[Influence of cochlear parameters on the current practice in cochlear implantation : Development of a concept for personalized medicine. German version]. / Einfluss cochleärer Parameter auf die aktuelle Cochleaimplantatversorgung : Entwicklung eines Konzepts für die personalisierte Medizin.

Since the introduction of cochlear implants into clinical routine, the interest in measuring cochlear parameters, particularly the cochlear duct length (CDL) has increased, since these can have an influence on the correct selection of the electrode. On the one hand, coverage of an optimal frequency band is relevant for a good audiological result, and on the other hand, cochlear trauma due to too deep insertion or displacement of the electrode must be avoided. Cochlear implants stimulate the spiral ganglion cells (SGC). The number of SGC and particularly their distribution can also have an influence on the function of a cochlear implant. In addition, the frequency assignment of each electrode contact can play a decisive role in the postoperative success, since the frequency distribution of the human cochlea with varying CDL shows substantial interindividual differences. The aim of this work is to provide an overview of the methods used to determine the cochlear parameters as well as of relevant studies on the CDL, the number and distribution of SGZ, and the frequency assignment of electrode contacts. Based on this, a concept for individualized cochlear implantation will be presented. In summary, this work should help to promote individualized medicine in the field of cochlear implants in the future, in order to overcome current limitations and optimize audiological outcomes.

Influence of cochlear parameters on the current practice in cochlear implantation : Development of a concept for personalized medicine.

Since the introduction of cochlear implants into clinical routine, the interest in measuring cochlear parameters, particularly the cochlear duct length (CDL) has increased, since these can have an influence on the correct selection of the electrode. On the one hand, coverage of an optimal frequency band is relevant for a good audiological result, and on the other hand, cochlear trauma due to too deep insertion or displacement of the electrode must be avoided. Cochlear implants stimulate the spiral ganglion cells (SGC). The number of SGC and particularly their distribution can also have an influence on the function of a cochlear implant. In addition, the frequency assignment of each electrode contact can play a decisive role in the postoperative success, since the frequency distribution of the human cochlea with varying CDL shows substantial interindividual differences. The aim of this work is to provide an overview of the methods used to determine the cochlear parameters as well as of relevant studies on the CDL, the number and distribution of SGZ, and the frequency assignment of electrode contacts. Based on this, a concept for individualized cochlear implantation will be presented. In summary, this work should help to promote individualized medicine in the field of cochlear implants in the future, in order to overcome current limitations and optimize audiological outcomes.

[Development of a smartphone app for neuromuscular facial training. German Version]. / Entwicklung einer Smartphone-App für neuromuskuläres Fazialistraining.

BACKGROUND: Several studies have demonstrated a significant benefit of neuromuscular facial training in the rehabilitation of patients with facial palsy. However, printed instructions for home training are often not of optimum quality and associated with low adherence to therapy. Professional guidance, e.g., by occupational therapists, is regarded as being of high quality, but is associated with a high cost burden, particularly in chronic forms of disease. OBJECTIVE: The idea to develop a smartphone app for facial training arose from the above-described situation. The aim was to provide structured exercises for the mimic muscles in the sense of neuromuscular training with visual feedback via the front camera of the device. MATERIALS AND METHODS: A native app architecture in iOS was chosen to implement the graphical and content-related concept. In the Apple Xcode (Apple, Cupertino, California, US) development environment, the app's code was written in the Swift programming language (Apple) and the graphical user interface was created. RESULTS: An app prototype was implemented that provides step-by-step instructions on selected mimic exercises via animated smileys. The duration and speed of the exercise can be varied within a limited range. In the development environment, the correct functionality of both physical and virtual devices was successfully tested. CONCLUSION: App-based facial training offers attractive opportunities to motivate patients for improved adherence to treatment, which could hypothetically lead to a better outcome. Evaluation of this question is planned in a clinical trial after completion of the development.

Development of a smartphone app for neuromuscular facial training.

BACKGROUND: Several studies have demonstrated a significant benefit of neuromuscular facial training in the rehabilitation of patients with facial palsy. However, printed instructions for home training are often not of optimum quality and associated with low adherence to therapy. Professional guidance, e.g., by occupational therapists, is regarded as being of high quality, but is associated with a high cost burden, particularly in chronic forms of disease. OBJECTIVE: The idea to develop a smartphone app for facial training arose from the above-described situation. The aim was to provide structured exercises for the mimic muscles in the sense of neuromuscular training with visual feedback via the front camera of the device. MATERIALS AND METHODS: A native app architecture in iOS was chosen to implement the graphical and content-related concept. In the Apple Xcode (Apple, Cupertino, CA, US) development environment, the app's code was written in the Swift programming language (Apple) and the graphical user interface was created. RESULTS: An app prototype was implemented that provides step-by-step instructions on selected mimic exercises via animated smileys. The duration and speed of the exercise can be varied within a limited range. In the development environment, the correct functionality of both physical and virtual devices was successfully tested. CONCLUSION: App-based facial training offers attractive opportunities to motivate patients for improved adherence to treatment, which could hypothetically lead to a better outcome. Evaluation of this question is planned in a clinical trial after completion of the development.

[20 Years of Bilateral Cochlear Implantation - an Analysis of the Implanted Patients]. / 20 Jahre bilaterale Cochleaimplantation ­ eine Analyse seither implantierter erwachsener Patienten.

Binaural hearing is essential for localization abilities and improves the speech perception in noise. Since 20 years, bilateral cochlear implantation is routinely performed to restore binaural hearing. In this cross-sectional study, we evaluated speech perception in quiet (Freiburger monosyllables, Hochmair-Schulz-Moser (HSM) sentence test, each at 70 dB) and in noise (HSM test, signal-to-noise ratio 10 dB) in 103 out of 165 adult patients who were bilaterally implanted in Würzburg between 1995 and June 2014. In almost half the patients, the second implanted side showed the better speech perception. Compared to the first implanted side, the average monosyllable scores with bilateral implants were improved from 54 to 63% and the HSM scores from 86 to 96%. In noise the speech perception improved from 47 to 65%. The speech perception of the second implanted side was independent of the time interval between the implantation of both sides in this cohort of postlingually deafened patients. This cross-sectional data underline the importance of bilateral cochlear implantation for speech understanding in quiet and even more in noise and thus, for the everyday life. For this, bilateral cochlear implantation should be the generally accepted standard in the treatment of deaf patients.

[Direct Drive Simulation - Sound-Simulation of the Vibrant Soundbridge®]. / Direct Drive Simulation - Klangsimulation des Vibrant Soundbridge®-Hörens.

BACKGROUND: The Direct-Drive-Simulation (DDS) tends to simulate the sound quality of hearing with the active middle ear implant Vibrant Soundbridge(®) (VSB). Up to now a scientific evaluation of the validity is missing. Furthermore, the test procedure has not been described yet. Aim of this study was to evaluate the test validity and to describe the test realization in detail. MATERIAL AND METHODS: 10 patients evaluated their sound impression on scales from 1 to 10 concerning sound quality during DDS, postoperative free field testing at least 3 month after the first fitting of the VSB and in the everyday life situation. 3 patients were implanted bilaterally. Together, 36 data sets could be analyzed. RESULTS: Coupling of the Floating Mass Transducer (FMT), which was placed inside of a silicone probe during DDS was successful in all cases. In 11 out of 13 cases the coupling quality was judged as "good" an only in 2 cases as "medium". None of the patients needed local anesthesia. Comparing the evaluation of the sound impression during DDS preoperatively, and with the implanted VSB in free field testing and in everyday life no significant differences were found. CONCLUSION: The DDS offers the possibility of a realistic preoperative sound simulation of the "VSB-hearing" in case of sensorineural hearing loss. Thus, the test is supposed to facilitate the patient's decision towards possible treatment options. The specialist gets additional information regarding the indication especially when audiologic indication criteria are critical. The DDS should be a basic part of the preoperative diagnostic prior to VSB-implantation.

[CORRECTION OF HEMOSTASIS DISORDER IN HEMORRHAGIC SHOCK].

It is a clinical case of successful correction of hemostasis disorder in hemorrhagic shock. This case demonstrates the need to perform advanced tests that assess hemostatic system in patients with ongoing bleeding. Using of thromboelastography helped us to make a comprehensive assessment of hemostatic system that allowed to detect the point of application of drugs and substitution therapy. Coagulation disorder was treated by intravenous injection of Ca2+. In this case the cause of hypocalcemia was combination offactors such as electrolytes losing during massive bleeding and progressing metabolic acidosis. Therefore, monitoring the level of ionized calcium is especially important in patients undergoing massive blood loss and receiving large doses of donor blood components.

Human mesenchymal stem cells promote cancer motility and cytokine secretion in vitro.

Interactions of human mesenchymal stem cells (hMSC) with tumors are controversially discussed since there is evidence for both tumor progression as well as tumor inhibition by hMSC. The objective of the present study is to investigate whether hMSC support cell motility and cytokine secretion in a head and neck squamous cell carcinoma cell line (HLaC 78). A spheroid model was generated in which the ultrastructure of spheroids was analyzed using scanning electron microscopy (SEM). The migration capability was monitored in a monolayer as well as in a spheroid model. The variation in migration and secretion of interleukin (IL)-6, IL-8 and vascular endothelial growth factor (VEGF), as well as the expression of the multidrug resistance gene (MDR-1) was investigated. Finally, the alteration in the cell cycle was analyzed by flow cytometry. SEM showed a tight cell-cell contact with extensive secretion of extracellular matrix. The migration and invasion capability of HLaC 78 was enhanced by hMSC. Cancer cell motility was also increased by hMSC as well as secretion of the cytokines IL-6, IL-8 and VEGF. hMSC did not induce the expression of MDR-1 in HLaC 78, and there was no alteration in the cell cycle of HLaC 78 after cocultivation with hMSC. Our results confirm the important role of hMSC in cancer biology since both an enhancement of cell motility as well as cytokine secretion could be shown. However, based on these findings and those in the current literature, caution must be applied when using hMSC as a carrier for tumor therapy in cancer treatment.

Combining skin and olfactory α-synuclein seed amplification assays (SAA)-towards biomarker-driven phenotyping in synucleinopathies.

Seed amplification assays (SAA) are becoming commonly used in synucleinopathies to detect α-synuclein aggregates. Studies in Parkinson's disease (PD) and isolated REM-sleep behavior disorder (iRBD) have shown a considerably lower sensitivity in the olfactory epithelium than in CSF or skin. To get an insight into α-synuclein (α-syn) distribution within the nervous system and reasons for low sensitivity, we compared SAA assessment of nasal brushings and skin biopsies in PD (n = 27) and iRBD patients (n = 18) and unaffected controls (n = 30). α-syn misfolding was overall found less commonly in the olfactory epithelium than in the skin, which could be partially explained by the nasal brushing matrix exerting an inhibitory effect on aggregation. Importantly, the α-syn distribution was not uniform: there was a higher deposition of misfolded α-syn across all sampled tissues in the iRBD cohort compared to PD (supporting the notion of RBD as a marker of a more malignant subtype of synucleinopathy) and in a subgroup of PD patients, misfolded α-syn was detectable only in the olfactory epithelium, suggestive of the recently proposed brain-first PD subtype. Assaying α-syn of diverse origins, such as olfactory (part of the central nervous system) and skin (peripheral nervous system), could increase diagnostic accuracy and allow better stratification of patients.

Labeling Adipose-Derived Stem Cells with Hoechst 33342: Usability and Effects on Differentiation Potential and DNA Damage.

Adipose-derived stem cells (ASCs) have been extensively studied in the field of stem cell research and possess numerous clinical applications. Cell labeling is an essential component of various experimental protocols and Hoechst 33342 (H33342) represents a cost-effective and easy methodology for live staining. The purpose of this study was to evaluate the labeling of rat ASCs with two different concentrations of H33342 (0.5 µg/mL and 5 µg/mL), with particular regard to usability, interference with cell properties, and potential DNA damage. Hoechst 33342 used at a low concentration of 0.5 µg/mL did not significantly affect cell proliferation, viability, or differentiation potential of the ASCs, nor did it cause any significant DNA damage as measured by the olive tail moment. High concentrations of 5 µg/mL H33342, however, impaired the proliferation and viability of the ASCs, and considerable DNA damage was observed. Undesirable colabeling of unlabeled cocultivated cells was seen in particular with higher concentrations of H33342, independent of varying washing procedures. Hence, H33342 labeling with lower concentrations represents a usable method, which does not affect the tested cell properties. However, the colabeling of adjacent cells is a drawback of the technique.

The differentiation of hMSCs counteracts their migration capability and pro-angiogenic effects in vitro.

Human mesenchymal stem cells (hMSCs) have been applied therapeutically in numerous clinical trials. The pro-angiogenic effects of hMSCs, as well as their strong tumor tropism, have been shown both in vitro and in vivo. Some studies suggest using hMSCs as potential drug-carriers for tumor therapy. In previous investigations by our group, the pro-tumorigenic effects of hMSCs on head and neck squamous cell carcinoma (HNSCC) were shown. However, the influence of hMSCs on tumor vascularization as well as the possibility of its inhibition are yet to be elucidated. The cytokine patterns of the HNSCC cell line FaDu, native hMSCs (hMSCs-nat), hMSCs differentiated into adipocytes (hMSCs-adip) and osteocytes (hMSCs-ost) were evaluated. Human umbilical vein endothelial cells (HUVECs) were co-cultured with FaDu cells, hMSCs-nat, hMSCs-adip and hMSCs-ost. The capillary tube formation assay was applied. Furthermore, the migration capability of hMSCs-nat, hMSCs-adip and hMSCs-ost towards FaDu cells was measured in a Transwell system. Spheroids were cultured from hMSCs-nat, FaDu cells and DiI-labeled HUVECs. FaDu cells, hMSCs-nat, hMSCs-adip and hMSCs-ost released a wide range of cytokines and growth factors, e.g., IL-6, IL-8, IL-10, GRO and MCP. In the capillary tube formation assay, HUVECs generated significantly longer tubes after co-cultivation with hMSCs-nat as compared to HUVECs alone and FaDu. Differentiation into adipocytes and osteocytes counteracted the tube formation. The adipogenic differentiation did not alter hMSC motility, whereas osteogenic differentiation significantly inhibited hMSC migration. Generation of multi-cellular spheroids from hMSCs-nat, FaDu cells and DiI-labeled HUVECs was possible. Florescence microscopy revealed that all HUVECs were present in the spheroid core. Taken together, hMSCs-nat have a pro-angiogenic effect. The effects are counteracted by the differentiation of hMSCs towards osteogenic and adipogenic lineages. The differentiation of stem cells into different lineages may be a promising solution to generating carriers for cancer therapy without pro-tumorigenic properties.

Different effects of an oligonucleotide uptake stimulating protein on leukemic cells in their primitive and differentiated state.

The single stranded [3H]oligonucleotide uptake by HL-60 human promyelocyte and K562 human erythroleukemia cells was stimulated 20-45-fold by DUSF (DNA uptake stimulating protein), and this effect was drastically reduced (to 1.6-13x) if the cells were induced to differentiate. The oligonucleotide uptake stimulating effect of DUSF was not altered in HL-60 and K562 cells, if the proliferation of the cells was inhibited by hydroxyurea (HU) treatment. The oligonucleotide uptake by separated granulocytes and mononuclear cells from healthy donors was not stimulated by DUSF, while the uptake of oligonucleotides by myeloid and lymphoid leukemic cells was greatly stimulated (10-15x). The uptake of oligonucleotides by differentiated mononuclear cells of healthy donors could not be stimulated by DUSF, but the oligonucleotide uptake was greatly increased (11x) by DUSF if the cells were subjected to blast transformation.

Large cystic optic glioma.

A 5 1/2-year-old boy developed a huge cyst in his chiasmal glioma 4 years after radiation therapy. The cyst produced obtundation but was successfully treated.

Frequent methylation of p16INK4A and p14ARF genes implicated in the evolution of chronic myeloid leukaemia from its chronic to accelerated phase.

The frequency and mechanism of p16(INK4A) and p14(ARF) gene alterations were studied in cell samples from 30 patients with Philadelphia (Ph) chromosome-positive chronic myeloid leukaemia (CML), both at diagnosis and at the onset of the accelerated phase (AP) of the disease. No alterations in the p16(INK4A) or p14(ARF) genes were found in any of the chronic phase (CP) samples. DNA sequencing analyses detected p16(INK4A) or p14(ARF) mutations in 17 AP samples. All mutations were heterozygous without loss of the other allele. Aberrant methylation of the p16(INK4A) or p14(ARF) promoters was found in 14 of 30 AP samples. The most common situation was the simultaneous methylation of both promoters. Our data indicate that p16(INK4A) and p14(ARF) are primary targets for inactivation by promoter methylation in the acceleration of CML. Transcriptional silencing of the p16(INK4A) and p14(ARF) genes may be important in the conversion of CML from the CP to the AP.

Antithrombin III determination by rate (kinetic) nephelometry.

Rate nephelometry immunological antithrombin III determination was elaborated with Beckman Immunochemistry System. The measuring can be carried out within 60 sec from 20 microliters plasma. The results show a close correlation with those of gained by the radial immunodiffusion method (r = 0.91( and by Coatest (Kabi-Ortho) (r = 0.77). Both laser-nephelometric and usual non-nephelometric anti-antithrombin III serum (Behring) may be applied.

Antiretroviral immune response and plasma interferon in different phases of chronic granulocytic leukemia.

Forty patients with chronic granulocytic leukemia (CGL) were tested for antibodies and lymphocytes reacting with gibbon ape leukemia virus (GaLV) and baboon endogenous virus (BaEV) antigens as well as for plasma interferon levels. Antibodies reacting with envelope antigens of GaLV and BaEV were found frequently and in high titers in patients with the quiescent phase of CGL but rarely and in low titers in the accelerated and blastic phase of the disease. Results of radioimmunoprecipitation studies were in concordance with those obtained in virus neutralization experiments. Cellular and humoral cytotoxic activity of blood plasma and lymphocyte samples against autologous tumor cells showed a similar phase-specific distribution. Most of these activities could be blocked by GaLV and BaEV gp70 antigens. Elevated plasma interferon (IFN)-alpha levels were found in the quiescent and accelerated phase of CGL, whereas no significant differences could be detected between IFN levels of patients with the blastic crisis of CGL and those of the control persons. Follow up studies of four patients confirmed this stage-specific distribution of antiretroviral immune and interferon response.

Co-expression of c-abl and c-myb oncogenes in Philadelphia chromosome-negative, bcr-negative chronic myeloid leukaemia.

Three cases of Philadelphia (Ph) chromosome-negative, bcr-negative chronic myeloid leukaemia (CML) have been investigated for oncogene expression by Northern blot and cytoplasmic RNA dot blot hybridization. Considerably high levels of expression of c-abl and c-myb were observed in all cases. In the Ph-negative cells the normal 6.0 and 7.0 kb c-abl and 3.8 kb c-myb transcripts were found. No amplification of c-abl or c-myb oncogenes was detected in the DNAs of Ph-negative CML cells. Data suggest that co-operation between the overexpressed c-abl and c-myb oncogenes is causally related to Ph-negative bcr-negative CML.

HTLV-related markers in a Hungarian patient with adult T-cell leukemia.

Monoclonal integration of DNA sequences related to, but not identical to HTLV-I provirus was detected in the peripheral blood lymphocytes of a Hungarian male suffering from ATL. The patient and his parents showed serological cross-reactivity with both HTLV-I and HTLV-II group-specific antigens. Restriction enzyme analysis with EcoRI, PstI, BamHI, HindIII and SacI revealed structural similarity of the provirus integrated in the DNA of ATL cells to HTLV-I but not to HTLV-II. Data suggest that this provirus and HTLV-I are similar to each other along gag and pol regions, but they are different in the env region.

Comparison of bone scan, computed tomography, and magnetic resonance imaging in the diagnosis of active sacroiliitis.

Quantitative bone scan (QBS), computed tomography (CT), and magnetic resonance imaging (MRI) have each been used to confirm the diagnosis of active sacroiliitis (SI) in patients with low back pain (LBP). The authors prospectively evaluated 19 patients referred for symptoms of possible inflammatory LBP (group I), 26 seronegative spondyloarthropathy (SNSP) patients with LBP (group II, inflammatory or mechanical), and 5 SNSP patients without LBP (group III) to determine which radiological scan alone or in combination with other serological tests (Westergren erythrocyte sedimentation rate, C-reactive protein, HLA-B27, immunoglobulin A) was most useful in confirming a clinical diagnosis of active inflammatory SI. All patients were followed up for a minimum of 1 year to confirm the clinical diagnosis and evaluate response to therapy. Eight of 19 group I patients had active SI clinically or on plain radiographs on follow-up evaluation. Of these patients, 5 had abnormal QBS (71%), 3 had abnormal CT scans (38%), and 8 had abnormal MRI scans (100%, type I lesions). These type I MRI lesions were indicative of active inflammation manifested as subcortical bone marrow edema. The remaining 11 group I patients had negative scans for SI. Ten of 26 group II patients with LBP had SI diagnosed clinically and confirmed with positive QBS (60%), CT (100%), and MRI (100%, type I lesions). The remaining 16 group II patients had mechanical LBP without active SI clinically and had negative QBS (88%), CT (19%), and MRI (100%, normal or type II lesions). These type II MRI lesions represented old postinflammatory lesions with either fibrosis or fat replacement. All 5 group III patients had negative scans for active SI. Three patients (2 group I and group II) with inflammatory SI treated with sulfasalazine showed marked improvement on serial MRI scans. Westergren erythrocyte sedimentation rate, C-reactive protein, immunoglobulin A, and CT scan alone or in combination with other tests were not reliable predictors of active SI. Positive QBS and HLA-B27 tests were the best combination of screening tests with 82% predictability of inflammatory SI in whites, and QBS alone had an 80% predictability in black patients. However, MRI, which had 100% predictability, was the best single test for confirming active inflammatory SI.

Demonstration of HTLV-related proviral DNA sequences and antibodies reactive with HTLV internal proteins in an Hungarian patient with Sézary syndrome.

DNA sequences distantly related to the proviral DNA of HTLV-I were found in the leukemic cells of a Hungarian patient suffering from Sézary syndrome. Serum samples from the patient contained antibodies reactive with the internal core polypeptides of HTLV-I and HTLV-II, but not with the env gene encoded type-specific HTLV antigens. The husband and daughter of the patient also had antibodies of the same specificity. These findings suggest the presence of a virus distantly related to HTLV-I and HTLV-II.