Impact of Endoplasmic Reticulum Stress in Otorhinolaryngologic Diseases.

The endoplasmic reticulum (ER) is an important organelle for normal cellular function and homeostasis in most living things. ER stress, which impairs ER function, occurs when the ER is overwhelmed by newly introduced immature proteins or when calcium in the ER is depleted. A number of diseases are associated with ER stress, including otorhinolaryngological diseases. The relationship between ER stress and otorhinolaryngologic conditions has been the subject of investigation over the last decade. Among otologic diseases associated with ER stress are otitis media and hearing loss. In rhinologic diseases, chronic rhinosinusitis, allergic rhinitis, and obstructive sleep apnea are also significantly associated with ER stress. In this review, we provide a comprehensive overview of the relationship between ER stress and otorhinolaryngological diseases, focusing on the current state of knowledge and mechanisms that link ER stress and otorhinolaryngologic diseases.

Salivary cotinine levels in children with otolaryngological disorders.

OBJECTIVE: To determine if salivary cotinine, a biomarker for tobacco smoke exposure, is elevated more often or to a higher degree in children meeting criteria for tonsillectomy or tympanostomy tube insertion. METHODS: Saliva samples were obtained from 3 groups of children for salivary cotinine measurement. Group 1 served as healthy controls. Group 2 consisted of subjects meeting tympanostomy tube criteria. Group 3 consisted of patients meeting tonsillectomy criteria. Environmental tobacco smoke (ETS) exposure was defined as a salivary cotinine concentration ≥1.0 ng/mL. Demographic data, smoke exposure history, and co-morbidities were also determined. RESULTS: 331 patients were included, with 112 in Group 1, 111 in Group 2, and 108 in Group 3. No differences were encountered for smoke exposure by history or smoker's identity, salivary cotinine level, or frequency of positive cotinine results. 42.6% of Group 1 had positive salivary cotinine compared to 51.8% of Group 2 and 47.7% of Group 3. Group 1 had a mean salivary cotinine level of 2.42 ng/mL compared to 2.54 ng/mL in Group 2 and 2.60 ng/mL in Group 3. The frequency of positive cotinine levels was higher than expected based on parental history. Among subjects with positive cotinine levels, 93 had no ETS exposure, and 64 had ETS exposure by history. CONCLUSION: Approximately 50% of children who undergo tonsillectomy and tympanostomy tube insertion have objective evidence of ETS exposure. Parental history underestimates passive smoke exposure, which can impact perioperative care.

Oxidative Stress and Low Glutathione in Common Ear, Nose, and Throat Conditions: A Systematic Review.

Context • Oxidative stress and tissue-damaging, oxygen (O2)-related, free-radical formation is inherent in human metabolism, and the tissues of the ear, nose, and throat (ENT) have an increased exposure to injury from those substances. Because glutathione (GSH) is a major component in an antioxidant defense against oxidative damage in ENT tissues, a review of the impact of lowered GSH and oxidative stress in conditions associated with the upper respiratory tract is warranted. Objective • The review intended to summarize the role that oxidative stress and GSH play. Design • The research team performed a literature review from 1980 to the present that was based on the following keywords: oxidative stress, oxidation, antioxidant, and GSH in common ENT conditions. The review found the following conditions: (1) rhinitis, (2) allergic rhinitis, (3) chronic rhinosinusitis (CRS), (4) CRS with polyps, (5) otitis media with effusion, (6) chronic otitis media (COM), (7) COM and cholesteatoma, (8) tympanic membrane sclerosis, (9) tonsillitis, (10) Meniere's disease, (11) laryngeal conditions, and (12) chronic cough. Results • ENT conditions have been found to be associated with oxidative stress and with low GSH. A limited number of the reviewed studies discussed antioxidant use or repletion of GSH. Although only a few reports support the use of GSH or antioxidants as adjuncts in the management of ENT conditions, no reports of side effects were found related to their use. Conclusions • Many ENT conditions are associated with oxidative stress and decreased GSH, both locally in the affected tissues and systemically. The oxidative stress of those conditions may be related to depletion of GSH, which is increased by the higher levels of O2 in the upper respiratory tract. A small number of studies have reported clinical benefits from the use of an antioxidant or GSH support. The findings of benefits and the lack of reports of side effects suggest that the clinical use of antioxidants and support with GSH in ENT conditions may be considered as adjuncts to conventional management and that more research is warranted.

Expressions and roles of periostin in otolaryngological diseases.

Periostin is a 90-kDa member of the fasciclin-containing family; it functions as part of matricellular proteins, and its production by airway epithelial cells is induced by IL-4 and IL-13. Periostin is secreted by fibroblasts and upregulated in the airway epithelia of patients with bronchial asthma; it is considered to contribute to remodeling under this pathological condition. However, despite many studies in diverse research areas, our overall understanding of this intriguing molecule is still inadequate. Here, we integrate the available evidence on periostin expression and its roles in otolaryngological diseases, including allergic rhinitis, chronic rhinosinusitis with nasal polyps, aspirin-induced asthma, organized hematoma, eosinophilic otitis media, and IgG4-related disease. Periostin might be involved as an important structural mediator in pathological processes such as insult and injury, Th2-driven inflammation, extracellular matrix restructuring, fibrosclerosis, tumor angiogenesis, and tissue remodeling.

[The prooxidant system. Approaches to the choice of research algorithm].

The regulatory function of the processes involving free radicals known to maintain cellular vital activity and their role as an intermediate stage of many vitally important enzymatic reactions attract the attention of researchers interested in the mechanisms of production and inactivation of free radicals. Investigations into prooxidant and antioxidant systems along with evaluation of the intensity of free-radical oxidation make it possible to resolve many problems including elucidation of dynamic activity of pathological process, prognosis of various pathological conditions, and the choice of possible methods for the correction of prooxidant/antioxidant balance in patients with ENT diseases. The development of algorithms and methods for the assessment of parameters of activity of the prooxidant system allows for their stage by stage measurement and evaluation.

[Pharmacokinetics analysis of tebipenem pivoxil in a phase II clinical trial in otolaryngological infections].

In a phase IIb clinical study (dose-finding test, 450 mg dosing group: 150 mg t.i.d., 500 mg dosing group: 250 mg b.i.d., 900 mg dosing group: 300 mg t.i.d.) of tebipenem pivoxil (TBPM-PI) for treatment of otolaryngological infections in adults, TBPM concentrations in the patient plasma were quantified. The primary pharmacokinetic parameters such as ka, kel, Vd/F and Tlag were estimated by the Bayesian method and then the secondary pharmacokinetic parameters such as tmax, Cmax, t1/2 and AUC were calculated. As for the patients whose primary parameters were not properly estimated by the Bayesian method, the secondary parameters were calculated by the trapezoidal method. The primary pharmacokinetic parameters obtained by the Bayesian method in 450 mg dosing group (150 mg t.i.d.), 500 mg dosing group (250 mg b.i.d.), and 900 mg dosing group (300 mg t.i.d.) were 5.64 +/- 2.76, 5.11 +/- 3.06 and 2.51 +/- 1.13 hr(-1) for ka, 1.75 +/- 0.25, 2.03 +/- 0.10 and 1.34 +/- 0.27 hr(-1) for kel, 17.62 +/- 5.09, 15.83 +/- 6.14 and 19.34 +/- 8.80 L for Vd/F, and 0.48 +/- 0.11, 0.38 +/- 0.03 and 0.39 +/- 0.26 hr for Tlag, respectively. The secondary parameters obtained by the Bayesian method and the trapezoidal method were 0.85 +/- 0.29, 0.81 +/- 0.33 and 1.18 +/- 1.53 hr for tmax, 5.08 +/- 2.05, 7.92 +/- 4.02 and 8.69 +/- 4.01 microg/ml for Cmax, 0.40 +/- 0.06, 0.34 +/- 0.01 and 0.54 +/- 0.10 hr for t1/2, 5.22 +/- 1.90, 7.93 +/- 4.04 and 13.62 +/- 6.29 microg x hr/ml for AUC after each dosing (AUC(0-8h) or AUC(0-12h)) and 15.65 +/- 5.70, 15.85 +/- 8.08 and 40.87+/- 18.87 microg x hr/ml for AUC(0-24h), respectively. As shown in the above, Cmax and AUC after each dosing were increased with a rise in the dose level, and AUC(0-24h) was increased with a rise in the total dose level per day. Regardless of the dosage, tmax was about 0.8-1.2 hr and t1/2 was about 0.3-0.5 hr, showing almost constant values. Changes in the regimen and dosage did not influence the pharmacokinetic properties of TBPM-PI. Pharmacokinetics of TBPM-PI in adult patients with otolaryngological infection were similar to those in healthy subjects.

Population pharmacokinetics of tebipenem pivoxil (ME1211), a novel oral carbapenem antibiotic, in pediatric patients with otolaryngological infection or pneumonia.

Tebipenem pivoxil (TBPM-PI, ME1211) has been under development as the world's first oral carbapenem for treatment of otolaryngological/respiratory infections caused by drug-resistant S. pneumoniae in pediatric patients. In order to treat these infections effectively, it is important to design optimal dosing regimens based on the pharmacokinetics/pharmacodynamics (PK/PD) relationships, which can be characterized by clarifying the pharmacokinetics of tebipenem (TBPM) in the pediatric population. We therefore performed an population pharmacokinetic analysis using plasma TBPM concentrations obtained from pediatric patients with otolaryngological infection or bacterial pneumonia (0.5-16 years old; n=217, 395 points), after repeated oral administration of TBPM-PI at a dose of 4 or 6 mg/kg b.i.d. A one-compartment model with first-order absorption was adopted. In analysis, weight-normalized creatinine clearance (Ccr) and age were the most significant covariates that respectively explained inter-subject variability in weight-normalized apparent clearance (CL/F) and volume of distribution (Vd/F) of TBPM. The CL/F of TBPM increased with Ccr, and the Vd/F decreased with age. Based on the results of the present analysis, validity of the presently recommended dosage regimen of TBPM-PI in pediatric patients is discussed.

[Free radicals and antioxidants in otorhinolaryngology]. / Volné radikály a antioxidanty v otorhinolaryngologii.

Free radicals in otorhinolaryngology participate in the pathogenesis of many diseases. Antioxidants can act or preventively or ameliorate the diseases. Oxidative stress, in which is the predominance of free radicals to antioxidants, is present in many states like inflammation, atherosclerosis or tumors. Antioxidant capacity is increased not only by the application of antioxidants, but also due to positive emotions. In nasal and paranasal diseases is the role of the nitroxide radical very important. Vasocontrictive drugs decrease its level, pathologically increased levels are observed in asthma, allergic rhinitis and in sinusitis. Nitroxide protects organism against microorganisms and viruses. Oxidative stress supports the origin of nasal polyposis, takes part in disturbances of the hearing. Increased reactive oxygen species are engaged in tinnitus. In otitis media the level of lipoperoxides may be the marker of the severity of the disease. In Ménicre's syndrome the total antioxidant capacity is decreased. It is possible to conclude, that free radicals and antioxidants play an important role in otorhinolaryngological diseases.

Expression of somatostatin receptors in inflammatory lesions and diagnostic value of somatostatin receptor scintigraphy in patients with ANCA-associated small vessel vasculitis.

OBJECTIVE: To assess the usefulness of somatostatin receptor (SSTR) scintigraphy for the evaluation of disease activity in the upper and lower respiratory tract in ANCA-associated vasculitis (AASV). METHODS: Thirty-two consecutive patients with AASV were subjected to SSTR scintigraphy as part of their initial diagnostic evaluation and follow-up. The presence of SSTRs in inflammatory lesions was evaluated with immunohistochemistry in selected cases. RESULTS: In AASV, specificity of SSTR scintigraphy for active vs non-active disease was 96% for pulmonary disease and 100% for ear, nose and throat (ENT) involvement, while sensitivity was 86% and 68%, respectively. Absence of previously present tracer accumulation characterized treatment responders, and treatment resistance was reflected by repeated positive scintigraphy. We could demonstrate the expression of SSTRs in lung and mucosal biopsies obtained from patients with active Wegener's granulomatosis and with microscopic polyangiitis. CONCLUSION: SSTR scintigraphy is useful for the assessment of AASV, indicating disease activity, disease extent and treatment efficacy. SSTRs are expressed in both granulomatous as well as non-granulomatous AASV.

Components of the diurnal cortisol cycle in relation to upper respiratory symptoms and perceived stress.

OBJECTIVE: The purpose of this study was to investigate the relationship between the diurnal pattern of salivary free cortisol to perceived stress and susceptibility to symptoms of upper respiratory illness (URI). METHODS: Salivary free cortisol concentration was determined in 34 healthy participants (students) at eight time points, synchronized to awakening, on 2 consecutive days. Participants completed a standard questionnaire to assess perceived stress and subsequently kept a daily record of social proximity and symptoms of upper respiratory illness for 2 weeks. RESULTS: Participants characterized by consistently larger awakening responses went on to report significantly more URI symptoms. Participants with less pronounced diurnal decline (flatter profiles) reported fewer URI symptoms. The two cortisol components were themselves related and interacted such that participants high on an interactive vector reported approximately three times more URI symptoms than other participants. The URI-associated cortisol components (dynamic changes) were not related to perceived stress, but underlying cortisol secretory activity (overall levels) in the first 45 minutes after awakening was. Dynamic components were, however, related to a social proximity measure, which in turn was related to URI symptoms. Proximity and the interactive cortisol vector together explained a substantial (28%) percentage of the variance in URI symptom reports. The cortisol vector independently and significantly explained 12% of the variation; the proximity measure independently and nonsignificantly contributed 6% of the variation. CONCLUSIONS: URI symptoms were associated with two related dynamic components of the cortisol cycle as determined by synchronization to awakening, whereas stress was related to a measure of overall secretory activity.

Concentrations of ofloxacin in ear and nasal tissues.

The results of two kinetic studies examining soft tissue, cartilage and bone after uptake of oral ofloxacin [administered as 200 mg twice daily (study I/nose) or 400 mg once daily (study II/ear)] show that antibiotic concentrations lie within the therapeutic range. Findings demonstrate that 400 mg ofloxacin daily is a compliance-enhancing and effective approach to the treatment of ENT-related infections, in particular those caused by problem organisms such as Pseudomonas aeruginosa.

Changes in copper, zinc and iron content in serum and saliva in various otorhinolaryngological ailments.

Copper, zinc and iron concentrations were determined in blood serum and parotid saliva of patients with various otorhinolaryngological disorders such as sinusitis, rhinitis, otitis and amygdalitis. Comparing results between individuals of control group and patients significant differences were observed in concentrations of the metals studied as a result of the different infections diseases.

[The role of IgE in recurrent ORL infections in children]. / Rôle des IgE dans les infections ORL récidivantes de l'enfant.

The high incidence of bacterial super-infection in atopic individuals has long been known, especially in asthma and atopic dermatitis. In recurrent ENT infections in children, increased IgE levels are found in half the cases; this increase results from two main mechanisms: a predisposition to allergy (often with positive RASTs), and certain viral infections: respiratory syncytial virus, para-influenzae, and measles, that trigger production of partly non-specific serum IgEs. In the latter situation, the increased IgE levels are both a cause and a consequence of recurrent infections. More recently, in some forms of atopic dermatitis (infant and Buckley syndrome), attention has been drawn to the severity of viral superinfections (herpes, chickenpox, vaccine), which is directly correlated with the IgE levels. The mechanism of such infections is unclear: the local increase in IgE levels is responsible for degranulation of mastocytes which in turn results in edema, fissures of mucosae and congestion; an effect on the lymphocytic response is possible, with inhibition of the production of certain lymphokines, especially interleukins.

Timentin--clinical and pharmacokinetic evaluation in otorhinolaryngology.

The efficacy and tolerance of Timentin was studied in 41 patients with various infections of the ears, nose and throat. The pharmacokinetics of Timentin were determined in pus, mucosa and polyps of the nose and paranasal sinuses, the tonsils and submandibular gland as well as in the interstitial fluid collected in Redon vacuum drainage. Experimental pharmacokinetic studies in the guinea pig were performed in the inner ear and eye fluids and in serum. Ticarcillin and clavulanic acid concentrations were determined by a microbiological micromethod. The clinical studies demonstrated that Timentin was very effective and well tolerated. The clinical and experimental pharmacokinetic studies provide a good explanation of this high degree of effectiveness.

[Transport of cefotetan into the otorhinolaryngeal tissues].

The tissue specimens were taken to evaluate the efficacy of cefotetan (CTT), a new cephamycin antibiotic, for otorhinolaryngological infectious diseases. The concentrations of CTT in palatine tonsils, maxillary sinus mucosa, wall of maxillary sinus cysts, discharge from otitis media and saliva were studied. The serum level determined at 3 hours following intravenous injection of 1 g of the drug was 49.2 micrograms/ml (n = 4). The serum level at 12 hours following intravenous injection of 2 g of the drug was 14.4 micrograms/ml (n = 4). 15-25% of the serum levels of CTT were demonstrated in palatine tonsils, 20.7-35.7% in maxillary sinus mucosa. We detected high levels of CTT in the effusion of acute maxillary sinusitis, 24.0 micrograms/ml (2 g, i.v., 90 min.), 26.3 micrograms/ml (1 g, i.v., 120 min.). On the other hand, we detected only a few per cent of the serum level of CTT in the effusion of chronic maxillary sinusitis.

[Potassium metabolism and content of the body in hypertension]. / Obmen i soderzhanie kaliia v organizme bol'nykh gipertonicheskoi bolezn'iu.

Potassium metabolism was studied with the use of 42K nuclide in 68 patients with hypertensive disease, stage I-III (WHO classification) without signs of cardiac and renal insufficiency and in 13 persons of the control group, total body volume with tritium oxide dilution and central haemodynamics with radiocardiography were also recorded. Patients with the stable course of arterial hypertension show decreased potassium metabolism in the body, apparently with deterioration of the tissue metabolism. Decrease of the total metabolised potassium was seen in patients with hypertensive disease only in the sclerotic stage of illness, it is more marked in men than in women. Decrease of potassium content in the body did not depend on the duration and severity of arterial hypertension and on the changes in central haemodynamics. It is concluded that more information on total potassium content in the body is gained with calculated percentage to the predicted normal values in milliequivalents per liter of total water in the body.