No abstract

Owing to limited self-healing capacity, tendon ruptures and healing remain major orthopedic challenges. Increasing evidence suggests that post-traumatic inflammatory responses, and hence, cytokines are involved in both cases, and also in tendon exercise and homeostasis. This review summarizes interrelations known between the cytokines interleukin (IL)-1β, tumor necrosis factor (TNF)α, IL-6 and vascular endothelial growth factor (VEGF) in tendon to assess their role in tendon damage and healing. Exogenic cytokine sources are blood-derived leukocytes that immigrate in damaged tendon. Endogenous expression of IL-1β, TNFα, IL-6, IL-10 and VEGF was demonstrated in tendon-derived cells. As tendon is a highly mechanosensitive tissue, cytokine homeostasis and cell survival underlie an intimate balance between adequate biomechanical stimuli and disturbance through load deprivation and overload. Multiple interrelations between cytokines and tendon extracellular matrix (ECM) synthesis, catabolic mediators e.g. matrix-degrading enzymes, inflammatory and angiogenic factors (COX-2, PGE2, VEGF, NO) and cytoskeleton assembly are evident. Pro-inflammatory cytokines affect ECM homeostasis, accelerate remodeling, amplify biomechanical adaptiveness and promote tenocyte apoptosis. This multifaceted interplay might both contribute to and interfere with healing. Much work must be undertaken to understand the particular interrelation of these inflammatory and regulatory mediators in ruptured tendon and healing, which has relevance for the development of novel immunoregulatory therapeutic strategies.

Tendon injury induces a local inflammatory response, characterized by the induction of pro-inflammatory cytokines. The aim of the present study was to analyze the effects of TNFa, IL-6 and IL-10 on key parameters of tendon homeostasis. Cultured primary human tenocytes were treated with the recombinant cytokines IL-6, IL-10, TNFa, or combinations of TNFa with IL-6 and IL-10 (10 ng/mL, 6, 24 h). Expression of type I collagen, elastin, MMP-1, TNFa, IL-1b, IL-6, IL-10, and suppressors of cytokine signaling (SOCS1, 3) was analyzed with the use of RTD-PCR, immunocytochemistry, and Western blot analysis. In response to TNFa, tenocytes reduced their type I collagen deposition but increased their elastin gene expression and highly upregulated their expression for MMP-1, pro-inflammatory (TNFa, IL-1b) and immunoregulatory (IL-6, IL-10) cytokines. TNFa stimulation augmented SOCS1, whereas SOCS3 expression in tenocytes was also induced by IL-6. The treatment of tenocytes with IL-6 and IL-10 had no effect on cytokine expression. Neither IL-6 nor IL-10 modulated the observed effects of TNFa significantly. These results indicate that TNFa strongly activates the tenocytes to amplify their own TNFa expression and, subsequently, that of other regulatory cytokines and matrix degrading enzymes. However, the impact of IL-6 and IL-10 on tenocytes remains unclear. ß

Cellular levels of the rapidly degraded c-myc protein play an important role in determining the proliferation status of cells. Increased levels of c-myc are frequently associated with rapidly proliferating tumor cells. We show here that myc boxes I and II, found in the N termini of all members of the myc protein family, function to direct the degradation of the c-myc protein. Both myc boxes I and II contain sufficient information to independently direct the degradation of otherwise stably expressed proteins to which they are fused. At least part of the myc box-directed degradation occurs via the proteasome. The mechanism of myc box-directed degradation appears to be conserved between yeast and mammalian cells. Our results suggest that the myc boxes may play an important role in regulating the level and activity of the c-myc protein.The c-myc protein is a short-lived, nuclear phosphoprotein that has a role as a regulator of several biological processes, including cell proliferation and apoptosis. Elevation in the levels of c-myc is a widespread phenomenon in a large variety of tumors from a range of species. Studies of c-myc proteins in tumor cells led to the proposal that they are involved in the transcriptional control of genes required for cellular replication (5, 30). The c-myc protein has motifs that are characteristic of transcription factors, the leucine zipper and basic helixloop-helix (bHLHZip) dimerization and DNA binding domains (20,21,48,58). To become an active transactivator, c-myc dimerizes with another bHLHZip protein, max (3,4,12). Blackwell et al. (11) showed that c-myc recognizes the DNA sequence CACGTG, a motif which is present in various target promoters. The genes encoding ␣-prothomyosin (22), PAI-1 (57), ornithine decarboxylase (74), ECA39 (9), eIF-4E (37), Cdc25 (23), rcl (45), and MrDb (26) have been demonstrated to be activated by c-myc. In addition, c-myc is able to repress transcription from the adenovirus major late promoter (46) and from the promoters for c-EBP␣ (16), albumin (25), cyclin D (54), and gadd45 (50).It has previously been shown that c-myc can function as a transactivator in Saccharomyces cerevisiae (3). Expression of c-myc and its dimerization partner max led to activation of a lacZ reporter gene with a CACGTG site in the promoter. In addition, Amati et al. (3) and Lech et al. (43) demonstrated that the N-terminal domain of c-myc functions as a transactivator in yeast when fused to a heterologous DNA binding domain (DBD) from serum response factor or LexA. In mammalian cells, a c-myc-GAL4 DBD chimera has been used to define an N-terminal transactivation domain of 143 amino acids (38), and the same region is a functional transactivator in yeast (51).Identification and characterization of the N-myc, s-myc, Lmyc, and B-myc proteins showed that there is a family of myc proteins that have highly homologous regions (6,39,44,68,70). Two of these regions lie within the transactivation domain and have been termed myc homology box I (MBI) and myc homology box II (MBII). MBI and ...

The aim of this study was to compare the efficacy and safety profile of XEN microstent implantation with trabeculectomy (TET) in a comparable group of open-angle glaucoma cases in a retrospective, monocentric, single-surgeon setting. Each treatment group consisted of 100 eyes of 100 patients. At regular follow-up visits during the first 12 months after surgery, the following assessments were conducted and compared: intraocular pressure (IOP), number of IOP-lowering medications applied, best-corrected visual acuity (BCVA) and visual field testing. In both groups mean IOP was significantly reduced (p < 0.001). Mean IOP dropped from 24.8 ± 7.8 to 14.8 ± 4.0 mmHg in the TET and from 24.5 ± 6.7 to 16.6 ± 4.8 mmHg in the XEN group. The number of active compounds in the prescribed medication dropped from 3.3 ± 1.2 to 1.3 ± 1.4 in the TET and from 3.0 ± 1.1 to 1.4 ± 1.5 in the XEN group. BCVA and mean defect of static automated perimetry did not show a change of statistical significance in either group. Complications were more frequent after TET (p = 0.005) while postoperative needling was more frequent in the XEN group (p = 0.021). TET and XEN led to a significant reduction of IOP and IOP-lowering medication, while BCVA and visual field indices remained mostly unaltered over a 12-month postsurgical follow-up.

In a real-world setting, eyes with DME considered refractory to anti-VEGF therapy after three monthly injections which were switched to DEX implant and had better visual and anatomical outcomes at 12 months than those that continued treatment with anti-VEGF therapy.

Over a follow-up of 24 months, vision improved in diabetic macular edema eyes after treatment with dexamethasone implants, both in eyes that were treatment naive and eyes refractory to anti-vascular endothelial growth factor treatment; however, improvement was greater in naive eyes.

Purpose To investigate disorganization of retinal inner layers (DRIL) as a biomarker in eyes with diabetic macular oedema (DME) treated by intravitreal dexamethasone (DEX) implant. Methods Multicentre, retrospective study including eyes with DME treated with DEX implant and follow‐up of 12 months after the first injection. OCT scans were evaluated for the presence of DRIL and other structural features. Best corrected visual acuity (BCVA) and central subfield thickness (CST) were recorded at baseline and at 2, 4, 6 and 12 months after treatment. Correlation between DRIL at baseline and outcomes after DEX treatment and the change in DRIL were analysed. Results A total of 177 eyes (177 patients; naïve, n = 131; refractory, n = 46) were included. Patients without DRIL at baseline gained significantly more vision and enjoyed greater reduction in CST over 12 months (both p = 0.03). DRIL at the boundary between the ganglion cell‐inner plexiform complex and inner nuclear layer improved in 48/64 eyes (75%, p < 0.001), while DRIL between the inner nuclear layer and outer plexiform layer improved in 27/77 eyes (35%, p = 0.004). Conclusions This is the first study to show that DEX implant has the potential to ameliorate DRIL. Patients without DRIL at baseline have a favourable outcome. DRIL may serve a robust biomarker in DME treated by DEX implant.