Lubricin Protects the Temporomandibular Joint Surfaces from Degeneration

The temporomandibular joint (TMJ) is a specialized synovial joint essential for the mobility and function of the mammalian jaw. The TMJ is composed of the mandibular condyle, the glenoid fossa of the temporal bone, and a fibrocartilagenous disc interposed between these bones. A fibrous capsule, lined on the luminal surface by the synovial membrane, links these bones and retains synovial fluid within the cavity. The major component of synovial fluid is lubricin, a glycoprotein encoded by the gene proteoglycan 4 (Prg4), which is synthesized by chondrocytes at the surface of the articular cartilage and by synovial lining cells. We previously showed that in the knee joint, Prg4 is crucial for maintenance of cartilage surfaces and for regulating proliferation of the intimal cells in the synovium. Consequently, the objective of this study was to determine the role of lubricin in the maintenance of the TMJ. We found that mice lacking lubricin have a normal TMJ at birth, but develop degeneration resembling TMJ osteoarthritis by 2 months, increasing in severity over time. Disease progression in Prg4−/− mice results in synovial hyperplasia, deterioration of cartilage in the condyle, disc and fossa with an increase in chondrocyte number and their redistribution in clusters with loss of superficial zone chondrocytes. All articular surfaces of the joint had a prominent layer of protein deposition. Compared to the knee joint, the osteoarthritis-like phenotype was more severe and manifested earlier in the TMJ. Taken together, the lack of lubricin in the TMJ causes osteoarthritis-like degeneration that affects the articular cartilage as well as the integrity of multiple joint tissues. Our results provide the first molecular evidence of the role of lubricin in the TMJ and suggest that Prg4−/− mice might provide a valuable new animal model for the study of the early events of TMJ osteoarthritis

Autopodial development is selectively impaired by misexpression of chordin-like 1 in the chick limb

AbstractChordin-like 1 (CHRDL1) is a secreted bone morphogenetic protein (BMP) antagonist expressed in mesenchymal tissues whose function in development of the skeleton has not been examined in detail. Here we show Chrdl1 is dynamically expressed in the early distal limb bud mesenchyme, with expression becoming downregulated as development proceeds. Chrdl1 expression is largely excluded from the critical signaling center of the posterior limb bud, the Zone of Polarizing Activity (ZPA), as has been described for the BMP antagonist Gremlin (GREM1) (Scherz et al., 2004, Science, 305, 396–399). Unlike Grem1, Chrdl1 is expressed in the hindlimb by a small subset of ZPA cells and their descendants suggesting divergent regulation and function between the various BMP antagonists. Ectopic expression of Chrdl1 throughout the avian limb bud using viral misexpression resulted in an oligodactyly phenotype with loss of digits from the anterior limb, although the development of more proximal elements of the zeugopod and stylopod were unaffected. Overgrowths of soft tissue and syndactyly were also observed, resulting from impaired apoptosis and failure of the anterior mesenchyme to undergo SOX9-dependent chondrogenesis, instead persisting as an interdigital-like soft tissue phenotype. Sonic hedgehog (SHH) and fibroblast growth factor (FGF) signaling were upregulated and persisted later in development, however these changes were only detected late in limb development at timepoints when endogenous Grem1 would normally be downregulated and increasing BMP signaling would cause termination of Shh and Fgf expression. Our results suggest that the early stages of the GREM1–SHH–FGF signaling network are resistant to Chrdl1-overexpression, leading to normal formation of proximal limb structures, but that later Bmp expression, impaired by ectopic CHRDL1, is essential for formation of the correct complement of digits

Gene expression of catabolic inflammatory cytokines peak before anabolic inflammatory cytokines after ACL injury in a preclinical model

Background: The response of the joint to anterior cruciate ligament (ACL) injury has not been fully characterized. In particular, the characterization of both catabolic factors, including interleukin-6 (IL-6), interleukin-8 (IL-8), and markers of ongoing tissue damage (CRP), and anabolic factors, including vascular endothelial growth factor (VEGF), transforming growth factor β-induced (TGFβI), and the presence of CD163+ macrophages, have not been well defined. In this study, we hypothesized ACL injury would catalyze both catabolic and anabolic processes and that these would have different temporal profiles of expression. Methods: Adolescent Yucatan minipigs were subjected to ACL transection. Within the joint, gene expression levels of IL-6, IL-8, VEGF, and TGFβI were quantified in the synovium, ligament, and provisional scaffold located between the torn ligament ends at days 1, 5, 9, and 14 post-injury. Macrophage infiltration was also assessed in the joint tissues over the two week period. Serum C-reactive protein (CRP) levels were measured at multiple time points between 1 hour to 14 days after injury. Results: Increases in IL-6 and IL-8 gene expression peaked at day 1 after injury in the synovium and ligament. CRP levels were significantly increased at day 3 before returning to pre-injury levels. VEGF and TGFβI gene expression did not significantly increase until day 9 in the synovium and were unchanged in the other tissues. CD163+ macrophages increased in the ligament and synovium until day 9. Conclusion: Taken together, these results suggest that the response within the joint is primarily catabolic in the first three days after injury, switching to a more anabolic phase by nine days after injury. The effect of medications which alter these processes may thus depend on the timing of administration after injury

The Ursinus Weekly, May 18, 1964

Quipping Ramblers roam through the bluegrass: Group scores with relaxed style • Graduation speakers named: Knettler at Baccalaureate, Ciardi at Commencement;; Updike and Weiss receive honorary degrees • Girls flock east, flee UC doldrums • Faculty upholds MSGA decision: Exception noted in one case • Women program Big-Little Sister activities • Thomas and Moser win in run-off • APO seeks funds for proposed service project • UC freshmen to take part in WIP panel • Doanes take year leave, teach at Miles College • PSEA elects new officers • Editorial: Ursinus men? • War in the name of peace • Letters to the editor • Ruby 1900 edition • Crossettes avenge W.C. loss; Arch-rival crushed 14-4 • Tennis improves in winning 1 of 3 • Baseball has winning week with victories in 2 of 3 • Tennis drops 3rd; Blanked 5-0 by WC • Trackmen tromp as W.C. and Muhlenberg bow • Greek gleanings • Parsons to teach on Summer grant • Final examination schedulehttps://digitalcommons.ursinus.edu/weekly/1274/thumbnail.jp

Benefit of linking hospital resource information and patient-level stroke registry data

Variation in the delivery of evidence-based care affects outcomes for patients with stroke. A range of hospital (organizational), patient, and clinical factors can affect care delivery. Clinical registries are widely used to monitor stroke care and guide quality improvement efforts within hospitals. However, hospital features are rarely collected. We aimed to explore the influence of hospital resources for stroke, in metropolitan and regional/rural hospitals, on the provision of evidence-based patient care and outcomes. The 2017 National Audit organizational survey (Australia) was linked to patient-level data from the Australian Stroke Clinical Registry (2016–2017 admissions). Regression models were used to assess the associations between hospital resources (based on the 2015 Australian National Acute Stroke Services Framework) and patient care (reflective of national guideline recommendations), as well as 90–180-day readmissions and health-related quality of life. Models were adjusted for patient factors, including the severity of stroke. Fifty-two out of 127 hospitals with organizational survey data were merged with 22 832 Australian Stroke Clinical Registry patients with an admission for a first-ever stroke or transient ischaemic attack (median age 75 years, 55% male, and 66% ischaemic). In metropolitan hospitals (n = 42, 20 977 patients, 1701 thrombolyzed, and 2395 readmitted between 90 and 180 days post stroke), a faster median door-to-needle time for thrombolysis was associated with ≥500 annual stroke admissions [−15.9 minutes, 95% confidence interval (CI) −27.2, −4.7], annual thrombolysis >20 patients (−20.2 minutes, 95% CI −32.0, −8.3), and having specialist stroke staff (dedicated medical lead and stroke coordinator; −12.7 minutes, 95% CI −25.0, −0.4). A reduced likelihood of all-cause readmissions between 90 and 180 days was evident in metropolitan hospitals using care pathways for stroke management (odds ratio 0.82, 95% CI 0.67–0.99). In regional/rural hospitals (n = 10, 1855 patients), being discharged with a care plan was also associated with the use of stroke clinical pathways (odds ratio 3.58, 95% CI 1.45–8.82). No specific hospital resources influenced 90–180-day health-related quality of life. Relevant to all international registries, integrating information about hospital resources with clinical registry data provides greater insights into factors that influence evidence-based care

Epidemiology, Public Health, and the Rhetoric of False Positives

BACKGROUND: As an observational science, epidemiology is regarded by some researchers as inherently flawed and open to false results. In a recent paper, Boffetta et al. [Boffetta P, McLaughlin JK, LaVecchia C, Tarone RE, Lipworth L, Blot WJ. False-positive results in cancer epidemiology: a plea for epistemological modesty. J Natl Cancer Inst 100:988-995 (2008)] argued that "epidemiology is particularly prone to the generation of false-positive results." They also said "the tendency to emphasize and over-interpret what appear to be new findings is commonplace, perhaps in part because of a belief that the findings provide information that may ultimately improve public health" and that "this tendency to hype new findings increases the likelihood of downplaying inconsistencies within the data or any lack of concordance with other sources of evidence." The authors supported these serious charges against epidemiology and epidemiologists with few examples. Although we acknowledge that false positives do occur, we view the position of Boffetta and colleagues on false positives as unbalanced and potentially harmful to public health. OBJECTIVE: We aim to provide a more balanced evaluation of epidemiology and its contribution to public health discourse. DISCUSSION: Boffetta and colleagues ignore the fact that false negatives may arise from the very processes that they tout as generating false-positive results. We further disagree with their proposition that false-positive results from a single study will lead to faulty decision making in matters of public health importance. In practice, such public health evaluations are based on all the data available from all relevant disciplines and never to our knowledge on a single study. CONCLUSIONS: The lack of balance by Boffetta and colleagues in their evaluation of the impact of false-positive findings on epidemiology, the charge that "methodological vigilance is often absent" in epidemiologists' interpretation of their own results, and the false characterization of how epidemiologic findings are used in societal decision making all undermine a major source of information regarding disease risks. We reaffirm the importance of epidemiologic evidence as a critical component of the foundation of public health protection

The Big Yes and the Little No

Program for the sixth annual RISD Cabaret held in the cellar at the top of the Waterman Building. Design and layout by Nonie Close.https://digitalcommons.risd.edu/liberalarts_cabaret_programs/1005/thumbnail.jp

Decision-making of English Netball Superleague umpires: Contextual and dispositional influences

Objectives. The decisions made by officials have a direct bearing on the outcomes of competitive sport contests. In an exploratory study, we examine the interrelationships between the decisions made by elite netball umpires, the potential contextual and environmental influences (e.g., crowd size), and the umpires’ dispositional tendencies – specifically, their propensity to deliberate and ruminate on their decisions. Design/Method. Filmed footage from 60 England Netball Superleague matches was coded using performance analysis software. We measured the number of decisions made overall, and for home and away teams; league position; competition round; match quarter; and crowd size. Additionally, 10 umpires who officiated in the matches completed the Decision-Specific Reinvestment Scale (DSRS). Results. Regression analyses predicted that as home teams’ league position improved the number of decisions against away teams increased. A model comprising competition round and average league position of both teams predicted the number of decisions made in matches, but neither variable emerged as a significant predictor. The umpire analyses revealed that greater crowd size was associated with an increase in decisions against away teams. The Decision Rumination factor was strongly negatively related to the number of decisions in Quarters 1 and 3, this relationship was driven by fewer decisions against home teams by umpires who exhibited higher Rumination subscale scores. Conclusions. These findings strengthen our understanding of contextual, environmental, and dispositional influences on umpires’ decision-making behaviour. The tendency to ruminate upon decisions may explain the changes in decision behaviour in relation to the home team advantage effect

Evidence for Reduced Drug Susceptibility without Emergence of Major Protease Mutations following Protease Inhibitor Monotherapy Failure in the SARA Trial

Background Major protease mutations are rarely observed following failure with protease inhibitors (PI), and other viral determinants of failure to PI are poorly understood. We therefore characterized Gag-Protease phenotypic susceptibility in subtype A and D viruses circulating in East Africa following viral rebound on PIs. Methods Samples from baseline and treatment failure in patients enrolled in the second line LPV/r trial SARA underwent phenotypic susceptibility testing. Data were expressed as fold-change in susceptibility relative to a LPV-susceptible reference strain. Results We cloned 48 Gag-Protease containing sequences from seven individuals and performed drug resistance phenotyping from pre-PI and treatment failure timepoints in seven patients. For the six patients where major protease inhibitor resistance mutations did not emerge, mean fold-change EC50 to LPV was 4.07 fold (95% CI, 2.08–6.07) at the pre-PI timepoint. Following viral failure the mean fold-change in EC50 to LPV was 4.25 fold (95% CI, 1.39–7.11, p = 0.91). All viruses remained susceptible to DRV. In our assay system, the major PI resistance mutation I84V, which emerged in one individual, conferred a 10.5-fold reduction in LPV susceptibility. One of the six patients exhibited a significant reduction in susceptibility between pre-PI and failure timepoints (from 4.7 fold to 9.6 fold) in the absence of known major mutations in protease, but associated with changes in Gag: V7I, G49D, R69Q, A120D, Q127K, N375S and I462S. Phylogenetic analysis provided evidence of the emergence of genetically distinct viruses at the time of treatment failure, indicating ongoing viral evolution in Gag-protease under PI pressure. Conclusions Here we observe in one patient the development of significantly reduced susceptibility conferred by changes in Gag which may have contributed to treatment failure on a protease inhibitor containing regimen. Further phenotype-genotype studies are required to elucidate genetic determinants of protease inhibitor failure in those who fail without traditional resistance mutations whilst PI use is being scaled up globally