CR1 Knops blood group alleles are not associated with severe malaria in the Gambia

The Knops blood group antigen erythrocyte polymorphisms have been associated with reduced falciparum malaria-based in vitro rosette formation (putative malaria virulence factor). Having previously identified single-nucleotide polymorphisms (SNPs) in the human complement receptor 1 (CR1/CD35) gene underlying the Knops antithetical antigens Sl1/Sl2 and McC(a)/McC(b), we have now performed genotype comparisons to test associations between these two molecular variants and severe malaria in West African children living in the Gambia. While SNPs associated with Sl:2 and McC(b+) were equally distributed among malaria-infected children with severe malaria and control children not infected with malaria parasites, high allele frequencies for Sl 2 (0.800, 1,365/1,706) and McC(b) (0.385, 658/1706) were observed. Further, when compared to the Sl 1/McC(a) allele observed in all populations, the African Sl 2/McC(b) allele appears to have evolved as a result of positive selection (modified Nei-Gojobori test Ka-Ks/s.e.=1.77, P-value <0.05). Given the role of CR1 in host defense, our findings suggest that Sl 2 and McC(b) have arisen to confer a selective advantage against infectious disease that, in view of these case-control study data, was not solely Plasmodium falciparum malaria. Factors underlying the lack of association between Sl 2 and McC(b) with severe malaria may involve variation in CR1 expression levels

Defining the baseline transcriptional fingerprint of rabbit hamstring autograft

Anterior cruciate ligament (ACL) injuries are common and of high relevance given their significant effects on patient function, quality of life, and posttraumatic arthritis. To date, investigators have reported on the expression of genes classically associated with tendon and ligament reconstruction, including decorin (DCN) and collagen type 1 (COL1A1 and COL1A2). However, the transcriptional fingerprint for hamstring tendons, one of the most common autografts used for ACLR, remains to be determined. The purpose of this study was to characterize the baseline transcriptional state of semitendinosus autografts in a rabbit model for ACLR and to employ such characterization to guide scientifically-driven target gene selection for future analyses. Next generation RNA sequencing was performed on whole semitendinosus autografts from four New Zealand White rabbits (mean age: 193 ± 0 days, mean weight: 2.78 kg ± 0.15 kg) and subsequently analyzed using gene enrichment and protein-protein interaction network analysis. Decorin, Secreted Protein Acidic and Cysteine Rich (SPARC), Collagen type 1, and Proline and Arginine Rich End Leucine Rich Repeat Protein (PRELP) and were determined to be the highest expressed genes with tendon-associated ontology. These results strengthen the association between genes such as DCN, COL1A1, and COL1A2 and tendon tissues as well as provide the novel addition of further high-expression, tendon characteristic genes such as SPARC and PRELP to provide guidance as to which molecules serve as high-signal candidates for future ACL research. In addition, this paper provides open-access to the expression fingerprint of hamstring autograft for ACLR in New Zealand White rabbits, thus providing a readily-accessible collaborative reference, in alignment with ethical animal research principles

Loss of histone methyltransferase Ezh2 stimulates an osteogenic transcriptional program in chondrocytes but does not affectcartilage development

Ezh2 is a histone methyltransferase that suppresses osteoblast maturation and skeletal development. We evaluated the roleof Ezh2 in chondrocyte lineage differentiation and endochondral ossification. Ezh2 was genetically inactivated in the mesenchymal, osteoblastic, and chondrocytic lineages in mice using the Prrx1-Cre,Osx1-Cre, and Col2a1-Cre drivers, respectively. Wild-type and conditional knockout mice were phenotypically assessed by grossmorphology, histology, and micro-CT imaging. Ezh2-deficient chondrocytes in micromass culture models were evaluated usingRNA-sequencing, histologic evaluation, and western blotting. Aged mice with Ezh2 deficiency were also evaluated for prematuredevelopment of osteoarthritis using radiographic analysis. Ezh2 deficiency in murine chondrocytes reduced bone density at 4 weeks of age, although caused no other gross developmentaleffects. Knockdown of Ezh2 in chondrocyte micromass cultures resulted in a global reduction in trimethylation of histone 3lysine 27 (H3K27me3) and altered differentiation in vitro. RNA-seq analysis revealed enrichment of an osteogenic gene expressionprofile in Ezh2 deficient chondrocytes. Joint development proceeded normally in the absence of Ezh2 in chondrocytes withoutinducing excessive hypertrophy or premature osteoarthritis in vivo. In summary, loss of Ezh2 reduced H3K27me3 levels, increased expression of osteogenic genes in chondrocytes, and resulted ina transient post-natal bone phenotype. Remarkably, Ezh2 activity is dispensable for normal chondrocyte maturation and endochondralossification in vivo, even though it appears to have a critical role during early stages of mesenchymal lineage-commitment

Does Anterior Cruciate Ligament Reconstruction Protect the Meniscus and Its Repair?: A Systematic Review

Background: Anterior cruciate ligament (ACL) tear and meniscal injury often co-occur. The protective effect of early ACL reconstruction (ACLR) on meniscal injury and its repair is not clear. Critical literature review can support or change clinical strategies and identify gaps in the available evidence. Purpose: To assess the protective effect of ACLR on the meniscus and provide clinical guidelines for managing ACL tears and subsequent meniscal injury. We aimed to answer the following questions: (1) Does ACLR protect the meniscus from subsequent injury? (2) Does early ACLR reduce secondary meniscal injury compared with delayed ACLR? (3) Does ACLR protect the repaired meniscus? Study Design: Systematic review; Level of evidence, 4. Methods: A systematic review was performed through use of MEDLINE and Embase electronic databases according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Search terms included ACL, reconstruction, and meniscus. Studies describing primary ACLR and nonoperative treatment in adult patients were included, as well as studies indicating timing of ACLR. The included articles were assessed individually for risk of bias through use of the modified Cochrane Risk of Bias and MINORS (Methodological Index for Nonrandomized Studies) tools. Results: One level 2 randomized controlled trial and several level 3 and 4 studies indicated a protective effect of ACLR on meniscal injury compared with nonoperative treatment. There was weak (level 3) evidence of the protective effect of early ACLR on the meniscus. Meniscal repair failure was less frequent in patients with ACL reconstruction than in patients with ACL deficiency (level 4). Conclusion: The evidence collected in this review suggests a protective effect of ACLR for subsequent meniscal injury (level 2 evidence). ACLR should be performed within 3 months of injury (level 3 evidence). Meniscal injury requiring surgical repair in the ACL-deficient knee should be treated with repair accompanied by ACLR (level 3 evidence). The paucity of level 2 studies prevents the formation of guidelines based on level 1 evidence. There is a strong clinical need for randomized or prospective trials to provide guidelines on timing of ACLR and meniscal repair

The regenerative effect of different growth factors and platelet lysate on meniscus cells and mesenchymal stromal cells and proof-of-concept with a functionalized meniscus implant

Meniscus regeneration could be enhanced by targeting meniscus cells and mesenchymal stromal cells (MSCs) with the right growth factors. Combining these growth factors with the Collagen Meniscus Implant (CMI®) could accelerate cell ingrowth and tissue formation in the implant and thereby improve clinical outcomes. Using a transwell migration assay and a micro-wound assay, the effect of insulin-like growth factor-1, platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), transforming growth factor beta 1 (TGF-β1), fibroblast growth factor, and platelet lysate (PL) on migration and proliferation of meniscus cells and MSCs was assessed. The formation of extracellular matrix under influence of the above-mentioned growth factors was assessed after 28 days of culture of both MSCs and meniscus cells. As a proof of concept, the CMI® was functionalized with a VEGF binding peptide and coated with platelet-rich plasma (PRP) for clinical application. Our results demonstrate that PDGF, TGF-β1, and PL stimulate migration, proliferation, and/or extracellular matrix production of meniscus cells and MSCs. Additionally, the CMI® was successfully functionalized with a VEGF binding peptide and PRP which increased migration of meniscus cell and MSC into the implant. This study demonstrates proof of concept of functionalizing the CMI® with growth factor binding peptides. A CMI® functionalized with the right growth factors holds great potential for meniscus replacement after partial meniscectomy

Determining utility values in patients with anterior cruciate ligament tears using clinical scoring systems

BACKGROUND: Several instruments and clinical scoring systems have been established to evaluate patients with ligamentous knee injuries. A comparison of individual articles in the literature is challenging, not only because of heterogeneity in methodology, but also due to the variety of the scoring systems used to document clinical outcomes. There is limited information about the correlation between used scores and quality of life with no information being available on the impact of each score on the utility values. The aim of this study was to compare the most commonly used scores for evaluating patients with anterior cruciate ligament (ACL) injuries, and to establish corresponding utility values. These values will be used for the interpretation and comparison of outcome results in the currently available literature for different treatment options. METHODS: Four hypothetical vignettes were defined, based on different levels of activities after rupture of the ACL to simulate typical situations seen in daily practice. A questionnaire, including the Health Utility Index (HUI) for utility values, the IKDC subjective score, the Lysholm and the Tegner score, was created and 25 orthopedic surgeons were asked to fill the questionnaire for each hypothetical patient as proxies for all patients they had treated and who would fit in that hypothetical vignette. RESULTS: The utility value as an indicator for quality of life increased with the level of activity. Having discomforts already during normal activities of daily living was rated with a mean utility value of 0.37 ± 0.19, half of that of a situation where mild sport activity was possible without discomfort (0.78 ± 0.11). All investigated scores were able to distinguish clearly (p < 0.05) between the hypothetical vignettes. However, the utility values correlated best with the IKDC subjective score (r = 0.86, p < 0.001) followed by the Lysholm score (r = 0.77, p < 0.001) and the Tegner score (r = 0.77, p < 0.001). CONCLUSIONS: Here we report the correlation between the most commonly used scores for the assessment of patients with a ruptured ACL and utility values as an indicator of quality of life. Assumptions were based on expert opinions to provide a possible transformation algorithm. The IKDC subjective knee score showed the highest correlation to the quality of life (i.e. HUI) in patients with a ruptured ACL. Confirmation of our results is needed by systematic inclusion of a measurement instrument for utility values in future clinical studies beside the already used clinical knee scoring systems

An Expert Consensus Statement on the Management of Large Chondral and Osteochondral Defects in the Patellofemoral Joint

© The Author(s) 2020. Background: Cartilage lesions of the patellofemoral joint constitute a frequent abnormality. Patellofemoral conditions are challenging to treat because of complex biomechanics and morphology. Purpose: To develop a consensus statement on the functional anatomy, indications, donor graft considerations, surgical treatment, and rehabilitation for the management of large chondral and osteochondral defects in the patellofemoral joint using a modified Delphi technique. Study Design: Consensus statement. Methods: A working group of 4 persons generated a list of statements related to the functional anatomy, indications, donor graft considerations, surgical treatment, and rehabilitation for the management of large chondral and osteochondral defects in the patellofemoral joint to form the basis of an initial survey for rating by a group of experts. The Metrics of Osteochondral Allografts (MOCA) expert group (composed of 28 high-volume cartilage experts) was surveyed on 3 occasions to establish a consensus on the statements. In addition to assessing agreement for each included statement, experts were invited to propose additional statements for inclusion or to suggest modifications of existing statements with each round. Predefined criteria were used to refine statement lists after each survey round. Statements reaching a consensus in round 3 were included within the final consensus document. Results: A total of 28 experts (100% response rate) completed 3 rounds of surveys. After 3 rounds, 36 statements achieved a consensus, with over 75% agreement and less than 20% disagreement. A consensus was reached in 100.00% of the statements relating to functional anatomy of the patellofemoral joint, 88.24% relating to surgical indications, 100.00% relating to surgical technical aspects, and 100.00% relating to rehabilitation, with an overall consensus of 95.5%. Conclusion: This study established a strong expert consensus document relating to the functional anatomy, surgical indications, donor graft considerations for osteochondral allografts, surgical technical aspects, and rehabilitation concepts for the management of large chondral and osteochondral defects in the patellofemoral joint. Further research is required to clinically validate the established consensus statements and better understand the precise indications for surgery as well as which techniques and graft processing/preparation methods should be used based on patient- and lesion-specific factors