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Biomedical subjects

Wolfgang Arnold

Publications and source records attributed to Wolfgang Arnold.

At least 19 recordsLinked to original sources
PubMed2006

Round window stimulation with an implantable hearing aid (Soundbridge) combined with autogenous reconstruction of the auricle - a new approach.

BACKGROUND: Congenital malformations of the auricle are often combined with atresia of the outer ear canal and malformations of the ossicles, representing aesthetic as well as functional deficits. Optimal treatment should therefore address both aspects equally. This report describes a new approach, combining the reconstruction of the auricle with implantation of an active middle ear hearing aid, stimulating the round window membrane. METHOD: A 33-year-old male patient, with bilateral ear microtia, fibrous atresia of the external ear canals and malformation of the ossicles due to Treacher Collins-Franceschetti syndrome was included in the study. In stage one, the cartilage framework of the new auricle, made of autogenous rib cartilage, was fabricated and implanted. During stage two, the auricle was elevated, a retro-auricular sulcus was formed and a Vibrant MED-EL Soundbridge device was implanted. The transducer was coupled to the round window membrane. RESULTS: Both functional and aesthetical results were favourable. Aided thresholds were between 15 and 30 dB in the frequency range of 0.75-6 kHz, monosyllabic word understanding at 65 dB SPL increased from 0 to 80%. DISCUSSION: Combining aesthetic and functional rehabilitation, autogenous reconstruction of a new auricle together with the implantation of an active middle ear hearing aid, coupled to the round window membrane, is a promising new approach.

Adult↗
PubMed2006

Bone conduction in a three-dimensional model of the cochlea.

Hearing sensations are caused by air- and bone-guided sound. Of course, other biological materials like tendons, muscles and tissue are also involved during conduction of sound. To study the influence of bone conduction, a formerly developed finite element model was excited by harmonic pressure signals at the cochlea wall. The clinical finding during middle ear surgery, namely the increase in bone conduction sensitivity with removed footplate, was confirmed. Other psychoacoustic effects with bone conduction are described in the early experiments by Bárány, who proved the cancellation of air- and bone-conducted sound in humans. The simultaneous stimulation of the cochlea wall and the phase-reversed stimulation of the stapes footplate in the finite element model confirmed his findings. Further clues to the solution of unsolved problems in audiology and middle ear pathology are given.

Acoustic Stimulation↗
PubMed2006

Representation of acoustic signals in the human cochlea in presence of a cochlear implant electrode.

BACKGROUND: In subjects with remaining low frequency hearing, combined electric-acoustic stimulation (EAS) of the auditory system is a new therapeutic perspective. Intracochlear introduction of a cochlear implant electrode, however, may alter the biomechanical properties of the inner ear and thus affect perception of acoustic stimuli. STUDY DESIGN: Based on histological observations of morphologic changes after cochlear implantation in cadaveric and post mortem studies the effects of basilar membrane (BM) stiffening in the ascending basal and middle turns of the cochlea due to close contact of the BM with the electrode were simulated in a 3D-computational finite element model of the inner ear. To verify our simulated results, pre- and postoperative pure-tone audiograms of 13 subjects with substantial residual hearing, who underwent cochlear implantation, were evaluated. RESULTS: In the scenario of partial BM-fixation, acoustic energy of middle (2 kHz) and high (6 kHz) frequency was focused basally and apically to the fixed section, increasing BM displacement amplitudes up to 6 dB at a stimulation level of 94 dB (SPL). Lower frequencies were not affected by fixation in the basal and middle turn of the cochlea. In implanted subjects, a small but significant decrease of thresholds was observed at 1.5 kHz, a place in tonotopy adjacent to the tip region of the implanted electrode. CONCLUSION: Our model suggests that stiffening of the basilar membrane adjacent to an implanted electrode into the basal and middle cochlear turn did not affect BM movement in the low frequency area. Focussing of acoustic energy may increase perception in regions adjacent to the fixed section. Observations in implanted subjects were concordant with our model predictions. High frequencies, however, should not be amplified in patients using EAS to avoid disturbances in discrimination due to tonotopically incorrect frequency representation.

Acoustic Stimulation↗
PubMed2006

Sphingosine-1-phosphate modulates spiral modiolar artery tone: A potential role in vascular-based inner ear pathologies?

OBJECTIVE: The mechanisms regulating spiral modiolar artery (SMA) tone are not known, yet their characterization is pivotal for understanding inner ear blood flow regulation. Sphingosine-1-phosphate (S1P), known to stimulate vasoconstriction in several vascular beds, is a candidate regulator of SMA tone with potential pathophysiological relevance. METHODS: Gerbil SMAs were isolated, cannulated and pressurized (30 mm Hg transmural) for experimentation under near-in vivo conditions. For functional experiments, vascular diameter and intracellular Ca2+ were simultaneously measured. Standard RT-PCR and immunohistochemical techniques were also employed. RESULTS: mRNA transcripts encoding sphingosine kinase, S1P phosphohydrolase and three S1P receptors (S1P(1-3)) were detected in the SMA. S1P induced dose-dependent vasoconstriction of the SMA (EC50 = 115 nmol/L), and enhanced the apparent Ca2+-sensitivity of the contractile apparatus. Noradrenaline did not elicit vasoconstriction. The Rho kinase inhibitor Y27632 (1 micromol/L) reversed S1P-induced vasoconstriction and the S1P-mediated enhancement of Ca2+-sensitivity. RhoA was observed to translocate to the plasma membrane in response to stimulation with 30 micromol/L S1P. CONCLUSION: We conclude that all key signalling pathway constituents are present at the mRNA level for S1P to act as an endogenous regulator of SMA tone. S1P stimulates potent, RhoA/Rho kinase-dependent SMA vasoconstriction and Ca2+ sensitization. The high sensitivity to S1P suggests that SMA vasoconstriction is likely to occur under pathological conditions that increase intramural S1P concentrations (i.e., inflammation). From a clinical perspective, the present study identifies new potential therapeutic targets for the treatment of vascular-based, "stroke-like" inner ear pathologies: the enzymes responsible for S1P bioavailability and the S1P receptors.

Amides↗
PubMed2006

Targeting cancer cells: magnetic nanoparticles as drug carriers.

Magnetic drug targeting employing nanoparticles as carriers is a promising cancer treatment avoiding side effects of conventional chemotherapy. We used iron oxide nanoparticles covered by starch derivatives with phosphate groups which bound mitoxantrone as chemotherapeutikum. In this letter we show that a strong magnetic field gradient at the tumour location accumulates the nanoparticles. Electron microscope investigations show that the ferrofluids can be enriched in tumour tissue and tumour cells.

Animals↗
PubMed2006

Genetic background of different cancer cell lines influences the gene set involved in chromosome 8 mediated breast tumor suppression.

Several lines of evidence suggest that chromosome 8 is likely to harbor tumor-suppressor genes involved in breast cancer. We showed previously that microcell-mediated transfer of human chromosome 8 into breast cancer cell line MDA-MB-231 resulted in reversion of these cells to tumorigenicity and was accompanied by changes in the expression of a breast cancer-relevant gene set. In the present study, we demonstrated that transfer of human chromosome 8 into another breast cancer cell line, CAL51, strongly reduced the tumorigenic potential of these cells. Loss of the transferred chromosome 8 resulted in reappearance of the CAL51 phenotype. Microarray analysis identified 78 probe sets differentially expressed in the hybrids compared with in the CAL51 and the rerevertant cells. This signature was also reflected in a panel of breast tumors, lymph nodes, and distant metastases and was correlated with several prognostic markers including tumor size, grading, metastatic behavior, and estrogen receptor status. The expression patterns of seven genes highly expressed in the hybrids but down-regulated in the tumors and metastases (MYH11, CRYAB, C11ORF8, PDGFRL, PLAGL1, SH3BP5, and KIAA1026) were confirmed by RT-PCR and tissue microarray analyses. Unlike with the corresponding nontumorigenic phenotypes demonstrated for the MDA-MB-231- and CAL51-derived microcell hybrids, the respective differentially expressed genes strongly differed. However, the majority of genes in both gene sets could be integrated into a similar spectrum of biological processes and pathways, suggesting that alterations in gene expression are manifested at the level of functions and pathways rather than in individual genes.

Animals↗
PubMed2006

Molecular detection of measles virus in primary cell cultures of otosclerotic tissue.

CONCLUSION: Primary cell cultures were established from otosclerotic/otospongiotic footplate bone particles. Although this procedure is time-consuming, the quality and quantity of RNA isolated from these cells were much higher in comparison with the direct isolation of RNA from footplate bone samples and the preparation was more suitable for the detection of measles virus (MeV) RNA. OBJECTIVE: Morphological and biochemical investigations suggest that persistent MeV infection participates in the development of otosclerotic foci. However, this hypothesis is controversial because the detection of MeV in otosclerotic foci is inconsistent since the results are dependent on the presence and stage of foci in the investigated bone particles. Unfortunately, this cannot be confirmed before investigation. To study the presence of the MeV by different techniques in otosclerotic foci, stapes footplate fragments were collected during stapedectomy from patients suffering from clinical otosclerosis. MATERIALS AND METHODS: MeV-specific RT-PCR was performed on total RNA isolated directly from four fresh frozen footplate bone fragments and from the cells of 16 primary cultures of otosclerotic tissue samples. In order to rescue persisting MeV, the primary footplate cells were cocultured with MeV permissive B95a cells. RESULTS: MeV was not detected in RNA from fresh frozen otosclerotic materials, but analysis of the RNA from 5 of the 16 primary cell cultures showed MeV-positive results. Nucleotide sequencing of a 317 bp MeV-specific RT-PCR fragment confirmed the presence of the MeV RNA genome. Here, we report the first determination of MeV sequences in total RNA isolated from primary cells cultured from otosclerotic tissue. Persisting MeV in primary footplate cells could not be recovered by coculturing with B95a cells.

Adult↗
PubMed2005

Pharmacological reversal of endothelin-1 mediated constriction of the spiral modiolar artery: a potential new treatment for sudden sensorineural hearing loss.

BACKGROUND: Vasospasm of the spiral modiolar artery (SMA) may cause ischemic stroke of the inner ear. Endothelin-1 (ET-1) induces a strong, long-lasting constriction of the SMA by increasing contractile apparatus Ca2+ sensitivity via Rho-kinase. We therefore tested several Rho-kinase inhibitors and a cell-permeable analogue of cAMP (dbcAMP) for their ability to reverse ET-1-induced constriction and Ca2+-sensitization. METHODS: The present study employed SMA isolated from gerbil temporal bones. Ca2+sensitivity was evaluated by correlating vascular diameter and smooth muscle cell [Ca2+]i, measured by fluo-4-microfluorometry and videomicroscopy. RESULTS: The Rho-kinase inhibitors Y-27632, fasudil, and hydroxy-fasudil reversed ET-1-induced vasoconstriction with an IC50 of 3, 15, and 111 micromol/L, respectively. DbcAMP stimulated a dose-dependent vasodilation (Ec50 = 1 mmol/L) and a reduction of [Ca2+]i (EC50 = 0.3 micromol/L) of ET-1-preconstricted vessels (1 nmol/L). Fasudil and dbcAMP both reversed the ET-1-induced increase in Ca2+ sensitivity. CONCLUSION: Rho-kinase inhibition and dbcAMP reversed ET-1-induced vasoconstriction and Ca2+-sensitization. Therefore, Rho-kinase inhibitors or cAMP modulators could possess promise as pharmacological tools for the treatment of ET-1-induced constriction, ischemic stroke and sudden hearing loss.

Journal Article↗
PubMed2005

REDD1 integrates hypoxia-mediated survival signaling downstream of phosphatidylinositol 3-kinase.

Cancer cells frequently evade apoptosis during tumorigenesis by acquiring mutations in apoptotic regulators. Chronic activation of the PI 3-kinase-Akt pathway through loss of the tumor suppressor PTEN is one mechanism by which these cells can gain increased protection against apoptosis. We report here that REDD1 (RTP801) can act as a transcriptional downstream target of PI 3-kinase signaling in human prostate cancer cells (PC-3). REDD1 expression is markedly reduced in PC-3 cells treated with LY294002 (LY) or Rapamycin and strongly induced under hypoxic conditions in a hypoxia-inducible factor-1 (HIF-1)-dependent manner. Loss of function studies employing antisense molecules or RNA interference indicate that REDD1 is essential for invasive growth of prostate cancer cells in vitro and in vivo. Reduced REDD1 levels can sensitize cells towards apoptosis, whereas elevated levels of REDD1 induced by hypoxia or overexpression desensitize cells to apoptotic stimuli. Taken together our data designate REDD1 as a novel target for therapeutic intervention in prostate cancer.

Apoptosis↗
PubMed2005

A network of clinically and functionally relevant genes is involved in the reversion of the tumorigenic phenotype of MDA-MB-231 breast cancer cells after transfer of human chromosome 8.

Several investigations have supposed that tumor suppressor genes might be located on human chromosome 8. We used microcell-mediated transfer of chromosome 8 into MDA-MB-231 breast cancer cells and generated independent hybrids with strongly reduced tumorigenic potential. Loss of the transferred chromosome results in reappearance of the malignant phenotype. Expression analysis identified a set of 109 genes (CT8-ps) differentially expressed in microcell hybrids as compared to the tumorigenic MDA-MB-231 and rerevertant cells. Of these, 44.9% are differentially expressed in human breast tumors. The expression pattern of CT8-ps was associated with prognostic factors such as tumor size and grading as well as loss of heterozygosity at the short arm of chromosome 8. We identified CT8-ps networks suggesting that these genes act cooperatively to cause reversion of tumorigenicity in MDA-MB-231 cells. Our findings provide a conceptual basis and experimental system to identify and evaluate genes and gene networks involved in the development and/or progression of breast cancer.

Breast Neoplasms↗
PubMed2005

Characterization of {gamma}-aminobutyric acid type A receptor-associated protein, a novel tumor suppressor, showing reduced expression in breast cancer.

Frequent allelic loss of the chromosomal region 17p13 in breast cancer has suggested that more tumor suppressor genes, besides p53, are located in this region. By doing suppression subtractive hybridization to detect differentially expressed genes between the breast cancer cell line CAL51 and a nontumorigenic microcell hybrid CAL/17-1, we identified the gene for the gamma-aminobutyric acid type A (GABA(A)) receptor associated protein (GABARAP), located on 17p13.1. GABARAP displayed high expression levels in the microcell hybrid CAL/17-1 but only weak expression in CAL51 and other breast cancer cell lines tested. Furthermore, we observed large vesicles in CAL/17-1 by immunofluorescence staining, whereas no signal could be detected in the tumor cell line. GABARAP mRNA expression and protein expression were significantly down-regulated in invasive ductal and invasive lobular carcinomas compared with normal breast tissue measured by semiquantitative reverse transcription-PCR and immunohistochemistry, respectively. We assessed that neither mutations in the coding region of the gene nor hypermethylation of CpG islands in the promoter region are responsible for loss of gene expression in CAL51; however, 5-aza-2'-deoxycytidine treatment was effective in gene up-regulation, suggesting a methylation-dependent upstream effect. Stable transfection of GABARAP into CAL51 resulted in an increase of gene expression and remarkably influenced the ability of colony formation in soft agar and the growth rate in vitro and, moreover, suppressed the tumorigenicity of the cells in nude mice. In summary, our data suggest that GABARAP acts via a vesicle transport mechanism as a tumor suppressor in breast cancer.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Canalolithiasis of the superior semicircular canal: an anomaly in benign paroxysmal vertigo.

According to the canalolithiasis theory, benign paroxysmal vertigo (BPPV) is caused by gravity-dependent movements of otoconial debris that collects in the endolymph of the posterior semicircular canal. Other parts of the vestibular organ are rarely affected, and it is mainly the horizontal canal that is affected by this atypical form of BPPV. Canalolithiasis of the superior semicircular canal must be considered an anomaly because the superior semicircular canal is the highest point of the vestibular organ and debris normally cannot collect in this special location. Until now, BPPV of the superior canal has mainly been dealt with theoretically in the literature. The authors present three patients with canalolithiasis of the superior semicircular canal and offer direct proof of the condition using high-resolution 3D MRI.

Adult↗
PubMed2004

ST18 is a breast cancer tumor suppressor gene at human chromosome 8q11.2.

We have identified a gene, ST18 (suppression of tumorigenicity 18, breast carcinoma, zinc-finger protein), within a frequent imbalanced region of chromosome 8q11 as a breast cancer tumor suppressor gene. The ST18 gene encodes a zinc-finger DNA-binding protein with six fingers of the C2HC type (configuration Cys-X5-Cys-X12-His-X4-Cys) and an SMC domain. ST18 has the potential to act as transcriptional regulator. ST18 is expressed in a number of normal tissues including mammary epithelial cells although the level of expression is quite low. In breast cancer cell lines and the majority of primary breast tumors, ST18 mRNA is significantly downregulated. A 160 bp region within the promoter of the ST18 gene is hypermethylated in about 80% of the breast cancer samples and in the majority of breast cancer cell lines. The strong correlation between ST18 promoter hypermethylation and loss of ST18 expression in tumor cells suggests that this epigenetic mechanism is responsible for tumor-specific downregulation. We further show that ectopic ST18 expression in MCF-7 breast cancer cells strongly inhibits colony formation in soft agar and the formation of tumors in a xenograft mouse model.

Animals↗
PubMed2004

Novel slow- and fast-type drug release round-window microimplants for local drug application to the cochlea: an experimental study in guinea pigs.

Novel drug release microimplants (0.8 x 1.14 mm; custom-made by Leiras, now Schering OY, Finland) of slow- and fast-release types containing either 0.9 mg beclomethasone or no drug at all were placed unilaterally onto the round-window membrane (RWM) of 45 guinea pigs for a maximum duration of 28 days. The following parameters were tested on days 1, 14 and 28 after implantation: threshold levels of beclomethasone in the perilymph of the scala tympani, auditory brain stem responses (ABR thresholds and ABR threshold shifts), RWM morphology and hair cell loss (cytocochleograms). None of the animals in the non-implanted control group (n = 5) or placebo implant group (n = 15), but all animals in the slow-release-type implant group (n = 15) and fast-release-type implant group (n = 15) revealed the presence of beclomethasone on day 1 (34.9 and 64.3 pg/microl, respectively), day 14 (43.8 and 46.9 pg/microl, respectively) and day 28 after implantation (4.7 and 60.5 pg/microl, respectively). Histology of the RWMs appeared normal, and cytocochleograms revealed no inner hair cell loss and outer hair cell loss within normal ranges (from 0.5 +/- 0.4 to 0.8 +/- 0.2% per cochlea) in both ears in all experimental groups at any time during examination (days 1, 14 and 28). Initial values of ABR thresholds at 3, 6, 9 and 12 kHz did not differ significantly in any of the experimental groups. In non-implanted controls, no significant differences of ABR thresholds were observed in all frequencies tested in either ear on days 1, 14 and 28 compared to initial values, and ABR threshold shifts ranged from -3 +/- 5 dB (min.) to +5 +/- 7 dB (max.). On day 28 after implantation, there were no significant differences of ABR threshold shifts between this and the implant groups, except for 6 kHz of the slow-release device. Therefore, the placebo implants, the slow-release and the fast-release beclomethasone implants appear suitable for further experiments.

Animals↗
PubMed2004

PKN3 is required for malignant prostate cell growth downstream of activated PI 3-kinase.

Chronic activation of the phosphoinositide 3-kinase (PI3K)/PTEN signal transduction pathway contributes to metastatic cell growth, but up to now effectors mediating this response are poorly defined. By simulating chronic activation of PI3K signaling experimentally, combined with three-dimensional (3D) culture conditions and gene expression profiling, we aimed to identify novel effectors that contribute to malignant cell growth. Using this approach we identified and validated PKN3, a barely characterized protein kinase C-related molecule, as a novel effector mediating malignant cell growth downstream of activated PI3K. PKN3 is required for invasive prostate cell growth as assessed by 3D cell culture assays and in an orthotopic mouse tumor model by inducible expression of short hairpin RNA (shRNA). We demonstrate that PKN3 is regulated by PI3K at both the expression level and the catalytic activity level. Therefore, PKN3 might represent a preferred target for therapeutic intervention in cancers that lack tumor suppressor PTEN function or depend on chronic activation of PI3K.

Animals↗
PubMed2004

Tumor suppressor activity of profilin requires a functional actin binding site.

Profilin 1 (PFN1) is a regulator of the microfilament system and is involved in various signaling pathways. It interacts with many cytoplasmic and nuclear ligands. The importance of PFN1 for human tissue differentiation has been demonstrated by the findings that human cancer cells, expressing conspicuously low PFN1 levels, adopt a nontumorigenic phenotype upon raising their PFN1 level. In the present study, we characterize the ligand binding site crucial for profilin's tumor suppressor activity. Starting with CAL51, a human breast cancer cell line highly tumorigenic in nude mice, we established stable clones that express PFN1 mutants differentially defective in ligand binding. Clones expressing PFN1 mutants with reduced binding to either poly-proline-stretch ligands or phosphatidyl-inositol-4,5-bisphosphate, but with a functional actin binding site, were normal in growth, adhesion, and anchorage dependence, with only a weak tendency to elicit tumors in nude mice, similar to controls expressing wild-type PFN1. In contrast, clones expressing a mutant with severely reduced capacity to bind actin still behaved like the parental CAL51 and were highly tumorigenic. We conclude that the actin binding site on profilin is instrumental for normal differentiation of human epithelia and the tumor suppressor function of PFN1.

Actin Cytoskeleton↗
PubMed2004

Optimum primary tone level setting for measuring high amplitude DPOAEs in guinea pigs.

A special stimulus paradigm needs to be applied when distortion product otoacoustic emission (DPOAE) input/output functions are used to investigate the loss of sensitivity and loss of compression of outer hair cell cochlear amplifiers during noise exposure, drug treatment, etc. This stimulus paradigm should be able to reflect cochlear non-linear compressive sound processing known from direct basilar membrane measurements. Such a paradigm has already been established for humans that accounts for the different compression of the primary tones at the DPOAE generation site at f2 with L1 = 0.4 L2 + 39 dB SPL ('scissor paradigm'). The purpose of the present study was to develop an equivalent parameter setting for guinea pigs. Ninety-six different L1 - L2 combinations were presented to 24 ears in 18 pigmented guinea pigs at seven f2 frequencies between 2 and 16 kHz. L2 ranged from 20 to 60 dB SPL, L1 from 20 to 65 dB SPL. An extreme value analysis was performed to achieve the maximum DPOAE level for L1 in relation to L2. Linear regression analysis yielded a scissor paradigm specific to guinea pigs (L1 = 0.46 L2 + 41 dB SPL) which is similar to that of humans.

Acoustic Stimulation↗