Gregor Bran

Hereditary hemorrhagic telangiectasia: an update on clinical manifestations and diagnostic measures

ZusammenfassungDie hereditäre hämorrhagische Teleangiektasie (HHT), auch als Morbus Rendu-Osler-Weber bekannt, ist eine autosomal-dominant vererbte Erkrankung des Gefäßbindegewebes. Die Erkrankung wird charakterisiert durch die klassische Trias bestehend aus (muko-)kutanen Teleangiektasien, arteriovenösen Malformationen mit rezidivierender Epistaxis und Hämorrhagien sowie der Heredität. Eine Vielzahl unterschiedlicher klinischer Manifestationsformen der HHT sind beschrieben worden. In mehr als 90% der Fälle stellt die Epistaxis das klinische Erstsymptom dar, wodurch Hals-Nasen-Ohrenärzten eine wichtige Schlüsselrolle in der Diagnosestellung und der Behandlung der HHT zukommt. Trotz neuester diagnostischer und therapeutischer Entwicklungen ist eine Heilung dieser, den Betreffenden in seiner Lebensqualität oft einschränkenden Erkrankung nicht möglich. Außer der Nase sind vor allem die Haut, die Lunge, das Hirn, die Leber und der Gastrointestinaltrakt von arterio-venösen Malformationen (AVM) befallen. Die Entstehung der HHT wird im wesentlichen Mutationen zweier Gene zugeschrieben. Zum einen handelt es sich hierbei um Endoglin (ENG) auf Chromosom 9q33-q34 und activin-receptor like kinase (ALK1) auf Chromosom 12q13. Mutationen von Endoglin werden dem HHT Typ 1 zugeschrieben mit einer Inzidenz von bis zu 40% für pulmonale arteriovenöse Malformationen (AVM). Mutationen von ALK1 entsprechen dem HHT Typ 2 mit einer Inzidenz von bis zu 14% für pulmonale AVM. Diese Arbeit dient zum besseren Verständnis der Komplexität der HHT-Erkrankung, wobei anhand einer Übersicht zur aktuellen Literatur vor allem ein Schwerpunkt auf die klinischen Manifestationsformen, die Molekulargenetik und die Diagnosemöglichkeiten gelegt werden soll. Therapeutische Optionen in der Behandlung der HHT sind hier bewusst nicht erwähnt worden, da sie Gegenstand einer weiteren Arbeit sind. Dadurch, dass die HHT häufiger vorkommt als vermutet und eine weite Bandbreite klinischer Manifestationen aufweisen kann, stellt sie für viele Subspezialisierungen eine enorme Herausforderung dar, die ein eingehendes interdisziplinäres diagnostisches Screening in der Behandlung verlangt.SummaryHereditary hemorrhagic telangiectasia (HHT), also known as Rendu-Osler-Weber disease, is an autosomal dominant disorder of the fibrovascular tissue. It is characterized by the classic triad of (muco-)cutaneous telangiectases, arteriovenous malformations with recurrent epistaxis and hemorrhages, and inheritance. A wide variety of clinical manifestations in HHT have been described. In more than 90% of the patients, nosebleeds are the first predominant symptom, therefore ENT physicians often play a key role as far as diagnosis and management of the disease are concerned. In spite of recent diagnostic and therapeutic progress, a cure for this often burdening and handicapping disease is still not available. Apart from affecting the nose, arteriovenous malformations (AVMs) may also affect the skin, lungs, brain, liver and gastrointestinal tract. The two known genes that are implicated in HHT are endoglin (ENG) located on chromosome 9q33-q34 and activin-receptor-like kinase (ALK1) located on chromosome 12q13. Mutations of ENG are observed in HHT type 1 with an incidence up to 40% for pulmonary AVMs, whereas mutations of ALK1 are observed in HHT type 2 with an incidence of only 14% for pulmonary AVMs, which clinically distinguishes these two types of mutation. The emphasis of this paper is mainly on the clinical manifestation, molecular genetics and diagnosis of HHT, taking account of current literature on HHT in order to better understand the complexity of the disease. Recent therapeutic options in the treatment of HHT have been omitted from this paper as they are subject of a following paper. HHT is more common than previously thought and shows a broad range of different clinical organ manifestations that can be sources of substantial morbidity and mortality, making HHT a continuing challenge for many sub-specialties where interdisciplinary diagnostic screening is mandatory in the management of the disease.

Anatomic Changes After Hyoid Suspension for Obstructive Sleep Apnea: An MRI Study

OBJECTIVE: To assess the effects of isolated hyoid suspension on subjective and objective parameters of obstructive sleep apnea and to evaluate changes in upper airway anatomy with the help of standardized magnetic resonance imaging. STUDY DESIGN AND SETTING: Fifteen patients received isolated hyoid suspension. Changes in respiratory disturbance index were assessed with polysomnography, and anatomical changes with standardized magnetic resonance imaging. Snoring, daytime sleepiness, and functional parameters were assessed with questionnaires. Lateral x-ray cephalometry was performed preoperatively. RESULTS: Mean respiratory disturbance index was reduced from 35.2 ± 19.1 to 27.4 ± 26.2. Forty percent of the patients were classified as responders. Daytime sleepiness improved significantly. Relevant changes in upper airway anatomy could not be detected. There were no remarkable differences between responders and nonresponders in regard to imaging. CONCLUSIONS: Hyoid suspension is effective only in a subgroup of patients and does not lead to relevant changes in airway diameters in the awake patient. Magnetic resonance imaging and x-ray cephalometry do not add additional information for patient selection. SIGNIFICANCE: The reported clinical effects of hyoid suspension are more likely due to functional changes in airway collapsibility than to an enlargement of the upper airway.

Classification of the external auditory canal cholesteatoma.

Objectives/Hypothesis: The external auditory canal cholesteatoma (EACC) is a rare disease in the field of otolaryngology. Only 1 in 1,000 new otologic patients present with this entity, which was first described by Toynbee. The aim of this article is to classify EACC by different histopathologic and clinical findings of patients presenting to the Department of Otolaryngology at the University of Mannheim, Germany.

Volumetric tissue reduction in radiofrequency surgery of the tongue base.

OBJECTIVES: Radiofrequency surgery is a minimally invasive technique for the treatment of the tongue base in sleep-disordered breathing. The aim of this study was to evaluate the changes in upper airway anatomy induced by radiofrequency surgery with MRI. STUDY DESIGN AND SETTING: 10 patients with sleep-disordered breathing were treated with radiofrequency surgery at tongue base. MRI measurements were performed before and after surgery with the help of a recently published protocol. RESULTS: The mean total number of energy delivered per patient was 4750 ± 1641 Joule. Relevant changes could be observed neither for tongue volume or dimension nor for retrolingual space. CONCLUSIONS: Changes in upper airway anatomy could not be demonstrated. The effects of radiofrequency surgery of the tongue base may more likely be a result of changes in upper airway collapsibility. SIGNIFICANCE: Functional effects of surgical interventions in sleep-disordered breathing should be considered in addition to mechanistic concepts alone.

Lesion Formation in Radiofrequency Surgery of the Tongue Base

Objectives Temperature controlled radiofrequency volumetric tissue reduction (RFVTR) of the tongue base is a minimally invasive technique for the treatment of obstructive sleep apnea. But despite its widespread use, little is yet known about in vivo effects in humans. Such knowledge would be essential for evidence‐based criteria in the selection of energy application.

Apoptosis in Bone for Tissue Engineering

Bone loss due to congenital defects, trauma, improper fracture fixation, metabolic disturbances, infections, or after tumor resection represents a major clinical problem in head and neck surgery. To address these issues, different types of scaffolds, growth factors and cell sources -- alone or in various combinations -- have been applied for development of bioartificial bone tissues. Although these applications have received increasing interest, use of autologous bone grafts is still considered as the gold standard for tissue repair. Despite progress in some areas of tissue regeneration, significant translation into clinical practice has not been achieved. Reasons for this impass include rejection of engineered tissue implants by the immune system, limited blood supply, or morbidity of the donor site. During the process of bone regeneration, approximately 50-70% of osteoblasts undergo apoptosis. Apoptosis is a naturally occurring cell death pathway induced in a variety of cell types and is associated with caspase activation or caspase mediation. It is recognized as an important component of embryogenesis and tissue morphogenesis and, in adult skeletons, it contributes substantially to physiological bone turnover, repair, and regeneration. Intracellular mechanisms are orchestrated by a variety of proteins, the interplay of which seems to vary, depending on the differentiation state of the cell or the current status of the tissue. Closing gaps in current knowledge of the apoptosis of bone and understanding the mechanisms of cell death in tissue engineered bone will improve results in the translation from bench to bedsite. This review aims to provide a broad overview of the current general concepts in apoptosis with a special focus on its regulation in osteoblasts and its significance for bone tissue engineering.

Auricular Keloids: Combined Therapy With a New Pressure Device

OBJECTIVE To develop a new, custom-made pressure device that can be used with established designs as an adjuvant therapy for optimized treatment of auricular keloids. METHODS Seven patients (4 males, 3 females; mean [SD] age, 22.6 [8.3] years) were treated with surgical excision and corticosteroid injection followed by application of our new auricular pressure device. RESULTS All patients tolerated the adjuvant therapy and wore the device overnight for 5 nights per week. Usage was not interrupted or cancelled. No recurrence was observed during the follow-up period (mean [SD] duration of follow-up, 24 [6] months). All patients were satisfied with the results; none described pruritus, pain, or dysesthesia. CONCLUSION Overnight usage of the new pressure device seems to be a safe and effective extension of established auricular keloid therapy with the potential for prophylaxis of recurrence.

In vitro analysis of integrin expression in stem cells from bone marrow and cord blood during chondrogenic differentiation.

The use of adult mesenchymal stem cells (MSC) in cartilage tissue engineering has been implemented in the field of regenerative medicine and offers new perspectives in the generation of transplants for reconstructive surgery. The extracellular matrix (ECM) plays a key role in modulating function and phenotype of the embedded cells and contains the integrins as adhesion receptors mediating cell–cell and cell–matrix interactions. In our study, characteristic changes in integrin expression during the course of chondrogenic differentiation of MSC from bone marrow and foetal cord blood were compared. MSC were isolated from bone marrow biopsies and cord blood. During cell culture, chondrogenic differentiation was performed. The expression of integrins and their signalling components were analysed with microarray and immunohistochemistry in freshly isolated MSC and after chondrogenic differentiation. The fibronectin‐receptor (integrin a5b1) was expressed by undifferentiated MSC, expression rose during chondrogenic differentiation in both types of MSC. The components of the vitronectin/osteopontin‐receptors (avb5) were not expressed by freshly isolated MSC, expression rose with ongoing differentiation. Receptors for collagens (a1b1, a2b1, a3b1) were weakly expressed by undifferentiated MSC and were activated during differentiation. As intracellular signalling components integrin linked kinase (ILK) and CD47 showed increasing expression with ongoing differentiation. For all integrins, no significant differences could be found in the two types of MSC. Integrin‐mediated signalling seems to play an important role in the generation and maintenance of the chondrocytic phenotype during chondrogenic differentiation. Especially the receptors for fibronectin, vitronectin, osteopontin and collagens might be involved in the generation of the ECM. Intracellularly, their signals might be transduced by ILK and CD47. To fully harness the potential of these cells, future studies should be directed to ascertain their cellular and molecular characteristics for optimal identification, isolation and expansion.

Tissue engineering in head and neck reconstructive surgery: what type of tissue do we need?

Craniofacial tissue loss due to congenital defects, disease or injury is a major clinical problem. The head and neck region is composed of several tissues. The most prevalent method of reconstruction is autologous grafting. Often, there is insufficient host tissue for adequate repair of the defect side, and extensive donor site morbidity may result from the secondary surgical procedure. The field of tissue engineering has the potential to create functional replacements for damaged or pathologic tissues.

Co-expression of different angiogenic factors in external auditory canal cholesteatoma.

Objective Although external auditory canal cholesteatoma (EACC) was first described in 1850, its cause remains surprisingly unclear. Angiogenesis, the formation of new blood vessels, is essential to normal development and wound healing in adults. Abnormal regulation of angiogenesis has been implicated in the pathogenesis of several disorders. The aim of this study was to analyse angiogenesis regulator expression in EACC. Materials and Methods Cryostat sections of 13 investigated EACC tissue samples and normal control tissue were immunostained for angiogenic hepatocyte growth factor (HGF)/scatter factor (SF), its c-Met receptor and vascular endothelial growth factor (VEGF) using a standard streptavidin–biotin complex procedure. Staining against von Willebrand factor (vWF) served as an endothelial marker. Statistical analysis was performed semiquantitatively. Results The assayed angiogenic factors were all present in the EACC tissue, and partly overexpressed. vWF was detected in the apical layers of the matrix epithelium. Positive immunoreactivity for c-Met and VEGF was detectable in all layers of the EACC epithelium; however, adjacent tissue did not express c-Met and VEGF. HGF/SF was predominantly expressed in the adjacent perimatrix tissue and fibroblasts in particular were stained positive. Conclusions The presence of vWF in the apical part of the matrix depicted the attempt at angiogenesis in this part of the EACC. The detection of VEGF and c-Met in the epithelial part of the EACC implied that their origin may be epithelial, while HGF/SF may be secreted or stored in the adjacent mesenchymal EACC tissue. The angiogenic factors investigated seem to play an important role in establishing that EACC occurs by modulation of angiogenesis.