Retrospective single center analysis of outcome, risk factors and therapy in steroid refractory graft-versus-host disease after allogeneic hematopoietic cell transplantation.

Acute and chronic graft-vs.-host disease (aGvHD and cGvHD) are major complications after allogeneic hematopoietic cell transplantation (HCT) leading to substantial morbidity and mortality. This retrospective single-center study analyzes incidence, therapy, and outcome of GvHD in n = 721 patients ≥18 years having received allogeneic HCT 2004-2013 with a special focus on steroid refractory GvHD. Acute (n = 355/49.2%) and chronic (n = 269/37.3%) GvHD were mainly treated by steroids in first-line therapy. The proportion of steroid refractory aGvHD and cGvHD was 35.7% and 31.4%, respectively. As there is no standard therapy for steroid refractory GvHD, a range of different agents was used. In aGvHD, the overall response rate (ORR) of steroid refractory GvHD to second-line treatment was 27.4%. Mycophenolate mofetil (MMF) and mTOR inhibitors led to superior response rates (ORR 50.0% and 53.3%, respectively). In steroid refractory cGvHD therapy, ORR was 44.4%. Use of calcineurin inhibitors (CNI; n = 11/45.5%), MMF (n = 18/50.0%), mTOR inhibitors (n = 10/60.0%), and extracorporeal photophoresis (ECP; n = 16/56.3%) showed ORR above average. Targeted therapies lead to responses in 7.7% (n = 13). This data may help to improve the design of future prospective clinical studies in GvHD.

[Prognostic assessment in private healthcare insurance part 2 : Risk supplement for accidental endoprostheses]. / Prognosebeurteilung in der Privaten Unfallversicherung Teil 2 : "Risikozuschlag" bei unfallbedingten Endoprothesen.

After examining the causes of an accident the medical expert working in the area of private health care insurance under the general accident insurance (AUB) sample conditions must ascertain incapacity within a period of time that has been contractually agreed between the parties involved. In addition, this must also state their position on the question as to whether there may exist any circumstances up to the latest possible point in time in insurance terms that would comprise an adequate prognosis of a future change in the long-term condition. This requires a high probability. In contrast to scientifically based findings serving as a prognosis of osteoarthritis, in the case of endoprostheses forecasts can only be based on medical experience, which in this case has to satisfy the standard of proof of a high level of probability, since necessary replacement operations after insertion of a prosthesis are sufficiently probable. The prosthesis supplements that have been applied to date in the context of an assessment of prognosis have their justification. In applying them, however, it must be considered on one hand that this supplement is comprised of an equally weighted proportion for future risk and on the other hand a preventive portion. This increases in significance with different prostheses on one and the same limb.

[Prognostic assessment in private healthcare insurance part 1 : Risk of osteoarthritis]. / Prognosebeurteilung in der Privaten Unfallversicherung Teil 1 : Arthroserisiko.

After examining the cause of an accident the medical expert working in the area of private health care insurance under the general accident insurance (AUB) sample conditions must ascertain incapacity within a period of time that has been contractually agreed upon between the parties involved. In addition, this person must also state their position on the question as to whether there may exist any circumstances up to the latest possible point in time in insurance terms that would comprise an adequate prognosis of a future change in the long-term condition. This requires a high probability.The sole risk of the evolution of the functional deficit arising from a proven or prognosticated post-traumatic osteoarthritis is excluded from this standard of proof which means that flat-rate risk supplements are not suited to this individualized approach and thus do not apply.

Selection and characterisation of FVIII-specific single chain variable fragments.

The development of inhibitory anti-FVIII antibodies is currently the most severe complication in the treatment of haemophilia A patients. Inhibitor eradication can be achieved by immune tolerance induction (ITI). Recent findings suggest a correlation between the FVIII-specific IgG subclass distribution and the duration or outcome of ITI. To quantify FVIII-specific IgG subclasses in patients' plasma FVIII-specific IgG standards are required. Here, the isolation of FVIII-specific single chain variable fragments (scFvs) from synthetic phage display libraries and the characterisation of their FVIII domain specificity are described. The isolated scFv 1G10, which binds to the FVIII A2 domain, was cloned into the context of the four human IgG (hIgG) subclasses and expressed in mammalian cells. Purified 1G10-hIgG1, -hIgG2, -hIgG3 and -hIgG4 are used as standards to determine the absolute amounts and relative contribution of the different FVIII-specific IgG subclasses in future studies. The results from these studies will eventually add to understanding the role of the FVIII-specific IgG subclass distribution as prognostic factor for the outcome of ITI.

Treatment of chronic tinnitus with θ burst stimulation: a randomized controlled trial.

OBJECTIVE: To test whether 4 weeks of bilateral repetitive transcranial magnetic stimulation (rTMS) to the temporal or temporoparietal cortex is effective and safe in the treatment of chronic tinnitus. METHODS: In this controlled 3-armed trial, 48 patients with chronic tinnitus were treated with 4 weeks (20 sessions) of bilateral continuous theta burst stimulation (cTBS) at the Tübingen University Hospital. They were randomized to stimulation above the temporal cortex, the temporoparietal cortex, or as sham condition behind the mastoid. Patients were masked for the stimulation condition. Tinnitus severity was assessed after 2 and primarily 4 weeks of treatment and at 3 months follow-up with the tinnitus questionnaire and by a tinnitus change score. Audiologic safety was monitored by pure-tone and speech audiometry after 2 and 4 weeks of cTBS. RESULTS: Tinnitus severity was slightly reduced from baseline by a mean (SD) 2.6 (8.2) after sham, 2.4 (8.0) after temporoparietal, 2.2 (8.3) after temporal treatment of 16 patients each, but there was no significant difference between sham treatments and temporal (confidence interval [CI] -5.4 to +6.7) or temporoparietal cTBS (CI -5.9 to +6.3) or real cTBS (CI -7 to +5.1). Patients' global evaluation of tinnitus change after treatment did not indicate any effects. Audiologic measures were unaffected by treatment. CONCLUSIONS: Treating chronic tinnitus for 4 weeks by applying cTBS to the temporal or temporoparietal cortex of both hemispheres appears to be safe but not more effective than sham stimulation. However, these results are not to be generalized to all forms of rTMS treatments for tinnitus.

Semicircular canal dehiscence in HR multislice computed tomography: distribution, frequency, and clinical relevance.

The literature about bony defects in the semicircular canal system is highly inconsistent. Therefore, we analyzed a series of 700 high-resolution multislice CT examinations of the temporal bone for semicircular canal dehiscencies. An unselected group of ENT patients with different clinical symptoms and variable age was chosen. We found semicircular canal dehiscence in 9.6% of temporal bones, superior semicircular canal was affected mostly (8%), less common posterior semicircular canal (1.2%); only in 3 cases (0.4%), lateral semicircular canal showed dehiscence. In 60% of SSC dehiscence, we registered bilateral manifestation. The so-called "third mobile window" in semicircular canal dehiscence causes a great variety of clinical symptoms like vertigo, nystagmus, oscillopsies, hearing loss, tinnitus and autophonia. Comparison with anatomic studies shows that CT examination implies the risk of considerable overestimation; this fact emphasizes the important role of clinical and neurophysiological testing.

Disturbances of basal and postprandial insulin secretion and clearance in obese patients with type 2 diabetes mellitus.

Hyperinsulinemia of nondiabetic overweight and obese subjects is associated with weight-dependent increased insulin secretion and decreased insulin clearance. The present analysis examines whether similar effects can be observed in overweight and obese patients with type 2 diabetes mellitus (DM2). Additionally basal and postprandial insulin secretion and clearance were analyzed in relation to duration of disease. In a random sample of 348 DM2 patients basal plasma insulin concentrations were significantly higher in most BMI groups compared to matched nondiabetic (ND) controls. The weight-dependent increase of basal insulin in DM2 was primarily the result of reduced clearance rather than augmented secretion. Postprandial insulin concentrations were lower in DM2 patients and did not show any BMI-related increase. The weight-dependent reduction of postprandial insulin clearance was absent in DM2. At the time of diagnosis basal insulin concentration was higher and secretion was comparable to ND subjects and this did not change with duration of diabetes. The early postprandial insulin response was still comparable between DM2 and ND subjects at the time of diagnosis but deteriorated with longer duration of disease. The later postprandial response at diagnosis (AUC 90-180) was characterized by significantly greater insulin secretion and concentration while later on the 3-fold higher secretion was paralleled by comparable peripheral plasma concentrations due to a significantly greater postprandial insulin clearance in DM2. In conclusion, the present data indicate that apart from disturbances of insulin secretion substantial changes of insulin clearance contribute to inadequate peripheral insulin concentrations in obese DM2 patients.

[Porous polyethylene implants for ear reconstruction of middle to high-grade ear defects]. / Rekonstruktion mittel-bis hochgradiger Ohrdefekte mit Hilfe poröser Polyethylenimplantate.

The incidence of middle to high-grade ear malformations in Germany is approximately 150 per year. For many years autologous rib cartilage has been used for ear reconstruction as a framework material. In spite of a good biocompatibility of autologous rib cartilage there are potential risks of framework deformity as well as donor site morbidity. The advantages of osseo-integrated implants have provided patients with predictable esthetic results, durability and improved retention of the ear prostheses. Porous polyethylene ear implants (Medpor®) have been used for over 20 years as a suitable framework material. The advantages of this promising technique are good biocompatibility, short hospitalization time and the possibility of a one-step reconstruction of total or subtotal ear defects. The reconstruction of ear malformations with porous polyethylene ear implants is possible even in patients over 6 years old. Moreover, polyethylene promotes revascularization due to its porous structure, resulting in a good incorporation at the implantation site. The use of porous polyethylene ear implants permits a more expedient, less invasive and reliable reconstruction in moderate or high-grade ear malformations with very convincing results.

[Ear reconstruction using porous polyethylene implants. Effect of cortisone on edema reduction and healing process]. / Ohrrekonstruktionen mit Hilfe poröser Polyethylenimplantate. Einfluss der Ödemprophylaxe mit Kortison auf den Heilungsverlauf.

INTRODUCTION: Porous polyethylene implants are increasingly used for ear reconstruction. Although the material used exhibits good biocompatibility, swelling and edema formation frequently occur after implantation, which may be treated by prophylactic cortisone therapy. The aim of the present study was to analyze the effects of cortisone therapy on the postoperative healing process. PATIENTS AND METHODS: Between 2006 and 2010 porous polyethylene implants (Medpor®) were used for ear reconstruction of high-grade ear deformities in 23 patients (m:f=11:12; age: 17.2±12.4 years). For this purpose, 11 patients were treated systemically with cortisone (3 mg/kg body weight Solu-Decortin H) for the first 3 postoperative days, whereas 12 patients (controls) did not receive cortisone. Postoperatively, we analyzed the time course of edema formation, complications and the reconstructive result. RESULTS: Rejection or extrusion of the polyethylene implants was not observed in any of the patients (n=23) during a postoperative observation period of up to 3.5 years. Within 3-12 months after ear reconstruction all patients exhibited a completely shaped ear. Administration of cortisone had no significant effect on postoperative edema formation or the reconstructive end result. CONCLUSION: Porous polyethylene implants are well suited for the reconstruction of moderate to high-grade ear deformities. Since administration of cortisone does not significantly affect the postoperative healing process, prophylactic cortisone treatment following ear reconstruction with porous polyethylene implants should be omitted with regard to potential side effects.

Perioperative steroid administration inhibits angiogenic host tissue response to porous polyethylene (Medpor) implants.

Porous polyethylene (Medpor) is an alloplastic biomaterial, which is commonly used in plastic and reconstructive surgery. In the present study, we analyzed the effect of perioperative steroid administration on the inflammatory and angiogenic host tissue response to implanted Medpor. For this purpose, Medpor was implanted into the dorsal skinfold chamber of prednisolone-treated and vehicle-treated (control) balb/c mice and analyzed by means of intravital fluorescence microscopy over a 14-day period. Incorporation of the implants was evaluated by histology. An aortic ring assay and Western blot analyses were performed to determine in vitro the effect of prednisolone on angiogenesis. Implantation of Medpor did not induce a leukocytic inflammatory host tissue response. However, in prednisolone-treated and control animals giant cells could be detected at the interface between the implants and the surrounding granulation tissue as a typical indicator for a chronic foreign body reaction. Interestingly, perioperative prednisolone administration inhibited vascularisation of the implants, as indicated by a significantly decreased functional density of newly developing capillary blood vessels. Accordingly, prednisolone suppressed in vitro endothelial sprouting and tube formation in the aortic ring assay and reduced proliferating cell nuclear antigen (PCNA), Tie2, vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP)-9 expression of murine endothelioma cells. In conclusion, prednisolone treatment inhibits the early vascularisation of Medpor implants due to direct inhibition of distinct angiogenic mechanisms. Therefore, perioperative steroid therapy should be avoided in case of Medpor implantation to achieve a rapid incorporation of the biomaterial at the implantation site.

Analysis of the high affinity IgE receptor genes reveals epistatic effects of FCER1A variants on eczema risk.

BACKGROUND: High levels of total and allergen-specific IgE levels are a key feature in allergic diseases. The high-affinity receptor for IgE, which is composed of one alpha (FCER1A), one beta (FCER1B), and two gamma (FCER1G) subunits, represents the central receptor of IgE-induced reactions. In a genome-wide association scan, we recently identified associations between functional FCER1A variants and total serum IgE levels. Previous studies had reported linkage and association of FCER1B variants with IgE and atopic traits. The FCER1G gene has not yet been investigated with regard to atopy. Filaggrin (FLG) is the strongest known risk gene for eczema, in particular the allergic subtype of eczema. METHODS: We investigated the association of FCER1A, FCER1B, and FCER1G variants with IgE in a large population-based cohort (n = 4261) and tested for epistatic effects using the model-based multifactor dimensionality reduction (MB-MDR) method. In addition, we investigated a potential interaction between FLG and FCER1A variants in a large collection of eczema cases (n = 1018) and population controls. RESULTS: Three strongly correlated FCER1A polymorphisms were significantly associated with total and specific IgE levels as well as allergic sensitization. No associations were seen for FCER1B and FCER1G. After adjustment for FLG effects, a significant epistatic effect of the FCER1A variants rs10489854 and rs2511211 on eczema risk was detected. CONCLUSIONS: These results suggest that FCER1A variants by themselves and in combination influence IgE levels and act synergistically to influence eczema risk.

[Posttraumatic gusher phenomenon following fracture of the petrous bone]. / Posttraumatisches Gusher-Phänomen nach Felsenbeinquerfraktur.

The gusher phenomenon is a very rare complication that may occur during stapedectomy or cochleostomy. A sudden perilymphatic flow of cerebrospinal fluid can be seen following platinotomy. The cause is an abnormal connection between subarachnoid and perilymphatic spaces due to congenital malformation, leading to an abnormally wide cochlear aqueduct or due to an internal auditory canal fistula. We describe a case of posttraumatic gusher phenomenon after a fracture of the petrous bone.

[Cartilage grafts generated by tissue engineering. Histomorphological, immunochemical and biomechanical properties]. / Gezüchtete Knorpeltransplantate. Histomorphologische, immunhistochemische und biomechanische Charakterisierung.

BACKGROUND: The main technique used in tissue engineering for the generation of autologous cartilage grafts is the production of autologous transplant material from living cells or tissues and/or cell matrices. Incompletely absorbed residual fibrous matter, unforeseeable interactions between cells and biological materials and uneven cell distribution of cells in the cell carriers still present unsolved problems. METHODS: For these reasons a three-dimensional aggregate culture system was developed in which cells can generate cartilaginous tissue without the use of biomaterials. Chondrocytes and adult mesenchymal stem cells were used for this purpose and generate cartilaginous tissue with various phenotypes both in the aggregate culture system and in the athymic nude mouse model. The newly generated cartilage was subjected to histomorphological, immunochemical and biochemical investigation. RESULTS: After 3 weeks of in vitro aggregate culture the chondrocytes of all subclasses formed cartilaginous tissue. After 6 weeks' in vivo maturation in the athymic nude mouse model the new cartilage was found to differ in typical phenotype depending on the native cartilage used. CONCLUSIONS: Cartilage cells of various subclasses and adult mesenchymal stem cells generate cartilaginous tissue corresponding to their own phenotypes in a 3D aggregate culture system. This culture system is a promising method of producing cartilage grafts for use in reconstructive head and neck surgery.

Transforming growth factor-beta1-antisense modulates the expression of hepatocyte growth factor/scatter factor in keloid fibroblast cell culture.

Abnormal wound healing processes can result in hypertrophic scars and keloids. Transforming growth factor-beta1 (TGF-beta1) and hepatocyte growth factor/scatter factor (HGF/SF) are biphasic growth factor cytokines in physiologic and pathophysiologic conditions. Findings have shown TGF-beta1 to be pivotal in the formation of keloid tissue. Therefore, neutralizing antibodies may allow wound healing without keloid formation. As reported, TGF-beta1 is antagonized by HGF/SF. Some authors have reported that exogenous administration of HGF/SF prevented scar formation. Hence, this study targeted TGF-beta1 and determined the levels of HGF/SF in fibroblast cell culture. Keloid tissue was taken from seven patients. Another seven patients with mature nonhypertrophic scar served as controls. All tissues were cultured, and fibroblast cultures were used for further experiments. The TGF-beta1 antisense was administered at 3 and 6 micromol/ml, and HGF/SF levels were determined after 16, 24, and 48 h of incubation. The levels of HGF/SF showed significant differences after incubation with antisense oligonucleotides. The increasing antisense levels resulted in increased HGF/SF levels (up to 87.66 pg/ml after 48 h of incubation). In conclusion, targeting TGF-beta1 resulted in significantly increased levels of HGF/SF. The clinical relevance could include the use of locally administered HGF/SF in protein or gene form to minimize formation of keloids. Nevertheless, wound healing is the result of many interacting cytokines, so neutralizing or targeting one protein could result in no significant effect.

[Zenker's diverticulum treated by transoral diverticulostomy: technique and results]. / Die Technik der transoralen Divertikulostomie bei Zenker-Divertikeln - Langzeitresultate und Literaturvergleich.

AIM OF THE STUDY: The surgical technique of transoral diverticulostomy by a modified Endo-GIAtrade mark Stapler (Multifire Endo GIA, Tyco Healthcare) is described. Experiences of this procedure in 31 patients are analysed and compared with different endoscopic and conventional surgical therapies of Zenker's diverticula, which are reported in the literature. METHOD: From January 1996 to December 2005, 31 transoral diverticulostomies were performed. All patients were included porspectively into the study. The median follow-up time after diverticulostomy was 54 months. Manometry, pH-study of the esophagus, endoscopy and swallow radiography were performed before and after surgery. All patients completed the Gastrointestinal quality of live index (GQLI) and the Grosshadern dysphagia score (GHDS). RESULTS: Subjective comfort of the patients as measured by the Smiley Index, the GQLI and the GHDS was increased significantly (p < 0.001) after therapy. Manometry showed that the upper esophageal sphincter functioned normally before and after intervention. A gastrografin swallow excluded leakage at the stapler suture-line in all cases. A conversion to a conventional cricomyotomy with resection of the diverticulum had to be performed once due to a dissection of the esophagus that occurred during insertion of the spreader. In one patient a bleeding out of the suture line was successfully treated with a metal clip. A prothesis broke due to the insertion of the spreader. Two patients developed relapses during the follow-up period of 54 months. CONCLUSION: Compared to standard procedure the endoscopic minimal-invasive therapy proved to be safer. The operation time and the postoperative stay are shorter.

Cognitive deficits in narcolepsy.

The aim of the investigations was to explore the nature and the severity of cognitive deficits in narcolepsy patients. In two studies, narcolepsy patients were compared with matched control subjects on a range of attention, memory and executive control tasks. Impairments were only observed on attention and executive function tasks which involved higher demands on inhibition or task management abilities whereas relatively routine memory and attention tasks yielded intact performance in narcolepsy patients. The overall pattern of results indicates an executive control deficit in narcolepsy which might be related to a reduction of available cognitive processing resources because of the need for continuous allocation of resources to monitoring and maintenance of vigilance.

[Plastic surgery to correct deformities of the ear]. / Plastische Korrektur bei Ohrdeformitäten: Wie Ohren angelegt, umgeformt und neu aufgebaut werden.

For the plastic-surgical correction of mild deformities of the ears, well-proven incisional and suturing techniques are available. Only in exceptional cases is skin grafting or the use of cartilage ersatz material required. In the plastic surgical treatment of moderate to severe ear deformities, in contrast, not only incisional and suturing techniques, but also free skin grafts and ersatz materials are needed. At the ENT Department of the Ludwig-Maximilian University in Munich, plastic reconstruction of moderate to severe deformities of the external ear using porous polyethylene implants instead of rib cartilage grafts has been practiced with success for the past two years or so. Porous polyethylene implants provide good results and may help to avoid pre- and postoperative morbidity at donor site defects.

[Niikawa-Kuroki syndrome. Which characteristics must the HNO doctor consider in its diagnosis]. / Niikawa-Kuroki-Syndrom. An welche Besonderheiten muss der HNO-Arzt bei der Diagnose denken?

Niikawa-Kuroki syndrome (Kabuki make-up syndrome) is a congenital disorder with characteristic facial features and possibly anomalies of the skeletal system and internal organs. There is an increasing number of reports of patients with combined hearing impairment, inner ear deformities or sensorineural hearing impairment. In addition, the patients often suffer from therapy-resistant chronic otitis media. In addition to multiple cardiac and renal deformities, our 3 year old patient has a hearing impairment due to chronic otitis media with chronic otorrhea, and requires a hearing aid. A high-definition CT scan of the petrosal bone revealed, for the first time in a patient with Niikawa-Kuroki syndrome, a large vestibular aqueduct syndrome and deformities of the vestibular system. We examine the problems involved with treating chronic otorrhea in chronic otitis media and providing patients with BTE hearing aids.