Mid- to Long-Term Survival of Geriatric Patients with Primary Septic Arthritis of the Shoulder: A Retrospective Study over a Period of 20 Years.

Septic arthritis of the shoulder is an urgent medical emergency that often occurs in elderly patients and is associated with high morbidity and mortality. Retrospectively, 56 patients aged ≥60 years, treated for primary septic monoarthritis of the shoulder at a maximum care hospital between 1 July 2001, and 30 July 2022, were included in this study. The primary aim of the study was analyzing survival rates and different bacteria in these patients. For statistical analysis, Kaplan-Meier curves were used for survival probability and the log-rank test was used to compare a survival probability of 5 years. The mean patient age was 78.7 years and a mean follow-up time of 3011.8 days. The mean survival of the entire study population was 920.3 days or 2.5 years. Significantly impaired 5-year survival was found only with increasing age and higher American Society of Anesthesiologists (ASA) physical status (PS) classification scores. Eight different types of bacteria were detected in the synovial fluid cultures. A total of 42 of 48 overall pathogens was Gram-positive and 6 were Gram-negative bacteria. Staphylococcus aureus was identified as the most frequent variant. We conclude that the mean survival is significantly shortened within the first 5 years with increasing age and ASA PS classification.

MRI Characteristics and Alterations in Patellar Height in Patients with Patellar Tendinopathy-A Retrospective Study.

(1) Background: Patellar tendinopathy (PT) is an overuse condition of the knee extensor mechanism characterized by ventral knee pain at the lower pole of the patella and limited functionality. (2) Methods: In this retrospective study, a group of patients with PT (n = 41) was compared with a control group (n = 50) in terms of patient-related data and magnetic resonance imaging (MRI) characteristics. (3) Results: Patellar height was higher in the PT patient group and there was a significant difference in Caton-Deschamps index (CD) compared to the control group (p = 0.021). Patients with PT showed a lower patella-patellar tendon angle (PPTA) (p = 0.011). The patellar tendon thickness (PTT) in the proximal (PTTprox), middle (PTTmid) and distal (PTTdistal) part of the tendon was significantly thickened (p < 0.001). Increased signal intensity in MRI was detected in symptomatic tendons over 6 months compared to a duration of less than 6 months (p = 0.025). A significant relationship between the PTTprox and an increased signal intensity was observed (p < 0.001). (4) Conclusions: Patients with PT showed a significant difference in the patellar height and PPTA. With persistence of symptoms over 6 months, MRI seems suitable to detect the morphologic tendon changes and further identify patients suitable for surgical procedures.

Complement Regulation in Immortalized Fibroblast-like Synoviocytes and Primary Human Endothelial Cells in Response to SARS-CoV-2 Nucleocapsid Protein and Pro-Inflammatory Cytokine TNFα.

Background: Case reports are available showing that patients develop symptoms of acute arthritis during or after recovery from SARS-CoV-2 infection. Since the interrelation is still unknown, our aim was to study the impact of the SARS-CoV-2 nucleocapsid protein (NP) on human fibroblast-like synoviocytes and human endothelial cells (hEC) in terms of complement and cytokine regulation. Methods: Non-arthritic (K4IM) synoviocyte, arthritic (HSE) synoviocyte cell lines and primary hEC were stimulated with recombinant NP and/or TNFα. Analyses of cell viability, proliferation, gene and protein expression of cytokines and complement factors were performed. Results: NP suppressed significantly the vitality of hEC and proliferation of HSE. NP alone did not induce any significant changes in the examined gene expressions. However, NP combined with TNFα induced significantly higher TNFα in HSE and K4IM as well as higher IL-6 and CD55 gene expression in HSE and suppressed C3aR1 gene expression in hEC. HSE proliferated twice as fast as K4IM, but showed significantly lesser gene expressions of CD46, CD55, CD59 and TNFα with significantly higher IL-6 gene expression. CD35 gene expression was undetectable in K4IM, HSE and hEC. Conclusions: NP might contribute in combination with other inflammatory factors to complement regulation in arthritis.

Complement Proteins C5/C5a, Cathepsin D and Prolactin in Chondrocytes: A Possible Crosstalk in the Pathogenesis of Osteoarthritis.

INTRODUCTION: Both increased activity of the complement system (CS) and the role of the pituitary hormone prolactin (PRL) are implicated in osteoarthritis (OA) pathogenesis. Besides, Cathepsin D (CatD) activity is increased in the context of OA and can exert not only proteolytic but also non-proteolytic effects on cells. For the first time, possible crosstalk between two separate humoral systems: the CS and the PRL hormone systems in chondrocytes are examined together. METHODS: Primary human articular chondrocytes (hAC) were stimulated with complement protein C5 (10 µg /mL), PRL (25 ng/mL), CatD (100 ng/mL), or anaphylatoxin C5a (25 ng/mL) for 24 h or 72 h, while unstimulated cells served as controls. In addition, co-stimulations of C5 or PRL with CatD were carried out under the same conditions. The influence of the stimulants on cell viability, cell proliferation, and metabolic activity of hAC, the chondrosarcoma cell line OUMS-27, and endothelial cells of the human umbilical cord vein (HUVEC) was investigated. Gene expression analysis of C5a receptor (C5aR1), C5, complement regulatory protein CD59, PRL, PRL receptor (PRLR), CatD, and matrix metal-loproteinases (MMP)-13 were performed using real-time PCR. Also, collagen type (Col) I, Col II, C5aR1, CD59, and PRL were detected on protein level using immunofluorescence labeling. RESULTS: The stimulation of the hAC showed no significant impairment of the cell viability. C5, C5a, and PRL induced cell growth in OUMS-27 and HUVEC, but not in chondrocytes. CatD, as well as C5, significantly reduced the gene expression of CatD, C5aR1, C5, and CD59. PRLR gene expression was likewise impaired by C5, C5a, and PRL+CatD stimulation. On the protein level, CatD, as well as C5a, decreased Col II as well as C5aR1 synthesis. CONCLUSIONS: The significant suppression of the C5 gene expression under the influence of PRL+CatD and that of CD59 via PRL+/-CatD and conversely a suppression of the PRLR gene expression via C5 alone or C5a stimulation indicates an interrelation between the two mentioned systems. In addition, CatD and C5, in contrast to PRL, directly mediate possible negative feedback of their own gene expression.

Complement Regulation in Human Tenocytes under the Influence of Anaphylatoxin C5a.

A central part of the complement system, the anaphylatoxin C5a was investigated in this study to learn its effects on tenocytes in respect to understanding the potential expression of other crucial complement factors and pro-inflammatory mediators involved in tendinopathy. Human hamstring tendon-derived tenocytes were treated with recombinant C5a protein in concentrations of 25 ng/mL and 100 ng/mL for 0.5 h (early phase), 4 h (intermediate phase), and 24 h (late phase). Tenocytes survival was assessed after 24 h stimulation by live-dead assay. The gene expression of complement-related factors C5aR, the complement regulatory proteins (CRPs) CD46, CD55, CD59, and of the pro-inflammatory cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-6 was monitored using qPCR. Tenocytes were immunolabeled for C5aR and CD55 proteins. TNFα production was monitored by ELISA. Tenocyte survival was not impaired through C5a stimulation. Interestingly, the gene expression of C5aR and that of the CRPs CD46 and CD59 was significantly reduced in the intermediate and late phase, and that of TNFα only in an early phase, compared to the control group. ELISA analysis indicated a concomitant not significant trend of impaired TNFα protein synthesis at 4 h. However, there was also an early significant induction of CD55 and CD59 mediated by 25 ng/mL anaphylatoxin C5a. Hence, exposure of tenocytes to C5a obviously evokes a time and concentration-dependent response in their expression of complement and pro-inflammatory factors. C5a, released in damaged tendons, might directly contribute to tenocyte activation and thereby be involved in tendon healing and tendinopathy.

Complement regulation in tenocytes under the influence of leukocytes in an indirect co-culture model.

INTRODUCTION: The present in vitro study was undertaken to learn about the effects of leukocytes on tenocytes in respect to complement regulation simulating an inflammatory scenario of the traumatized tissue. METHODS: Human hamstring tendon-derived tenocyte monolayers were co-cultured indirectly with human leukocytes (either Peripheral Blood Mononuclear Cells [PBMCs] or neutrophils) using a transwell system with/without (+ /wo) 10 ng/ml tumor necrosis factor α (TNFα) for 4 and 24 h. Tenocyte and leukocyte cell survival was assessed by live-dead assay. Tenocyte gene expression of TNFα, the anaphylatoxin receptor C5aR and the cytoprotective complement regulatory proteins (CRP) CD46, CD55 and CD59 was monitored using qPCR. TNFα was detected in the culture supernatants using ELISA. RESULTS: C5aR gene expression was significantly induced by TNFα after 4 h, but impaired in the presence of leukocytes + TNFα after 24 h. At 4 h, PBMCs activated by TNFα induced the CRP CD46 gene expression. However, CD55 was significantly suppressed after 24 h by neutrophils + /woTNFα. Leukocytes activated by TNFα decreased also significantly the gene expression of the more downstream acting CRP CD59 after 4 h. TNFα gene expression and ELISA analysis revealed an amplified TNFα expression/release in tenocyte co-cultures with PBMC + /woTNFα, probably contributing to complement regulation. CONCLUSION: TNFα might represent a crucial soluble mediator exerting diverse time-dependent effects on tenocyte complement regulation.

Anatomical feature of knee joint in Aachen minipig as a novel miniature pig line for experimental research in orthopaedics.

BACKGROUND: The pig is a commonly used large animal model, since pigs share anatomical and physiological similarities with humans. In contrast to other experimental pig lines the Aachen minipig, as a robust novel minipig does not require housing with any barrier. To estimate transferability of results to human conditions, pig lines should be thoroughly characterized. PURPOSE: Therefore, we analyzed the anatomical pecularities of the knee joint of the novel "Aachen minipig" line raised for experimental conditions. METHODS: Eight knee joints of four adult Aachen minipigs were dissected measuring the dimensions of typical landmarks using a digital caliper. Hybrid pig and human knee joints served as controls. Cartilage of the Aachen minipig (trochlear groove, femoral condyles, menisci) were assessed histologically. RESULTS: The Aachen minipig shared its knee joint anatomy with the hybrid pig. In comparison to humans, peculiarities of the pig were demonstrated in the Aachen minipig: the lateral meniscus and the lateral tibial joint surface were significantly longer than the medial counterparts. The fibular head was covered by fibrocartilage and completely integrated into the lateral lower joint surface. The cartilage at the joint areas usually used for cartilage repair studies was in average 0.66±0.04mm thick. The porcine anterior cruciate ligament (ACL) attached with two bundles at the anterior tibial plateau separated from each other by the lateral anterior meniscotibial ligament. Aachen minipig articular and meniscal cartilage presented the typical histoarchitecture. CONCLUSIONS: The Aachen minipig reflects porcine anatomical peculiarities, which should be considered, especially for meniscus and ACL reconstruction.

IL-10 Could Play a Role in the Interrelation between Diabetes Mellitus and Osteoarthritis.

The association between osteoarthritis (OA), obesity and metabolic syndrome suggests an interrelation between OA and diabetes mellitus (DM). Little is known about the role of anti-inflammatory cytokine interleukin (IL)-10 in the interrelation between OA and DM. Hence, the effects of IL-10 under hyperglycemia (HG) and hyperinsulinemia (HI) in human articular chondrocytes (hAC) and chondrosarcoma cell line Okayama University Medical School (OUMS)-27 were examined. HAC and OUMS-27, cultured in normoglycemic (NG) and HG conditions were stimulated with insulin and/or IL-10. Cell survival, metabolic activity, proliferation and extracellular matrix (ECM) synthesis were immunocytochemically examined. No significant differences in vitality of hAC neither in pure NG (NGw/o) nor HG (HGw/o) conditions were found. Applying HI and/or IL-10 in both conditions reduced significantly the vitality of hAC but not of OUMS-27. HG impaired significantly hAC metabolism. When combined with HI + IL-10 or IL-10 alone it decreased also significantly hAC proliferation compared to NGw/o. In OUMS-27 it induced only a trend of impaired proliferation compared to NGw/o. hAC but not OUMS-27 reduced significantly their collagen type (col) I, SOX9 and proteoglycan (PG) synthesis in HG combined with HI +/- IL-10 compared to NGw/o. IL-10 could not moderate HI and HG effects. In contrast to hAC OUMS-27 showed limited sensitivity as DM model.

A rare variation of intrinsic and extrinsic hand muscles represented by a bi-ventered first lumbrical extending into the carpal tunnel combined with bilateral fifth superficial flexor digitorum tendon regression.

A rare unilateral variation of the first left lumbrical muscle was discovered in a female Caucasian cadaver dissected during a first year anatomy course at the Paracelsus Medical University - Nuremberg, Germany. The muscle possessed two venters with the first originating near the medial epicondyle of the humerus together with the intramuscular tendon of the superficial flexor digitorum tendon, and the second presenting as a regular first lumbrical muscle with radial palmar origin from first tendon of the deep flexor digitorum muscle. Both muscle bellies were connected by a 1.42mm thick tendon that passed beneath the median nerve and ran through the carpal tunnel. The second belly was enlarged and entered the distal part of the carpal tunnel. Interestingly, the donor revealed further rare variations such as a bilateral regression of the fifth superficial flexor tendons to an obviously non functional connective tissue strand, lack of both palmaris longus muscles, a discoid lateral meniscus in the left knee, and reduction of the plantaris muscle to a fascia-like structure on the right leg. Lumbrical muscle variations extending into the carpal tunnel, especially those associated with auxiliary tendons, have significant clinical relevance due to their association with carpal tunnel syndrome.

Osteoarthritis and the Complement Cascade.

Accumulating evidence demonstrates that complement activation is involved in the pathogenesis of osteoarthritis (OA). However, the intimate complement regulation and cross talk with other signaling pathways in joint-associated tissues remain incompletely understood. Recent insights are summarized and discussed here, to put together a more comprehensive picture of complement involvement in OA pathogenesis. Complement is regulated by several catabolic and inflammatory mediators playing a key role in OA. It seems to be involved in many processes observed during OA development and progression, such as extracellular cartilage matrix (ECM) degradation, chondrocyte and synoviocyte inflammatory responses, cell lysis, synovitis, disbalanced bone remodeling, osteophyte formation, and stem cell recruitment, as well as cartilage angiogenesis. In reverse, complement can be activated by various ECM components and their cleavage products, which are released during OA-associated cartilage degradation. There are, however, some other cartilage ECM components that can inhibit complement, underlining the diverse effects of ECM on the complement activation. It is hypothesized that complement might also be directly activated by mechanical stress, thereby contributing to OA. The question arises whether keeping the complement activation in balance could represent a future therapeutic strategy in OA treatment and in the prevention of its progression.

The interrelation of osteoarthritis and diabetes mellitus: considering the potential role of interleukin-10 and in vitro models for further analysis.

INTRODUCTION: Today, not only the existence of an interrelation between obesity/adipositas and osteoarthritis (OA) but also the association of OA and diabetes mellitus (DM) are widely recognized. Nevertheless, shared influence factors facilitating OA development in DM patients still remain speculative up until now. To supplement the analysis of clinical data, appropriate in vitro models could help to identify shared pathogenetic pathways. Informative in vitro studies could later be complemented by in vivo data obtained from suitable animal models. MATERIALS AND METHODS: Therefore, this detailed review of available literature was undertaken to discuss and compare the results of currently published in vitro studies focusing on the interrelation between OA, the metabolic syndrome and DM and to propose models to further study the molecular pathways. RESULTS: The survey of literature presented here supports the hypothesis that the pathogenesis of OA in DM is based on imbalanced molecular pathways with a putative crucial role of antiinflammatory cytokines such as IL-10. CONCLUSION: Future development of versatile micro-scaled in vitro models such as combining DM and OA on chip could allow the identification of common pathogenetic pathways and might help to develop novel therapeutic strategies.

Complement gene expression is regulated by pro-inflammatory cytokines and the anaphylatoxin C3a in human tenocytes.

Interplay between complement factors, regulatory proteins, anaphylatoxins and cytokines could be involved in tendon healing and scar formation. The expression and regulation of complement factors by cytokines or anaphylatoxins are completely unclear in tendon. Hence, the gene expression of the anaphylatoxin receptors C3aR, C5aR and cytoprotective complement regulatory proteins (CRPs) was analysed in human tendon, cultured primary tenocytes and to directly compare the general expression level, additionally in human leukocytes. Time-dependent regulation of complement by cytokines and the anaphylatoxin C3a was assessed in cultured tenocytes. Gene expression of the anaphylatoxin receptors C3aR, C5aR and the CRPs CD46, CD55 and CD59 was detected in tendon, cultured tenocytes and leukocytes, whereas CD35 could only be found in tendon and leukocytes. Compared with cultured tenocytes, complement expression was higher in tendon and compared with leukocytes C3aR, C5aR, CD35 and CD55, but not CD46 and CD59 gene expression levels were lower in tendon. C3aR mRNA was up-regulated by both TNFα and C3a in cultured tenocytes in a time-dependent manner whereby C5aR gene expression was only induced by C3a. IL-6 or C3a impaired the CRP gene expression. C3a stimulation lead to an up-regulation of TNFα and IL-1ß mRNA in tenocytes. Degenerated tendons revealed an increased C5aR and a reduced CD55 expression. The expression profile of the investigated complement components in tendon and cultured tenocytes clearly differed from that of leukocytes. Tenocytes respond to the complement split fragment C3a with CRP suppression and enhanced pro-inflammatory cytokine gene expression suggesting their sensitivity to complement activation.