Reduction of inflammatory slan (6-sulfo LacNAc) dendritic cells in psoriatic skin of patients treated with etanercept.

Dermal dendritic cells (DCs) play a central role in the immunopathology of psoriasis. We previously identified slanDCs as pro-inflammatory TNF-α, IL-23- and IL-12-producing DCs in human blood and as prominent inflammatory dermal TNF-α secreting and CD11c-positive DC subset in psoriasis. Here, we ask for the effects of TNF-α-inhibition on inflammatory slanDCs in skin and blood of 10 patients with psoriasis during 24 weeks of treatment with etanercept. Treatment with etanercept reduced the frequency of dermal slanDCs but did not induce apoptosis as determined by lack of increased active caspase-3-expression. In parallel, we found increased frequencies of slanDCs in blood which expressed lower levels of HLA-DR. Stimulating slanDCs isolated from the blood of healthy donors in vitro induced a strong production of IL-1ß, IL-6, IL-23 and IL-12p70. This capacity was efficiently reduced in the presence of etanercept, thereby indicating that TNF-α is an autocrine stimulus for maturation and pro-inflammatory cytokine production of slanDCs. In vivo, we noticed that treatment with etanercept did reduce the number of dermal slanDCs in parallel to the overall expression of TNF-α and IL-23p19. However, successful treatment did not down-regulated the percentage of dermal slanDCs that stained positive for TNF-α and IL-23p19 indicating that remaining slanDCs kept their pro-inflammatory capacity. This study provides novel insights into the immune regulatory properties of etanercept at the level of inflammatory slanDCs in vivo in skin and blood as well as in vitro.

Neurite outgrowth on a fibronectin isoform expressed during peripheral nerve regeneration is mediated by the interaction of paxillin with alpha4beta1 integrins.

BACKGROUND: The regeneration of peripheral nerve is associated with a change in the alternative splicing of the fibronectin primary gene transcript to re-express embryonic isoforms containing a binding site for alpha4beta1 integrins that promote neurite outgrowth. Here we use PC12 cells to examine the role of the interaction between paxillin and the alpha4 integrin cytoplasmic domain in neurite outgrowth. RESULTS: Expression of alpha4 with mutations in the paxillin-binding domain reduced neurite outgrowth on recombinant embryonic fibronectin fragments relative to wild type alpha4. Over-expression of paxillin promoted neurite outgrowth while a mutant isoform lacking the LD4 domain implicated in the regulation of ARF and Rac GTPases was less effective. Optimal alpha4-mediated migration in leucocytes requires spatial regulation of alpha4 phosphorylation at Ser988, a post-translational modification that blocks paxillin binding to the integrin cytoplasmic domain. In keeping with this alpha4(S988D), which mimics phosphorylated alpha4, did not promote neurite outgrowth. However, alpha4 was not phosphorylated in the PC12 cells, and a non-phosphorylatable alpha4(S988A) mutant promoted neurite outgrowth indistinguishably from the wild type integrin. CONCLUSION: We establish the importance of the alpha4 integrin-paxillin interaction in a model of axonal regeneration and highlight differing dependence on phosphorylation of alpha4 for extension of neuronal growth cones and migration of non-neural cells.

Extra benefit of a second cochlear implant with respect to health-related quality of life and tinnitus.

OBJECTIVE: To evaluate whether the second cochlear implant (CI) provides any extra benefit with respect to health-related quality of life, tinnitus, and auditory abilities. DESIGN: The data were evaluated using validated questionnaires before and after the first and second CI supply. Preimplantation data were collected retrospectively. PATIENTS: Forty postlingually deafened adults, 11 male and 29 female subjects were included in this study. All patients were sequentially bilaterally implanted with a multi-channel CI for at least 6 months. RESULTS: The health-related quality of life assessed with the Nijmegen Cochlear Implant Questionnaire further increased after the second CI. In patients with initially higher level of tinnitus annoyance measured with the Tinnitus Questionnaire, the scores decreased after the first CI and remained steady after the second CI. Patients with initially lower level of tinnitus annoyance had a further decrease of the Tinnitus Questionnaire score after the second CI. Additionally, the second CI induced further improvement of auditory abilities, as assessed by the Oldenburg Inventory and the Freiburg monosyllable test in quiet and the HSM and Oldenburg sentence tests in noise. The quality of life scores correlated with the auditory abilities, especially after the second CI. CONCLUSION: The present study provides evidence that the second CI leads to further increase in quality of life and reduction of tinnitus annoyance in addition to improvement of auditory abilities as compared with the first CI. Patients with bilateral CIs benefit from additional positive effects in all these fields.

Elderly patients benefit from cochlear implantation regarding auditory rehabilitation, quality of life, tinnitus, and stress.

OBJECTIVES/HYPOTHESIS: To determine the effect of cochlear implantation on quality of life, speech performance, tinnitus, perceived stress, and coping strategy in patients aged≥70 years in comparison with younger patients. STUDY DESIGN: Retrospective study. METHODS: A total of 55 postlingually deafened adults who were unilaterally implanted with a multichannel cochlear implant for at least 6 months were included in the study. Twenty patients were aged≥70 years (70-84 years), and 35 patients were <70 years (19-67 years). Speech perception was measured using the Freiburg monosyllable test in quiet and the Hochmair-Schulz-Moser sentence test. In addition, the patients filled in six validated questionnaires. RESULTS: Speech perception and subjectively assessed auditory ability were similar in the two age groups after implantation. Disease-specific quality of life was improved in patients aged≥70 years and even to a higher extent as compared to younger patients. Tinnitus annoyance and perceived stress were reduced in elderly patients to the same extent as in younger patients in the case of high initial severity level. The scores for the coping subdomain "seeking support" were reduced in elderly patients. CONCLUSIONS: The present study provides evidence that cochlear implantation constitutes a very successful procedure of auditory rehabilitation, even for patients aged ≥70 years. In addition, elderly patients benefit from implantation, with increased quality of life and reduced tinnitus and stress.

Cochlear implantation has a positive influence on quality of life, tinnitus, and psychological comorbidity.

OBJECTIVES: To determine the effect of cochlear implantation (CI) on health-related quality of life (HRQoL), tinnitus, and psychological comorbidity in patients with severe to profound postlingual hearing loss and to analyze the relationship between these parameters. STUDY DESIGN: Prospective study. METHODS: Using six validated questionnaires, we evaluated the pre-CI and post-CI scores of HRQoL, tinnitus, perceived stress, symptoms of depression and anxiety, and coping strategies in 43 patients implanted unilaterally with a multichannel implant for at least 6 months. RESULTS: In addition to improvements in hearing, speech understanding, and disease-specific HRQoL, psychological comorbidity was reduced and coping strategies were improved following CI. In the 39 tinnitus patients, their tinnitus was reduced. We found negative correlations between HRQoL and stress, depression, and anxiety. Pre-CI, tinnitus severity did not correlate with HRQoL and psychological comorbidity. However, patients with a high-level tinnitus had lower HRQoL as well as a higher level of perceived stress and anxiety symptoms than patients with a low-level tinnitus and no/incidental tinnitus before CI. Moreover, patients with severe hearing loss had a higher level of perceived symptoms of stress and depression than patients with profound hearing loss before CI. CONCLUSIONS: The present study provides evidence that tinnitus and psychological comorbidity may play an important role in the rehabilitation of CI patients, and that there is a correlation between HRQoL and these parameters. In addition to hearing tests, tinnitus, stress, and psychological comorbidity should be assessed using validated questionnaires before and after CI. This will help to improve the rehabilitation process.

Apical membrane maturation and cellular rosette formation during morphogenesis of the zebrafish lateral line.

Tissue morphogenesis and cell sorting are major forces during organ development. Here, we characterize the process of tissue morphogenesis within the zebrafish lateral line primordium, a migratory sheet of cells that gives rise to the neuromasts of the posterior lateral line organ. We find that cells within this epithelial tissue constrict actin-rich membranes and enrich apical junction proteins at apical focal points. The coordinated apical membrane constriction in single Delta D-positive hair cell progenitors and in their neighbouring prospective support cells generates cellular rosettes. Live imaging reveals that cellular rosettes subsequently separate from each other and give rise to individual neuromasts. Genetic analysis uncovers an involvement of Lethal giant larvae proteins in the maturation of apical junction belts during cellular rosette formation. Our findings suggest that apical constriction of cell membranes spatially confines regions of strong cell-cell adhesion and restricts the number of tightly interconnected cells into cellular rosettes, which ensures the correct deposition of neuromasts during morphogenesis of the posterior lateral line organ.

Regulation of muscle development by DPF3, a novel histone acetylation and methylation reader of the BAF chromatin remodeling complex.

Chromatin remodeling and histone modifications facilitate access of transcription factors to DNA by promoting the unwinding and destabilization of histone-DNA interactions. We present DPF3, a new epigenetic key factor for heart and muscle development characterized by a double PHD finger. DPF3 is associated with the BAF chromatin remodeling complex and binds methylated and acetylated lysine residues of histone 3 and 4. Thus, DPF3 may represent the first plant homeodomains that bind acetylated lysines, a feature previously only shown for the bromodomain. During development Dpf3 is expressed in the heart and somites of mouse, chicken, and zebrafish. Morpholino knockdown of dpf3 in zebrafish leads to incomplete cardiac looping and severely reduced ventricular contractility, with disassembled muscular fibers caused by transcriptional deregulation of structural and regulatory proteins. Promoter analysis identified Dpf3 as a novel downstream target of Mef2a. Taken together, DPF3 adds a further layer of complexity to the BAF complex by representing a tissue-specific anchor between histone acetylations as well as methylations and chromatin remodeling. Furthermore, this shows that plant homeodomain proteins play a yet unexplored role in recruiting chromatin remodeling complexes to acetylated histones.