Longitudinal changes in hearing threshold levels for noise-exposed military personnel.

PURPOSE: Military personnel are exposed to variable and sometimes very high noise in their professional environment. The aim of this study is to evaluate through a longitudinal study if our hearing conservation program has to be adapted to consider specific interventions for subgroups of our military population still subject to a higher risk of hearing loss. METHODS: We conducted a retrospective longitudinal study in 2015-2016 to describe the evolution of hearing threshold levels of military personnel as measured during periodic audiometric screening over a period of 6 years (2009-2014) after the implementation of our hearing conservation program. A linear mixed model explored the relationship of pure-tone average (PTA) on 3, 4 and 6 KHz with probability of noise exposure, gender, age at baseline, time since baseline, hearing loss at baseline and ear. RESULTS: For 18,672 military individuals, our results show a small but statistically significant increase of 0.08 dB per year in PTA on 3, 4 and 6 KHz over the 6-year period that is consistently decelerating as a function of time. An additional annual increase of hearing thresholds due to higher age and moderate and high probability of exposure to noise was also found. CONCLUSIONS: No major adaptation of our hearing conservation program is required but efforts should be strengthened to better evaluate and counsel older individuals and subjects exposed to noise regarding avoidance of noise and correct use of personal hearing protection.

Severe spontaneous epistaxis: retrospective study in a tertiary ENT centre.

PURPOSE: To investigate the clinical profile and outcomes of different treatment strategies in patients hospitalized for spontaneous severe epistaxis. METHODS: This is a retrospective descriptive study of a case series of patients hospitalized for epistaxis in the University Hospital of Ghent between 2005 and 2012. RESULTS: 124 patients with, respectively, 132 episodes were included. 64% were male. The mean age was 65 years. 73% had comorbidities of which arterial hypertension was the most common. 61% were taking one or more antithrombotics and in 25.7% a recent change in the medication schedule took place. 47% of the episodes necessitated a vascular intervention. The most performed surgery was endoscopic sphenopalatine artery ligation. The 1-year success rate of conservative treatment was 47% and of vascular intervention 81%. No significant difference between the recurrence rates and need for vascular intervention of the different comorbidities and medications was detected using Pearson chi-squared and Fisher's exact testing. The overall 5-year survival rate was 83.6%. CONCLUSIONS: The typical pattern of a patient presenting with severe epistaxis was a patient in the sixth decade, male, suffering from comorbidities and taking one or more antithrombotic agents. Based on the above-mentioned success rates of the different treatment options, we think all centres treating epistaxis should apply a well-defined protocol to guide the decision when to proceed with surgery. Furthermore, prospective research needs to precisely investigate the role played by comorbidities and their treatment in the occurrence of epistaxis and to test the effectiveness of proposed algorithms.

Remodeling and Repair in Rhinosinusitis.

Remodeling refers to the development of specific but potentially irreversible structural changes in tissue. Caucasian eosinophilic chronic rhinosinusitis (CRS) with polyps associated or not with cystic fibrosis was discriminated by edema from CRS without nasal polyps, characterized by extensive fibrotic fields. However, changes in epithelial and extracellular matrix structures are common findings in all types of chronic inflammatory diseases of upper airways, but rarely specific and highly variable in extend. Recent studies have shown that remodeling in CRS appears to occur in parallel, rather than purely subsequent to inflammation. Furthermore, some preferential remodeling associations can be recognized. Tremendous efforts have been put in research on coagulation factors, cytokines, growth factors, and proteases supporting all phases of upper airway remodeling. The current exploration of other CRS sub-groups and of the particular link with concomitant asthma aims to optimize the classification of CRS and its staging modes and to develop novel therapies.

[Why, when and how to monitor new oral anticoagulants]. / Pourquoi, quand et comment doser les nouveaux anticoagulants oraux?

Several direct oral anticoagulants (DOACs) are now widely used in the prevention and treatment of thromboembolic events. Unlike vitamin K antagonists, DOACs exhibit predictable pharmacokinetics and pharmacodynamics. DOACs are to be administered at fixed doses without routine coagulation monitoring. However, in some patient populations or specific clinical circumstances, measurement of drug exposure may be useful, such as in suspected overdose, in patients with a haemorrhagic or thromboembolic event during treatment with an anticoagulant, in those with acute renal failure, or in patients who require urgent surgery. This article provides practical guidance on laboratory testing of DOACs in routine practice and summarizes the influence of DOACs on commonly used coagulation assays.

Tinnitus, anxiety and automatic processing of affective information: an explorative study.

Anxiety is found to play an important role in the severity complaint of tinnitus patients. However, when investigating anxiety in tinnitus patients, most studies make use of verbal reports of affect (e.g., self-report questionnaires and/or interviews). These methods reflect conscious appraisals of anxiety, but do not map underlying processing mechanisms. Nonetheless, such mechanisms, like the automatic processing of affective information, are important as they modulate emotional experience and emotion-related behaviour. Research showed that highly anxious people process threatening information (e.g., fearful and angry faces) faster than non-anxious people. Therefore, this study investigates whether tinnitus patients process affective stimuli (happy, sad, fearful, and angry faces) in the same way as highly anxious people do. Our sample consisted out of 67 consecutive tinnitus patients. Relationships between tinnitus severity, pitch, loudness, hearing loss, and the automatic processing of affective information were explored. Results indicate that especially in severely distressed tinnitus patients, the severity complaint is highly related to the automatic processing of fearful (r = 0.37, p < 0.05), angry (r = 0.44, p < 0.00) and happy (r = -0.44, p < 0.00) faces, and these relationships became even stronger after controlling for hearing loss. Furthermore, in contrast with findings on the relation between audiological characteristics (pitch and loudness) and conscious report of anxiety, we did find that the audiological characteristic, loudness, tends to be in some degree related to the automatic processing of fearful faces (r = 0.25, p = 0.08). We conclude that tinnitus is an anxiety-related problem on an automatic processing level.

Tinnitus severity and its association with cognitive and somatic anxiety: a critical study.

Tinnitus has been defined as a phantom auditory perception. Research indicates the necessity to make a distinction between the physical symptom and the subjective severity of the tinnitus symptom, since especially the latter seems to vary among patients. The relationship between tinnitus severity and psychological variables has been well established. Anxiety is considered to be an important variable for understanding the differences in the subjective tinnitus severity. Although many studies confirm the relationship between anxiety and tinnitus severity, most studies do not take the possibility of shared method variance and content overlap between questionnaires into account. Furthermore, anxiety is a broad concept and contains both a cognitive and somatic dimension. Research including both dimensions of anxiety in tinnitus population is rare. According to us two conditions must be fulfilled before theorization on the relation is useful: (1) the presence of clinically relevant cognitive and/or somatic anxiety, (2) evidence of a substantial or "real" relationship. In our sample, almost 60% reported more than average cognitive anxiety and 40.8% reported clinical relevant somatic anxiety. After controlling for content overlap between the questionnaires used, the relation between tinnitus severity and cognitive and somatic anxiety remains significant. Two hypothetical models concerning this relationship that deserve future research attention are described.

Different types of tissue composition in inflammatory or reparative upper airway disorders.

BACKGROUND: Composition changes of extracellular matrix (ECM) can lead to functional disorders of the upper airways (UA). The aim of this study was to systematically measure both the association patterns and the correlation degree between tissue composition parameters in UA inflammatory diseases. METHODOLOGY: Nasal samples were obtained from patients with chronic rhinosinusitis with (CRS+NP), without nasal polyps (CRS), with post-operative adhesions (S) and normal nasal mucosa (NM). A reproducible semi-quantitative method, which takes epithelial and lamina propria damages into account was applied for haematoxylin and eosin, alpha-smooth muscle actin, reticulin, elastin, laminin and collagen type IV stainings. RESULTS: The most severe cases of epithelial shedding have been found in a significant higher amount in CRS+NP when compared with NM. The most severe cases of inflammatory reaction were mainly found in CRS+NP. CRS+NP had significantly more severe cases of oedema than NM. Excluding elastin, networks in other ECM proteins were found modified in fibrotic fields but to a lesser extend in oedematous regions in all conditions. CONCLUSION: Although non specific, oedema in the lamina propria is a key-feature of CRS+NP, while fibrosis, massively present in CRS and S, affects profoundly the distribution of ECM proteins in these areas.

Actual concepts in rhinosinusitis: a review of clinical presentations, inflammatory pathways, cytokine profiles, remodeling, and management.

Rhinosinusitis (RS) is a heterogeneous group of diseases. It is a significant and increasing health problem that affects about 15% of the population in Western countries. It has a substantial impact on patients' health-related quality of life and daily functioning and represents a huge financial burden to society and the health care system as a result of the direct and indirect costs. In addition, RS is not well-understood, and little is known about the etiology and pathophysiology. In the past decade, many papers have been published that have changed our understanding of RS. RS is commonly classified into acute and chronic RS based on symptom duration. In acute RS, an inflammatory reaction initiated by a viral infection characterizes most uncomplicated, mild to moderate cases. Therefore, the first line of treatment for these cases are intranasal steroids and not antibiotics. In severe and complicated cases, antibiotics combined with topical steroids remain the treatment of choice. On the other hand, chronic RS is actually subdivided into two distinct entities (chronic rhinosinusitis with and without polyps), as growing evidence indicates that these entities have specific inflammatory pathways and cytokine profiles. The authors review recent data regarding the clinical presentations, cytokine profiles, tissue remodeling, and modalities of treatment for each form of RS.

Ultrasound submucosal inferior nasal turbinate reduction technique: histological study of wound healing in a sheep model.

AIM OF THE STUDY: To describe histological changes after application of an ultrasound tissue reduction (UTR) technique in a newly introduced sheep model to study inferior nasal turbinate mucosal wound healing. MATERIALS AND METHODS: An experimental study in a sheep model. Stromal fibrosis, submucosal interstitial space volume (ISV), mucosal epithelial cell necrosis, mucosal inflammation and blood vessels' engorgement in inferior turbinate samples were assessed after application of UTR using hematoxylin/eosin staining in 12 turbinate samples after different time points. Histological grading was performed using a 4-point scale RESULTS: After one week, extensive development of fibrosis (p = 0.006) and significant reduced stromal ISV (p < 0.001) compared to controls were observed. The degree of fibrosis and the stromal ISV remained constant during the 8-week period. The extensive epithelial cell necrosis observed at week 1, diminished later, so that at 8 weeks no significant difference with controls in the necrosis extent was noted. Significant reduction of engorgement of blood vessels in the submucosal layer was noted after 8 weeks (p = 0.008, compared with baseline). Mucosal inflammation, while pronounced at week 1 (p = 0.005, compared with baseline), was normalized at week 8. CONCLUSION: Due to the rapid induction of extensive fibrosis, to the limited inflammation reaction, to the moderate degree of epithelial necrosis, to the reduction of subepithelial ISV and the persistence of these features till week 8 at least, UTR emerges as an effective minimally invasive technique for inferior nasal turbinate volume reduction.

Therapeutic management of allergic diseases.

Allergic diseases are characterized by the activation of inflammatory cells and by a massive release of mediators. The aim of this chapter was to describe succinctly the modes of action, indications, and side effects of the major antiallergic and antiasthmatic drugs. When considering the ideal pharmacokinetic characteristics of a drug, a poorly metabolized drug may confer a lower variability in plasma concentrations and metabolism-based drug interactions, although poorly metabolized drugs may be prone to transporter-based disposition and interactions. The ideal pharmacological properties of a drug include high binding affinity, high selectivity, and appropriate association and dissociation rates. Finally, from a patient perspective, the frequency and route of administration are important considerations for ease of use.

Physiologically based pharmacokinetics (PBPK).

Allometric scaling is widely used to predict human pharmacokinetic parameters from preclinical species, and many different approaches have been proposed over the years to improve its predictive performance. Nevertheless, prediction errors are commonly observed in the practical application of simple allometry, for example, in cases where the hepatic metabolic clearance is mainly determined by enzyme activities, which do not scale allometrically across species. Therefore, if good correlation was noted for some drugs, poor correlation was observed for others, highlighting the need for other conceptual approaches. Physiologically based pharmacokinetic (PBPK) models are now a well-established approach to conduct extrapolations across species and to generate simulations of pharmacokinetic profiles under various physiological conditions. While conventional pharmacokinetic models are defined by drug-related data themselves, PBPK models have richer information content and integrate information from various sources, including drug-dependent, physiological, and biological parameters as they vary in between species, subjects, or with age and disease state. Therefore, the biological and mechanistic bases of PBPK models allow the extrapolation of the kinetic behavior of drugs with regard to dose, route, and species. In addition, by providing a link between tissue concentrations and toxicological or pharmacological effects, PBPK modeling represents a framework for mechanistic pharmacokinetic-pharmacodynamic models.

Population pharmacokinetic and pharmacodynamic analysis in allergic diseases.

In this chapter, we introduce the concepts and methodologies of population analysis as applied to analyzing pharmacokinetic and pharmacodynamic data. One of the key determining characteristics of the population approach is that through it, one seeks not only to characterize deterministic trends in the data, but also to identify and estimate the magnitudes of the important sources of variability within the data. The first section of this chapter provides an introduction to the primary concepts of, and motivation for, population modeling by way of a hypothetical case study. Then, the various methodologies that have been employed throughout the history of population analysis are described in further detail. Of these, the most commonly employed today is nonlinear mixed-effects (NLME) modeling. Finally, notable examples of the application of population PK and PK/PD modeling to treatments for allergies and asthma are discussed. Population PK models have frequently been used to extrapolate exposures to special populations, such as pediatrics, as well as to optimize treatment regimens and trial designs for these populations. Population PK/PD models have most frequently been applied to analyzing and interpreting data from wheal and flare trials, but are also becoming increasingly important in the analysis of PD data from monoclonal antibodies.

Drug interactions.

Drugs for allergy are often taken in combination with other drugs, either to treat allergy or other conditions. In common with many pharmaceuticals, most such drugs are subject to metabolism by P450 enzymes and to transmembrane transport. This gives rise to considerable potential for drug-drug interactions, to which must be added consideration of drug-diet interactions. The potential for metabolism-based drug interactions is increasingly being taken into account during drug development, using a variety of in silico and in vitro approaches. Prediction of transporter-based interactions is not as advanced. The clinical importance of a drug interaction will depend upon a number of factors, and it is important to address concerns quantitatively, taking into account the therapeutic index of the compound.

Drug metabolism and pharmacokinetics.

In this article, aspects of absorption, distribution, metabolism, and excretion have been described bearing in mind the pathogenesis of allergic diseases and their possible therapeutic opportunities. The importance of the routes of administration of the different therapeutic groups has been emphasized. The classical aspects of drug metabolism and disposition related to oral administration have been reviewed, but special emphasis has been given to intranasal, cutaneous, transdermal, and ocular administration as well as to the absorption and the subsequent bioavailability of drugs. Drug-metabolizing enzymes and transporters present in extrahepatic tissues, such as nasal mucosa and the respiratory tract, have been particularly discussed. As marketed antiallergic drugs include both racemates and enantiomers, aspects of stereoselective absorption, distribution, metabolism, and excretion have been discussed. Finally, a new and promising methodology, microdosing, has been presented, although it has not yet been applied to drugs used in the treatment of allergic diseases.

Pharmacokinetics in special populations.

Pharmacokinetics are typically dependent on a variety of physiological variables (e.g., age, ethnicity, or pregnancy) or pathological conditions (e.g., renal and hepatic insufficiency, cardiac dysfunction, obesity, etc.). The influence of some of these conditions has not always been thoroughly assessed in the clinical studies of antiallergic drugs. However, the knowledge of the physiological grounds of the pharmacokinetics can provide some insight for predicting the potential alterations and guiding the initial prescription strategies. It is important to recognize that both pharmacokinetic and pharmacodynamic differences between populations should be considered. The available information on drugs used for the therapy of allergic diseases is reviewed in this chapter.

Does rhinitis lead to asthma?

Rhinitis and asthma are commonly linked even if the precise pathological mechanisms explaining the relationship are not fully understood. Although there is increasing evidence that rhinitis may influence the development of asthma, there remain many gaps in our understanding of the processes involved. The complexity of this relationship is mainly due to the multiple interactions between genetic background, environmental factors and the specific host reaction. Epidemiological surveys have highlighted significant clinical associations and identified some factors that favour the progression from rhinitis to asthma. Basic research has demonstrated numerous similarities in inflammatory and immunological mechanisms.

Pharmacological management of nasal polyposis.

Nasal polyposis affects nearly 4% of the total population in Western countries, and presents a real challenge to the physician because of its severity, chronicity and recurrence rate. Characteristic histomorphological features of polyps are an eosinophilic inflammation and the destruction of connective tissue; recent research has focused on cytokines, chemokines, growth factors and metalloproteinases to explain these features, as the aetiology of nasal polyposis remains largely unclear. Currently, topical and systemic corticosteroids are first-choice drug therapy approaches, and good evidence from controlled trials is available for topical, but not for systemic, corticosteroid therapy. Surgery is indicated if adequate drug treatment fails, which often needs to be maintained after surgery. There is limited experience for other drugs, such as antihistamines, leukotriene antagonists and frusemide (furosemide), which may be added to corticosteroid therapy in selected patients. Aspirin (acetylsalicylic acid) desensitisation may be a therapeutic option for patients who do not respond to corticosteroids or surgery. Recently, antibiotics such as macrolides have been suggested to have therapeutic activity based on their anti-inflammatory properties but large-scale controlled trials are lacking. New approaches are currently evolving, specifically targeting eosinophilic recruitment (chemokine receptor 3, eotaxin) and inflammation (interleukin-4, -5, -13), immunoglobulin-E, or tissue remodeling by reducing the activity of metalloproteinases. This review summarises current knowledge on pathogenesis as well as established and future approaches in the pharmacological management of bilateral eosinophilic nasal polyposis.

Endoscopic and microscopic paraseptal transsphenoidal approach to the sella turcica.

OBJECTIVES: To establish the feasibility of the paraseptal approach to the sella and to demonstrate the superiority of the endoscopic over the microscopic vision during pituitary surgery. STUDY DESIGN: Prospective monocentric study. METHODS: Nine consecutive patients with a pituitary tumour were operated since November 2002. The surgical procedure consisted of a paraseptal approach of the sella with use of a rigid endoscope. Pre- and postoperative (3 months after surgery) symptoms, Magnetic Resonance Imaging (MRI) findings, endocrine and ophthalmic assessment, and intraoperative findings were recorded. RESULTS: One patient presented a CSF leak with a successful peroperative repair. Regarding symptom resolution, headache disappeared during the early postoperative period in case of pituitary apoplexy. All cases of preoperative hemianopsia and diplopia but one improved significantly. Two patients recovered preoperative deficient hormonal functions and six patients did not require substitution therapy any more. No nasal packing was needed except in one case. Considering the healing course, the mucosa repair inside the sphenoid sinus was quicker with Surgicel removal at week 4. Postoperative MRI demonstrated a residual parasellar nodule in 3 out of 6 cases of macroadenoma. Only one required radiation therapy. These results are commented through comparison with the transseptal approach and with surgery exclusively using the microscope. CONCLUSIONS: The paraseptal transsphenoidal approach to the sella turcica using the telescope is at least as effective as the conventional transseptal approach using the operating microscope only. It provides a wide access to the pituitary fossa and an optimal vision of the critical areas. The absence of postoperative nasal packing improves significantly the comfort of the patient during the first postoperative hours.