[Molecular laryngology : A new chapter in the understanding of laryngeal diseases]. / Molekulare Laryngologie : Ein neues Kapitel im Verständnis laryngealer Erkrankungen.

BACKGROUND: Despite considerable advances in laryngological research, there is still a plethora of (benign) vocal fold pathologies that cannot be treated causally. This is due to the limited accessibility and sensitive microarchitecture of the vocal folds, which cannot be investigated at a cellular level. Consequently, current pathophysiological knowledge is frequently based on macroscopic findings. The impact of interventions is mainly evaluated endoscopically or via indirect diagnostic methods. OBJECTIVE: The aim of this article is to discuss state-of-the-art biotechnological methods used in laryngological research, illustrated by practical examples. RESULTS: In recent years, animal and in vitro experiments have significantly contributed to a continuous expansion of knowledge in this field, particularly regarding vocal fold inflammation and scar formation. Vocal fold fibroblasts, the most important cellular component of the lamina propria, can be accredited a central role in these processes. CONCLUSION: Our knowledge regarding macroanatomy and macropathophysiology of several pathologies has increased considerably in recent years. In vitro trials have shown, e.g., that vocal fold fibroblasts in an inflammatory setting secrete less profibrotic and proinflammatory cytokines when exposed to vibration. Early vocal exercises after surgical interventions on the vocal folds may therefore promote better wound healing and consequently improved phonation. Research in molecular laryngology should create a solid basis of knowledge for subsequent clinical studies.

Comprehensive investigation of saliva replacement liquids for the treatment of xerostomia.

The sensation of dry mouth also referred to as xerostomia is becoming increasingly common worldwide. Current treatment strategies include topical agents, sialagogues and saliva substitutes. The latter have been reported to be ineffective as special physicochemical features of natural saliva have so far been ignored (e.g., buffer capacity, osmolality, etc.). The aim of this study was to comprehensively investigate the most relevant physicochemical properties of three products frequently used in the clinics and compare them to unstimulated whole saliva (UWS). Sialin-Sigma®, Glandomed® and Xylitol CVS HealthTM Dry Mouth Spray were characterized regarding their pH, osmolality, electrical conductivity, buffer capacity, rheological behaviour, microstructure, surface tension and wettability and compared to UWS. The influence of residual saliva was examined under consideration of the conditions of xerostomia to assess whether the quantity given in the instruction for use is appropriate. All three products showed significant differences to UWS regarding the values received. Only Xylitol CVS HealthTM Dry Mouth Spray showed a comparable wettability. It could be further determined that the recommended doses were too low. These data can not only be used for an improved understanding of saliva, but also for the development of a replacement fluid to successfully alleviate xerostomia.

Exploring stimulation patterns for electrical stimulation of the larynx using surface electrodes.

PURPOSE: Functional electrical stimulation (FES) is considered an upcoming treatment modality for a number of laryngeal diseases. However, sound data are scarce when it comes to surface FES to treat voice disorders. Aim of the present study was to identify and differentiate suitable surface FES patterns to activate internal laryngeal muscles. METHODS: Non-invasive FES was performed in a cohort of 17 elderly woman. Our user-customized electrical stimulation setup allowed us to deliver ten different stimulation patterns (rectangular and sawtooth shaped) with variation of frequency and amplitude. Stimulation outcome, i.e., vocal fold (VF) reaction, was continuously verified by transnasal endoscopy. RESULTS: Responses to FES using ten different stimulation patterns varied inter-individually. None of the stimulation parameter sets could elicit a VF reaction in all participants. CONCLUSION: Based on our findings we conclude that individual fitting is necessary when defining surface stimulation parameters. To overcome limitations of previous studies, devices with freely programmable patterns are required as shown here. Endoscopic control of VF reaction is absolutely essential to ensure effectiveness of the delivered patterns.

Towards an in vitro fibrogenesis model of human vocal fold scarring.

BACKGROUND: Vocal fold (VF) scarring remains a therapeutic dilemma and challenge in modern laryngology. To facilitate corresponding research, we aimed to establish an in vitro fibrogenesis model employing human VF fibroblasts (hVFF) and the principles of macromolecular crowding (MMC). METHODS: Fibrogenesis was promoted by addition of transforming growth factor-ß1 to standard medium and medium containing inert macromolecules (MMC). Hepatocyte growth factor (HGF) and Botox type A were tested for their antifibrotic properties in various doses. Experiments were analyzed with respect to the biosynthesis of collagen, fibronectin, and α-smooth muscle actin using immunofluorescence, silver stain and western blot. RESULTS: MMC led to favourable enhanced deposition of collagen and other extracellular matrix components, reflecting fibrotic conditions. Low doses of HGF were able to dampen profibrotic effects. This could not be observed for higher HGF concentrations. Botox type A did not show any effects. CONCLUSION: Based on the principles of MMC we could successfully establish a laryngeal fibrogenesis model employing hVFF. Our finding of dose-dependent HGF effects is important before going into clinical trials in humans and has never been shown before. Our model provides a novel option to screen various potential antifibrotic compounds under standardized conditions in a short time.

The unsolved chapter of vocal fold scars and how tissue engineering could help us solve the problem.

Vocal fold scarring is a relatively small field in scar research with prerequisites found nowhere else. The deterioration of the delicate tri-layered micro-structure of the epithelium of the vocal folds leads to impaired vibration characteristics resulting in a permanent hoarse and breathy voice. Tissue engineering approaches could help to restore the pre-injury status. Despite a considerable progress in this field during the last years, routine clinical applications are not available so far. One reason might be that vocal fold fibroblasts, as the responsible cell type for fibrogenesis, have very particular properties that are only poorly characterized. Moreover, in vivo trials are costly and time consuming and a representative in vitro model does not exist so far. These particular circumstances lead to innovative in vitro strategies and concepts such as macro-molecular crowding that can also be applied in adjacent fields.

Vocal fold scars: current concepts and future directions. Consensus report of the Phonosurgery Committee of the European Laryngological Society.

Scarring of the vocal folds leads to a deterioration of the highly complex micro-structure with consecutively impaired vibratory pattern and glottic insufficiency. The resulting dysphonia is predominantly characterized by a reduced vocal capacity. Despite the considerable progress in understanding of the underlying pathophysiology, the treatment of scarred vocal folds is still an unresolved chapter in laryngology and phonosurgery. Essential for a successful treatment is an individual, multi-dimensional concept that comprises the whole armamentarium of surgical and non-surgical (i.p. voice therapy) modalities. An ideal approach would be to soften the scar, because the reduced pliability and consequently the increased vibratory rigidity impede the easiness of vibration. The chosen phonosurgical method is determined by the main clinical feature: Medialization techniques for the treatment of glottic gap, or epithelium freeing techniques for improvement of vibration characteristics often combined with injection augmentation or implantation. In severe cases, buccal mucosa grafting can be an option. New developments, include treatment with anxiolytic lasers, laser technology with ultrafine excision/ablation properties avoiding coagulation (Picosecond infrared laser, PIRL), or techniques of tissue engineering. However, despite the promising results by in vitro experiments, animal studies and first clinical trials, the step into clinical routine application has yet to be taken.

Experience of 11 years use of cidofovir in recurrent respiratory papillomatosis.

Recurrent respiratory papillomatosis (RRP) is a viral induced disease, associated with exophytic epithelial lesions affecting the upper airways. Problem of treatment is the high recurrence of papilloma growth after surgical removal; therefore adjuvant therapy schemes have been established. Cidofovir was one of the agents used off-label in adjuvant therapy in the last years. However, there is ongoing discussion about the effectiveness and possible side effects. Aim of our study was to share our experience in treatment of RRP with cidofovir during the last 11 years. We analyzed all the data of patients treated for RRP at the Department for Phoniatrics of the Medical University of Graz between 1999 and 2011. 25 out of the 34 treated patients are at the moment under complete remission, in six patients partial remission could be achieved and two patients showed poor response to therapy, therefore the treatment with cidofovir was stopped. 21 patients received one cycle of monthly cidofovir, 11 patients received two and one patient three cycles of therapy. Number of procedures reached from one to six during each cycle. Average cumulative dose of one cycle was 79.7 mg (15-277.5 mg), in one patient 435 mg were used. One patient developed temporary, borderline neutropenia without symptoms. Despite the retrospective approach of this study with the limitation of several incomplete records, our results show promising long-term effects of adjuvant use of cidofovir. During this period, we did not observe any relevant side effects.

[Vocal fold scars: pathogenesis, diagnosis, therapy]. / Stimmlippennarben: Pathogenese, Diagnostik, Therapie.

Scarring of the vocal folds leads to a deterioration of the highly complex microstructure with consecutively impaired vibratory pattern and glottic insufficiency. The resulting dysphonia is predominantly characterized by a reduced vocal capacity. Despite considerable progress in the understanding of the underlying pathophysiology, treatment of scarred vocal folds is still an unresolved chapter in laryngology and phonosurgery. Decisive for successful treatment is an individual, multidimensional concept that comprises the whole armamentarium of surgical and nonsurgical (e.g. voice therapy) modalities. The chosen phonosurgical method is determined by the main clinical feature: medialization techniques for treatment of glottic insufficiency, or epithelium-freeing techniques for improvement of vibration characteristics often combined with injection augmentation or implantation. In severe cases, buccal mucosa grafting can be an option. New developments include treatment with angiolytic lasers [pulse dye laser, PDL; potassium titanyl phosphate (KTP) laser], or techniques of tissue engineering. However, despite promising results with in vitro experiments, animal studies and first clinical trials, application in clinical routine has not yet been achieved.

Syphilis is back: presentation of three cases at the ENT department.

PROBLEM: Syphilis is a sexually-transmitted disease caused by the spirochete Treponema pallidum, and is transmitted either through sexual contact or vertically across the placenta. Rates of infection were at a low point in the early 1990s. Since then, increasing numbers of new cases of infections have been observed in all Western countries. AIM: Presentation of three patients with syphilis who presented within a short period of time in an ENT outpatient clinic. CONCLUSIONS: One must be aware of the increasing incidence of syphilis, even in head and neck disciplines. Typical symptoms of an early infection are an ulcerous lesion in the mouth, with or without cervical lymphadenopathy. The main therapy is high doses of penicillin G administered intramuscularly. Other simultaneous sexually-transmitted diseases, especially HIV infection, must be excluded. Unnoticed and untreated patients may develop late and life-threatening complications.

A transthyroidal method for arytenoid adduction: a basic anatomical study.

INTRODUCTION: Arytenoid adduction is a very effective procedure for medializing the posterior part of the vocal fold in vocal fold paralysis. Major drawback of the method is the technically sometimes-difficult access to the arytenoid with increased postoperative morbidity. Aim of this study was to provide basic anatomical data regarding the accessibility of the arytenoid cartilage through a thyroplasty window. Furthermore, to investigate the feasibility of an arytenoid adduction by fixation of a surgical screw to the arytenoid cartilage by using this approach. MATERIALS AND METHODS: 10 cadaver larynges, six female and four male, were dissected and measured for our points of interest. A standard manufacture-made surgical screw attached to a suture was anchored to the fovea oblonga of the arytenoid cartilage. RESULTS: Our anatomical measurements proved a mean distance from the posterior edge of the thyroid window to the arytenoid of about 8-9 mm in male larynges and 7-8 mm in female larynges. The distances did not differ significantly between the sexes. Pulling the anchored surgical screw medializes the posterior part of the vocal fold. DISCUSSION: Our data showed that there is a very constant morphometric relation between the thyroplasty window and the arytenoid cartilage. It is known that gender-related differences result in a veritable laryngeal dimorphism in nearly all absolute laryngeal dimensions. These differences appear to a much lesser extend in the distances from the surface to the depth, as was confirmed in our series. Using these findings led us to identification of the fovea oblonga near the muscular process as the most favorable point for fixation of a surgical screw through a conventional thyroplasty window. Pulling the attached suture medializes the arytenoid cartilage.

[First clinical experience with a moderately bent laryngoscope for endolaryngeal surgery]. / Erste klinische Erfahrungen mit einem gebogenen Laryngoskopierohr für die endolaryngeale Chirurgie.

INTRODUCTION: In this article we describe the successful use of a moderately bent laryngoscope in two different patient cases. MATERIALS: We developed a prototype of a 20 degrees bent laryngoscope. The moderate curvature allows insertion of the laryngoscope without using any optical device. The operation is performed via a laterally attached 30 degrees nasal endoscope and a monitor, with slightly bent instruments. Previous work by our group showed that when a bent laryngoscope was used, the forces on the oropharyngeal tissues were significantly reduced. Furthermore, the use of these laryngoscopes significantly improves the exposure of the endolarynx. RESULTS: We present two cases in which insertion of a conventional straight laryngoscope was not possible due to anatomical reasons. However, the operations could be performed successfully with the bent laryngoscope.

Pitch synchronous changes of the anterior cricothyroid gap by using ultrasonography.

OBJECTIVES: The purpose of this study was to describe changes of the anterior cricothyroid space during respiration and phonation by using ultrasonography. Furthermore, to assess and correlate laryngeal dimensions in a large cohort of voice healthy men. STUDY DESIGN: Epidemiological study. METHODS: Ultrasound examinations of the laryngeal skeleton, as well as of the cricothyroid space were performed in 64 voice healthy, elderly male subjects. This was done during respiration, phonation in midrange, and high phonation. RESULTS: We could not find any significant correlation concerning lengths of the cricothyroid space when correlated with voice range, highest or lowest frequency. General anthropometric parameters such as body height, weight, or body mass index did not show any considerable correlation with dimensions of the laryngeal skeleton. CONCLUSION: Functionally orientated surgery of the larynx requires exact knowledge of the anatomy and landmarks of the laryngeal skeleton. Topographic relations and dimensions between the thyroid and cricoid cartilages play an important role in cricoid approximation.

[Jet ventilation in laryngotracheal surgery]. / Die Jet-Ventilation in der operativen Laryngologie.

Conventional endotracheal intubation can be a limiting factor in endolaryngeal and endotracheal surgery. Tubeless jet ventilation can overcome this problem and provides an unlimited operation field to the surgeon. Since the development of first jet ventilation systems, many modifications have been performed and are used permanently in daily clinical routine. The aim of this work is to provide an overview of widely used jet ventilation systems and furthermore to list all advantages, as well as disadvantages of this technique in laryngotracheal surgery.

[Do clinical symptoms and laryngoscopic findings of laryngo-pharyngeal reflux correlate?]. / Korrelieren die klinischen Symptome und lupenlaryngoskopischen Befunde des laryngo-pharyngealen Refluxes miteinander?

BACKGROUND: ENT specialists are often confronted with symptoms which are related to laryngo-pharyngeal reflux. The high prevalence, as well as therapy with PPIs (proton pump inhibitors) has recently raised controversies. Goal of our study was to survey laryngeal tissue irritation signs, as well as reflux associated complaints in a cohort of "healthy" men. Furthermore to describe if and to which grade subjective symptoms correlate with clinical signs. METHODS: We surveyed in a prospective, population based study cohort of 64 men the prevalence of laryngeal irritation signs with laryngoscopy (based on the Reflux Finding Score--RFS) and reflux associated complaints (Reflux Symptoms Index--RSI). RESULTS: A third of all volunteers had pathological values as assessed by the RSI questionnaire. Laryngoscopy revealed only in six men signs suspicious of LPR. Symptoms and laryngoscopic findings did not correlate. CONCLUSION: In most cases no clinical substrate could be identified in symptoms usually contributed to LPR. These are often non specific and a careful examination of other factors should be taken.

Hyperplastic epithelial lesions of the vocal folds: combined use of exfoliative cytology and laryngostroboscopy in differential diagnosis.

The mainstay of successful tumor therapy is early detection of neoplastic tissue. Although exfoliative cytology has proven to be a reliable tool, its importance is still underestimated. Laryngostroboscopy is the most important tool for functional investigation in laryngological and phoniatric diagnosis. Stroboscopic evaluation allows early detection of infiltrative processes of the vocal folds. Aim of our study was to demonstrate that combination of both, exfoliative cytology and stroboscopy, provides a highly sensitive and easy to perform method in differential diagnosis of epithelial hyperplastic lesions of the vocal folds. In 130 patients with varying degrees of vocal fold keratosis up to glottic cancer, preoperative layngostroboscopy was performed. Stroboscopy was classified pathological in case of reduced or abolished amplitude of vocal fold vibration and/or reduced or abolished mucosal wave propagation. Under general anaesthesia histology with corresponding cytological specimens were obtained. The latter were classified in three groups reaching from normal (I), dysplastic (II), up to malignant (III) cytology. Invasive carcinoma was diagnosed in 32 cases by histology, corresponding malignant cytology was found in 21 specimens (sensitivity: 74%). By certain combination of cytology with pathological stroboscopy, a sensitivity of more than 97% can be achieved. Combination of cytology and stroboscopy allows detection of glottic cancer with a sensitivity of 97%, in contrast to 74% as found by cytology alone. This combination can be used as preliminary or sorting procedure and gives the opportunity of early detection, as well as for follow-up examinations. For repeated biopsies can cause scars with consecutive voice impairment, this procedure is very smooth but nevertheless reliable method.

[Comparability and conversion of Stimmstörungsindex (SSI) and Voice Handicap Index (VHI)]. / Vergleichbarkeit und Umrechnung von Stimmstörungsindex (SSI) und Voice Handicap Index (VHI).

BACKGROUND: The Voice Handicap Index (VHI) has been established internationally as a reliable tool for describing voice-dependent quality of life. Nawka developed a new score by using 12 questions out of the VHI, called SSI (Stimmstörungsindex) . The SSI has proven its role in daily clinical routine, main problem remains a lack of comparability of the SSI (range: 0 - 48) to the internationally established VHI (Voice Handicap Index) (range: 0 - 120). Aim of our study was to demonstrate that by a simple multiplication of SSI scores a statistically significant correlation with scores of the VHI can be achieved. METHODS: 210 consecutive patients of the ENT University Hospital Graz were evaluated by the German version of VHI. We calculated total score of VHI as well as the score of the SSI. By multiplication of the SSI scores by 2.5 we calculated a new score, called "VHI-korr". This score was compared with the VHI. RESULTS: We can demonstrate that by simple multiplication of the SSI scores by 2.5 a statistically significant correlation to the VHI can be achieved (r = 0.98; p < 0.01). CONCLUSION: The SSI- based "VHI-korr" provides good international comparability of voice disorders with VHI and allows to maintain the common use of SSI in daily clinical routine.

Incidence and clinical relevance of herniation of the mylohyoid muscle with penetration of the sublingual gland.

Swelling of the submandibular region may cause problems in daily clinical diagnosis and requires further exploration. Ultrasonic examination provides a simple, non-invasive and radiation-free method. The goal of our study was to show the high incidence of herniation of the mylohyoid muscle with penetration of the sublingual glands, in some cases clinically imposing as permanent swelling. Penetration was classified into four grades (Grade 0-III). In course of routine examinations of the neck by ultrasound, the anterior part of the mylohyoid muscle was observed in 124 consecutive patients from our outpatient's clinic, presenting with unclear swelling of the neck, mostly due to lymph nodes. In resting position and during swallowing the degree of penetration of the sublingual gland through the mylohyoid muscle was staged. Almost 60% of patients showed an affection of the mylohyoid muscle at either site of varying degrees. In 40% only a thinning of the muscle could be noticed (grade I), whereas in 21 patients (17%) a significant herniation of the gland during swallowing could be observed (grade II). In two patients (2%) a constant breach of the mylohyoid muscle with permanent herniation of the gland imposing as swelling could be seen (grade III). Occasional or permanent penetration of the sublingual gland through the mylohyoid muscle is not a rare finding and can be found in almost every fifth individual using ultrasound. This may impose clinically as permanent swelling and may be of value in the differential diagnosis of swelling in the submandibular region.

Calcium supply, bone mineral density and genetically defined lactose maldigestion in a cohort of elderly men.

OBJECTIVE: To examine a relationship of molecularly defined lactose malabsorption (LM; by LCT-polymorphism) to calcium supply, bone mineral density (BMD) and parameters of bone metabolism in an elderly male cohort. Furthermore, to reveal gender differences in BMD, calcium consumption rates and parameters of bone metabolism according to LCT polymorphism in an existing female cohort. SETTING AND SUBJECTS: A total of 239 men, aged 61+/-9 yr, were available from a former population based study cohort. All men were of Caucasian origin and came from the same region. Blood was sampled for genotyping of the LCT polymorphism and determination of markers of bone metabolism. All participants underwent physical examination, measurement of bone density and completed a standardized calcium questionnaire. Identical procedures had been carried out in a female cohort before (no. 350). RESULTS: Distribution of the LCT genotype in the study cohort was 27% CC (associated with LM; adult-type hypolactasia), 55% TC and 18% TT (lactase persistence). Amounts of total ingested calcium were similar among the three genotype groups. Amounts of consumed milk were generally low in men, LCT polymorphism did not influence rates of milk consumption for men preferred other sources of calcium. BMD, markers of bone metabolism and fracture rates did not differ. General anthropometric characteristics did not differ between the LCT groups either. CONCLUSIONS: Under conditions of low milk intake LCT polymorphism does not alter bone density, markers of bone metabolism and fractures in this cohort of elderly Caucasian men.

Adult-type hypolactasia and calcium availability: decreased calcium intake or impaired calcium absorption?

UNLABELLED: Adult-type hypolactasia, as mediated by a widespread genetic predisposition, not only reduces calcium intake but also calcium absorption in the presence of high amounts of lactose and may, therefore, promote osteoporosis. A lactose-reduced diet and lactose-free calcium supplements may reverse this imbalance. INTRODUCTION AND HYPOTHESIS: Adult-type hypolactasia (HL) defined by the LCT(-13910) polymorphism may reduce calcium intake by reducing dairy consumption and, therefore, promote osteoporosis. This study aimed to evaluate whether lactose also decreases intestinal calcium absorption in subjects with HL and whether lactose-reduced diet and lactose-free calcium supplementation as recommended could maintain bone mineral density (BMD). METHODS: Based on LCT genotyping, 73 postmenopausal women with and without HL underwent a conventional H(2) breath test with a concomitant oral strontium absorption test lasting 150 minutes, which closely reflects intestinal calcium absorption. In addition, we compared bone-specific laboratory parameters, lumbar and femoral BMD, and spinal radiographs to a similar bone assessment 5 years earlier. RESULTS: LCT genotyping and functional lactose malabsorption tests were highly correlated. Dairy product consumption was reduced by 80% in HL individuals. During concomitant lactose application, mean strontium absorption was blunted by 54% in HL subjects after 150 minutes (1272 +/- 629 microg/L vs. 2020 +/- 1130 microg/L in lactose tolerant subjects, p=0.001). Nevertheless, BMD in HL subjects remained stable with lactose-free calcium supplements during the observation period. CONCLUSION: Both decreased calcium intake as well as lactose-associated impaired calcium absorption may predispose subjects with HL to osteoporosis. Lactose-free calcium supplementation may help to maintain BMD in HL subjects.

Molecularly-defined lactose malabsorption, milk consumption and anthropometric differences in adult males.

BACKGROUND: Lactose malabsorption (LM) may be associated with reduced skeletal calcium content. Diagnosis to date has been based on indirect methods, with a high false-negative rate. Identification of the LCT polymorphism led to development of a PCR-based test. AIM: To evaluate the PCR-based test compared to a combination the hydrogen breath test and the lactose tolerance test, and investigate anthropometrical differences, changes in bone mineral density and oral calcium intake according to LCT polymorphism and milk-drinking habits. METHODS: All participants (n = 278) underwent clinical examination, with measurement of height, weight and bone density (DXA), and were genotyped for LCT polymorphism (LCT CC or LCT TT: CC is associated with LM). A subgroup (n = 51) had a hydrogen breath test and a lactose tolerance test, in addition to genotyping. RESULTS: Detection of LM by LCT polymorphism was highly significant (p = 0.001). The correlation between LCT genotype and self-reported milk-intolerance or dislike of milk with was slight, but the correlation with functional tests was highly significant. Non-milk-drinkers were lighter (-5 kg) and significantly shorter (-4 cm) than milk-drinkers (p = 0.07 and 0.04, respectively). Total calcium consumption was lower among non-milk-drinkers by about 18% (p = 0.03). DISCUSSION: Genotyping is an economic, quick and convenient method for diagnosing lactose malabsorption, with results comparable to existing tests. Sufficient calcium consumption may be relevant to body growth, as milk-drinkers were taller. Negative calcium bone balance may be prevented when provision is made for adequate calcium intake.