Holger Kaftan

Clinical Predictors for Germline Mutations in Head and Neck Paraganglioma Patients: Cost Reduction Strategy in Genetic Diagnostic Process as Fall-Out

Multiple genes and their variants that lend susceptibility to many diseases will play a major role in clinical routine. Genetics-based cost reduction strategies in diagnostic processes are important in the setting of multiple susceptibility genes for a single disease. Head and neck paraganglioma (HNP) is caused by germline mutations of at least three succinate dehydrogenase subunit genes (SDHx). Mutation analysis for all 3 costs approximately US

Effects of Topically Applied Dexamethasone on Mucosal Wound Healing Using a Drug-Releasing Stent

2,700 per patient. Genetic classification is essential for downstream management of the patient and preemptive management of family members. Utilizing HNP as a model, we wanted to determine predictors to prioritize the most heritable clinical presentations and which gene to begin testing in HNP presentations, to reduce costs of genetic screening. Patients were tested for SDHB, SDHC, and SDHD intragenic mutations and large deletions. Clinical parameters were analyzed as potential predictors for finding germline mutations. Cost reduction was calculated between prioritized gene testing compared with that for all genes. Of 598 patients, 30.6% had SDHx germline mutations: 34.4% in SDHB, 14.2% SDHC, and 51.4% SDHD. Predictors for an SDHx mutation are family history [odds ratio (OR), 37.9], previous pheochromocytoma (OR, 10.9), multiple HNP (OR, 10.6), age <or=40 years (OR, 4.0), and male gender (OR, 3.5). By screening only preselected cases and a stepwise approach, 60% cost reduction can be achieved, with 91.8% sensitivity and 94.5% negative predictive value. Our data give evidence that clinical parameters can predict for mutation and help prioritize gene testing to reduce costs in HNP. Such strategy is cost-saving in the practice of genetics-based personalized health care.

Frequency analysis of snoring sounds during simulated and nocturnal snoring

Objective/Hypothesis: Evaluation of the impact of continuously topically released dexamethasone using a drug‐releasing stent on quality of regenerated mucosa after full thickness injury in the paranasal sinuses.

Effects of a dexamethasone-releasing stent on osteoneogenesis in a rabbit model.

Despite several ways of investigation, such as clinical examination, drug-induced sleep endoscopy and pressure measurement of the upper airway, it is still difficult to locate the site of snoring exactly. Frequency analysis of snoring sounds is described as a promising diagnostic tool. The aim of the study was to examine simulated snoring under conditions awake, record the produced snoring sounds and compare those sounds with nocturnal snoring. A total of 50 snoring male patients were examined clinically by flexible nasal endoscopy and simulated snoring under conditions awake, and the simulated snoring sounds were recorded. Additionally, nocturnal snoring sounds were recorded during nighttime polysomnography. Snoring events were analyzed by fast-fourier-transformation and the intensity peaks 1–5 were evaluated. Rhythmic and non-rhythmic snoring events were distinguished depending on present obstructive apneas. Clinical and polysomnographical data were correlated with the results of the frequency analysis of the snoring sounds. Simulated snoring sounds revealed a low frequency of 200 Hz in intensity peaks 1 and 2 with an increase up to 3,000 Hz in peaks 3–5. Similar frequency patterns were detected in rhythmic nocturnal snoring. Non-rhythmic snoring events revealed frequency patterns between 2,000 and 3,000 Hz in all five intensity peaks. Simulated snoring resembles rhythmic nocturnal snoring with low-frequency intensity peaks, whereas non-rhythmic snoring revealed high frequencies. The examination during simulated snoring and frequency analysis of snoring sounds might contribute in locating the pathogenesis of snoring.

The Upper Airway in Sleep-Disordered Breathing : A Clinical Prediction Model

Background This study is an evaluation of wound healing in an animal model for surgery of frontal sinusitis and treatment effect of topically released dexamethasone using a drug-releasing stent with special emphasis of osteoneogenesis. Methods A prospective, controlled, randomized, double-blinded animal study was performed. Nineteen New Zealand white rabbits were subjected to surgery via an external approach, a 4-mm circular wound was created on the medial side of the maxillary sinus and the underlying bone was denuded of periosteum. The wound was covered in a randomized fashion with either a silicone foil or a new dexamethasone-releasing stent system. Twelve to 30 days later, the animals were killed and a histological examination was performed. Results In comparison with the baseline bony thickness (40 micrometer) obtained in one animal, osteoneogenesis occurred on both paranasal sides but was significantly less if a dexamethasone-releasing stent was applied (117 [95% CI, 116–128]; 52 [95% CI, 43–64]; p < 0.001). Maximal bony thickness was observed in both treatment groups between days 20 and 25 with a tendency toward a higher percentage decrease in the dexamethasone-treated sides (p < 0.08). Using a visual analog scale (0–5) a significantly smoother bony surface was observed for dexamethasone (2 [95% CI, 1.1–1.9]; 2 [95% CI, 1.8–2.2]; p < 0.01). Conclusion Using a new drug-releasing stent system, dexamethasone efficiently decreases postoperative osteoneogenesis in a standardized animal wound model for endoscopic sinus surgery. Therefore, the use of this system may be of value to decrease restenosis rates using corticosteroids in selected patients after frontal sinus surgery, especially the endoscopic modified Lothrop procedure.

The impact of the microphone position on the frequency analysis of snoring sounds

An examination of the upper airway in patients with suspected sleep disordered breathing (SDB) is recommended prior to nighttime polysomnography (PSG) despite a reported low predictive value of those examinations. The aim of this study was to evaluate the data of the clinical examination and to create a clinical prediction model.

Delay of tympanic membrane wound healing in rats with topical application of a tyrosine kinase inhibitor.

Frequency analysis of snoring sounds has been reported as a diagnostic tool to differentiate between different sources of snoring. Several studies have been published presenting diverging results of the frequency analyses of snoring sounds. Depending on the position of the used microphones, the results of the frequency analysis of snoring sounds vary. The present study investigated the influence of different microphone positions on the outcome of the frequency analysis of snoring sounds. Nocturnal snoring was recorded simultaneously at six positions (air-coupled: 30 cm middle, 100 cm middle, 30 cm lateral to both sides of the patients’ head; body contact: neck and parasternal) in five patients. The used microphones had a flat frequency response and a similar frequency range (10/40 Hz–18 kHz). Frequency analysis was performed by fast Fourier transformation and frequency bands as well as peak intensities (Peaks 1–5) were detected. Air-coupled microphones presented a wider frequency range (60 Hz–10 kHz) compared to contact microphones. The contact microphone at cervical position presented a cut off at frequencies above 300 Hz, whereas the contact microphone at parasternal position revealed a cut off above 100 Hz. On an exemplary base, the study demonstrates that frequencies above 1,000 Hz do appear in complex snoring patterns, and it is emphasised that high frequencies are imported for the interpretation of snoring sounds with respect to the identification of the source of snoring. Contact microphones might be used in screening devices, but for a natural analysis of snoring sounds the use of air-coupled microphones is indispensable.

Inhibition of epidermal growth factor receptor by erlotinib: wound healing of experimental tympanic membrane perforations.

An animal model of chronic tympanic membrane (TM) perforation is needed for experiments on supporting wound healing of TM perforations. The epidermal growth factor receptor (EGFR) has been implicated in the regulation of wound healing. The object of this study was to investigate the efficacy of topical EGFR‐inhibitor (erlotinib) to arrest wound healing of experimental TM perforation in rats. Bilateral instrumental myringotomies were performed in 13 male rats. A solution of erlotinib (10 mg/mL) was applied to one TM of each animal and vehicle only (control group) to the other side. The application procedure was repeated on both sides daily for 12 consecutive days. Thereafter, tympanic membranes were observed weekly for a total of 30 days. The mean healing period was found to be 12.1 days in the group with erlotinib and 6.4 days in the control group. The difference was significant. We observed differences in the histologic parameters between erlotinib group and control group. The inhibition of EGFR by topical application of erlotinib did delay the healing rate of myringotomies but seems not to be suitable to create a chronic TM perforation in rat.

Topical application of transforming growth factor-β1 in acute traumatic tympanic membrane perforations: an experimental study in rats

Hypothesis: Inhibition of epidermal growth factor receptor (EGFR) may arrest wound healing of experimental tympanic membrane perforation in rats. Background: An animal model of chronic tympanic membrane perforation is needed for experiments on supporting wound healing of tympanic membrane perforations. The EGFR has been implicated in the regulation of wound healing. Methods: Thirty animals were administered 80 or 40 mg/kg/d EGFR tyrosine kinase inhibitor, or vehicle only for 5 days. The right-sided tympanic membrane of each animal was perforated at Day 2. Rat ears were inspected repeatedly to analyze the status of perforation. Tympanic membranes were examined histologically. Results: Unfortunately, five animals in the 80-mg/kg group and four in the 40-mg/kg group died before they reached their scheduled endpoint. Taking into account the small sample sizes, we observed a delayed closure of perforations in the 80-mg/kg group and differences in the histologic parameters between treated groups and control group. Conclusion: The inhibition of EGFR by systemic application of erlotinib seems not to be suitable to create a chronic tympanic membrane perforation in rat.

The influence of inhibition of the epidermal growth factor receptor on tympanic membrane wound healing in rats

High transforming growth factor‐β1 (TGF‐β1) expression in combination with fibrotic scar was observed in human tympanic membranes containing a chronic perforation. The purpose of this study was to investigate whether application of exogenous TGF‐β1 to experimentally created tympanic membrane perforations might induce a nonhealing tympanic membrane perforation. Bilateral myringotomies were performed in 20 rats. In 10 animals, a single dose of TGF‐β1 (0.1 μg) was topically applied to the left tympanic membrane after perforation. In the second part of the study with 10 animals, repeated applications of TGF‐β1 at a higher concentration were tested. In both groups, the opposite ears received vehicle alone. Tympanic membranes were observed for a total of 5 weeks. The effect of TGF‐β1 on the healing of the tympanic membranes was evaluated by closure rates and histology. In the single application group, the healing process was not delayed. Repeated applications of TGF‐β1 did cause a faster perforation closure and a thicker tympanic membrane. Topical TGF‐β1 applied to a traumatic tympanic membrane perforation does not create a chronic perforation at the concentrations and modes of application used in this study.