Perception of Specific Musical Attributes in Dependence of the Insertion Depth of Cochlear Implant Electrodes Using the Montreal Battery of Evaluation of Amusia.

HYPOTHESIS: The insertion angle of the electrode array has an influence on the perception of different musical features. BACKGROUND: A deeper insertion of the electrodes is associated with a greater coverage of the cochlea with possible stimulus locations. This could lead to an improved or extended perception of pitches and pitch changes as well as to a better perception of contours in musical pieces. METHODS: A Montreal Battery of Evaluation of Amusia test battery was conducted with a collective of 19 cochlear implant (CI) users and 9 normal-hearing subjects. For the CI users, the insertion angles of the intracochlear electrode arrays were calculated using Otoplan software. RESULTS: Compared with normal-hearing users, CI users performed worse in the detection of melodic features of music. CI users performed better with temporal features than with melodic features. An influence of the insertion depth of the electrodes on the results of the Montreal Battery of Evaluation of Amusia could be proven neither for Cochlear nor for MED-EL CI users. CONCLUSION: Deeper insertion of electrode arrays may only better approximate the spatial-frequency map. Alone, it does not have an effect on better detection and identification of pitch and tonality and, consequently, better perception of musical attributes. Anatomy-based calculation of electrode locations and matching to characteristic frequencies will be sought in subsequent studies.

Discrepancy of the subjective perception of the nasal appearance between independent individuals and patients undergoing functional rhinoplasty (fRPL).

PURPOSE: Satisfaction with the nasal appearance is a crucial outcome parameter in functional rhinoplasty (fRPL). The visual analogue scale is a suitable instrument not only for the preoperative patient assessment, but also as a patient-reported outcome measure in fRPL. In this study, we analyzed whether a high discrepancy in the preoperative subjective perception of the nasal appearance between patients and other individuals predicts a lower level of satisfaction with the postoperative result and hence a worse outcome of fRPL. METHODS: Standardized facial pictures of patients (n = 80) who underwent fRPL were taken preoperatively, 3 and 12 months postoperatively. In addition, patients were asked to complete the German version of the Utrecht Outcome Assessment Questionnaire in Aesthetic Rhinoplasty (D-OAR). The standardized facial pictures of the patients were presented to surgeons as well as to examiners without a medical background, and they were asked to evaluate the patients' nasal appearance using the visual analogue scale. RESULTS: The external evaluation of patient's nasal appearance was 1.7 points higher in median than the patient's subjective perception (range -5.7-7.00). A large discrepancy between self- and external estimation significantly correlates with higher D-OAR values (r = 0.539, p < 0.001). Patients with high scores in the D-OAR trick questions, indicating a body dysmorphic disorder, show a significant larger discrepancy between the external- and the self-assessment (2.8 ± 0.5 vs. 1.4 ± 0.3, mean ± SEM, p = 0.017). CONCLUSIONS: Large discrepancies between the self and external assessment of the nasal appearance are associated with a high-perceived influence of the appearance of the nose on the quality of life in patients undergoing functional rhinoplasty. That might be an indicator for unrealistic expectations concerning the postoperative outcome. Knowledge about this factor helps to identify the need for intensive discussion about possibilities and limitations of the planned procedure to avoid postoperative dissatisfaction.

Increased levels of S100A8/A9, IL-1ß and IL-18 as a novel biomarker for recurrent tonsillitis.

BACKGROUND: Acute tonsillitis represents one of the most frequent reasons patients seek primary medical care and otorhinolaryngology consultation. Therefore, recurrent episodes of acute tonsillitis (RAT), also called chronic tonsillitis, exhaust a substantial amount of medical and financial resources. Diagnosis of tonsillitis depends on a physical examination, which therefore does not allow for a reliable differentiation between viral and bacterial infection. However, the frequency of bacterial infections during the previous three years is currently being used as the major deciding factor in patient selection for tonsillectomy. The aim of the present study was to determine an objective biomarker to help in the identification of patients suffering from recurrent tonsillitis. RESULTS: By analyzing a panel of cytokines and chemokines in serum and saliva of patients with RAT compared to healthy controls, increased levels of IL-1ß (153.7 ± 48.5 pg/ml vs 23.3 ± 6.6 pg/ml, p = 0.021), IL-18 (120.2 ± 16.5 vs 50.6 ± 9.3 pg/ml, p = 0.007) and/or S100A8/A9 (996 ± 102 ng/ml vs 546 ± 86 ng/ml, p = 0.042) could be observed in patients suffering from RAT. Cut-off values of these parameters were determined and combined to a new RAT-score allowing for reliable identification of patients suffering from recurrent tonsillitis with a sensitivity of 95% and a specificity of 88%. CONCLUSION: The RAT-score represents the first objective criterion as a tool for the diagnosis of recurrent tonsillitis and it also improves patient selection for tonsillectomy.

Evaluation of the QUANTUM BLUE sCAL rapid test as a point of care tool to identify patients with peritonsillar abscess.

S100A8/A9 (Calprotectin) serves as a biomarker for various inflammatory diseases, such as for peritonsillar abscess (PTA). Recently, the PTA score was developed for reliable PTA identification. It uses a combination of characteristic clinical symptoms and elevated calprotectin levels in serum and saliva to determine this score. Although well-established point-of-care tests (POCT) to determine serum or faecal calprotectin levels exist, a reliable and rapid tool to analyse salivary calprotectin has not yet been described. In this study, we analysed the potential of the QUANTUM BLUE sCAL Test (QBT, BÜHLMANN Laboratories AG, Switzerland) to determine S100A8/A9 levels during outpatient management. These QBT measurements are combined with other clinical factors to determine the PTA score. Significantly higher calprotectin levels were determined by QBT in patients with PTA compared to healthy controls. The receiver operating characteristic (ROC) curves for the QBT revealed cut-off values of 2940 ng/ml (sensitivity = 0.88, specificity = 0.78) in serum and 5310 ng/ml (sensitivity = 0.80, specificity = 0.50) in saliva. By adding the QBT results to determine PTA values, a ROC analysis provided a statistical cut-off score of 2.5 points to identify the existence of a PTA with a sensitivity of 100% and a specificity of 89.3%. The QUANTUM BLUE sCAL Test (QBT) is an appropriate POCT to determine serum and salivary calprotectin levels. Thus, PTA scores can be determined within a short time frame by applying the QBT during outpatient management.

Anamnesis as a Prognostic Factor in Cochlear Implantation in Adults.

INTRODUCTION: This study aims to analyze possible preoperative factors taken from the medical history that may assist the otolaryngologist in counseling an adult patient before cochlear implantation (CI). OBJECTIVE: Analysis of preoperative factors taken during the initial patient presentation for a possible prognostic role in the auditory rehabilitation outcome. METHODS: A cohort of 232 (272 CI implantations) postlingually deafened adults was evaluated in this study. Hearing results at 1, 2, and up to 3 years postoperatively were compared with various preoperative factors: living status, cause of deafness, gender, side of implantation, residual hearing, and duration of deafness. Postoperative hearing performance was measured based on the German Freiburg monosyllabic word test and the Oldenburg sentence test. RESULTS: Duration of deafness showed a negative correlation to word recognition and a positive correlation to increased speech reception threshold in sentence testing. A significant decline in hearing outcome was shown starting around the second decade of deafness. Residual hearing as defined in our cohort and side of implantation showed limited benefit in speech understanding. Living status, gender, and cause of deafness did not show any prognostic value. CONCLUSION: In this retrospective review it could be shown that simple case history information can only provide limited prognostic insight before CI. The duration of deafness is the most reliable anamnestic factor present on initial patient evaluation.

IL-8 and IFN-γ as Preoperative Predictors of the Outcome of Tonsillectomy.

OBJECTIVES: Tonsillectomy (TE) and tonsillotomy (TO) due to recurrent episodes of acute tonsillitis (RAT) belong to the most frequent surgical procedures. However, an adequate objective marker predicting the outcome of TE/TO preoperatively is missing. METHODS: Patients with RAT who underwent TE/TO (n = 31) were included in this pilot study. A panel of cytokines and chemokines in serum and saliva were determined preoperatively. Health-related quality of life was assessed pre- and postoperatively by the Tonsillectomy Outcome Inventory-14. RESULTS: Health-related quality of life improved significantly after surgery. Increased serum levels of interleukin-8 (IL-8) and interferon gamma (IFN-γ) are associated with a less successful outcome. No correlation between the number of acute tonsillitis episodes and the health-related quality of life after TE or TO could be observed. CONCLUSIONS: Tonsillectomy and TO improve health-related quality of life independently from the number of past acute tonsillitis episodes. Interleukin-8 and IFN-γ in serum may serve as promising markers, predicting the benefit of TE or TO for patients preoperatively.

Prognostic factors in cochlear implantation in adults: Determining central process integrity.

The purpose of this study is to examine various preoperative factors that can play a role in the auditory rehabilitation outcome of cochlear implant (CI) recipients. In order to determine the level of integrity of central processing preoperatively, special attention was given to residual hearing, duration of deafness, and cochlear nerve diameter as prognostic factors. A cohort of 232 (272 CI implantations) postlingually deafened adults was evaluated in this study. Hearing results at 1, 2 and up to 3 years postoperatively were compared with various preoperative factors: promontory stimulation testing, residual hearing, duration of deafness, and magnetic resonance imaging of the cochlear nerve. Postoperative hearing performance was measured based on the German Freiburg monosyllabic word test and the Oldenburg sentence test. Postoperative hearing performance showed a significant improvement in each consecutive year after implantation. Duration of deafness showed a negative correlation to word recognition and a positive correlation to increased signal-to-noise-ratio in sentence testing. A significant decline in hearing outcome was shown starting around the second decade of deafness corresponding to 66% of life spent in deafness. MR imaging of cochlear nerve diameter shows a positive correlation of larger nerve diameter to better speech understanding. Promontory stimulation testing did not show any prognostic value. In this retrospective review it could be shown that there is an intricate interaction in the preoperative variables: duration of deafness - as well as the ratio of life spent in deafness; residual hearing; and cochlear nerve diameter.

Structured literature review of patient-reported outcome (PRO) instruments in adult tonsillectomy or tonsillotomy.

BACKGROUND: Instruments that measure the patient-reported outcome and quality of life are essential to assess the treatment success of any medical intervention. This review represents valid and reliable outcome assessment instruments for tonsillectomy (TE) and tonsillotomy (TO) in adult patients as TE/TO still belong to one of the most common performed surgical procedures. METHODS: A systematic review of the literature in the MEDLINE, PubMed, Web of Science and Cochrane Library was conducted. Studies describing reliable and valid patient-reported outcome measures (PROM) in adults with regard to the perioperative as well as postoperative follow-up after TE/TO were examined. Thus, studies without PROMs or PROMs only relating to children as well as studies in non-English/non-German language or without any detailed information were excluded. RESULTS: Four thousand four hundred forty studies were identified. Thirteen reliable and valid patient-reported outcome assessment instruments presenting the perioperative and postoperative outcome were analysed. Four generic questionnaires are included that are used to measure the outcome after TE/TO in adults. Four disease-specific questionnaires relating to obstructive sleep apnea (OSA) and sleep disordered breathing (SDB) as well as two TE/TO specific questionnaires are validated for adults. With regard to the perioperative outcome including parameters like pain, nausea, vomiting, satisfaction three assessment instruments are analysed. CONCLUSION: This review describes the currently available, reliable and valid generic and disease-specific instruments assessing the perioperative as well as postoperative outcome to evaluate the treatment success after TE/TO in adult patients. Therefore, this study improves the selection of the appropriate patient-reported outcome assessment instrument to assess the quality of life in adults undergoing TE/TO.

Influence of the Subjective Body Image on the Outcome of Functional Rhinoplasty.

Improvement of nasal breathing is considered to be the major aspect of functional rhinoplasty (fRPL). Nevertheless, simultaneous aesthetic modifications can be required to achieve sufficient functional enhancement. Thus, the aim of this study was to assess the influence of the subjective perception of the nasal appearance on the outcome of fRPL. Patients undergoing fRPL were asked to complete the German version of the Utrecht Questionnaire for Outcome Assessment in Aesthetic Rhinoplasty (D-OAR) preoperatively, 1, 3 and 12 months after surgery. The patients' satisfaction with the procedure's result was determined using a five-point Likert scale 1, 3 and 12 months after rhinoplasty. In total, 87 patients (42 males and 45 females) with a median age of 25 years undergoing fRPL were included in this study. Compared to males, females showed diminished VAS scores (4.03 ± 2.02 vs 2.71 ± 1.96, p = 0.006) and higher D-OAR scores during preoperative outpatient consultation (13.34 ± 5.00 vs 16.07 ± 5.62, p = 0.020). An increase in the VAS score and a decrease in the D-OAR score were observed independent of gender post-operatively. Significant correlations between the patients' satisfaction and the D-OAR score at each time point of assessment were demonstrated, whereas no significant correlation between the post-operative patients' satisfaction and the initial D-OAR score could be identified. These results demonstrate the importance of body image and the subjective perception of the nasal appearance in particular in patients undergoing fRPL which should be taken into consideration of surgeons preoperatively. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Adaption and validation of the nasal obstruction symptom evaluation scale in German language (D-NOSE).

BACKGROUND: Questionnaires have proven their worth in detecting changes in quality of life after medical interventions. The Nasal Obstruction Symptom Evaluation scale (NOSE) is a reliable and valid tool to identify restrictions of quality of life in patients with nasal problems. The aim of this prospective study was the validation of the German version of the NOSE scale (D-NOSE). METHODS: Adaption of the NOSE in German language was performed by forward and backward translation process. Patients undergoing functional septorhinoplasty were asked to complete the D-NOSE preoperatively, one, three or twelve months after surgery. Healthy volunteers served as controls. Reliability, validity and responsiveness of the D-NOSE were determined. RESULTS: The D-NOSE showed a good internal consistency as well as good inter-item, item-total correlation and a satisfactory test-retest reliability. The convincing validity of the adapted NOSE scale was approved by good construct validity and an excellent discriminant validity. Furthermore, a high sensitivity to identify clinical changes due to an intervention indicates a good responsiveness of the D-NOSE. CONCLUSIONS: The adapted German version of the NOSE questionnaire (D-NOSE) is an appropriate and validated tool to assess the influence of nasal obstruction in quality of life in German speaking patients.

S100 proteins in rheumatic diseases.

Rheumatic diseases are characterized by sterile inflammation that causes severe long-term damage to various organ systems. A growing body of evidence supports a pivotal role for the pro-inflammatory calcium-binding S100 family of proteins in the pathogenesis of rheumatic diseases. Some S100 proteins are released at the site of inflammation and act as danger-associated molecular pattern molecules by activating pattern recognition receptors. Increased concentrations of S100 proteins in serum and synovial fluid closely correlate with disease activity in several rheumatic diseases and serve as useful biomarkers for monitoring disease activity. Some S100 proteins are also valid biomarkers for predicting response to treatment, systemic organ involvement or disease flares in rheumatic diseases. Analyses of knockout mouse models have confirmed a functional role for S100 proteins, particularly S100A8 and S100A9, in rheumatic diseases, indicating that blocking the expression, release or function of these proteins might be an innovative therapeutic strategy. Owing to their local pattern of expression, specific mechanism of release and autoregulatory effects, such therapeutic approaches would primarily target the local inflammatory process and present only minor risks of systemic adverse effects.

Potential of the Novel PTA Score to Identify Patients with Peritonsillar Inflammation Profiting from Medical Treatment.

Peritonsillar inflammation is a common characteristic of both peritonsillar abscess (PTA) and peritonsillitis (PC). The aim of the present study was to apply the PTA score as an objective criterion to identify patients with peritonsillar inflammation (PI) who might profit from medical treatment. Hence, the recently developed PTA score was applied retrospectively on patients suffering from acute tonsillitis, peritonsillitis, and peritonsillar abscess. Analysis of the clinical data, the follow-up, and the initial PTA score was performed. Patients with peritonsillar inflammation show significant higher PTA score values compared to patients with acute tonsillitis without peritonsillar inflammation and healthy controls. Patients with a PTA score ≤ 2 profited from medical treatment consisting of antibiotics in 92.3% of the cases. In 89.2% of the patients with a PTA score > 2, pus was detected during abscess relief. Patients with peritonsillar inflammation who profited from medical treatment had significantly reduced PTA score values and a reduced duration of hospitalization compared to the patients with abscess relief. Thus, the PTA score has the potential as an objective criterion to identify patients with peritonsillar inflammation profiting from medical treatment. Hence, application of the PTA score helps to determine an optimal, individualized treatment approach and might reduce utilization of medical resources.

Development and Validation of a Brief Four-Component Questionnaire to Identify Patient's Motivation to Undergo Functional Rhinoplasty.

Outcome of functional rhinoplasty depends on different domains such as functional and aesthetic improvement. The aim of this study was to develop a brief and comprehensible questionnaire to identify patient motivation to undergo rhinoplasty and to measure the outcome of an intervention within a short time during outpatient consultation. Patients undergoing rhinoplasty were asked to complete the Rhinoplasty Outcome Evaluation (ROE) questionnaire, the Nasal Obstruction Symptom Evaluation (NOSE) scale, and the Utrecht Questionnaire for Outcome Assessment in Aesthetic Rhinoplasty (OAR) preoperatively, as well as one, three, and twelve months postoperatively. Patient satisfaction after surgery was assessed at postoperative consultations using a five-point Likert scale. Principle component analysis was performed to reveal the main domains, which were detected by the different questionnaires. Items with the strongest loading on a factor were identified by correlation matrix. Influence of the nasal appearance on the quality of life, troubles with nasal breathing, subjective perception of nasal appearance, and the wish for modification or alteration were found to be the four important domains of the questionnaires. The questions with the strongest loading on these domains were compiled and the four-component questionnaire (4CQ) was developed. The 4CQ is a very effective instrument to obtain a comprehensive impression of the varied determinants representing the major motifs to undergo functional rhinoplasty within a short time. The preoperative assessment of the 4CQ allows an estimation concerning the expected outcome.

Imaging, myeloid precursor immortalization, and genome editing for defining mechanisms of leukocyte recruitment in vivo.

Recruitment of leukocytes from the blood to sites of inflammation poses a promising target for new diagnostic and therapeutic approaches. We aimed to develop a novel method to non-invasively analyze molecular mechanisms of leukocyte migration in pre-clinical models of inflammation in vivo. Methods: We used the ER-HoxB8 system to transiently immortalize murine myeloid precursors from wildtype and CD18- as well as MRP14-deficient mice. A VLA4α-/- cell line was generated by CRISPR/Cas9-mediated gene editing. We analyzed the migration of wildtype and knockout leukocytes in vivo by optical and nuclear imaging in mice with irritant contact dermatitis, cutaneous granuloma, experimental arthritis and myocardial infarction. Results: Transient immortalization, gene editing and in vivo imaging can be combined to analyze migratory mechanisms of murine leukocytes, even for gene deletions resulting in lethal phenotypes in mice. We reliably confirmed known migratory defects of leukocytes deficient for the adhesion molecules CD18 or VLA4α. Also, using our new method we identified a new role of the most abundant calcium-binding proteins in phagocytes and major alarmins in many inflammatory diseases, MRP8 and MRP14, for transmigration in vivo. Conclusion: We provide a combinatorial approach to rapidly characterize molecular mechanisms of leukocyte recruitment in vivo, with the potential to aid in identification of diagnostic and therapeutic targets in inflammatory pathologies.

The Visual Analog Scale as a Comprehensible Patient-Reported Outcome Measure (PROM) in Septorhinoplasty.

The patient's satisfaction with the esthetic result is a major criterion of success in septorhinoplasty. However, the idea of esthetic perfection varies greatly and primarily depends on subjective perception. Hence, patient-reported instruments are important and necessary to assess the outcome in septorhinoplasty. To analyze the potential of the visual analog scale (VAS) as a patient-reported outcome measure in septorhinoplasty, the perception of the nasal appearance was assessed by a VAS pre- and postoperatively in 213 patients undergoing septorhinoplasty. Furthermore, in this prospective study, the patients' satisfaction concerning the procedure's result was analyzed using a five-point Likert scale. Females had lower preoperative VAS scores but a higher increase compared to males. Patients with lower initial VAS scores showed a higher improvement in the VAS score postoperatively compared to patients with higher initial VAS scores. Satisfaction with the result depends on the increase in the VAS score value. The VAS scale is a short and comprehensible tool to assess patients' perception of nasal appearance preoperatively and represents an appropriate instrument to assess the esthetic patient-reported outcome in septorhinoplasty.Level of Evidence IV This journal requires that authors assign a level of evidence to each article. For a full description of these evidence-based medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Increased Levels of S100A8/A9 in Patients with Peritonsillar Abscess: A New Promising Diagnostic Marker to Differentiate between Peritonsillar Abscess and Peritonsillitis.

Peritonsillar abscess (PTA) is a very frequent reason for urgent outpatient consultation and otolaryngological hospital admission. Early, correct diagnosis and therapy of peritonsillar abscess are important to prevent possible life-threatening complications. Based on physical examinations, a reliable differentiation between peritonsillar cellulitis and peritonsillar abscess is restricted. A heterodimeric complex called calprotectin consists of the S100 proteins A8 and A9 (S100A8/A9) and is predominantly expressed not only in monocytes and neutrophils but also in epithelial cells. Due to its release by activated phagocytes at local sites of inflammation, we assumed S100A8/A9 to be a potential biomarker for peritonsillar abscess. We examined serum and saliva of patients with peritonsillitis, acute tonsillitis, peritonsillar abscess, and healthy controls and found significantly increased levels of S100A8/A9 in patients with PTA. Furthermore, we could identify halitosis, trismus, uvula edema, and unilateral swelling of the arched palate to be characteristic symptoms for PTA. Using a combination of these characteristic symptoms and S100A8/A9 levels, we developed a PTA score as an objective and appropriate tool to differentiate between peritonsillitis and peritonsillar abscess with a sensitivity of 92% and specificity of 93%.

Reliability and validity of the German version of the Utrecht Questionnaire for Outcome Assessment in Aesthetic Rhinoplasty (D-OAR).

The outcome of aesthetic rhinoplasty is determined by the patient's subjective satisfaction with the nasal appearance which is difficult to assess. The Utrecht Questionnaire for Outcome Assessment in Aesthetic Rhinoplasty (OAR) is a brief and reliable instrument to assess the influence of the subjective nasal appearance on quality of life in patients undergoing aesthetic rhinoplasty. Preoperative application of this questionnaire reveals important aspects and possible disturbances of the body image which could be negative predictors concerning the result. On the other hand, it represents an appropriate tool to assess the postoperative outcome. The aim of this study was to determine the validity, reliability and responsiveness of the adapted German version of the OAR (D-OAR). The adaption of the OAR to German language was performed by a forward and backward translation process. Patients undergoing rhinoplasty were asked to complete the D-OAR preoperatively, 1, 3 and 12 months after procedure and healthy volunteers without any nasal complaints served as controls to test validity, reliability and responsiveness. An excellent internal consistency, a good test-retest reliability and good inter-item and item-total correlations demonstrated a good reliability of the D-OAR. The convincing validity of the adapted version was proven by an excellent discriminant and a sufficient content validity. Significant differences between pre- and postoperative D-OAR scores revealed a good responsiveness of the instrument. Hence, with a sufficient validity, reliability and sensitivity to changes, the D-OAR is a short and helpful instrument to assess the subjective perception of the nasal appearance in German patients.

Coexistence of sarcoidosis and metastatic lesions: A diagnostic and therapeutic dilemma.

Sarcoidosis, a chronic, inflammatory disease that affects various different organs, is characterized by noncaseating epitheloid granulomas. This systemic inflammatory process is associated with an increased risk of cancer. Several cases of sarcoidosis that mimic metastatic tumor progression in radiological findings have been reported so far. However, there are also cases that have presented a coexistence of sarcoidosis and metastasis, which have caused a diagnostic and therapeutic dilemma. Due to inadequate current therapies, a reliable differentiation between benign and malignant lesions is crucial. This review focuses on the residual risk of the coexistence of metastases within radiological suspicious lesions in patients with a history of solid tumors and sarcoidosis, as well as immunological findings, in order to explain the potential associations. Sarcoidosis has the potential to promote metastasis as it includes tumor-promoting and immune-regulating cell subsets. Notably, myeloid derived suppressor cells may serve a pivotal role in metastatic progression in patients with sarcoidosis. In addition, the present review also evaluates the potential novel diagnostic approaches, which may be able to differentiate between metastatic lesions and sarcoidosis. The risk of coexistent metastasis in sarcoidosis lesions must be considered by clinical practitioners, and a multidisciplinary approach may be required to avoid misdiagnosis and the subsequent unnecessary surgery or insufficient treatments.

Transcriptome assessment reveals a dominant role for TLR4 in the activation of human monocytes by the alarmin MRP8.

The alarmins myeloid-related protein (MRP)8 and MRP14 are the most prevalent cytoplasmic proteins in phagocytes. When released from activated or necrotic phagocytes, extracellular MRP8/MRP14 promote inflammation in many diseases, including infections, allergies, autoimmune diseases, rheumatoid arthritis, and inflammatory bowel disease. The involvement of TLR4 and the multiligand receptor for advanced glycation end products as receptors during MRP8-mediated effects on inflammation remains controversial. By comparative bioinformatic analysis of genome-wide response patterns of human monocytes to MRP8, endotoxins, and various cytokines, we have developed a model in which TLR4 is the dominant receptor for MRP8-mediated phagocyte activation. The relevance of the TLR4 signaling pathway was experimentally validated using human and murine models of TLR4- and receptor for advanced glycation end products-dependent signaling. Furthermore, our systems biology approach has uncovered an antiapoptotic role for MRP8 in monocytes, which was corroborated by independent functional experiments. Our data confirm the primary importance of the TLR4/MRP8 axis in the activation of human monocytes, representing a novel and attractive target for modulation of the overwhelming innate immune response.

Highly pathogenic influenza viruses inhibit inflammatory response in monocytes via activation of rar-related orphan receptor RORα.

Infections with highly pathogenic avian influenza viruses (HPAIV) in humans lead to systemic disease associated with cytokine storm and multiorgan failure. In this study we aimed to identify the role of monocytes for the host response to HPAIV infection. Using genome-wide microarray analysis, we surprisingly demonstrate a reduced immune response of human monocytes to HPAIV H5N1 compared to human influenza A viruses. In bioinformatic analyses we could reveal a potential role of the Rar-related orphan receptor alpha (RORα) for the gene expression pattern induced by H5N1. RORα is known as an inhibitor of NF-κB signaling. We provide evidence that in monocytes RORα is activated by H5N1, resulting in inhibited NF-κB signaling. Using murine Hoxb8-immortalized RORα⁻/⁻, monocytes rescued NF-κB signaling upon H5N1 infection, confirming the biological relevance of RORα as an H5N1-induced mediator of monocytic immunosuppression. In summary, our study reveals a novel RORα-dependent escape mechanism by which H5N1 prevents an effective inflammatory response of monocytes blocking NF-κB-dependent gene expression.