David Holzmann

Defective epithelial barrier in chronic rhinosinusitis: The regulation of tight junctions by IFN-γ and IL-4

BACKGROUND Chronic rhinosinusitis (CRS) is a common disease with still unclear pathophysiologic mechanisms. Epithelial tight junctions (TJs) have been shown to be involved in different chronic disorders, including bronchial asthma, inflammatory bowel diseases, and skin disorders. The regulation of epithelial barrier function and TJ expression has not been extensively studied in patients with CRS and in the paranasal sinus epithelium thus far. OBJECTIVE We sought to elucidate the TJ expression pattern in the epithelium of the sinonasal mucosa and its regulation in patients with CRS. METHODS Trans-tissue resistance was measured in biopsy specimens from healthy control subjects and patients with CRS with and without nasal polyps. TJ protein expression was determined by using immunofluorescence, Western blotting, and real-time PCR. Primary epithelial cell cultures from patients with CRS and control subjects were used in air-liquid interface (ALI) cultures for the measurement of transepithelial resistance (TER) and TJ expression. The effect of IFN-γ, IL-4, and IL-17 on ALI cultures was assessed. RESULTS A decreased trans-tissue resistance was found in biopsy specimens from patients with CRS with nasal polyps along with an irregular, patchy, and decreased expression of the TJ molecules occludin and zonula occludens 1. TER was reduced in ALI cultures from patients with CRS with nasal polyps. The cytokines IFN-γ and IL-4 decreased TER, whereas IL-17 did not have any influence on epithelial integrity. CONCLUSION A defective epithelial barrier was found in patients with CRS with nasal polyps along with a decreased expression of TJ proteins. The disruption of epithelial integrity by IFN-γ and IL-4 in vitro indicates a possible role for these proinflammatory cytokines in the pathogenesis of patients with CRS.

Effects of sinus surgery in patients with cystic fibrosis after lung transplantation: a 10-year experience

Chronic infectious rhinosinusitis with Pseudomonas aeruginosa is common in cystic fibrosis and may result in allograft infection after lung transplantation. Sinus surgery followed by nasal care may reduce these adverse effects. Sinus surgery was performed in 37 patients with cystic fibrosis after transplantation. Bacteriology of sinus aspirates (n=771) and bronchoalveolar lavage (BAL) (n=256) was correlated with clinical data. Sinus surgery was successful in 54% and partially successful in 27% of patients. A significant correlation between negative sinus aspirates and negative BAL and between positive sinus aspirates and positive BAL (P <0.0001) was found. Successful sinus management led to a lower incidence of tracheobronchitis and pneumonia (P =0.009) and a trend toward a lower incidence of bronchiolitis obliterans syndrome (P =0.23). Sinus surgery followed by daily nasal douching may control posttransplant lower airway colonization and infection. In the long term, this concept may lead to less bronchiolitis obliterans syndrome by decreasing bronchiolar inflammation.

Subjective and objective results after bilateral cochlear implantation in adults.

Objective: To assess and compare subjective and objective results after bilateral cochlear implantation with a special emphasis on time interval between the first and second implant. Study Design: Clinical trial. Setting: Tertiary referral center. Patients: All consecutively bilaterally implanted adult patients who had used the second implant for more than 6 months were selected for the study. They had to have the mental capacity to answer questions regarding their hearing abilities and fill out a questionnaire (n = 34). Twenty-nine patients (85%) finally could be included in the study (age at first implantation, 31.0 ± 16 yr [mean ± standard deviation {SD}], time to second implantation, 5.6 ± 5.7 yr [mean ± SD]). In all patients, a full insertion (21 electrodes) of the implant was achieved. For the subjective part of the study, the patients were matched with unilaterally implanted subjects selected according to specified criteria. Interventions: Sequential or simultaneous cochlear implantation with a Nucleus device. Main Outcome Measures: Speech comprehension measures were performed using the Oldenburger sentences in quiet and in noise with unilateral and bilateral implant use. Summation effect, head shadow effect, squelch effect, and interaural difference in quiet and noise were calculated. Advantage for binaural stimulation with respect to the unilateral condition was assessed for each individual. Additionally, a localization test was performed using 12 speakers arranged in a circle. Subjective benefit was assessed by a questionnaire (The Speech, Spatial and Qualities of Hearing Scale). Results were analyzed with special emphasis on effects of timing and intervals. Results: There was a statistically significant advantage for the head shadow effect test (p < 0.05) when the sound source was located on the activated side. There was also a statistically significant correlation of the subjective and objective results and a strong correlation of the interaural difference of speech intelligibility in quiet and the time interval between the first and the second implant (p < 0.001; r2 = 55%). In the bi-implanted state, an interaural difference of 18 ± 27% and 3 ± 2.2 dB signal-to-noise ratio (mean ± SD) was measured in quiet and noise, respectively. The mean results for the bilateral condition for the summation effect, the squelch effect, and speech discrimination in quiet were better than in the unilateral condition but were not statistically significant. The subjective results of the bilateral group were better in all categories than the results of the unilateral group but were just below statistical significance. Conclusion: Speech understanding in noise is improved with bilateral cochlear implantation with unambiguous evidence that the second implant expands the sound field for effective speech recognition. Communication in daily life is facilitated, as determined by the subjective Speech, Spatial and Qualities of Hearing Scale test. The correlation of the subjective and objective results confirms the practical benefits in daily activities. Although there was improvement with a second Cochlear implant even after a long implantation interval, short intervals lead to better results.

Long‐Term Results of Endonasal Sinus Surgery in Sinonasal Papillomas

Objective To assess the value of endonasal sinus surgery in the management of sinonasal papillomas.

Sinonasal, genital and acrolentiginous melanomas show distinct characteristics of KIT expression and mutations.

KIT aberrations predict the outcome of targeted therapies in acrolentiginous (ALM) and mucosal (MM) melanoma patients. KIT immunoreactivity and mutation status was assessed in 41 ALM and 25 MM patients. Of these, 19 ALM and 15 MM patients had matched primary and metastatic lesions. P-ERK was investigated in a subset of 9 ALM and 7 MM matched primary/metastatic pairs by immunohistochemistry. Heterogeneous KIT immunoreactivity was observed in both primary and metastatic lesions. Mutations were present in four of 41 ALM (10%) and five of 25 MM (20%) patients. Only vulvar mucosal samples carried KIT mutations in contrast to sinonasal lesions (p = 0.0109). In KIT-mutated tumours, the mutations were present in KIT expressing as well as KIT negative cells, as shown by Laser Capture Microdissection (LCM). P-ERK expression was preferentially found in metastases. KIT mutations predict treatment outcome with KIT inhibitors. Therefore, especially vulvar melanoma patients should be screened for activating KIT mutations.

Lateral Dural Sinus Thrombosis in Childhood

Objectives: To present etiology, diagnosis, and treatment of dural sinus thrombosis (DST) in children. To discuss the diagnostic role of contrast‐enhanced computed tomography (CECT) and to evaluate the controversial treatment modalities of anticoagulation, surgical drainage of the infected sinus, and ligation of the internal jugular vein (IJV).

Outcome of sinonasal melanoma: Clinical experience and review of the literature

Primary sinonasal malignant melanoma (SNMM) is a rare clinical entity. There is neither a classification nor a staging system nor an evidence‐based treatment concept established. Our objective was to find potential risk factors predicting the outcome.

Dual nature of T cell―epithelium interaction in chronic rhinosinusitis

BACKGROUND T-cell infiltration of submucosa, release of proinflammatory cytokines leading to epithelial activation, and contributions to inflammation are observed in chronic rhinosinusitis (CRS). OBJECTIVES Molecular mechanisms and kinetics of T-cell interaction with sinus epithelium leading to activation followed by subsequent apoptosis of epithelial cells were the focus of the current study. METHODS Primary human sinus epithelial cells and T cells generated from sinus tissues of healthy individuals and patients with CRS with or without allergy and sinus tissue biopsies were characterized in terms of activation (surface marker expression, cytokine production via real-time PCR, confocal microscopy, ELISA) and apoptosis (annexin V/7-amino-actinomycin D staining, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay, receptor expression by flow cytometry, confocal microscopy) of epithelial cells. RESULTS Primary human sinus epithelial cells isolated from patients with CRS were at an activated state with upregulated expression of HLA-DR, IFN-gamma-inducible protein 10, monokine induced by IFN-gamma, and TNF-related apoptosis-inducing ligand (TRAIL) compared with healthy individuals. The expressions of these chemokines, HLA-DR, TRAIL, and TNF receptor 2 were significantly induced by IFN-gamma, whereas TRAIL receptor 4 was downregulated. Epithelial cells started to undergo apoptosis 48 hours after IFN-gamma stimulation when the transcription of proinflammatory cytokines and chemokines decreased to initial levels. The essential factors for sinus epithelial apoptosis were T(H)1 cells and IFN-gamma. Epithelial apoptosis was enhanced by Fas-Fas-ligand and TRAIL-TRAIL receptor 2 interactions. Remarkable apoptosis of epithelial cells and shedding was observed in CRS in situ. CONCLUSION Epithelial cell interaction with activated T cells is a biphasic phenomenon in CRS. Initially activated T cells lead to activation and induction of proinflammatory functions of epithelial cells, and thereafter their apoptotic death, resulting in no more contribution to inflammation, takes place.

On the effectiveness of treatment options in epistaxis: an analysis of 678 interventions.

BACKGROUND Epistaxis represents one of the most common emergencies in ENT clinics around the world. It creates great physical and emotional stress to the patient as well as a financial burden on health-care systems. A lot of research has been performed with regard to aetiology and possible treatment, however, not much effort has been put into analysing the effectiveness of common treatment forms. It is the objective of this study to clarify which of these treatment forms is reliable. STUDY DESIGN Retrospective cohort study. LEVEL OF EVIDENCE 2b. METHODS Between 03/2007 and 04/2008, all epistaxis therapies including relapses and treatment failures at the University Hospital of Zurich have been documented using a computerised questionnaire. Different treatments were compared to each other. RESULTS An analysis of 678 interventions in 537 patients was performed with emphasis on failure proportions and time to occurrence. The estimated failure proportions of coagulation in anterior epistaxis accounts for 14%. Successful treatment of epistaxis in posterior bleedings could be achieved in 62% by packing and in 97% by surgery with a statistically significant difference between the respective groups. CONCLUSION Using our treatment options, anterior epistaxis can be cured reliably by cauterisation. Surgical therapies in posterior bleedings are able to successfully salvage failed packing therapies.

Impact of Sinus Surgery on Pseudomonal Airway Colonization, Bronchiolitis Obliterans Syndrome and Survival in Cystic Fibrosis Lung Transplant Recipients

Background: Lung transplantation (LTx) is a therapy for patients with cystic fibrosis (CF) end-stage lung disease. Pseudomonal airway colonization (PAC) is common in CF. Objectives: We investigated the influence of post-transplant sinus surgery and daily nasal douching on PAC after LTx and the influence of PAC on survival and bronchiolitis obliterans syndrome (BOS). Methods: CF patients transplanted at our centre were included (November 1992 to December 2009). Clinical data, including microbiological data before and after LTx were collected. Survival and BOS following LTx were compared for CF recipients with and without PAC by Kaplan-Meier statistics and Cox regression analysis. Results: Ninety-four CF patients were transplanted, of whom 82 (87%) underwent sinus surgery after transplantation, and 65% of 66 patients with pre-transplant PAC had persistent PAC after transplantation. Upper and lower PAC is related. Patients without PAC after transplantation had a significantly better survival rate, and BOS was less frequent with a later onset. PAC was the only significant parameter for the development of BOS stage 2 in the multivariate analysis for cytomegalovirus infection, acute rejection and PAC. Conclusions: Sinus surgery and daily nasal douching reduced PAC in LTx recipients. Absence of post-transplant PAC had a positive impact on post-transplant survival and the development of BOS.