[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.

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.

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.

[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.

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.

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.

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.

[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.

[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.

Impairment of energy metabolism in intact residual myocardium of rat hearts with chronic myocardial infarction.

The purpose of this study was to test the hypothesis that energy metabolism is impaired in residual intact myocardium of chronically infarcted rat heart, contributing to contractile dysfunction. Myocardial infarction (MI) was induced in rats by coronary artery ligation. Hearts were isolated 8 wk later and buffer-perfused isovolumically. MI hearts showed reduced left ventricular developed pressure, but oxygen consumption was unchanged. High-energy phosphate contents were measured chemically and by 31P-NMR spectroscopy. In residual intact left ventricular tissue, ATP was unchanged after MI, while creatine phosphate was reduced by 31%. Total creatine kinase (CK) activity was reduced by 17%, the fetal CK isoenzymes BB and MB increased, while the "adult" mitochondrial CK isoenzyme activity decreased by 44%. Total creatine content decreased by 35%. Phosphoryl exchange between ATP and creatine phosphate, measured by 31P-NMR magnetization transfer, fell by 50% in MI hearts. Thus, energy reserve is substantially impaired in residual intact myocardium of chronically infarcted rats. Because phosphoryl exchange was still five times higher than ATP synthesis rates calculated from oxygen consumption, phosphoryl transfer via CK may not limit baseline contractile performance 2 mo after MI. In contrast, when MI hearts were subjected to acute stress (hypoxia), mechanical recovery during reoxygenation was impaired, suggesting that reduced energy reserve contributes to increased susceptibility of MI hearts to acute metabolic stress.

[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.

Chemotactic response of osteoblastlike cells to transforming growth factor beta.

Transforming growth factor beta (TGF-beta) has multiple effects on bone cell metabolism in vitro but its exact role in bone remodeling still needs to be defined. Here we demonstrate that TGF-beta is chemotactic for osteoblastlike cells from fetal rat calvariae and osteoblastlike ROS 17/2.8 osteosarcoma cells. Maximal chemotaxis occurred at 5-15 pg/ml of TGF-beta and was observed with TGF-beta 1 and TGF-beta 2 at equivalent concentrations. Conditioned medium from osteoblastlike cells containing latent TGF-beta failed to stimulate chemotactic migration. However, chemotactic activity was observed in conditioned medium that had been transiently acidified. Since acidification is known to activate TGF-beta, these results suggest that only active TGF-beta is capable of inducing a chemotactic response. Preincubation of osteoblastlike cells with TGF-beta in concentrations from 10 pg/ml to 1 ng/ml for 48 h abolished a subsequent chemotactic response of these cells to TGF-beta, indicating that TGF-beta-induced chemotaxis is a transient phenomenon. Since TGF-beta may be released from the bone matrix and/or activated during bone resorption, the chemotactic activity of TGF-beta for osteoblastlike cells may be important for the recruitment of osteoblastlike cells to sites of bone remodeling.

Mitogenic responsiveness of human bone cells in vitro to hormones and growth factors decreases with age.

Bone loss with aging may at least in part be due to inadequate bone formation. In this study, we examined whether the proliferation of osteoblast-like cells in vitro in response to local and systemic factors might be attenuated with age. A total of 36 cultures of osteoblast-like cells were obtained from outgrowths of human trabecular bone. Parathyroid hormone, growth hormone, calcitonin, transforming growth factor beta, insulin-like growth factor I, and platelet-derived growth factor BB dose dependently increased DNA synthesis in all cultures. Increases in DNA synthesis with each of these factors were significantly negatively correlated with donor age in cultures obtained from the iliac crest bone of 50- to 70-year-old women. Cells from 61- to 70-year-old donors required approximately 10-fold higher concentrations of growth factors and hormones to yield comparable increases in DNA synthesis than cells from 51- to 60-year-old donors. A significant negative correlation between age and mitogenic responsiveness to platelet-derived growth factor and growth hormone, but not toward the other factors, was also observed in cultures from the femoral head trabecular bone of 60- to 90-year-old women. Our findings suggest that bone loss with aging may be partially due to a decreased capacity of osteoblasts to proliferate in response to systemic or locally released osteotropic factors.

Stimulation of bone matrix apposition in vitro by local growth factors: a comparison between insulin-like growth factor I, platelet-derived growth factor, and transforming growth factor beta.

Many recent in vitro studies have shown effects of insulin-like growth factor I (IGF I), platelet-derived growth factor (PDGF), and transforming growth factor-beta (TGF beta) on the proliferation and differential functions of bone-forming osteoblasts; however, the question whether these factors might ultimately lead to a net increase or decrease in bone formation has been difficult to assess. In this study, we have used an autoradiographic method based on the incorporation of [3H]proline into freshly synthesized bone matrix to determine the overall effects of these factors on bone matrix apposition in 21-day-old fetal rat calvariae. IGF I, PDGF, and TGF beta increased bone matrix apposition in a dose-dependent manner up to 2-fold within 48 h. In addition, they partially or completely reversed the inhibition of bone matrix apposition observed with PTH. Exogenously added TGF beta was significantly more potent than equimolar concentrations of PDGF or IGF I in stimulating bone formation. Matrix apposition was greatest when IGF I, PDGF, and TGF beta were added simultaneously to the culture medium, indicating that these factors can enhance each other in stimulating bone formation. In conclusion, our results provide direct evidence that IGF I, PDGF, and TGF beta are capable of stimulating bone formation in vitro.

Differential regulation of plasminogen activator and plasminogen activator inhibitor by osteotropic factors in primary cultures of mature osteoblasts and osteoblast precursors.

Plasminogen activators (PA) and plasminogen activator inhibitors (PAI) have been implicated in the process of extracellular matrix degradation. To study their role in bone matrix turnover, we examined the activity and regulation of PA and PAI in cultures of periosteal osteoblast-like precursor cells and mature osteoblast-like cells from fetal rat calvariae. Both cell populations released PA activity of the tissue type and a 50K PAI species into the culture medium. However, mature osteoblasts had a strikingly lower PA activity and higher PAI activity than periosteal precursor cells, indicating that osteoblast differentiation is associated with a marked decrease in the PA/PAI ratio. PTH and prostaglandin E2 transiently increased PA activity and decreased PAI activity. In contrast, transforming growth factor-beta decreased PA activity and increased PAI activity. Differential effects of these factors on PA and PAI activity may be involved in the regulation of extracellular matrix deposition by osteoblasts.

Differential effects of platelet-derived growth factor isoforms on plasminogen activator activity in fetal rat osteoblasts due to isoform-specific receptor functions.

We examined receptor binding and metabolic effects of the platelet-derived growth factor (PDGF) isoforms AA, AB, and BB in cultures of osteoblastic cells from fetal rat calvaria. Saturation binding experiments demonstrated the presence of 6,000 binding sites for PDGF-AA, 42,000 for PDGF-AB, and 60,000 for PDGF-BB. Binding competition experiments were compatible with the recently postulated model of three PDGF receptor subtypes with differential affinity for the PDGF isoforms. The effects of the PDGF isoforms on DNA synthesis, collagen synthesis, and alkaline phosphatase activity in osteoblasts strictly correlated with the number of available binding sites. Accordingly, PDGF-BB was the most potent isoform, PDGF-AB was slightly less potent, and PDGF-AA was the least potent. In contrast, we found that PDGF-BB was less potent than PDGF-AB in increasing plasminogen activator activity in the osteoblast-conditioned medium. Our data strongly suggest that the PDGF receptor subtypes in fetal rat osteoblasts not only selectively bind one or more PDGF isoforms, but are also capable of responding differently to these isoforms.

Molecular characterization of breast cancer cell lines by expression profiling.

PURPOSE: Gene expression patterns provide detailed insights into cellular regulation that reflect minor differences of cellular capacity not accessible by standard descriptions of the cellular phenotype or origin. METHODS: To identify fundamental differences and similarities we analyzed the gene expression patterns of four breast cancer cell lines: MCF-7, SK-BR-3, T-47D, and BT-474. RESULTS: Although only a small subset of genes (597) is represented on the Atlas-cDNA-Array (Clontech) used, clear differences in the expression of a number of genes could be detected. For example, unique high levels of expressions were found for the HLH-protein ID-1 (MCF-7) and the receptor tyrosine kinase erbB2 (SK-BR-3 and T-47D). Most genes analyzed were expressed at comparable levels in all cell lines studied. CONCLUSIONS: For interpretation of the results sets of genes that show similar variation of expression among the cells were grouped together. Furthermore, our analysis allows the assignment of similarity values that lead to a relation profile of the cell lines. How these results correlate with known biological properties of the cell lines is discussed. Additionally, we demonstrate that results obtained by cDNA-Array hybridization for expression of the ErbB receptor family correlate well with competitive RT-PCR, thus confirming the reliability of the cDNA-Array analysis.