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We describe the case of a patient who presented with sudden onset vertigo and bilateral deafness while under immune checkpoint therapy for metastatic bronchial carcinoma. Extensive audiologic assessment and vestibular function testing, as well as cranial magnetic resonance imaging (cMRI) and lumbar puncture was performed. The diagnostic workup confirmed bilateral sensorineural deafness and bilateral loss of vestibular function, while imaging revealed enhancement of the vestibulocochlear nerve. Initially, immunotherapy with PD-L1 antibody atezolizumab was the assumed cause of the described symptoms. However, further findings strengthened the suspicion of meningeosis neoplastica. The differential diagnoses of hearing loss and vestibulopathy in the context of platin-based chemotherapy, checkpoint inhibitor therapy and metastatic disease should be kept in mind for appropriate workup and therapy. Laryngoscope, 134:4347-4350, 2024., (© 2024 The Authors. The Laryngoscope published by Wiley Periodicals LLC on behalf of The American Laryngological, Rhinological and Otological Society, Inc.)

Background: Extended endoscopic endonasal surgery (EEES) is an essential part of treatment of various pathologies of the anterior skull base. In addition to significant improvements in the quality of life of affected patients and a lower complication profile compared to open skull base surgery, the therapeutic results are comparable if the indications are correct., Materials and Methods: Data of all endoscopic endonasal skull base procedures performed at the University Skull Base Center Hamburg under the direction of the Department of Otorhinolaryngology between June 2018 and November 2022 were retrospectively collected., Results: A total of 50 cases were identified. Of these, 56% (28/50) were malignant tumors, 24% (12/50) were benign pathologies with direct skull base involvement, and 20% (10/50) were anterior skull base defects with rhinoliquorrhea. In 96% (48/50) of cases, the preoperatively set goal of surgery (representative biopsy, complete resection, closure of the skull base defect) could be achieved. Complications grade III or higher according to Clavien-Dindo occurred in 4/50 cases. During the observation period, n = 5 olfactory neuroblastomas were diagnosed, all of which were exclusively and successfully operated on endoscopically., Conclusion: In recent years, the spectrum of endoscopically resectable pathologies of the anterior skull base has steadily expanded. In particular, midline-related tumors such as olfactory neuroblastoma or iatrogenic/idiopathic skull base defects with cerebrospinal fluid rhinorrhea are treated completely endoscopically with very good results. Nevertheless, there are also limitations to this technique. Due to high variance in the scope of frontobasal surgery, the extent, and the complex anatomy, as well as the overlapping responsibilities of the specialist disciplines, establishment of certified skull base centers and bundling of frontobasal surgery at these centers is highly relevant for quality assurance., (© 2024. The Author(s).)

Background: Acute mastoiditis (AM) is a potentially life-threatening condition primarily affecting children. To date, there are no consistent criteria or valid guidelines for the diagnosis and treatment of pediatric AM. Therefore, this study evaluates the clinical course of AM in terms of clinical signs and treatment. In addition, a novel classification scheme for the disease and a treatment algorithm is being proposed., Methods: Patient records over a 12-year period from a single center were reviewed to identify confirmed cases of AM in children. Data collected included clinical signs, body temperature, and infection parameters during the disease, as well as radiological imaging, antibiotics, and surgical as well as conservative treatment. In addition, a classification of the AM stages was established in accordance with the findings described and practical experience, consisting of four stages (1, mastoidal irritation; 2, mild AM; 3, advanced AM; 4, advanced AM and additional complications) with corresponding treatment recommendations. In the retrospective cohort, those AM cases that were treated alongside the classification were compared with the rest concerning clinical course and outcome., Results: A total of 109 patients (mean age, 3.8 ± 3.8 years) were included. The main symptoms at hospital admission were auricular protrusion (n = 73; 67.0%), fever (n = 56; 51.4%) with a mean temperature of 38.3 ± 1.1°C, and otalgia (n = 28; 25.7%). The mean laboratory-tested levels of leukocytes and C-reactive protein at the time of hospital admission were 15.96 ± 8.7/nl and 59.6 ± 54.0 mg/L, respectively. During winter, there was a higher prevalence of AM, with peak hospital admissions in April (n = 22). The most common pathogen was Streptococcus pyogenes (32 cases). Treatment was purely conservative in four cases, whereas the remaining cases underwent surgery (41× grommet insertion, 64× plus mastoidectomy). The outcome was generally good, but in eight patients a second surgical procedure had to be performed as they showed signs of clinical deterioration. A total of 101 patients were treated according to the proposed algorithm, and all of which had a good outcome without the need for further interventions., Conclusion: Based on clinical experience in a large cohort of pediatric AM patients, a novel diagnostic and treatment algorithm has been developed and successfully tested in a retrospective cohort for AM in children to prevent further complications and to ease its management by pediatricians and otorhinolaryngologists in the emergency setting., Competing Interests: Conflicts of interest and source of funding: The authors have no conflicts of interest or source of funding to disclose., (Copyright © 2023, Otology & Neurotology, Inc.)

Background: Sinonasal neoplasms, whether benign and malignant, pose a significant challenge to clinicians and represent a model area for multidisciplinary collaboration in order to optimize patient care. The International Consensus Statement on Allergy and Rhinology: Sinonasal Tumors (ICSNT) aims to summarize the best available evidence and presents 48 thematic and histopathology-based topics spanning the field., Methods: In accordance with prior International Consensus Statement on Allergy and Rhinology documents, ICSNT assigned each topic as an Evidence-Based Review with Recommendations, Evidence-Based Review, and Literature Review based on the level of evidence. An international group of multidisciplinary author teams were assembled for the topic reviews using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses format, and completed sections underwent a thorough and iterative consensus-building process. The final document underwent rigorous synthesis and review prior to publication., Results: The ICSNT document consists of four major sections: general principles, benign neoplasms and lesions, malignant neoplasms, and quality of life and surveillance. It covers 48 conceptual and/or histopathology-based topics relevant to sinonasal neoplasms and masses. Topics with a high level of evidence provided specific recommendations, while other areas summarized the current state of evidence. A final section highlights research opportunities and future directions, contributing to advancing knowledge and community intervention., Conclusion: As an embodiment of the multidisciplinary and collaborative model of care in sinonasal neoplasms and masses, ICSNT was designed as a comprehensive, international, and multidisciplinary collaborative endeavor. Its primary objective is to summarize the existing evidence in the field of sinonasal neoplasms and masses., (© 2023 The Authors. International Forum of Allergy & Rhinology published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngic Allergy and American Rhinologic Society.)

Purpose: There are no consensus guidelines regarding the postoperative treatment of the contralateral pathologically node-negative neck in oropharyngeal squamous cell carcinoma. This study aimed to determine if omission of postoperative irradiation of the contralateral pathologically node-negative neck affects oncological outcomes., Methods: We retrospectively identified 84 patients with primary surgical treatment including bilateral neck dissection and postoperative (chemo-)radiotherapy (PO(C)RT). Survival was analyzed using the log-rank test and the Kaplan-Meier method., Results: Patients showed no decrease in tumor-free, cause-specific (CSS), or overall survival (OS) when PO(C)RT of the contralateral pathologically node-negative neck was omitted. Increased OS was found in patients with unilateral PO(C)RT and especially an increased OS and CSS was found in unilateral PO(C)RT and in tumors arising from lymphoepithelial tissue., Conclusions: Omitting the contralateral pathologically node-negative neck appears to be safe in terms of survival and our retrospective study advocates further prospective randomized control de-escalation trials., (© 2023. The Author(s).)

Objectives: In head and neck squamous cell carcinoma (HNSCC), tumors negative for Human Papillomavirus (HPV) remain a difficult to treat entity and the morbidity of current multimodal treatment is high. Radiotherapy in combination with molecular targeting could represent suitable, less toxic treatment options especially for cisplatin ineligible patients. Therefore, we tested dual targeting of PARP and the intra-S/G2 checkpoint through Wee1 inhibition for its radiosensitizing capacity in radioresistant HPV-negative HNSCC cells., Materials and Methods: Three radioresistant HPV-negative cell lines (HSC4, SAS, UT-SCC-60a) were treated with olaparib, adavosertib and ionizing irradiation. The impact on cell cycle, G2 arrest and replication stress was assessed through flow cytometry after DAPI, phospho-histone H3 and γH2AX staining. Long term cell survival after treatment was determined through colony formation assay and DNA double-strand break (DSB) levels were assessed through quantification of nuclear 53BP1 foci in cell lines and patient-derived HPV± tumor slice cultures., Results: Wee1 and dual targeting induced replication stress but failed to effectively inhibit radiation-induced G2 cell cycle arrest. Single as well as combined inhibition increased radiation sensitivity and residual DSB levels, with the largest effects induced through dual targeting. Dual targeting also enhanced residual DSB levels in patient-derived slice cultures from HPV-negative but not HPV+ HNSCC (5/7 vs. 1/6)., Conclusion: We conclude that the combined inhibition of PARP and Wee1 results in enhanced residual DNA damage levels after irradiation and effectively sensitizes radioresistant HPV-negative HNSCC cells. Ex vivo tumor slice cultures may predict the response of individual patients with HPV-negative HNSCC to this dual targeting approach., Competing Interests: 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., (© 2023 The Authors.)

Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht.

Background/objectives Vestibular neuritis (VN) is one of the most common causes of peripheral vestibular neuropathy. The goal of this study is to investigate the possible infectious causes of VN in a large cohort of patients. Material and methods In total, 98 consecutive VN patients were enrolled in this retrospective study over a four-year period (04/2015-04/2019). Diagnosis of VN was made by clinical examination and functional diagnostics. We focused on infectious causes such as neurotropic viruses and Lyme disease (LD) and evaluated infection parameters as well as the concomitant diseases. Results In this cohort, we found pathologically elevated leukocytes or C-reactive protein (CRP) levels, and/or acute herpes simplex virus (HSV) infection, cytomegalovirus (CMV) infection and LD in 42 patients (42.85%). Leukocytes were elevated in 39 of 98 patients (39.8%) and the mean count was 9717 ± 2991 /μl. The group comparison between patients with vestibular loss (n=42) and patients with vestibular hypofunction (n=45) revealed a significant difference in regard to elevated leukocytes (p=0.028). In total, 28 of 53 patients (52.8%) were positive for HSV immunoglobulin (Ig) G and four of 53 patients were positive for HSV IgM (7.5%). Six of 53 patients (11.3%) were positive for LD IgM. Conclusion In this cohort, there was a large number of VN patients with infectious signs; several patients tested positive for HSV and LD. Therefore we recommend testing VN patients not only for HSV but also for LD and other neurotropic viruses. This approach enables to complement the standard VN treatment with a specific treatment., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Haeussler et al.)

Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht.

Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht.

Purpose: The aim was to analyze the incidence and survival of patients living with HIV (PLWH) with head and neck squamous cell carcinoma (HNSCC) and to compare with a control group of HIV-negative HNSCC patients., Methods: Clinicopathological data and predictors for overall survival (OS) and disease-free survival (DFS) were investigated (2009-2019)., Results: 50 of 5151 HNSCC patients (0.97%) were PLWH, and 76% were smokers. Age ≤ 60 years, HIV-PCR ≤ 50 copies, CD4 cells ≤ 200/mm 3 , cART treatment, T and UICC classification, oral cavity and nasal/paranasal sinuses, and therapy were significantly associated with OS in univariate analysis. In the multivariate analysis, only age and HIV-PCR independently predicted OS. The OS of the 50 PLWH was not significantly altered compared with the 5101 HIV-negative controls. However, OS and DFS were significantly inferior in advanced tumor stages of PLWH compared with an age-matched control group of 150 HIV-negative patients., Conclusions: PLWH were diagnosed with HNSCC at a significantly younger age compared to HIV-negative patients. Taking into account patient age at initial diagnosis, both OS and DFS rates in PLWH are significantly worse compared with a matched control group of HIV-negative patients in advanced tumor stages UICC III/IV. The prognosis (OS) is improved when taking cART treatment, the HIV viral load is undetectable and CD4 count is high., (© 2021. The Author(s).)

The subjective visual vertical (SVV) evaluates the function of the utricle, which, in patients with Menière's disease (MD), can be affected by endolymphatic hydrops. This study aimed to determine the SVV in MD patients during the chronic phase of illness compared to healthy participants. The second aim was to compare the SVV measurement tools: the analog bucket test, digital bucket test, and C-SVV© goggles. The SVV scores differed significantly between MD patients and the control group for the analog bucket test ( p < 0.001) and the C-SVV ® goggles ( p = 0.028), but no significance was shown when using the digital bucket test ( p = 0.062). When comparing the analog bucket test and the C-SVV ® goggles applying the calculated threshold (1.125° in analog bucket test, 2.5° in C-SVV ® goggles), the bucket test showed higher accuracy (bucket test 73.84%, C-SVV ® goggles 69.23%). When examining the influence of betahistine on SVV scores, there were no statistically significant differences in both the analog bucket test and C-SVV© goggles. We conclude that SVV test can be used as an additional tool to evaluate utricle function during the chronic phase of MD and that the analog bucket test produces the most reliable results. The intake of betahistine does not influence the perception of SVV.

The mouse is the most widely used animal model in hearing research. Immunohistochemistry and immunofluorescent staining of murine cochlear sections have, thus, remained a backbone of inner ear research. Since many primary antibodies are raised in mouse, the problem of "mouse-on-mouse" background arises due to the interaction between the anti-mouse secondary antibody and the native mouse immunoglobulins. Here, we describe the pattern of mouse-on-mouse background fluorescence in sections of the postnatal mouse cochlea. Furthermore, we describe a simple double-blocking immunofluorescence protocol to label mouse cochlear cryosections. The protocol contains a conventional blocking step with serum, and an additional blocking step with a commercially available anti-mouse IgG blocking reagent. This blocking technique virtually eliminates the "mouse-on-mouse" background in murine cochlear sections, while adding only a little time to the staining protocol. We provide detailed instructions and practical tips for tissue harvesting, processing, and immunofluorescence-labeling. Further protocol modifications are described, to shorten the duration of the protocol, based on the primary antibody incubation temperature. Finally, we demonstrate examples of immunofluorescence staining performed using different incubation times and various incubation temperatures with a commercially available mouse monoclonal primary antibody. © 2020 The Authors. Basic Protocol: Tackling the Mouse-on-Mouse Problem in Cochlear Immunofluorescence: A Simple Double-Blocking Protocol for Immunofluorescent Labeling of Murine Cochlear Sections with Primary Mouse Antibodies., (© 2020 The Authors.)

As cartilage is one of the few tissues in the human body that is not vascularized, the body has very limited capabilities to repair cartilage defects. Hence, novel condro-instructive biomaterials facilitating cartilage formation by implanted chondrocytes are required. In this work, an oxidized alginate-gelatin hydrogel system, alginate-di-aldehyde (ADA) and gelatin (GEL), was used to fabricate 3D printed grid-like structures for cartilage tissue engineering. Enzymatic and ionic crosslinking techniques using microbial transglutaminase (mTG) and divalent ions (CaCl 2 ) were combined to ensure long-term stability of the 3D printed structures. Human nasoseptal chondrocytes were embedded in ADA-GEL prior to 3D printing. Cell viability, proliferation, and metabolic activity were analyzed after 7 and 14 days. The influence of the enzymatic crosslinking and the 3D printing process on the primary human chondrocytes were investigated. It was found that neither the 3D printing process nor the crosslinking by mTG impaired chondrocyte viability. The formation of the main cartilage-specific extracellular matrix components collagen type II and cartilage proteoglycans was shown by immunohistochemical staining. The combination of enzymatic and ionic crosslinking for the 3D printing of ADA-GEL hydrogels is therefore a promising approach for the 3D cultivation of primary human chondrocytes for cartilage tissue engineering., 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 © 2020 Elsevier B.V. All rights reserved.)

Purpose: The non-invasive diagnosis of acute rhinosinusitis (ARS) remains an unresolved problem of modern otolaryngology. Analog diaphanoscopy of reduced transillumination (shading) could be enhanced by a digital image processing of the maxillary sinuses. By this means, the limited ergonomics of this safe and low-cost method can be overcome, and merits renewed the investigation. Here, we compared the diagnostic sensitivity and specificity of digital diaphanoscopy and computed tomography (CT) in detecting shading in the maxillary sinus., Materials and Methods: We examined 103 adults using both digital diaphanoscopy of the maxillary sinus and native-phase cranial CT. We developed a scoring system for investigation of shading in the maxillary sinus using diaphanoscopy and compared the sensitivity and specificity with that of CT. Also, we documented a follow-up of acute rhinosinusitis., Results: In diagnosing shading in the maxillary sinus, digital diaphanoscopy had a sensitivity of 86% and a specificity of 88%. Digital diaphanoscopy can be used not only in the screening of ARS but also for documentation of its course., Conclusion: This study supports the role of modern digital diaphanoscopy in the diagnosis of shading in the maxillary sinus, especially in patients with ARS when CT imaging is not recommended. The ergonomics of analog diaphanoscopy could be significantly improved for physicians and patients by the implementation of modern hardware and software components. Further development of the technique and the use of several discrete wavelengths will improve this method's sensitivity and specificity., 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 © 2020 Elsevier Inc. All rights reserved.)

Competing Interests: Jens Nee: Allg. Honorar für Vorträge/Beratung: ZOLL Medical Deutschland GmbH Bereich Temperature Management Solutions (TMS) Emil-Hoffmann-Straße 13 50996 Köln, Germany , Xenios AG, Im Zukunftspark 2, 74076 Heilbronn, Germany , C.R. Bard GmbH, Wachhausstr. 6, 76227 Karlsruhe, GermanyFresenius Medical Care GmbH, Else-Kröner-Straße 1, 61352 Bad Homburg, Germany

Acute low-tone sensorineural hearing loss (ALHL) is a type of idiopathic sudden sensorineural hearing loss. ALHL is rarely a solitary condition but rather co-occurs with vertigo and tinnitus, being an element of contemporary diagnostic criteria for Menière's disease (MD). The goal of our present study was to determine the value of ALHL for the early diagnosis of MD in patients presenting in the emergency room with ALHL as a main complaint. The files of 106 patients with ALHL who were admitted to the emergency room over the period of 7 years and 104 patients with acute high- tone sensorineural hearing loss (AHHL) from the same period were included in this retrospective study. Forty ALHL patients presented with recurrent episode of hearing loss and 66 remaining patients presented with ALHL for the first time. Of the latter group, 25 patients gave consent for the follow-up. First, we analyzed the difference in the occurrence of tinnitus and vertigo between the ALHL and AHHL groups. In patients with ALHL, the incidence of vertigo with tinnitus and the number of recurrent episodes were statistically higher than in patients with AHHL. Next, we focused on the ALHL follow-up group (25 patients). In that group, two patients had all MD symptoms at presentation, 18 had ALHL and tinnitus and five ALHL only. Of 18 patients with ALHL and tinnitus at admission, five developed vertigo and thus the triad of Menière's disease. None of the five patients with AHLH as a sole symptom developed MD during the follow-up time but four of them have developed tinnitus. Patients with recurrent ALHL had significantly higher incidence of MD than the patients with first episode. We conclude that some patients who present with ALHL and concomitant tinnitus or have recurrent episodes of ALHL are more likely to develop Menière's disease than these patients, who present with ALHL as a sole symptom. Nonetheless, we recommend otological follow-up for all patients presenting with ALHL.

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Purpose: Chronic hyperplasia of the inferior nasal concha is accompanied by a nasal obstruction; however, there is no standardised surgical treatment for this condition. Here, we compared the outcome of three surgical techniques frequently used to treat the hyperplasia of inferior turbinates: turbinectomy with lateralization, submucosal electrocautery and laser cautery additional to septoplasty., Materials and Methods: One hundred and nine patients participated in this prospective randomized study upon signing written consent. The subjects were randomly assigned to one of three intervention groups: 1) submucosal turbinectomy with lateralization, 2) submucosal electrocautery or 3) laser cautery. All groups were followed-up for up to 6months after surgical intervention. During the four follow-up appointments, the outcomes were measured with the modified German version of Sino-Nasal Outcome Test 20 questionnaire. In addition, the nasal breathing and the absolute nasal flow rates and respective mucosal component were determined by the anterior rhinomanometry., Results: Following surgery, the subjective and objective nasal obstruction decreased significantly in all three groups. Moreover, the subjective symptoms measured by modified Sino-Nasal Outcome Test 20 improved significantly, although there were some temporal differences between groups regarding subjective nasal obstruction, ear pressure, nasal discomfort, daytime fatigue, cough and dry mouth. The mucosal component of nasal congestion decreased significantly after surgery., Conclusions: All surgical techniques used to reduce the conchae mucosa led to a significant improvement in the objective and subjective nasal breathing and the quality of life. Septoplastic reduction proved to be of additional benefit., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The receptor for hyaluronan-mediated motility CD168 is associated with the processes of oncogenesis and metastasis. The objective of the present study was to determine the possible association between the expression and distribution of CD168 and the tumor stage of head-and-neck squamous cell carcinoma (SCC). Formalin-fixed and paraffin-embedded tumor samples obtained from 100 patients during primary resection of SCC from the oral cavity, oropharynx, hypopharynx or larynx were included in the present study. The patients were divided into two risk groups: Low risk, representing the early stage of completely resected SCCs with good-to-moderate differentiation, and the high-risk group, representing the advanced stage SCCs with positive resection margins, vascular invasion or locoregional metastasis. All specimens were stained with a monoclonal antibody against CD168. Percentage and staining intensity of CD168-positive cells were scored, and their spatial distribution within the tumor nests was noted. The results obtained were correlated with the tumor stage. The quantification of CD168 expression revealed significant differences between the two risk groups (t-test, P=0.002), with higher scores in tumors resected from the high-risk SSC group compared with those from the low-risk group. In addition, in the high-risk group, the CD168-positive cells were present predominantly in the periphery (70.4%) of tumor nests, whereas in the low-risk group, only 56.6% were located there; however, this trend did not reach the level of statistical significance. Taken together, the results from the present study suggested that CD168 expression patterns could potentially be used as a predictor of tumor aggressiveness, and therefore they may be a prognostic factor in head-and-neck SCC.

Group 3 innate lymphoid cells (ILC3s) are defined by the expression of the transcription factor RORγt, which is selectively required for their development. The lineage-specified progenitors of ILC3s and their site of development after birth remain undefined. Here we identified a population of human CD34(+) hematopoietic progenitor cells (HPCs) that express RORγt and share a distinct transcriptional signature with ILC3s. RORγt(+)CD34(+) HPCs were located in tonsils and intestinal lamina propria (LP) and selectively differentiated toward ILC3s. In contrast, RORγt(-)CD34(+) HPCs could differentiate to become either ILC3s or natural killer (NK) cells, with differentiation toward ILC3 lineage determined by stem cell factor (SCF) and aryl hydrocarbon receptor (AhR) signaling. Thus, we demonstrate that in humans RORγt(+)CD34(+) cells are lineage-specified progenitors of IL-22(+) ILC3s and propose that tonsils and intestinal LP, which are enriched both in committed precursors and mature ILC3s, might represent preferential sites of ILC3 lineage differentiation., (Copyright © 2014 Elsevier Inc. All rights reserved.)

IL-21 promotes Th17 differentiation, and Th17 cells that upregulate T-bet, IFN-γ, and GM-CSF drive experimental autoimmune diseases in mice. Anti-IL-21 treatment of autoimmune patients is therefore a therapeutic option, but the role of IL-21 in human T cell differentiation is incompletely understood. IL-21 was produced at high levels by human CD4(+) central memory T cells, suggesting that it is associated with early T cell differentiation. Consistently, it was inhibited by forced expression of T-bet or RORC2, the lineage-defining transcription factors of Th1 and Th17 effector cells, respectively. Although IL-21 was efficiently induced by IL-12 in naive CD4(+) T cells, it inhibited the generation of Th1 effector cells in a negative feedback loop. IL-21 was also induced by IL-6 and promoted Th17 differentiation, but it was not absolutely required. Importantly, however, IL-21 promoted IL-10 secretion but inhibited IFN-γ and GM-CSF production in developing Th17 cells, and consequently prevented the generation of polyfunctional Th1/17 effector cells. Moreover, in Th17 memory cells, IL-21 selectively inhibited T-bet upregulation and GM-CSF production. In summary, IL-21 is a central memory T cell-associated cytokine that promotes Th17 differentiation and IL-10 production, but inhibits the generation of potentially pathogenic Th1/17 effector cells. These findings shed new light on the role of IL-21 in T cell differentiation, and have relevant implications for anti-IL-21 therapy of autoimmune diseases., (Copyright © 2014 by The American Association of Immunologists, Inc.)

Hypothesizing that the implantation of non-articular (heterotopic) chondrocytes might be an alternative approach to support articular cartilage repair, we analyzed joint cartilage defect healing in the rabbit model after implantation of autologous auricle-derived (auricular) chondrocytes. Autologous lapine articular and auricular chondrocytes were cultured for 3 weeks in polyglycolic acid (PGA) scaffolds before being implanted into critical sized osteochondral defects of the rabbit knee femoropatellar groove. Cell-free PGA scaffolds and empty defects served as controls. Construct quality was determined before implantation and defect healing was monitored after 6 and 12 weeks using vitality assays, macroscopical and histological score systems. Neo-cartilage was formed in the PGA constructs seeded with both articular and auricular chondrocytes in vitro and in vivo. At the histological level, cartilage repair was slightly improved when using autologous articular chondrocyte seeded constructs compared to empty defects and was significantly superior compared to defects treated with auricular chondrocytes 6 weeks after implantation. Although only the immunohistological differences were significant, auricular chondrocyte implantation induced an inferior healing response compared with the empty defects. Elastic auricular chondrocytes might maintain some tissue-specific characteristics when implanted into joint cartilage defects which limit its repair capacity., (Copyright © 2014 Elsevier GmbH. All rights reserved.)

Memory B cells (mBCs) are a key to immunologic memory, yet their distribution within lymphoid organs and the individual role of these for mBC functionality remain largely unknown. This study characterized the distribution and phenotype of human (Ag-specific) mBCs in peripheral blood (PB), spleen, tonsil, and bone marrow. We found that the spleen harbors most mBCs, followed by tonsils, BM, and PB, and we detected no major differences in expression of markers associated with higher maturity. Testing the distribution of tetanus toxoid-specific (TT(+)) mBCs revealed their presence in PB during steady state, yet absolute numbers suggested their largest reservoir in the spleen, followed by tonsils. To explore the role of both tissues in the maintenance of reactive B cell memory, we revaccinated controls and splenectomized and tonsillectomized individuals with TT. All donor groups exhibited comparable emergence of anti-TT IgG, TT(+) plasma cells, and TT(+) mBCs in the PB, together with similar molecular characteristics of TT(+) plasma cells. In summary, human mBCs recirculate through PB and reside in different lymphoid organs that do not reflect different mBC maturity stages. The spleen and tonsil, although harboring the largest number of overall and TT(+) mBCs, appear to be dispensable to preserve adequate responsiveness to secondary antigenic challenge.

RORγt⁺ innate lymphoid cells (ILCs) are crucial players of innate immune responses and represent a major source of interleukin-22 (IL-22), which has an important role in mucosal homeostasis. The signals required by RORγt⁺ ILCs to express IL-22 and other cytokines have been elucidated only partially. Here we showed that RORγt⁺ ILCs can directly sense the environment by the engagement of the activating receptor NKp44. NKp44 triggering in RORγt⁺ ILCs selectively activated a coordinated proinflammatory program, including tumor necrosis factor (TNF), whereas cytokine stimulation preferentially induced IL-22 expression. However, combined engagement of NKp44 and cytokine receptors resulted in a strong synergistic effect. These data support the concept that NKp44⁺ RORγt⁺ ILCs can be activated without cytokines and are able to switch between IL-22 or TNF production, depending on the triggering stimulus., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Tissue trauma induces an inflammatory response associated with a cytokine release that may engage complement pathways. Cytokine-mediated complement expression may contribute to cartilage degradation. Hence, we analysed the complement expression profile in primary articular and non-articular chondrocytes and its interrelation with cytokines. The expression of the anaphylatoxin receptors (C3aR and C5aR) and the complement regulatory proteins (CPRs) CD35, CD46, CD55 and CD59 was studied in cultured articular, auricular and nasoseptal chondrocytes using RTD-PCR and immunofluorescence labelling. The complement profile of peripheral blood mononuclear cells (PBMCs) was opposed to the expression in articular chondrocytes. The time-dependent regulation (6 and 24 h) of these complement factors was assessed in articular chondrocytes in response to the cytokines TNFα, IL-10 or TNFα combined with IL-10 (each 10 ng/mL). C3aR, C5aR, CD46, CD55 and CD59 but almost no CD35 mRNA was expressed in any of chondrocyte types studied. The anaphylatoxin receptor expression was lower and that of the CRPs was higher in chondrocytes when compared with PBMCs. The majority of the studied complement factors were expressed at a significantly lower level in non-articular chondrocytes compared with the articular chondrocytes. TNFα significantly increased the C3aR expression in chondrocytes after 6 and 24 h. TNFα + IL-10 significantly downregulated C5aR and IL-10 significantly inhibited the CD46 and CD55 gene expression after 24 h. C5aR and CD55 could be localised in cartilage in situ. Anaphylatoxin receptors and CRPs are regulated differentially by TNFα and IL-10. Whether cytokine-induced complement activation occurs in response to cartilage trauma has to be further identified.

Background: The presurgical diagnostic for measurement of skull thickness for implantations of epithesis or bone anchored hearing aids is limited on computed tomography (CT) of petrosal bone up to now. Testing of ultrasound for measurement of skull thickness is the aim of our study ., Material and Methods: 20 patients has been included, which had got a computed tomography of nasal sinus, skull or petrosal bone. The potential localisations of implantations have been measured by 3D-reconstruction of computed tomography. The results have been statistical compared by sonographic investigations (7.5 MHz Soundhead) at the same localisation., Results: The mean skull thickness has been 5,2 mm in computed tomography. Comparison has described a mean skull thickness of 4,2 mm in sonography. Statistical comparison has shown that ultrasound has been measured statistical significant too small., Conclusions: The skull thickness can be described and measured by sonography. However mean skull thickness has been measured statistical significant too small. In spite of this, conclusions relating to presurgical diagnostic, for instance for the implantation of epithesis and bone anchored hearing aids, can be drawn by sonographic data.