee external rotation was the best predictor of peak hydrostatic pressure and peak maximum shear stress (38% and 25% of variances, respectively), followed by the knee extensor moment (21% and 25% of variances, respectively). Runners with PFP exhibit greater peak patella cartilage stress during running compared with pain-free individuals. The combination of knee external rotation and a high knee extensor moment best predicted the elevated peak stress during running.

Does Patella Tendon Tenodesis Improve Tibial Tubercle Distalization in Treating Patella Alta? A Computational Study.

BACKGROUND: Patellofemoral malalignment associated with patella alta may cause pain and arthritis; because of this, the condition sometimes is treated surgically. Two common procedures are tibial tubercle distalization with or without patellar tendon tenodesis. However, the biomechanical consequences of these interventions for patella alta are not clearly understood. QUESTIONS/PURPOSES: We evaluated changes in patellofemoral joint contact mechanics after tibial tubercle distalization and tibial tubercle distalization combined with patella tendon tenodesis. Specifically, we asked: (1) Are there biomechanical differences between these two types of procedures? (2) Is there an ideal range to distalize the patella? METHODS: Subject-specific finite-element models were created for 10 individuals with patella alta (mean Insall-Salvati ratio of 1.34 ± 0.05). Input parameters for the finite-element models included subject-specific joint geometry, quadriceps muscle forces, and weightbearing patellofemoral joint kinematics. Virtual operations were conducted to simulate the two procedures. For distalization, the tibial tubercle and patella were displaced distally 4 mm to 20 mm in 4-mm increments based on the original model. At each level of distalization, the patella tendon was attached back to its original insertion to simulate the additional tenodesis procedure. Cartilage stress, contact area, and contact forces were quantified and compared between procedures and distalization levels. RESULTS: Distalization and distalization + tenodesis reduced patellofemoral joint stress compared with the baseline of 1.02 ± 0.11 MPa. Distalization led to lower cartilage stress than distalization + tenodesis, and the effect size was relatively large (0.88 ± 0.10 MPa vs 0.92 ± 0.10 MPa; mean difference, 0.04 MPa [95% CI, 0.02 MPa-0.05 MPa], p < 0.01; effect size of 1.64 [Cohen's d], with Insall-Salvati ratio decreased to 0.95). For both procedures, the trend of stress reduction plateaued when the Install-Salvati ratio approached 0.95. CONCLUSIONS: Cartilage stress appears lower using distalization as opposed to distalization + tenodesis in this finite-element analysis simulation. An Insall-Salvati ratio of 0.95 may be an ideal level for distalization; further distalization does not show additional benefits. CLINICAL RELEVANCE: This study suggests that distalization may result in less stress than distalization + tenodesis, therefore future clinical research might be preferentially directed toward evaluating isolated distalization procedures.

Association of patella alignment with cartilage relaxation times and self-reported symptoms in individuals with patellofemoral degeneration.

To determine the cross-sectional and longitudinal associations of patella alignment with cartilage relaxation and patients' self-reported symptoms. Thirty participants with isolated patellofemoral joint (PFJ) degeneration (six males, 53.7 ± 9.3 years) and 24 controls (12 males, 47.6 ± 10.7 years) were included. Magnetic resonance assessment was performed to provide grading of structural abnormalities, cartilage relaxation times, and patella alignment. Self-reported symptoms were assessed using the self-administrated knee injury and osteoarthritis outcome score (KOOS). All participants were examined at baseline and 3 years. Statistical parametric mapping and Pearson partial correlation were used to evaluate the associations between patella alignment with cartilage relaxation times and self-reported symptoms, respectively. The analyses were performed between baseline (cross-sectional) as well as the baseline against 3 years (longitudinal). Results indicated that patella height and patella flexion were associated with T1ρ and T2 relaxation times at baseline (percentages of voxels showing significant correlation [PSV] = 10.1%-24.8%; mean correlations [R] = 0.34-0.36; mean p = 0.015-0.026). Furthermore, greater patella lateral alignment, lateral tilt, and lateral spin were associated with longer T2 times at 3 years (PSV = 11.0%-14.4%, R = 0.39-0.44, p = 0.017-0.028). Last, a higher patella was associated with a lower KOOS at baseline and at 3 years (R = -0.33 to -0.35). The study suggests that patella malalignment is a risk factor for worsening cartilage health, informing clinicians of a better rehabilitation program that targets PFJ degeneration.

Integrin α3 promotes TH17 cell polarization and extravasation during autoimmune neuroinflammation.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) caused by CNS-infiltrating leukocytes, including TH17 cells that are critical mediators of disease pathogenesis. Although targeting leukocyte trafficking is effective in treating autoimmunity, there are currently no therapeutic interventions that specifically block encephalitogenic TH17 cell migration. Here, we report integrin α3 as a TH17 cell-selective determinant of pathogenicity in experimental autoimmune encephalomyelitis. CNS-infiltrating TH17 cells express high integrin α3, and its deletion in CD4+ T cells or Il17a fate-mapped cells attenuated disease severity. Mechanistically, integrin α3 enhanced the immunological synapse formation to promote the polarization and proliferation of TH17 cells. Moreover, the transmigration of TH17 cells into the CNS was dependent on integrin α3, and integrin α3 deficiency enhanced the retention of CD4+ T cells in the perivascular space of the blood-brain barrier. Integrin α3-dependent interactions continuously maintain TH17 cell identity and effector function. The requirement of integrin α3 in TH17 cell pathogenicity suggests integrin α3 as a therapeutic target for MS treatment.

The physiological benefits of sitting less and moving more: Opportunities for future research.

Sedentary behavior (SB) and physical activity (PA) are important risk factors of cardiovascular disease morbidity and mortality. In addition to increasing the amount of moderate-to-vigorous PA (MVPA), the current PA guidelines recommend that adults should reduce SB, or any waking activity performed while sitting, reclining, or lying, with low energy expenditure. While mounting evidence has emphasized the benefits of increasing MVPA, little has focused on the effect of SB on health. Therefore, this review discusses the pathophysiological effects of SB and the potential physiological benefits of reducing/breaking up SB at the levels below the current guidelines for PA. Such knowledge is important, given that the majority of the United States population performs insufficient or no MVPA and is at high risk of being negatively impacted by SB. Interventions targeting sedentary time, such as breaking up SB by standing and moving, may be safe, feasible, and applicable to execute daily for a wide range of the population. This review also discusses the importance of monitoring SB in the era of the coronavirus disease 2019 (COVID-19) pandemic and the clinical implications of sitting less and moving more.

Longitudinal Changes of Patellar Alignment Before and After Anterior Cruciate Ligament Reconstruction With Hamstring Autograft.

BACKGROUND: Evidence has suggested that after anterior cruciate ligament (ACL) reconstruction (ACLR), individuals exhibit patellar malalignment; however, it is unknown if patellar alignment changes over time. PURPOSE: To examine the longitudinal changes in patellar alignment before, 6 months after, and 3 years after ACLR and to compare these variations, if present, with patellar alignment in controls. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: A total of 35 patients who had ACLR using hamstring autograft (19 male; age, 29.9 ± 7.7 years; body mass index, 23.8 ± 2.5) and 20 controls (13 male; age, 30.4 ± 4.8 years; body mass index, 24.3 ± 2.7) participated. All patients underwent bilateral knee magnetic resonance imaging with the knee in extension and 30° of flexion using sagittal T2-weighted, fat-saturated fast spin-echo images to assess patellar alignment in 6 degrees of freedom: anterior-posterior, medial-lateral, and superior-inferior translations; flexion; tilt; and spin. Patients who had ACLR were assessed before (ACL-deficient state) and 6 months and 3 years after ACLR, while control participants were only assessed once. One-way repeated-measures analysis of variance was used to examine patellar alignment across time in the ACLR group. If changes were present, the independent t test was carried out to examine the differences between ACLR knees and control knees. RESULTS: In the knee-extended condition, greater patellar lateral displacement was observed at the ACL-deficient state and 6 months after ACLR compared with 3 years after ACLR within the ACLR group (P < .001 and P = .043, respectively) and compared with the control group (P = .001 and P = .039, respectively). Greater patellar lateral tilt was observed at the ACL-deficient state compared with 3 years after ACLR (P = .003) and compared with the control group (P = .018). In the knee-flexed condition, greater anterior displacement was observed at the ACL-deficient state compared with 3 years after ACLR (P = .001) and compared with the control group (P = .011), and it was also observed at 6 months after ACLR compared with the control group (P = .019). Less lateral spin was observed at the ACL-deficient state (P = .042) and 6 months after ACLR (P = .004) compared with 3 years after ACLR and compared with the control group (P = .004 for both). No patellar alignment measures in the ACLR knees at 3 years were significantly different from those of the controls. CONCLUSION: Patellar malalignment in individuals before and after ACLR subjected to longitudinal changes, and the differences in alignment between ACLR and controls diminished over 3 years.

Selective Atrophy of the Vastus Medialis: Does It Exist in Women With Nontraumatic Patellofemoral Pain?

BACKGROUND: A commonly cited theory related to the pathomechanics of patellofemoral pain (PFP) states that atrophy of the vastus medialis (VM) muscle leads to lateral tracking of the patella. However, isolated atrophy of the VM or atrophy of the quadriceps muscle group as a whole, has not been consistently reported in this population. PURPOSE: To compare individual and total quadriceps muscle volumes between women with nontraumatic PFP and women without PFP as measured on magnetic resonance imaging scans. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: A total of 52 women with nontraumatic PFP and 64 women without PFP between the ages of 18 and 45 years participated. Magnetic resonance imaging scans of the thigh were obtained from the anterior inferior iliac spine to the tibial plateau. Individual quadriceps muscle cross-sectional area measurements were obtained from each image, and muscle volumes for the VM, vastus lateralis, vastus intermedius, and rectus femoris were calculated. Muscle volume measurements were expressed in absolute values and normalized to body mass. Separate 2-way mixed-factorial analysis of variance (group × muscle) were used to compare absolute and normalized individual muscle volumes between groups. Independent t tests were used to compare absolute and normalized total quadriceps volumes between groups. RESULTS: There was no difference in absolute and normalized individual muscle volumes between individuals with and those without PFP. Additionally, absolute and normalized total muscle volumes did not differ between groups. CONCLUSION: Our findings do not support the concept of preferential atrophy of the VM or generalized quadriceps atrophy in women with nontraumatic PFP.

Longitudinal analysis of the contribution of 3D patella and trochlear bone shape on patellofemoral joint osteoarthritic features.

To explore bone shape features that are associated with patellofemoral joint (PFJ) osteoarthritic features. Thirty subjects with PFJ degeneration (six males, 53.2 ± 9.8 years) and 23 controls (12 males, 48.1 ± 10.6 years) were included. Magnetic resonance (MR) assessment was performed to provide bone segmentation, morpholgocial grading, and cartilage relaxation times. In addition, subject self-reported symptoms were reported. Logistic regressions were used to identify the shape features that were associated with the presence and worsening of PFJ morphological lesions over 3 years, and worsening of self-reported symptoms. Statistical parametric mapping was used to evaluate the associations between shape features and cartilage relaxation times at 3 years. Results indicated that subjects with PFJ degeneration exhibited a trochlea with longer lateral condyle and shallower trochlear groove (adjusted odds ratio [OR] = 0.30; 95% confidence interval [CI]: 0.10, 0.86; P = .025). Subjects with worsening of PFJ degeneration exhibited a patella with equally distributed facets (adjusted OR = 3.14; 95% CI: 1.05, 9.37; P = .040) and lateral bump (adjusted OR = 0.14; 95% CI: 0.02, 0.83; P = .030). No shape features were associated with worsening of self-reported symptoms. Elevated T1ρ and T2 times at 3 years were associated with a patella with a lateral hook, equally distributed facets, round and thick as well as a trochlea larger in size (R = 0.38~0.46, P = .015~.025). The study demonstrated the ability of 3D statistical shape modeling to quantify patella and trochlear bone shape features that are associated with the presence and progression of PFJ osteoarthritic features.

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.

Essential cell-extrinsic requirement for PDIA6 in lymphoid and myeloid development.

In a forward genetic screen of N-ethyl-N-nitrosourea (ENU)-induced mutant mice for aberrant immune function, we identified mice with a syndromic disorder marked by growth retardation, diabetes, premature death, and severe lymphoid and myeloid hypoplasia together with diminished T cell-independent (TI) antibody responses. The causative mutation was in Pdia6, an essential gene encoding protein disulfide isomerase A6 (PDIA6), an oxidoreductase that functions in nascent protein folding in the endoplasmic reticulum. The immune deficiency caused by the Pdia6 mutation was, with the exception of a residual T cell developmental defect, completely rescued in irradiated wild-type recipients of PDIA6-deficient bone marrow cells, both in the absence or presence of competition. The viable hypomorphic allele uncovered in these studies reveals an essential role for PDIA6 in hematopoiesis, but one extrinsic to cells of the hematopoietic lineage. We show evidence that this role is in the proper folding of Wnt3a, BAFF, IL-7, and perhaps other factors produced by the extra-hematopoietic compartment that contribute to the development and lineage commitment of hematopoietic cells.

Tibiofemoral kinematics in the transverse and frontal planes influence the location and magnitude of peak patella cartilage stress: An investigation of runners with and without patellofemoral pain.

BACKGROUND: To determine whether the location and magnitude of peak patella cartilage stress varies among runners with and without patellofemoral pain. To determine whether tibiofemoral kinematics in the frontal and transverse planes predict peak lateral and medial patella cartilage stress. METHODS: Twelve recreational runners with patellofemoral pain and 10 pain-free controls participated. Peak patella cartilage stress was quantified using finite element models that incorporated subject-specific kinematic and kinetic data obtained during running. Chi-square analysis was used to determine whether the location of peak patella cartilage stress (medial or lateral) varied between groups. Student's t-tests were used to determine whether the magnitude of peak medial and lateral patella cartilage stress varied between groups. In addition, stepwise regression analysis was performed to determine if tibiofemoral kinematics were predictive of peak medial and lateral cartilage stress. FINDINGS: Among all subjects, 64% exhibited peak cartilage stress on the lateral patella facet. No group differences were found for the location and magnitude of peak cartilage stress on the medial or lateral facets. Tibiofemoral rotation in the transverse plane was the best predictor of peak lateral stress (45% of the variance, r = 0.67). Tibiofemoral rotation in the transverse plane was the best predictor of peak medial stress (44% of the variance, r = -0.67), followed by tibiofemoral rotation in the frontal plane (26% of the variance, r = 0.57). INTERPRETATIONS: The location and magnitude of peak patella cartilage stress was similar among runners with and without patellofemoral pain. Tibiofemoral kinematics in the frontal and transverse planes are predictive of cartilage stress on the medial and lateral patella facets.

Association Between Gait Kinetics and Symptomatic Progression in Persons With Patellofemoral With/Without Concurrent Tibiofemoral Osteoarthritis.

To identify the biomechanical risk factors associated with symptomatic progression at 1-year follow-up in persons with patellofemoral joint (PFJ) osteoarthritis (OA). Patients' self-reported Knee Injury and Osteoarthritis Outcome Score questionnaires, magnetic resonance (MR) imaging, and three-dimensional gait analysis were obtained in 53 subjects with PFJ OA at baseline and after 1 year. Joint OA was diagnosed on knee MR images if cartilage lesions existed. Progression was defined by worsening of patients' self-reported symptoms from baseline to 1 year exceeding the minimal detectable change score. Analysis of covariance was used to compare peak knee flexion moment, knee flexion moment impulse, and vertical ground reaction force loading rate between progressors and non-progressors. Seven (13.2%) subjects exhibited progression in self-reported symptoms at 1-year follow-up. When comparing to non-progressors, significantly higher peak knee flexion moment during first half of stance (p = 0.017) and higher moment impulse during the both halves of stance were observed among progressors (p = 0.020-0.040). Persons with symptomatic PFJ OA progression with or without concurrent tibiofemoral OA exhibited abnormal joint loading mechanics when compared with individuals who did not progress. Further work is needed to determine if modification to these loading variables results in a change in the symptomatic progression in these individuals. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2593-2600, 2019.

Abnormal Joint Loading During Gait in Persons With Hip Osteoarthritis Is Associated With Symptoms and Cartilage Lesions.

BACKGROUND: Hip joint loading in persons with hip osteoarthritis (OA) is not well studied, and its associations with symptoms and lesions are unknown. OBJECTIVES: To determine whether hip joint loading differs between people with and without radiographic hip OA, and to identify its associations with patients' symptoms and cartilage morphology. METHODS: Forty-eight patients (28 male; mean ± SD age, 56.0 ± 12.2 years) with hip OA and 95 controls (40 male; age, 43.2 ± 13.6 years) participated in this cross-sectional analysis. Pelvic radiographs, questionnaires, magnetic resonance imaging (MRI), and gait analysis were conducted. The Hip disability and Osteoarthritis Outcome Score (HOOS) was used to assess symptoms. Cartilage morphology was graded on MRI scans using the Scoring Hip Osteoarthritis with Magnetic Resonance Imaging (SHOMRI) system. Biomechanical variables included peak external hip joint moment (Newton meters per kilogram) and moment impulses (Newton meters times milliseconds per kilogram) in all planes. Generalized estimating equations were used to compare the biomechanical characteristics between groups. In the patients with OA, associations of moment impulses with HOOS and SHOMRI scores were assessed with partial correlations. RESULTS: The OA group exhibited higher peak external hip flexion and adduction moments (P<.001) and higher hip flexion, adduction, and external rotation moment impulses (P = .001-.039). Increased hip flexion moment impulses were correlated with worse HOOS subscale scores (r = -0.361 to -0.424, P<.05) and worse femoral SHOMRI grades (ρ = 0.256-0.315, P<.05). Increased hip external rotation moment impulses were correlated with worse femoral SHOMRI grades (ρ = 0.283-0.372, P<.05). CONCLUSION: Persons with hip OA exhibited abnormally high hip joint loads during walking, and high loads were associated with worse self-reported symptoms and cartilage morphology. J Orthop Sports Phys Ther 2019;49(12):917-924. Epub 14 Oct 2019. doi:10.2519/jospt.2019.8945.

LMBR1L regulates lymphopoiesis through Wnt/ß-catenin signaling.

Precise control of Wnt signaling is necessary for immune system development. In this study, we detected severely impaired development of all lymphoid lineages in mice, resulting from an N-ethyl-N-nitrosourea-induced mutation in the limb region 1-like gene (Lmbr1l), which encodes a membrane-spanning protein with no previously described function in immunity. The interaction of LMBR1L with glycoprotein 78 (GP78) and ubiquitin-associated domain-containing protein 2 (UBAC2) attenuated Wnt signaling in lymphocytes by preventing the maturation of FZD6 and LRP6 through ubiquitination within the endoplasmic reticulum and by stabilizing "destruction complex" proteins. LMBR1L-deficient T cells exhibited hallmarks of Wnt/ß-catenin activation and underwent apoptotic cell death in response to proliferative stimuli. LMBR1L has an essential function during lymphopoiesis and lymphoid activation, acting as a negative regulator of the Wnt/ß-catenin pathway.