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The present meta-analysis investigated the efficacy of intra-articular hyaluronic acid (HA) injections for knee osteoarthritis. The outcomes of interest were the visual analogue scale (VAS) and Western Ontario McMaster Osteo-Arthritis Index (WOMAC) scores. This study was conducted according to the 2020 PRISMA statement. All the randomised controlled trials (RCTs) comparing the efficacy of intra-articular HA injections versus placebo injections for knee osteoarthritis were accessed in September 2024. Data from 3851 patients were collected. In total, 64% (2467 of 3851 patients) were women, and the mean age of the patients was 63.5 ± 4.9 years. At baseline, good comparability was found for the mean age, BMI, percentage of women, and patient-reported outcome measures (PROMs). Studies which reported data from two to four weeks of follow-up evidenced a lower value of the subscales pain ( p < 0.0001) and stiffness ( p = 0.01) of the WOMAC score. No difference was observed in VAS at rest ( p = 0.4), VAS at exercise ( p = 0.1), and subscale function ( p = 0.4) of the WOMAC score. Studies which reported data from five to eight weeks of follow-up evidenced lower VAS at rest in favour of the HA group ( p = 0.01). No difference in the other PROMs of interest was observed: VAS at exercise ( p = 0.1), and the subscales pain ( p = 0.3), function ( p = 0.4), and stiffness ( p = 0.4) of the WOMAC score. The current level I of evidence suggests that intra-articular HA injections in the knee might reduce pain in the short term.

The present Bayesian network meta-analysis compared different types of polyethylene liners in total hip arthroplasty (THA) in terms of wear penetration (mm/year) and rate of revision. The type of liners compared were the crosslinked ultra-high molecular weight polyethylene (CPE/UHMWPE), Vitamin E infused highly cross-linked polyethylene (HXLPE-VEPE), modified cross-linked polyethylene (MXLPE), highly cross-linked polyethylene (HXLPE), Cross-linked polyethylene (XLPE). This study was conducted according to the PRISMA extension statement for reporting systematic reviews incorporating network meta-analyses of healthcare interventions. In June 2024, PubMed, Scopus, Embase, Google Scholar, and Cochrane databases were accessed. A time constraint was set from January 2000. All investigations which compared two or more types of polyethylene liners for THA were accessed. Only studies that clearly stated the nature of the liner were included. Data from 60 studies (37,352 THAs) were collected. 56% of patients were women. The mean age of patients was 60.0 ± 6.6 years, the mean BMI was 27.5 ± 2.0 kg/m 2 . The mean length of follow-up was 81.6 ± 44.4 months. Comparability was found at baseline between groups. XLPE and HXLPE liners in THA are associated with the lowest wear penetration (mm/year) and the lowest revision rate at approximately 7 years of follow-up., (© 2024. The Author(s).)

Rationale and Objectives: There are currently no studies investigating the in vivo stiffness of the most commonly used autografts for anterior cruciate ligament reconstruction (ACLR) using Shear wave elastography (SWE). We hypothesize that there are differences regarding the elastic properties between the three tendons commonly used for ACLR and that they are influenced by patient-related factors., Materials and Methods: 80 healthy subjects (25 females, 55 males, age: 25.33 ± 4.76 years, BMI: 23.76 ± 3.14 kg/m 2 , 40 semiprofessional athletes, athlete group [AG], age: 25.51 [19-29]; 40 healthy controls, control group [CG], age: 25.50 [20-29]) were recruited as participants. In addition to patient reported outcome scores, every participant underwent a standardized multimodal ultrasound protocol consisting of B-mode-ultrasound (B-US), Color Doppler-ultrasound (CD-US) and a SWE examination of the bilateral quadriceps tendon (QT), patellar tendon (PT) and semitendinosus tendon (ST)., Results: The highest shear wave velocity (SWV) were observed in ST (4.88 (4.35-5.52) m/s, ST vs QT, p = 0.005; ST vs PT, p < 0.001) followed by QT (4.61 (4.13-5.26) m/s, QT vs PT, p < 0.001) and PT (3.73 (3.30-4.68) m/s). Median QT, PT and ST stiffness was significantly higher in AG compared to CG. Male subjects tend to have stiffer QT and PT than female subjects. Positive correlation with SWV was obtained for age and activity level., Conclusion: There are significant differences regarding in vivo tendon stiffness between the most frequently used autograft tendon options for ACLR. The quantitative information obtained by SWE could be of particular interest for graft choice for ACLR., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Objectives: CT and MRI scans of the shoulder can lead to the identification of incidental findings (IF), which can have a major impact on the further treatment of the patient. The aim of this retrospective study was to record the prevalence of IF, incidentalomas (IT) and malignant IT for CT and MRI examinations of the shoulder and to investigate the effect of patient characteristics on the statistical occurrence of IF, IT and malignant IT., Materials and Methods: A total of 903 shoulder examinations (415 CT, 488 MRI) were retrospectively analyzed for the presence of IF, subsequently categorized (harmless IF, IT requiring clarification, malignant IT) and analyzed regarding patient characteristics. The statistical analysis was carried out using independent t- and chi-square tests. A significance level of p < 0.05 was set., Results: Among the 903 patients evaluated (436 female, 467 male), 153 (16.9%) patients experienced IF (harmless IF: 101 (11.2%) patients, IT: 94 (10.4%), malignant IT: 4 (0.4%). The average age of the patients without IF and IT was significantly lower compared to the patients with IF and IT (p < 0.001). While IF occurred in 31.1% of the CT, IF was only detected in 4.9% of the MRI (p < 0.001)., Conclusion: IF have a high prevalence (16.9%), especially in CT examinations of the shoulder, which increases with age. The exact detection and initiation of appropriate therapy is of great clinical importance, as early detection of life-threatening diseases enables more effective treatment and a potential gain in health and lifespan., Competing Interests: None., (© 2024 The Authors.)

This systematic review updates the currently available evidence on medial patella-femoral ligament (MPFL) reconstruction using allografts. The outcomes were measured with patient-reported outcome measures (PROMs), redislocation and complication rates. This study was performed according to the 2020 PRISMA guidelines using the PubMed, Scopus, Web of Science databases, accessed in February 2023. Studies examining the clinical outcomes of MPFL reconstruction with allografts in adolescents and children with recurrent patellofemoral instability (PFI) were included. Data from three trials, including 113 surgical procedures in 121 children, were retrieved. 40% (48/121) of the included patients were girls. The mean age of the patients was 14.7 ± 0.8 years, and the mean follow-up length was 38.1 ± 16.5 months. With MPFL allograft reconstruction, the Kujala score improved by 14.7% ( p < 0.0001) and the IKDC by 38.8% ( p < 0.0001). The rate of dislocations was 5% (6 of 121), reoperation for instability was 11% (13 of 121), and subluxation was 2% (1 of 47). Conclusion: These results encourage the use of allografts for MPFL reconstruction in adolescent patients with recurrent patellofemoral instability. Though patellofemoral instability is common in clinical practice, the current literature lacks clinical evidence on allograft MPFL reconstruction. Additional high-quality investigations are required to properly establish the long-term advantages of allograft MPFL and its complication rate.

Objective: The microscopic review of hematoxylin-eosin-stained images of focal cortical dysplasia type IIb and cortical tuber of tuberous sclerosis complex remains challenging. Both entities are distinct subtypes of human malformations of cortical development that share histopathological features consisting of neuronal dyslamination with dysmorphic neurons and balloon cells. We trained a convolutional neural network (CNN) to classify both entities and visualize the results. Additionally, we propose a new Web-based deep learning application as proof of concept of how deep learning could enter the pathologic routine., Methods: A digital processing pipeline was developed for a series of 56 cases of focal cortical dysplasia type IIb and cortical tuber of tuberous sclerosis complex to obtain 4000 regions of interest and 200 000 subsamples with different zoom and rotation angles to train a neural network. Guided gradient-weighted class activation maps (Guided Grad-CAMs) were generated to visualize morphological features used by the CNN to distinguish both entities., Results: Our best-performing network achieved 91% accuracy and 0.88 area under the receiver operating characteristic curve at the tile level for an unseen test set. Novel histopathologic patterns were found through the visualized Guided Grad-CAMs. These patterns were assembled into a classification score to augment decision-making in routine histopathology workup. This score was successfully validated by 11 expert neuropathologists and 12 nonexperts, boosting nonexperts to expert level performance., Significance: Our newly developed Web application combines the visualization of whole slide images with the possibility of deep learning-aided classification between focal cortical dysplasia IIb and tuberous sclerosis complex. This approach will help to introduce deep learning applications and visualization for the histopathologic diagnosis of rare and difficult-to-classify brain lesions., (© 2020 The Authors. Epilepsia published by Wiley Periodicals, Inc. on behalf of International League Against Epilepsy.)

CD4(+)CD25(+) regulatory T cells (Tregs) represent a specialized subpopulation of T cells, which are essential for maintaining peripheral tolerance and preventing autoimmunity. The immunomodulatory effects of Tregs depend on their activation status. Here we show that, in contrast to conventional anti-CD4 monoclonal antibodies (mAbs), the humanized CD4-specific monoclonal antibody tregalizumab (BT-061) is able to selectively activate the suppressive properties of Tregs in vitro. BT-061 activates Tregs by binding to CD4 and activation of signaling downstream pathways. The specific functionality of BT-061 may be explained by the recognition of a unique, conformational epitope on domain 2 of the CD4 molecule that is not recognized by other anti-CD4 mAbs. We found that, due to this special epitope binding, BT-061 induces a unique phosphorylation of T-cell receptor complex-associated signaling molecules. This is sufficient to activate the function of Tregs without activating effector T cells. Furthermore, BT-061 does not induce the release of pro-inflammatory cytokines. These results demonstrate that BT-061 stimulation via the CD4 receptor is able to induce T-cell receptor-independent activation of Tregs. Selective activation of Tregs via CD4 is a promising approach for the treatment of autoimmune diseases where insufficient Treg activity has been described. Clinical investigation of this new approach is currently ongoing.

Anti-EGFR monoclonal antibodies (mAb) like Cetuximab are commonly used for treatment of EGFR+ solid tumors mainly by exerting their therapeutic effect through inhibition of signal transduction. Additionally, IgG1 is a potent mediator of antibody-dependent cytotoxicity (ADCC). In case of the IgG1, Cetuximab induction of ADCC in vivo is controversially discussed. In our study, we investigated the efficiency of Cetuximab-mediated ADCC in a humanized mouse tumor model in vivo and analyzed the contribution of immunologic processes toward antitumor activity. Therefore, we used immunodeficient NOD/Scid mice transgenic for human MHC class I molecule HLA-A2 and adoptively transferred human HLA-A2+ PBMC after engraftment of human epidermoid cell carcinoma A431. Here, we show that high doses of anti-EGFR mAb induced strong tumor regression independent of the immune system. However, tumor regression by low doses of anti-EGFR mAb treatment was ADCC dependent and mediated by tumor infiltrating CD8+ T effector cells. This novel mechanism of ADCC conducted by CD8+ T effector cells was restricted to IgG1 anti-EGFR mAb, dependent of binding to CD16 on T cells and could be inhibited after EGFR blockade on tumor cells. Furthermore, CD8+ T effector cell-mediated ADCC was enhanced in the presence of IL-15 and strongly improved after glycosylation of anti-EGFR mAb indicating the potential of glycoengineered therapeutic mAb as efficient biologicals in cancer therapy., (© 2014 UICC.)

Background: In humans and mice naturally occurring CD4(+)CD25(+) regulatory T cells (nTregs) are a thymus-derived subset of T cells, crucial for the maintenance of peripheral tolerance by controlling not only potentially autoreactive T cells but virtually all cells of the adaptive and innate immune system. Recent work using Dicer-deficient mice irrevocably demonstrated the importance of miRNAs for nTreg cell-mediated tolerance., Principal Findings: DNA-Microarray analyses of human as well as murine conventional CD4(+) Th cells and nTregs revealed a strong up-regulation of mature miR-155 (microRNA-155) upon activation in both populations. Studying miR-155 expression in FoxP3-deficient scurfy mice and performing FoxP3 ChIP-Seq experiments using activated human T lymphocytes, we show that the expression and maturation of miR-155 seem to be not necessarily regulated by FoxP3. In order to address the functional relevance of elevated miR-155 levels, we transfected miR-155 inhibitors or mature miR-155 RNAs into freshly-isolated human and mouse primary CD4(+) Th cells and nTregs and investigated the resulting phenotype in nTreg suppression assays. Whereas miR-155 inhibition in conventional CD4(+) Th cells strengthened nTreg cell-mediated suppression, overexpression of mature miR-155 rendered these cells unresponsive to nTreg cell-mediated suppression., Conclusion: Investigation of FoxP3 downstream targets, certainly of bound and regulated miRNAs revealed the associated function between the master regulator FoxP3 and miRNAs as regulators itself. miR-155 is shown to be crucially involved in nTreg cell mediated tolerance by regulating the susceptibility of conventional human as well as murine CD4(+) Th cells to nTreg cell-mediated suppression.

Naturally occurring CD4(+)CD25(+) regulatory T cells (Tregs) represent a unique T-cell lineage that is endowed with the ability to actively suppress immune responses. Therefore, approaches to modulate Treg function in vivo could provide ways to enhance or reduce immune responses and lead to novel therapies. Here we show that the CD4 binding human immunodeficiency virus-1 envelope glycoprotein gp120 is a useful and potent tool for functional activation of human Tregs in vitro and in vivo. Gp120 activates human Tregs by binding and signaling through CD4. Upon stimulation with gp120, human Tregs accumulate cyclic adenosine monophosphate (cAMP) in their cytosol. Inhibition of endogeneous cAMP synthesis prevents gp120-mediated Treg activation. Employing a xenogeneic graft versus host disease model that has been shown to be applicable for the functional analysis of human Tregs in vivo, we further show that a single dose of gp120 is sufficient to prevent lethal graft versus host disease and that the tolerizing effect of gp120 is strictly dependent on the presence of human Tregs and their up-regulation of cAMP upon gp120-mediated activation. Our findings demonstrate that stimulation via the CD4 receptor represents a T-cell receptor-independent Treg activating pathway with potential to induce immunologic tolerance in vivo.

CD4(+)CD25(+)Foxp3(+) regulatory T cells (CD25(+) Treg cells) direct the maintenance of immunological self-tolerance by active suppression of autoaggressive T-cell populations. However, the molecules mediating the anergic state and regulatory function of CD25(+) Treg cells are still elusive. Using differential proteomics, we identified galectin-10, a member of the lectin family, as constitutively expressed in human CD25(+) Treg cells, while they are nearly absent in resting and activated CD4(+) T cells. These data were confirmed on the mRNA and protein levels. Single-cell staining and flow cytometry showed a strictly intracellular expression of galectin-10 in CD25(+) Treg cells. Specific inhibition of galectin-10 restored the proliferative capacity of CD25(+) Treg cells and abrogated their suppressive function. Notably, first identified here as expressed in human T lymphocytes, galectin-10 is essential for the functional properties of CD25(+) Treg cells.

Naturally occurring regulatory T cells (T reg cells) are a thymus-derived subset of T cells, which are crucial for the maintenance of peripheral tolerance by controlling potentially autoreactive T cells. However, the underlying molecular mechanisms of this strictly cell contact-dependent process are still elusive. Here we show that naturally occurring T reg cells harbor high levels of cyclic adenosine monophosphate (cAMP). This second messenger is known to be a potent inhibitor of proliferation and interleukin 2 synthesis in T cells. Upon coactivation with naturally occurring T reg cells the cAMP content of responder T cells is also strongly increased. Furthermore, we demonstrate that naturally occurring T reg cells and conventional T cells communicate via cell contact-dependent gap junction formation. The suppressive activity of naturally occurring T reg cells is abolished by a cAMP antagonist as well as by a gap junction inhibitor, which blocks the cell contact-dependent transfer of cAMP to responder T cells. Accordingly, our results suggest that cAMP is crucial for naturally occurring T reg cell-mediated suppression and traverses membranes via gap junctions. Hence, naturally occurring T reg cells unexpectedly may control the immune regulatory network by a well-known mechanism based on the intercellular transport of cAMP via gap junctions.

Naturally occurring CD4(+)CD25(+)FoxP3(+) regulatory T cells (CD25(+) Tregs) constitute a specialized population of T cells that is essential for the maintenance of peripheral self-tolerance. The immune regulatory function of CD25(+) Tregs depends upon their activation. We found that anti-CD4 antibodies activate the suppressive function of human CD25(+) Tregs in a dose-dependent manner. We demonstrate that CD4-activated CD25(+) Tregs suppress the proliferation of CD4(+) and CD8(+) T cells, their IL-2 and IFN-gamma production as well as the capacity of CD8(+) T cells to re-express CD25. By contrast, anti-CD4 stimulation did not induce suppressive activity in conventional CD4(+) T cells. These results identify CD4 as a trigger for the suppressive function of CD25(+) Tregs and suggest a possible CD4-mediated exploitation of these cells.

The induction of effective antigen-specific T-cell immunity to pathogens without the initiation of autoimmunity has evolved as a sophisticated and highly balanced immunoregulatory mechanism. This mechanism assures the generation of antigen-specific effector cells as well as the induction and maintenance of antigen-specific tolerance to self-structures of the body. As professional antigen-presenting cells of the immune system, dendritic cells (DC) are ideally positioned throughout the entire body and equipped with a unique capability to transport antigens from the periphery to lymphoid tissues. There is growing evidence that DC, besides their well-known immunostimulatory properties, also induce and regulate T-cell tolerance in the periphery. This regulatory function of DC is strictly dependent on their different stages of maturation and activation. Additionally, immunosuppressive agents and cytokines further influence the functions of maturing DC. The regulatory properties of DC include induction of T-cell anergy, apoptosis, and the generation of T-cells with regulatory capacities. This brief review summarizes the current knowledge about the immunoregulatory role of DC as guardians for the induction of T-cell immunity and tolerance.

Down-regulation of autoreactive T cell responses in vivo includes cell-contact-dependent as well as contact-independent mechanisms. Infectious tolerance is a contact-dependent mechanism used by naturally occurring CD25(+) T regulatory cells (Tregs) to confer suppressive activity upon conventional CD4(+) T cells thereby generating secondary T helper suppressor cells(Th(sup)), which inhibit T cell activation via soluble mediators. Here, we describe two distinct subsets of human Tregs, characterized by expression of either the alpha(4)beta(7) integrin or the alpha(4)beta(1) integrin. Upon activation, both subsets show an enhanced expression of FoxP3, recently described as a key transcription factor of murine Tregs. In addition, both are able to convey suppressive capacity to conventional CD4(+) T cells. However, the properties of Treg subsets are rather distinct: alpha(4)beta(7) (+)Tregs induce IL-10-producing Th(sup) (Tr1-like), whereas alpha(4)beta(1) (+) Tregs induce TGF-beta-producing Th(sup) (Th3-like). Our findings reconcile conflicting results by clearly demonstrating that suppression through naturally occurring CD25(+) Tregs is primary cell-contact-dependent but is subsequently followed by cell-contact-independent T cell inhibition mediated by second-generation Tr1- and Th3-like Th(sup) via the soluble factors IL-10 and TGF-beta.

The characterization of the proteome, a key activity in the post-genome era, is made extremely challenging by the microheterogeneity introduced by post translational modifications such as glycosylation in the diverse set of proteins expressed in a cellular system. High resolution separation systems, such as 2D-gel electrophoresis and more recently liquid chromatography (LC) have been used to fractionate these complex mixtures, however, subsequent mass analysis is hindered by the low level of the purified components. Off-line coupling of matrix assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF/MS) is an attractive technique for the analysis of such samples, but suffers from sensitivity to the degree of salt contamination that is unavoidable in the isolation of low level protein samples from biological extracts. In this publication we will report on a novel application of a commercially available system for the micro-purification of peptides and proteins. In this procedure micro-columns (normally used for sequencing of electroblotted samples) were used to rapidly purify protein digests or crude extracts of proteins in sufficient amounts for further analyses by protein sequencing and MALDI-TOF/MS. To demonstrate the applicability of these techniques we isolated and performed structural analysis of the following samples: a high-mannose glycopeptide isolated from a digest of the glycoprotein rt-PA, a poly-His tagged recombinant DNA-binding protein isolated by Ni2+-chelating agarose and a polyclonal antibody sample.

A simple capillary isoelectric focusing method in bare fused-silica capillaries under denaturing conditions was developed for the separation of the glyco-isoforms of recombinant tissue plasminogen activator (rTPA) which have pI values ranging from pH 6 to 8. The glycoprotein was denatured in 8 M urea and separated in the presence of 0.75% carrier ampholytes, 0.4% hydroxypropylmethylcellulose and 4 M urea. Excellent separation of the glyco-isoforms of rTPA was achieved. Good reproducibilities for peak area and migration times were obtained using pressure mobilization of the focused protein zones. The method optimized for rTPA was also successfully applied to other glycoproteins (recombinant human erythropoietin and a monoclonal antibody) with different carbohydrate contents (3-55%).