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Background: Although anterior cruciate ligament (ACL) tear-prevention programs may be effective in the (secondary) prevention of a subsequent ACL injury, little is known, yet, on their effectiveness and feasibility. This study assesses the effects and implementation capacity of a secondary preventive motor-control training (the Stop-X program) after ACL reconstruction.
Methods and design: A multicenter, single-blind, randomized controlled, prospective, superiority, two-arm design is adopted. Subsequent patients (18–35 years) with primary arthroscopic unilateral ACL reconstruction with autologous hamstring graft are enrolled. Postoperative guideline rehabilitation plus Classic follow-up treatment and guideline rehabilitation plus the Stop-X intervention will be compared. The onset of the Stop-X program as part of the postoperative follow-up treatment is individualized and function based. The participants must be released for the training components. The endpoint is the unrestricted return to sport (RTS) decision. Before (where applicable) reconstruction and after the clearance for the intervention (aimed at 4–8 months post surgery) until the unrestricted RTS decision (but at least until 12 months post surgery), all outcomes will be assessed once a month. Each participant is consequently measured at least five times to a maximum of 12 times. Twelve, 18 and 24 months after the surgery, follow-up-measurements and recurrence monitoring will follow. The primary outcome assessement (normalized knee-separation distance at the Drop Jump Screening Test (DJST)) is followed by the functional secondary outcomes assessements. The latter consist of quality assessments during simple (combined) balance side, balance front and single-leg hops for distance. All hop/jump tests are self-administered and filmed from the frontal view (3-m distance). All videos are transferred using safe big content transfer and subsequently (and blinded) expertly video-rated. Secondary outcomes are questionnaires on patient-reported knee function, kinesiophobia, RTS after ACL injury and training/therapy volume (frequency – intensity – type and time). All questionnaires are completed online using the participants’ pseudonym only.
Group allocation is executed randomly. The training intervention (Stop-X arm) consists of self-administered home-based exercises. The exercises are step-wise graduated and follow wound healing and functional restoration criteria. The training frequency for both arms is scheduled to be three times per week, each time for a 30 min duration. The program follows current (secondary) prevention guidelines.
Repeated measurements gain-score analyses using analyses of (co-)variance are performed for all outcomes.
Trial registration: German Clinical Trials Register, identification number DRKS00015313. Registered on 1 October 2018.
CCR8 leads to eosinophil migration and regulates neutrophil migration in murine allergic enteritis
(2019)
Allergic enteritis (AE) is a gastrointestinal form of food allergy. This study aimed to elucidate cellular and molecular mechanisms of AE using a murine model. To induce AE, BALB/c wild type (WT) mice received intraperitoneal sensitization with ovalbumin (an egg white allergen) plus ALUM and feeding an egg white (EW) diet. Microarray analysis showed enhanced gene expression of CC chemokine receptor (CCR) 8 and its ligand, chemokine CC motif ligand (CCL) 1 in the inflamed jejunum. Histological and FACS analysis showed that CCR8 knock out (KO) mice exhibited slightly less inflammatory features, reduced eosinophil accumulation but accelerated neutrophil accumulation in the jejunums, when compared to WT mice. The concentrations of an eosinophil chemoattractant CCL11 (eotaxin-1), but not of IL-5, were reduced in intestinal homogenates of CCR8KO mice, suggesting an indirect involvement of CCR8 in eosinophil accumulation in AE sites by inducing CCL11 expression. The potential of CCR8 antagonists to treat allergic asthma has been discussed. However, our results suggest that CCR8 blockade may promote neutrophil accumulation in the inflamed intestinal tissues, and not be a suitable therapeutic target for AE, despite the potential to reduce eosinophil accumulation. This study advances our knowledge to establish effective anti-inflammatory strategies in AE treatment.
Background. TLR ligands can promote Th1-biased immune responses, mimicking potent stimuli of viruses and bacteria. Aim. To investigate the adjuvant properties of dual TLR2/7 ligands compared to those of the mixture of both single ligands.
Methods. Dual TLR2/7 ligands: CL401, CL413, and CL531, including CL264 (TLR7-ligand) and Pam2CysK4 (TLR2-ligand), were used. Immune-modulatory capacity of the dual ligands with the individual ligands alone or as a mixture in mouse BMmDCs, BMmDC:TC cocultures, or BMCMCs was compared and assessed in naïve mice and in a mouse model of OVA-induced intestinal allergy.
Results. CL413 and CL531 induced BMmDC-derived IL-10 secretion, suppressed rOVA-induced IL-5 secretion from OVA-specific DO11.10 CD4+ TCs, and induced proinflammatory cytokine secretion in vivo. In contrast, CL401 induced considerably less IL-10 secretion and led to IL-17A production in BMmDC:TC cocultures, but not BMCMC IL-6 secretion, or IL-6 or TNF-α production in vivo. No immune-modulating effects were observed with single ligands. All dual TLR2/7 ligands suppressed DNP-induced IgE-and-Ag-specific mast cell degranulation. Compared to vaccination with OVA, vaccination with the mixture CL531 and OVA, significantly suppressed OVA-specific IgE production in the intestinal allergy model.
Conclusions. Based on beneficial immune-modulating properties, CL413 and CL531 may have utility as potential adjuvants for allergy treatment.