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Purpose: For decades, inflammation has been considered a cause of pharmacokinetic variability, mainly in relation to the inhibitory effect of pro-inflammatory cytokines on the expression level and activity of cytochrome P450 (CYP). In vitro and clinical studies have shown that two major CYPs, CYP2C19 and CYP3A4, are both impaired. The objective of the present study was to quantify the impact of the inflammatory response on the activity of both CYPs in order to predict the pharmacokinetic profile of their substrates according to systemic C-reactive protein (CRP)., Methods: The relationships between CRP concentration and both CYPs activities were estimated and validated using clinical data first on midazolam then on voriconazole. Finally, clinical data on omeprazole were used to validate the findings. For each substrate, a physiologically based pharmacokinetics model was built using a bottom-up approach, and the relationships between CRP level and CYP activities were estimated by a top-down approach. After incorporating the respective relationships, we compared the predictions and observed drug concentrations., Results: Changes in pharmacokinetic profiles and parameters induced by inflammation seem to be captured accurately by the models., Conclusions: These findings suggest that the pharmacokinetics of CYP2C19 and CYP3A4 substrates can be predicted depending on the CRP concentration.

External otitis is one of the most common infections in the head and neck region, as about 10% of all people suffer from it at least once during their life. It is an infection of the cutis and subcutis of the outer ear canal caused by bacteria, viruses, and fungus as well as allergens or degenerative toxic substances. A concomitant infection of the eardrum (myringitis) may develop. Patients typically present with unilateral, rarely bilateral, earache (otalgia), with accompanying hearing loss and sometimes discharge from the ear (otorrhea). In general, otalgia is one of the most common reasons for consulting a general practitioner in Germany (4.2-7.7%), especially for children up to 14 years.

Dictyostelium cells are professional phagocytes that are capable of handling particles of variable shapes and sizes. Here we offer long bacteria that challenge the uptake mechanism to its limits and report on the responses of the phagocytes if they are unable to engulf the particle by closing the phagocytic cup. Reasons for failure may be a length of the particle much larger than the phagocyte's diameter, or competition with another phagocyte. A cell may simultaneously release a particle and engulf another one. The final phase of release can be fast, causing the phagosome membrane to turn inside-out and to form a bleb. Myosin-II may be involved in the release by generating tension at the plasma membrane, it does however not accumulate on the phagosome to act there directly in expelling the particle. Labeling with GFP-2FYVE indicates that processing of the phagosome with phosphatidylinositol 3-phosphate begins at the base of a long phagosome already before closure of the cup. The decision of releasing the particle can be made even at the stage of the processed phagosome.

Inflammatory response is characterized by an increase of several cytokines. Some are known to modify drugs pharmacokinetic by reducing the expression levels of drug-metabolizing enzymes (DMEs) and transporters. This impact of inflammatory signaling is well established in hepatic cells, but not in intestinal cells. EpiIntestinal is a 3D human small intestinal tissue model with epithelial polarity, allowing good evaluation of metabolism and drug transport. This study aimed to analyze the effect of IL-6 on this tissue model. RNA sequencing was performed in cells incubated with 5, 10, or 20 ng/mL IL-6 for 8 h to 72 h to study the impact of IL-6 on drug metabolism and pharmacokinetics gene expression. The influence of IL-6 on the activity of cytochromes P450 (CYPs) was studied by measuring metabolite formation of specific substrates with LC-HRMS. Its impact on ATP-binding cassette (ABC) transport was evaluated by measuring intra- and extracellular substrates using spectrofluorometry. Exposure of EpiIntestinal cells to IL-6 resulted in reduction of some CYP mRNAs, such as CYP2C19, CYP2C9, and CYP3A4, by 40% to 50%. Activities of these CYPs were also decreased in EpiIntestinal cells by 20% to > 75%. IL-6 exposure did not modify ABCB1 and ABCCs transporter activities in this model. This study shows that gene expression levels and activities of drug-metabolizing enzymes and ABC transporters may be altered by the pro-inflammatory cytokine IL-6 in intestinal cells. If these results are confirmed in vivo, it may result in pharmacokinetic modifications, such as pre-systemic metabolism, with clinical effects, and require dosage adaptation.

The indications for cochlear implantation (CI) have expanded over the last few years. There is evidence that some adult patients with pre- or perilingual onset of deafness may gain from implantation. Similarly, CI in patients with single-sided deafness may offer significant benefits in terms of quality of life and social as well as academic development. In this setting, directional hearing may be restored and speech comprehension, especially in noise, may be optimized. In patients with intractable tinnitus and profound hearing loss, CI not only improves speech perception, but also helps to reduce the tinnitus in the deaf ear., (© 2018 S. Karger AG, Basel.)

Objective: Renal artery (RA) aneurysm (RAA) is a rare and complex disease. Treatment options for a RAA include endovascular surgery and open surgery with ex vivo repair or in situ reconstruction. This study evaluated the long-term outcome after vascular reconstruction of RAAs using the tailoring technique. Tailoring or aneurysmorrhaphy means a partial resection of the aneurysm with direct suture of the remaining arterial wall., Methods: A single-center retrospective study was conducted between January 1990 and December 2015. The tailoring technique was used to surgically repair 88 RAAs in 80 patients (52 women) with a mean age of 52.9 years. Patients' demographic data, vascular therapy, and renal function during follow-up were retrospectively evaluated., Results: The localization of the RAA was at the right kidney in 58 patients. The mean size of the aneurysm was 21.4 ± 9.7 mm (range, 8-67 mm). Hypertension was diagnosed in 56 patients, and 23 were asymptomatic. One RAA was ruptured. The overall morbidity rate was 16.3%, including bleeding (n = 4), RA stenosis (n = 3), RA occlusion (n = 4), RA dissection (n = 1), and myocardial infarction (n = 1). One patient died of myocardial infarction for a 30-day mortality rate of 1.3%. The 30-day primary patency rate was 90.0%. The 30-day secondary patency rate was 95.0%. Follow-up data were obtained from 71 patients who underwent tailoring in 78 RAAs. The mean follow-up period was 60.7 months (range 2-229 months). In 76.4% of patients with RAA and hypertension, RAA reconstruction contributed to the cure or improvement of hypertension. The long-term patency after RAA reconstruction was demonstrated in a Kaplan-Meier curve, with cumulative patency rates of 98.7%, 97.4%, 94.8%, and 92.3% after 18, 24, 36, and 48 months, respectively. Estimated survival rates were 98.8%, 97.5%, and 96.3% after 12, 48, and 60 months, with an estimated mean time of 216.5 ± 7.2 months., Conclusions: The tailoring technique is a safe and effective procedure with good long-term outcomes. RAA reconstruction contributed to the cure or improvement of renovascular hypertension., (Copyright © 2016 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Conclusions: Immunostaining of whole organ serial sections of the larynx is feasible and will allow analysis of cellular alterations in the undisturbed anatomical context of whole organ serial sections of the larynx., Objectives: Whole organ serial sections of the larynx have to date been used for conventional macroscopic evaluation of laryngeal tissues. The aim of this study was to establish a protocol for immunohistochemistry of whole organ sections of the larynx., Materials and Methods: Five laryngectomy specimens were obtained during surgery for advanced laryngeal carcinoma. Using a novel method for paraffin embedding, we chose the proliferation marker Ki-67 antigen as a model target for immunoreactivity on serial sections., Results: We were able to produce whole organ serial sections that could then be immunostained for Ki-67. A complete mapping of proliferating cells throughout the tumour, at the tumour front and in skip lesions was subsequently obtained.

Conclusions: The presented results add further support to the observation that laser microsurgery is the preferential surgical treatment for recurrent respiratory papillomatosis (RRP). A meticulous follow-up for early recognition of local recurrence and malignant transformation is recommended., Objectives: Endoscopic microsurgery continues to be the treatment of choice for RRP. The aim of this study was to evaluate the outcome of patients treated surgically. We focused on demographic data, recurrence rates, and treatment-related complications., Patients and Methods: The charts of 194 patients treated at our institution between 1963 and 1993 were analyzed retrospectively., Results: In all, 64 patients (33%) underwent a total of 137 operations using the CO2 laser; 130 patients (67%) underwent a total of 565 microlaryngeal operations by surgery with cold instruments. Five percent of the patients treated with conventional microlaryngeal surgery and none of the patients treated with laser surgery required tracheostomy (p<0.05). Postoperative glottic webs and scar formations were found in 6% of all patients after laser surgery and 20% after conventional surgery (p<0.05). The different methods of treatment did not affect the rate of recurrence (p=0.61) Malignant transformation or secondary airway carcinoma were observed in 4% of all patients.