Fibrin-coated collagen fleece versus absorbable dural sealant for sellar closure after transsphenoidal pituitary surgery: a comparative study.

Various surgical methods to prevent postoperative cerebrospinal fluid (CSF) leaks during transsphenoidal surgery have been reported. However, comparative studies are scarce. We aimed to compare the efficacy of a fibrin-coated collagen fleece (TachoSil) versus a dural sealant (DuraSeal) to prevent postoperative CSF leakage. We perform a retrospective study comparing two methods of sellar closure during endoscopic endonasal transsphenoidal surgery (EETS) for pituitary adenoma resection: TachoSil patching versus DuraSeal packing. Data concerning diagnosis, reconstruction technique, and surgical outcomes were analyzed. The primary endpoint was postoperative CSF leak rate. We reviewed 198 consecutive patients who underwent 219 EETS for pituitary adenoma from February 2007 and July 2018. Intraoperative CSF leak occurred in 47 cases (21.5%). A total of 33 postoperative CSF leaks were observed (15.1%). A reduction of postoperative CSF leaks in the TachoSil application group compared to the conventional technique using Duraseal was observed (7.7% and 18.2%, respectively; p = 0.062; Pearson exact test) although non-statistically significant. Two patients required lumbar drainage, and no revision repair was necessary to treat postoperative CSF rhinorrhea in Tachosil group. Fibrin-coated collagen fleece patching may be a valuable method to prevent postoperative cerebrospinal fluid (CSF) leaks during EETS for pituitary adenoma resection.

Inaccurate cortical tracking of speech in adults with impaired speech perception in noise.

Impaired speech perception in noise despite normal peripheral auditory function is a common problem in young adults. Despite a growing body of research, the pathophysiology of this impairment remains unknown. This magnetoencephalography study characterizes the cortical tracking of speech in a multi-talker background in a group of highly selected adult subjects with impaired speech perception in noise without peripheral auditory dysfunction. Magnetoencephalographic signals were recorded from 13 subjects with impaired speech perception in noise (six females, mean age: 30 years) and matched healthy subjects while they were listening to 5 different recordings of stories merged with a multi-talker background at different signal to noise ratios (No Noise, +10, +5, 0 and -5 dB). The cortical tracking of speech was quantified with coherence between magnetoencephalographic signals and the temporal envelope of (i) the global auditory scene (i.e. the attended speech stream and the multi-talker background noise), (ii) the attended speech stream only and (iii) the multi-talker background noise. Functional connectivity was then estimated between brain areas showing altered cortical tracking of speech in noise in subjects with impaired speech perception in noise and the rest of the brain. All participants demonstrated a selective cortical representation of the attended speech stream in noisy conditions, but subjects with impaired speech perception in noise displayed reduced cortical tracking of speech at the syllable rate (i.e. 4-8 Hz) in all noisy conditions. Increased functional connectivity was observed in subjects with impaired speech perception in noise in Noiseless and speech in noise conditions between supratemporal auditory cortices and left-dominant brain areas involved in semantic and attention processes. The difficulty to understand speech in a multi-talker background in subjects with impaired speech perception in noise appears to be related to an inaccurate auditory cortex tracking of speech at the syllable rate. The increased functional connectivity between supratemporal auditory cortices and language/attention-related neocortical areas probably aims at supporting speech perception and subsequent recognition in adverse auditory scenes. Overall, this study argues for a central origin of impaired speech perception in noise in the absence of any peripheral auditory dysfunction.

Fat1 deletion promotes hybrid EMT state, tumour stemness and metastasis.

FAT1, which encodes a protocadherin, is one of the most frequently mutated genes in human cancers1-5. However, the role and the molecular mechanisms by which FAT1 mutations control tumour initiation and progression are poorly understood. Here, using mouse models of skin squamous cell carcinoma and lung tumours, we found that deletion of Fat1 accelerates tumour initiation and malignant progression and promotes a hybrid epithelial-to-mesenchymal transition (EMT) phenotype. We also found this hybrid EMT state in FAT1-mutated human squamous cell carcinomas. Skin squamous cell carcinomas in which Fat1 was deleted presented increased tumour stemness and spontaneous metastasis. We performed transcriptional and chromatin profiling combined with proteomic analyses and mechanistic studies, which revealed that loss of function of FAT1 activates a CAMK2-CD44-SRC axis that promotes YAP1 nuclear translocation and ZEB1 expression that stimulates the mesenchymal state. This loss of function also inactivates EZH2, promoting SOX2 expression, which sustains the epithelial state. Our comprehensive analysis identified drug resistance and vulnerabilities in FAT1-deficient tumours, which have important implications for cancer therapy. Our studies reveal that, in mouse and human squamous cell carcinoma, loss of function of FAT1 promotes tumour initiation, progression, invasiveness, stemness and metastasis through the induction of a hybrid EMT state.

Tracking the Effects of Top-Down Attention on Word Discrimination Using Frequency-tagged Neuromagnetic Responses.

Discrimination of words from nonspeech sounds is essential in communication. Still, how selective attention can influence this early step of speech processing remains elusive. To answer that question, brain activity was recorded with magnetoencephalography in 12 healthy adults while they listened to two sequences of auditory stimuli presented at 2.17 Hz, consisting of successions of one randomized word (tagging frequency = 0.54 Hz) and three acoustically matched nonverbal stimuli. Participants were instructed to focus their attention on the occurrence of a predefined word in the verbal attention condition and on a nonverbal stimulus in the nonverbal attention condition. Steady-state neuromagnetic responses were identified with spectral analysis at sensor and source levels. Significant sensor responses peaked at 0.54 and 2.17 Hz in both conditions. Sources at 0.54 Hz were reconstructed in supratemporal auditory cortex, left superior temporal gyrus (STG), left middle temporal gyrus, and left inferior frontal gyrus. Sources at 2.17 Hz were reconstructed in supratemporal auditory cortex and STG. Crucially, source strength in the left STG at 0.54 Hz was significantly higher in verbal attention than in nonverbal attention condition. This study demonstrates speech-sensitive responses at primary auditory and speech-related neocortical areas. Critically, it highlights that, during word discrimination, top-down attention modulates activity within the left STG. This area therefore appears to play a crucial role in selective verbal attentional processes for this early step of speech processing.

Cortical Tracking of Speech-in-Noise Develops from Childhood to Adulthood.

In multitalker backgrounds, the auditory cortex of adult humans tracks the attended speech stream rather than the global auditory scene. Still, it is unknown whether such preferential tracking also occurs in children whose speech-in-noise (SiN) abilities are typically lower compared with adults. We used magnetoencephalography (MEG) to investigate the frequency-specific cortical tracking of different elements of a cocktail party auditory scene in 20 children (age range, 6-9 years; 8 females) and 20 adults (age range, 21-40 years; 10 females). During MEG recordings, subjects attended to four different 5 min stories, mixed with different levels of multitalker background at four signal-to-noise ratios (SNRs; noiseless, +5, 0, and -5 dB). Coherence analysis quantified the coupling between the time courses of the MEG activity and attended speech stream, multitalker background, or global auditory scene, respectively. In adults, statistically significant coherence was observed between MEG signals originating from the auditory system and the attended stream at <1, 1-4, and 4-8 Hz in all SNR conditions. Children displayed similar coupling at <1 and 1-4 Hz, but increasing noise impaired the coupling more strongly than in adults. Also, children displayed drastically lower coherence at 4-8 Hz in all SNR conditions. These results suggest that children's difficulties to understand speech in noisy conditions are related to an immature selective cortical tracking of the attended speech streams. Our results also provide unprecedented evidence for an acquired cortical tracking of speech at syllable rate and argue for a progressive development of SiN abilities in humans.SIGNIFICANCE STATEMENT Behaviorally, children are less proficient than adults at understanding speech-in-noise. Here, neuromagnetic signals were recorded while healthy adults and typically developing 6- to 9-year-old children attended to a speech stream embedded in a multitalker background noise with varying intensity. Results demonstrate that auditory cortices of both children and adults selectively track the attended speaker's voice rather than the global acoustic input at phrasal and word rates. However, increments of noise compromised the tracking significantly more in children than in adults. Unexpectedly, children displayed limited tracking of both the attended voice and the global acoustic input at the 4-8 Hz syllable rhythm. Thus, both speech-in-noise abilities and cortical tracking of speech syllable repetition rate seem to mature later in adolescence.

Toward an aerodynamic model of fricative consonants.

Determining the starting point of frication is a complex task involving aerodynamic factors dependent on adjustments controlling articulatory and laryngeal structures and on the regulation of air pressure. This study investigates the aerodynamic characteristics of the onset and offset of Belgian French fricative consonants using direct measurements of subglottal (Ps) and intraoral (Po) air pressure. Results show a higher difference between Ps and Po at the onset of voiced fricative consonants when compared to their voiceless counterparts. This accounts for the need for high air velocity through the glottal and consonantal constrictions for voiced fricatives. The offset of voiced fricatives is also characterized by a relatively large difference between Ps and Po, still lower for voiceless equivalents.

The human bitter taste receptor T2R38 is broadly tuned for bacterial compounds.

T2R38 has been shown to be a specific bacterial detector implicated in innate immune defense mechanism of human upper airway. Several clinical studies have demonstrated that this receptor is associated with the development of chronic rhinosinusitis (CRS). T2R38 was previously reported to bind to homoserine lactones (HSL), quorum sensing molecules specific of Pseudomonas Aeruginosa and other gram negative species. Nevertheless, these bacteria are not the major pathogens found in CRS. Here we report on the identification of bacterial metabolites acting as new agonists of T2R38 based on a single cell calcium imaging study. Two quorum sensing molecules (Agr D1 thiolactone from Staphylococcus Aureus and CSP-1 from Streptococcus Pneumoniae) and a list of 32 bacterial metabolites from pathogens frequently implicated in CRS were tested. First, we observed that HSL failed to activate T2R38 in our experimental system, but that the dimethylsulfoxide (DMSO), used as a solvent for these lactones may, by itself, account for the agonistic effect previously described. Secondly, we showed that both Agr D1 thiolactone and CSP-1 are inactive but that at least 7 bacterial metabolites (acetone, 2-butanone, 2-pentanone, 2-methylpropanal, dimethyl disulfide, methylmercaptan, γ-butyrolactone) are able to specifically trigger this receptor. T2R38 is thus much more broadly tuned for bacterial compounds than previously thought.

Chronic maxillary atelectasis and silent sinus syndrome: two faces of the same clinical entity.

Chronic maxillary atelectasis (CMA) and silent sinus syndrome (SSS) are rare clinical entities characterized by an implosion of the maxillary sinus that may or may not be associated with sinonasal symptoms, and are complicated by ipsilateral enophthalmos. The objective of this article is to discuss the definitions, physiopathology, clinical and radiographic characteristics, and surgical management of these entities. We retrospectively reviewed 18 patients (7 women, 11 men, aged 12-70 years) diagnosed and treated in the ear, nose, and throat departments of four Belgian teaching hospitals between 2000 and 2015. Nine patients had a history of sinus disease. In all cases, a computed tomography scan showed downward displacement of the orbital floor, increased orbital volume, and maxillary sinus contraction. Five patients met the criteria for grade II CMA and 13 for grade III CMA. Four patients met the criteria for SSS. All patients underwent wide endoscopic middle maxillary antrostomy. There were no orbital complications and all patients experienced resolution or a dramatic reduction of their symptomatology. Only one patient asked for an orbital floor reconstruction to correct a persisting cosmetic deformity. Although CMA and SSS are usually regarded as different entities in the literature, we believe that they lie on the same clinical spectrum. Treatment for both conditions is similar, i.e., middle meatal antrostomy to halt or even reverse the pathological evolution and reconstruction of the orbital floor in the event of persistent cosmetic deformity.

Left Superior Temporal Gyrus Is Coupled to Attended Speech in a Cocktail-Party Auditory Scene.

Using a continuous listening task, we evaluated the coupling between the listener's cortical activity and the temporal envelopes of different sounds in a multitalker auditory scene using magnetoencephalography and corticovocal coherence analysis. Neuromagnetic signals were recorded from 20 right-handed healthy adult humans who listened to five different recorded stories (attended speech streams), one without any multitalker background (No noise) and four mixed with a "cocktail party" multitalker background noise at four signal-to-noise ratios (5, 0, -5, and -10 dB) to produce speech-in-noise mixtures, here referred to as Global scene. Coherence analysis revealed that the modulations of the attended speech stream, presented without multitalker background, were coupled at ∼0.5 Hz to the activity of both superior temporal gyri, whereas the modulations at 4-8 Hz were coupled to the activity of the right supratemporal auditory cortex. In cocktail party conditions, with the multitalker background noise, the coupling was at both frequencies stronger for the attended speech stream than for the unattended Multitalker background. The coupling strengths decreased as the Multitalker background increased. During the cocktail party conditions, the ∼0.5 Hz coupling became left-hemisphere dominant, compared with bilateral coupling without the multitalker background, whereas the 4-8 Hz coupling remained right-hemisphere lateralized in both conditions. The brain activity was not coupled to the multitalker background or to its individual talkers. The results highlight the key role of listener's left superior temporal gyri in extracting the slow ∼0.5 Hz modulations, likely reflecting the attended speech stream within a multitalker auditory scene. SIGNIFICANCE STATEMENT: When people listen to one person in a "cocktail party," their auditory cortex mainly follows the attended speech stream rather than the entire auditory scene. However, how the brain extracts the attended speech stream from the whole auditory scene and how increasing background noise corrupts this process is still debated. In this magnetoencephalography study, subjects had to attend a speech stream with or without multitalker background noise. Results argue for frequency-dependent cortical tracking mechanisms for the attended speech stream. The left superior temporal gyrus tracked the ∼0.5 Hz modulations of the attended speech stream only when the speech was embedded in multitalker background, whereas the right supratemporal auditory cortex tracked 4-8 Hz modulations during both noiseless and cocktail-party conditions.

A case of lipoma arising in the eustachian tube.

We report a case of a lipoma inside the eustachian tube, an extremely rare location for this lesion. To the best of our knowledge, this is only the second such case that has been described in the literature. The patient was a 47-year-old man, a fighter pilot, who was referred to our hospital with a 3-year history of (1) fullness in the right ear secondary to recurrent serous otitis media and (2) right ear pain, which was especially acute during flights. Nasopharyngeal endoscopy, computed tomography, and magnetic resonance imaging detected the presence of a well-encapsulated lesion inside the eustachian tube; macroscopic and radiologic findings identified the mass as a lipoma. The lesion was completely removed via transnasal endoscopy. Histopathologic evaluation confirmed the diagnosis of lipoma. The patient's postoperative course was favorable, and he was able to fly again without any ear complaints. Radiologic examination is useful for the diagnosis and preoperative evaluation of this benign tumor. Lesions located in the lower part of the eustachian tube can be easily removed via a transnasal endoscopic approach.

Bony Regeneration of the Sella after Transsphenoidal Pituitary Surgery.

OBJECTIVE: The purpose of this study is to demonstrate the possible bony regrowth of the sella after transsphenoidal surgery without any intraoperative sellar reconstruction. METHODS: Radiologic findings of the sella were reviewed in patients with pituitary tumors treated by transsphenoidal surgery. In 17 patients who had postoperative cranial computed tomography scans, bony regeneration of the sellar floor was evaluated by comparing immediate and late postoperative scans. The bony opening reduction was measured in transverse and sagittal planes. RESULTS: The median bony opening diameter in the transverse plane was 8.8 mm (interquartile range [IQR] 5.7-11.4) on the first scan and 4.2 mm (IQR 0.8-6.8) on the second scan. In the sagittal plane, it was 4.8 mm (IQR 1.8-6.8) on the first scan and 2.9 mm (IQR 1.6-3.9) on the second scan. These changes occurred in a median time of 36 months (IQR 22-42). There was a statistically significant decrease of the bony opening diameters in both the transverse and sagittal planes (P < 0.0001 and P = 0.0004, respectively). Bone regeneration was observed in 16 of the 17 patients (approximately 94%). CONCLUSION: There is a natural bony regeneration of the sella after transsphenoidal pituitary surgery.

Endoscopic treatment for Zenker's diverticulum: long-term results (with video).

BACKGROUND: Diverticulotomy is a standard treatment for Zenker's diverticulum (ZD). This technique was adapted to flexible endoscopy. OBJECTIVE: We report our long-term results of ZD treatment by using flexible endoscopy assisted by a soft diverticuloscope. DESIGN: Follow-up study. SETTING: Academic hospital. Tertiary-care referral center. PATIENTS: A total of 150 patients with ZD were treated with the same technique from July 2002 to June 2011. INTERVENTION: The procedure was performed by using a soft diverticuloscope to expose the septum, which was then cut with a needle-knife, and the procedure was completed by use of endoclip placement at the bottom of the section. MAIN OUTCOME MEASUREMENTS: Symptoms were compared before and after the procedure, 1 month later, and at the end of follow-up. RESULTS: The median size of the ZD was 3 cm (range 1-8 cm). The endoscopic incision was performed in one session (range 1-3 sessions). Clinical success at 1 month was 90.3%. Four adverse events (2.2%) occurred and were managed conservatively. Symptom evaluation at 1 month and at the end of follow-up was obtained in 103 and 134 patients, respectively. The dysphagia score dropped from 1.88 to 0.29 (P < .01) and 0.34 (P < .05) at 1 month and at the end of follow-up, respectively (median 43 months, range 13-121 months). Regurgitations and chronic cough dropped from 73% and 27% to 11% and 2% at the end of follow-up, respectively. Symptom recurrence occurred in 31 patients (23.1%); among them 23 had a second treatment, and only 5 required a third one. LIMITATIONS: Retrospective study, single center. CONCLUSION: Endoscopic incision of ZD by using a soft diverticuloscope and completed by endoclips is safe and efficient at short term and long term.

Galectin-1, -3, -7 expressions in congenital and acquired pediatric cholesteatomas compared to external auditory canal skin.

OBJECTIVES: There is a classical distinction based on clinical criteria between acquired and congenital cholesteatomas. To determine if these two types of lesions show different immunohistochemical features, we have studied the expression patterns of three distinctive galectins (animal lectins implied especially in cellular proliferation and apoptosis) in both types of cholesteatomas and compared it to their expression patterns in external auditory canal skin. METHODS: Our study is based on nine acquired and eight congenital cholesteatomas, obtained from children during ear surgery. Six specimens of normal adult auditory meatal skin served as control. Specimens were analyzed by immunohistochemistry using monoclonal antibodies with galectin-1 and galectin-3, and a polyclonal antibody with galectin-7. RESULTS: We did not observe any differences in the galectin distribution pattern between congenital and acquired pediatric cholesteatomas. Compared to the control group, cholesteatomas present some particular features. There was no expression of galectin-1 and a lower expression of galectin-3 in the epithelium. Furthermore, we observed a preferentially nuclear distribution of galectin-7 in cholesteatomas, whereas it is essentially cytoplasmic in the control group. CONCLUSION: The data reported in this study suggest, on the basis of a lesser marked galectin-3 in cholesteatomas epithelium compared with an external auditory canal skin, that an immature keratinocytes population is at the origin of these lesions and that galectin-3 and galectin-7 play a part in the capacity as apoptosis modulators. Our study does not establish a difference in the galectin expressions of congenital and acquired cholesteatomas, but it constitutes however an additional argument in favor of the "undifferentiated" origin of keratinocytes in cholesteatomas.

¹8F-FDG PET/CT and MRI in the follow-up of head and neck squamous cell carcinoma.

We evaluated the diagnostic performance of (18)F-FDG PET/CT and MRI for the assessment of head and neck squamous cell carcinoma (HNSCC) relapse. Since early treatment might prevent inoperable relapse, we also evaluated THE performance of early unenhanced (18)F-FDG PET/CT in residual tumor detection. The study was prospectively performed on 32 patients who underwent (18)F-FDG PET/CT and MRI before treatment and at 4 and 12 months after treatment. (18)F-FDG PET/CT was also performed 2 weeks after the end of radiotherapy. Histopathology or a minimum of 18 months follow-up were used as gold standard. Before treatment (18)F-FDG PET/CT and MRI detected all primary tumors except for two limited vocal fold lesions (sensitivity 94%). MRI was more sensitive than (18)F-FDG PET/CT for the detection of local extension sites (sensitivity 75 vs 58%), but at the cost of a higher rate of false positive results (positive predictive value 74 vs 86%). For relapse detection at 4 months, sensitivity was significantly higher for (18)F-FDG PET/CT (92%) than for MRI (70%), but the diagnostic performances were not significantly different at 12 months. For the detection of residual malignant tissue 2 weeks post-radiotherapy, sensitivity and specificity of (18)F-FDG PET/CT were respectively 86 and 85% (SUV cut-off value 5.8). (18)F-FDG PET/CT is effective in the differentiation between residual tumor and radiation-induced changes, as early as 2 weeks after treatment of a primary HNSCC. For follow-up, performance of (18)F-FDG PET/CT and MRI are similar except for a higher sensitivity of (18)F-FDG PET/CT at 4 months.

Tumors involving the base of the skull: diagnostic and therapeutic approaches.

UNLABELLED: PROPOSE OF REVIEW: Surgical approaches of skull base tumors are complicated and invasive. We review all new therapeutic approaches that reduce the invasiveness of the surgery. RECENT FINDINGS: The development of minimal invasive surgery has completely changed the management of this kind of tumor and also the importance of the quality of life of the patient after surgery. Endoscopy and robotics represent the future of the surgery and therefore must increase resection and reduce complication. We review the articles in which new approaches were described and also the different steps of the procedure. New technologies are also reviewed. The second part is focused on stereotactic radiosurgery, and we review the principle of stereotactic radiosurgery and the results of large series with a long follow-up of tumor involving the skull base. SUMMARY: The knowledge of the new technology and also the result of stereotactic radiosurgery must help the physician in the choice of the treatment of skull base lesions.

Animal model for cholesteatoma induced in the gerbil: will the profiles of differentiation/growth-regulatory markers be similar to the clinical situation?

INTRODUCTION: Cholesteatoma is a benign tumor of the middle ear characterized by an aggressive and invasive potential. The only current treatment being surgery, it is important to have access to a reliable animal model to study and better understand cholesteatoma pathogenesis. Our study aimed to examine the biological validity of the most common experimental model of cholesteatoma: the Mongolian gerbil. MATERIAL AND METHODS: We have induced cholesteatoma by surgical ligature of the gerbil's external auditory duct. Quantitative comparison of eight biological markers involved in inflammation (macrophage migration inhibitory factor [MIF]), cell differentiation (retinoic acid receptors-alpha, -beta, and -gamma), and cell adhesion/apoptosis (galectins-1, -3, -7, and -8). The immunohistochemical staining was quantified by computer-assisted microscopy. RESULTS: Two immunohistochemical parameters were determined in sections. The labeling index (LI) represents the percentage of tissue area specifically stained, and the mean optical density (MOD) denotes the staining intensity index. The LI reveals statistically significant differences for each marker tested. The MOD also shows statistically significant differences except for MIF (P = .259). CONCLUSION: From the panel of markers, the majority of staining parameters was statistically significantly different between sections of the animal model and clinical specimen. These data do not support the concept of complete validity of the popular animal model.

Extracellular nucleotides regulate CCL20 release from human primary airway epithelial cells, monocytes and monocyte-derived dendritic cells.

Extracellular nucleotides regulate ion transport and mucociliary clearance in human airway epithelial cells (HAECs) via the activation of P2 receptors, especially P2Y(2). Therefore, P2Y(2) receptor agonists represent potential pharmacotherapeutic agents to treat cystic fibrosis (CF). Nucleotides also modulate inflammatory properties of immune cells like dendritic cells (DCs), which play an important role in mucosal immunity. Using DNA-microarray experiments, quantitative RT-PCR and cytokine measurements, we show here that UTP up-regulated approximately 2- to 3-fold the antimicrobial chemokine CCL20 expression and release in primary HAECs cultured on permeable supports at an air-liquid interface (ALI). Both P2Y(2) (ATPgammaS, UTP, INS365) and P2Y(6) (UDP, INS48823) agonists increased CCL20 release. UTP-induced CCL20 release was insensitive to NF-kappaB pathway inhibitors but sensitive to inhibitors of ERK1/2 and p38/MAPK pathways. Furthermore, UTP had no effect on interleukin-(IL)-8 release and reduced the release of both CCL20 and IL-8 induced by TNF-alpha and LPS. Accordingly, UTP reduced the capacity of basolateral supernatants of HAECs treated with TNF-alpha or LPS to induce the chemoattraction of both CD4(+) T lymphocytes and neutrophils. In addition, we show that, in monocyte-derived DCs, ATPgammaS, and UDP but not UTP/INS365-stimulated CCL20 release. Likewise, UDP but not ATPgammaS was also able to increase CCL20 release from monocytes. Pharmacological experiments suggested an involvement of P2Y(11) or P2Y(6) receptors through NF-kappaB, ERK1/2, and p38/MAPK pathways. Altogether, our data demonstrate that nucleotides may modulate chemokine release and leukocyte recruitment in inflamed airways by acting on both epithelial and immune cells. Our results could be relevant for further clinical investigations in CF.

Characterization of patterns of expression of protein kinase C-alpha, -delta, -eta, -gamma and -zeta and their correlations to p53, galectin-3, the retinoic acid receptor-beta and the macrophage migration inhibitory factor (MIF) in human cholesteatomas.

Cholesteatoma is a benign disease characterized by the presence of an unrestrained growth and the accumulation of keratin in the middle ear cavity. Due to roles in cell proliferation, apoptosis and differentiation members of the protein kinase C (PKC) family could be involved in disease progression. This study focuses on the expression of protein kinase C-alpha, -delta, -eta, -gamma and -zeta in the epithelial tissues of 56 human cholesteatomas and their correlations with those of previously characterized distributions of p53, galectin-3, retinoic acid receptor-beta (RARbeta) and macrophage migration inhibitory factor (MIF). We have previously reported this marker set to be correlated with keratinocyte differentiation in human cholesteatomas. Our present data clearly show that the percentage of PKC-alpha (but not PKC-delta, -gamma, -eta and -zeta)-immunopositive cells in epithelial tissue fro recurrent cholesteatomas was significantly higher than in non-recurrent cases. Correlations between the PKC isoenzymes and the biological markers were non-uniform. PKC-alpha (but not PKC-delta, -gamma, -eta and -zeta) expression in epithelial cholesteatoma cells correlated significantly and positively with the percentages of p53-immunopositive cells. The patterns of PKC-alpha and -delta expression, but not of PKC-gamma, -eta and -zeta, correlated significantly and positively with galectin-3 expression. In addition, the correlation levels between the expression of PKC-alpha and -delta and that of galectin-3 varied depending on the infection and recurrence status. Presence of RARbeta correlated significantly (and positively) with the expression of PKC-gamma and -zeta and also in relation to the infection and recurrence status. MIF correlated presence significantly (and positively) with that of the five PKCs under study, depending on whether the cholesteatomas were non-infected or infected as well as non-recurrent or recurrent. In conclusion, the present study suggests that modifications occurring at the level of keratinocyte differentiation in human cholesteatomas involve distinct effectors, to which the activation of PKC-alpha, -delta, -eta, -gamma and -zeta can be added.