Progress in basic research of otosclerosis.
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Humans↗
Biomedical subjects
W Arnold
Publications and source records attributed to W Arnold.
Persistent measles virus infection as a possible cause of otosclerosis: state of the art.
The etiopathogenesis of otosclerosis is still largely unexplained and remains controversial. Morphologic examinations have shown the presence of a chronic inflammation in otosclerotic tissue. Among the proposed explanations for this inflammation are an immunologic reaction against collagen, mutations of collagen gene 1A1, and a viral infection. In this paper, we focus on the role of measles virus in otosclerosis, and we review the current literature, devoting particular attention to a suspected paramyxoviral etiopathogenesis in Paget's disease. Our examination of footplate fragments by reverse transcription polymerase chain reaction testing in 95 patients with otosclerosis revealed the presence of measles virus RNA in 83% of cases. Quantification of measles virus immunoglobulin G (IgG) in otosclerosis patients indicated that the ratio of antimeasles virus IgG in total IgG was higher in perilymph than in serum. Furthermore, an almost identical incidence of otosclerosis and measles virus-caused mortality in women suggests that women are more susceptible to measles virus infection. Finally, since the introduction of the measles virus vaccination program in Europe, there has been a decline in the incidence of otosclerosis. Moreover, the average age of patients at diagnosis and surgery at our hospital has increased to 54 years. Our findings, when they are considered along with findings regarding the presence of paramyxoviral RNA in Paget's disease, support the hypothesis that measles virus is involved in the etiopathogenesis of otosclerosis.
Adolescent↗
[Assessment of outer hair cell function recovery by means of the DPOAE threshold].
Distortion product otoacoustic emissions (DPOAE) originate from nonlinear mechanical sound processing in the inner ear, mainly due to normal outer hair cell function. Outer hair cell impairment can be detected by means of DPOAE. With a special primary tone level paradigm which optimises the primary tone level difference over a wide stimulus level range (L1 = 0.4 L2 + 39 dB, L2 = 20 to 65 dB SPL, f2 = 0.5 to 8 kHz, f2/f1 = 1.2), DPOAE can be measured at levels close to the psychophysical hearing threshold. From the DPOAE growth functions, which are constructed from measurements at different stimulus levels, a DPOAE threshold can be defined (Boege et al., 1998), which can be interpreted as a threshold of mechanical processing by the outer hair cells. In this study, DPOAE thresholds were examined in 9 patients with reversible cochlear hearing loss, i.e. sudden deafness or noise trauma. With increasing hearing loss, low primary tone level DPOAE in particular decreased, and thus the DPOAE threshold increased. The DPOAE threshold makes it possible to detect mechanical sensitivity losses in a frequency-specific manner. Thus, loss of mechanical amplification may be differentiated from a non-mechanical cause of hearing loss.
Audiometry↗
Successful treatment of noise-induced cochlear ischemia, hypoxia, and hearing loss.
Cochlear blood flow (CoBF), perilymphatic partial pressure of oxygen (PL-pO2), cochlear microphonics (CMs), compound action potentials of the auditory nerve (CAPs), and auditory brainstem responses (ABRs) were studied in noise-exposed guinea pigs during and after the following treatments: intravenous infusion of isotonic saline (placebo); blood flow promoting drugs (hydroxyethyl starch = HES, pentoxifylline, betahistine, gingko biloba, naftidrofuryl); antiinflammatory agents (prednisolone, diclofenac sodium, histamine H1-receptor antagonist); isobaric oxygenation (IBO); and hyperbaric oxygenation (HBO) with and without supplements (simultaneous infusion of isotonic saline, pentoxifylline, prednisolone, or HES). It was found that PL-pO2 declined simultaneously with deterioration of CM, CAP, and ABR amplitudes after exposure to broad-band noise (bandwidth 1-12 kHz, 30 min, 106-dB SPL). CoBF decreased only 30 min after cessation of broad-band noise and progressed with cochlear hypoxia, while the hearing loss showed no further signs of deterioration and no recovery up to 3 h after exposure. Treatment (60 min) started 60 min after cessation of noise and was studied for a further 60 min. Isotonic saline did not influence the measuring parameters. Noise-induced cochlear hypoxia was compensated by IBO and more effectively by HBO with and without supplements, while other treatments had no sustained effect. A sustained therapeutic effect on noise-induced cochlear ischemia was achieved only by HES, HBO + HES, and pentoxifylline. However, the best therapeutic effect on noise-induced hearing loss was achieved with a combination of HBO and prednisolone, followed by monotherapy with prednisolone or HES with the result that not only did the CAPs and ABRs completely recover, the CMs also showed significant improvement, although full recovery did not occur. All other therapies were significantly less effective or did not improve noise-induced reduction of auditory evoked potentials.
Action Potentials↗
Role of S-100beta as potential autoantigen in an autoimmune disease of the inner ear.
In Lewis rats, adoptive transfer of T cells specific for the calcium-binding protein S-100beta mediates experimental autoimmune encephalomyelitis, but surprisingly also induced a marked labyrinthitis associated with impairment of hearing. This suggests that transfer of S-100beta-specific T cells into susceptible animals could be a novel model to study autoimmunity of inner ear diseases. The investigation demonstrated in detail an inner ear involving, central nervous system (CNS)-specific autoimmune disease in order to identify a putatively shared autoantigen(s) in these pathologies. In fact, the model will be a useful tool to investigate in detail, the pathological mechanisms of the human inner ear disease associated with Vogt-Koyanagi-Harada disease.
Animals↗
Nitrogen-containing bisphosphonates as carbocation transition state analogs for isoprenoid biosynthesis.
Nitrogen-containing bisphosphonates are potent bone antiresorptive agents as well as having herbicidal and antiparasitic activity, and are thought to act by inhibiting enzymes of the mevalonate pathway. Using molecular modeling and ab initio quantum chemical calculations, we show that bisphosphonates can act as aza-isoprenoid transition state analogs, thereby inhibiting isoprenoid biosynthesis. The two phosphonate groups of the 1,1-bisphosphonates readily dock into the diphosphate-Mg(2+) binding site in farnesyl diphosphate synthase, while the charged ammonium (or pyridinium or imidazolium) groups act as carbocation transition state analogs, whose binding is stabilized by a cluster of oxygen atoms in the active site cleft, and an overall negative electrostatic potential in this region. Enhanced activity is shown to correlate with increasing van der Waals stabilization due to N-alkylation, or the presence of a charged, planar (sp(2)-hybridized) aromatic residue in the carbocation binding site. These results are of general interest since they suggest a rational approach to bisphosphonate drug design.
Alkyl and Aryl Transferases↗
Extramedullary plasmacytoma: tumor occurrence and therapeutic concepts.
BACKGROUND: Extramedullary plasmacytoma (EMP) is a rare entity belonging to the category of non-Hodgkin lymphoma. EMPs make up 4% of all plasma cell tumors and occur mainly in the upper aerodigestive tract (UAD). Seven patients with EMP included in this evaluation were under the authors' care and have been clinically followed since 1990. Because there are no general guidelines for the treatment of patients with EMP, the authors tried to obtain detailed data about the occurrence of this disease and also reviewed the therapies that have been used. To do so, they evaluated all EMP cases published in the medical literature until now and included their own experience. METHODS: Based on the clinical course and follow-up of their own EMP patients, the authors evaluated and reinvestigated all EMP cases cited in MEDLINE, Index Medicus, DIMDI (Deutsches Institut fur medizinische Dokumentation und Information, Cologne, Germany), and the reference lists of the publications found through these sources. RESULTS: In a detailed literature search, more than 400 publications between 1905 and 1997 were found, and these revealed that EMP mainly occurs between the fourth and seventh decades of life. Seven hundred fourteen cases (82.2%) were found in the UAD, and 155 cases (17.8%) were found in other body regions. The following therapeutic strategies were used to treat patients with EMP of the UAD: radiation therapy alone in 44.3%, combined therapy (surgery and radiation) in 26.9%, and surgery alone in 21.9%. The median overall survival or recurrence free survival was longer than 300 months for patients who underwent combined intervention (surgery and radiation). This result was statistically highly significant (P = 0.0027, log rank test) compared with the results for patients who underwent surgical intervention alone (median survival time, 156 months) or radiation therapy alone (median survival time, 144 months). In most cases of non-UAD EMP, surgery was performed (surgery alone, 55.6%; surgery and radiation combined, 19.8%; radiation alone, 11.1%), but there were no statistical differences in survival (P = 0.62). Overall, after treatment for EMP in the UAD, 61.1% of all patients had no recurrence or conversion to systemic involvement (i.e., multiple myeloma, MM); however, 22.0% had recurrence of EMP, and 16.1% had conversion to MM. After treatment for EMP in non-UAD areas, 64.7% of all patients had no recurrence or MM, 21.2% had recurrence, and 14.1% had conversion to MM. CONCLUSIONS: The current investigation provides evidence that surgery alone gives the best results in cases of EMP of the UAD when resectability is good. However, if complete surgical tumor resection is doubtful or impossible and/or if lymph node areas are affected, then combined therapy (surgery and radiation) is recommended. These results, which were obtained from retrospective studies, should be confirmed in randomized trials comparing surgery with combined radiation therapy and surgery.
Adult↗
Lymph node detection of head and neck squamous cell carcinomas by positron emission tomography with fluorodeoxyglucose F 18 in a routine clinical setting.
BACKGROUND: Accurate determination of lymph node involvement is a prerequisite for individualized therapy in patients with squamous cell carcinoma of the head and neck region. In a previous study, we showed that positron emission tomography (PET) with fluorodeoxyglucose F 18 with and without attenuation correction is superior to magnetic resonance imaging for this purpose in a scientific setting. OBJECTIVE: To evaluate the diagnostic accuracy of a shortened PET protocol (acquisition time, 20 minutes) in a routine clinical setting. DESIGN: The results of static, nonattenuation-corrected PET performed on patients in 2 bed positions starting 40 minutes after the intravenous injection of 370 MBq of fluorodeoxyglucose F 18 and the results of morphologic procedures (computed tomography and magnetic resonance imaging) were compared prospectively in 70 patients for lymph node staging. Postoperative pathologic findings served as a criterion standard. SETTING: An academic medical center. RESULTS: The diagnostic accuracy of PET for detecting "neck sides" with malignant involvement was superior to morphologic procedures, with a sensitivity and specificity of 87% and 94%, respectively, compared with computed tomographic values of 65% and 47% and magnetic resonance imaging values of 88% and 41%, respectively. CONCLUSION: A short PET protocol that is suitable for routine clinical use is superior to morphologic procedures (computed tomography and magnetic resonance imaging) for the detection of lymph node involvement in head and neck squamous cell carcinomas.
Academic Medical Centers↗
Capsid protein-encoding genes of hamster polyomavirus and properties of the viral capsid.
On the basis of its genome organization the hamster polyomavirus (HaPV) is closely related to the murine polyomavirus Py. But HaPV infection, in contrast to Py infection, gives rise to two different tumor types; depending on the hamster strain used for infection, HaPV induces either epitheliomas or lymphomas. Although the HaPV virions were shown to be similar to those of Py and SV40, more precise information about the structure and protein composition of the HaPV capsid was still missing. Here we describe the primary structure of the capsid protein-encoding HaPV genes and the structure and protein composition of the HaPV capsid. Virions isolated from epitheliomas in HaPV-infected hamsters were shown by electron microscopy to be spherical particles with the typical icosahedral structure of polyomaviruses. However, in contrast to the capsids of SV40 and Py, a T = 7 laevo symmetry of HaPV capsids was observed. Separation of HaPV virions in SDS polyacrylamide gels and Western blotting with VP1-specific antisera identified VP1 as the major capsid protein species corresponding in its molecular weight to the predicted value of 41.8 kDa. Because of the presence of two potential translational initiation sites in the VP1 gene, the N-terminal amino acid sequence of virion VP1 was determined and found to start at the second initiation site. The amino acid homologies of HaPV capsid proteins shared with Py varied between 65.5% (VP1), 45.4% (VP3) and 44.6% (VP2), whereas the homologies to the relevant proteins of other polyomaviruses were found to range between 49.6-57.9% for VP1 and 28.9-41% for VP2/VP3.
Amino Acid Sequence↗
[Clinical significance of allergic reactions in glucocorticoid therapy].
BACKGROUND: Glucocorticoids are widely used in medicine. Within the last few years, however, patients have become very suspicious of corticoids. The attending physicians frequently has to use a great deal of persuasion prior to applying this very effective and often indispensable group of medication. PATIENTS: We report on four patients who developed allergic reactions (i.e. erythema in face and on body, itching, flushing, drop in blood pressure, respiratory distress, cold sweats, etc.) immediately after intravenous administration of prednisolone-21 hydrogen succinate (Solu-Decortin H, SDH). RESULTS: Three out of four patients had a positive reaction to an intracutaneous test with SDH, but no reaction to the additive sodium succinate. The prick test was negative in all patients. No specific IgE antibodies were detected in the serum of these patients. However allergic reaction to SDH must be presumed in at least three cases as it is difficult to detect glucocorticoid antibodies in serum and standardizes techniques are lacking. One female patient had a cross-reaction to prednisolon and dexamethasone. A renewed application of SDH was tolerated well by all patients when H1- and H2-receptors were blocked and calcium was administered to stabilize membranes. CONCLUSIONS: Allergic reactions after glucocorticosteroid therapy are only occasionally mentioned in literature, appear more often when the agent is applied topically, and may lead to dangerous complications in patients if administered intravenously. Therefore, when allergic reactions result from glucocorticoid therapy (immediate reactions should be suspect), corticosteroid allergy should be considered as a differential diagnosis.
Administration, Topical↗
[Clinical aspects of the osteolytic (inflammatory) phase of cochlear otosclerosis].
During the last years it has been demonstrated that the active stage of otosclerosis (French: otospongieuse) is caused by an osteolytic inflammation associated with a measles-virus infection. Under influences that are not yet well understood (e.g. estrogens), the osteolytic process is arrested and changed to osteoblast activity accompanied by new bone formation. This latter process can be understood as a scar formation. If the process takes place within the area of the oval window, it results in fixation of the stapes and conductive hearing loss. When the otosclerotic process is restricted to the cochlea, clinical signs are not well defined. We report on exemplary cases of progressive bilateral sensorineural hearing loss caused by otosclerosis, restricted to the cochlea. The characteristics of the clinical course include: 1. Bilateral asymmetric sensorineural hearing loss. 2. Roaring tinnitus. 3. Episodes of sudden hearing loss. 4. Excellent response to prednisolone therapy. 5. In the late stage of the disease a small but transitory conductive hearing loss. High resolution computed tomography in such cases reveals diffuse osteolytic foci within the cochlear walls. In severe cases of such progressive deafness we discuss an antiproliferative (immunosuppressive) therapy with cyclosporine and/or a radionuclide therapy with Sn-117 m, an isotope with a very small irradiation radius.
Adult↗
New approaches for inner ear therapy with glutamate antagonists.
In the mammalian cochlea neurotransmission between inner hair cells and afferent auditory neurons is probably mediated by glutamate or another related excitatory amino acid. Neurotoxicity induced by excessive glutamate release seems to play a crucial role in some pathological conditions of the cochlea, such as ischaemia or noise trauma. Thus, glutamate antagonists may be a new therapeutic strategy for different inner ear diseases. Because of their potential severe side-effects only a few glutamate antagonists have so far been adopted for clinical use. We used microiontophoretic techniques to compare the effects of memantine and caroverine on the glutamatergic transmission of inner hair cells of the guinea pig and tested the possibility of a local administration of memantine to the cochlea with a micropump. Memantine selectively inhibited the NMDA (N-methyl-D-aspartate) stimulated activity while caroverine blocked NMDA as well as AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) induced activity of inner hair cell afferents. With a flow rate of 1 microl/h the local administration of memantine via a cochleotomy was succeeded in a reversible blockade of the spontaneous and the NMDA induced firing of inner hair cell afferents. These results suggest that local application to the cochlea could be a feasible way to administer glutamate antagonists in sufficient amounts while avoiding systemic side-effects.
Animals↗
Ovine adenovirus vectors overcome preexisting humoral immunity against human adenoviruses in vivo.
Recombinant human adenoviruses (hAd) have become widely used as tools to achieve efficient gene transfer. However, successful application of hAd-derived vectors in clinical trials is limited due to immunological and potential safety problems inherent in their human origin. In this study, we describe a recombinant ovine adenovirus (OAV) as an alternative vector for gene transfer in vivo. In contrast to an hAd vector, the OAV vector was not neutralized by human sera. An OAV vector which contained the cDNA of the human alpha1-antitrypsin (hAAT) gene linked to the Rous sarcoma virus promoter was generated and administered systemically to mice. The level and duration of hAAT gene expression was similar to that achieved with an hAd counterpart in both immunocompetent and immunodeficient mice. However, the tissue distribution of the OAV vector differed from that observed for hAd vectors in that the liver was not the dominant target. Significantly, we demonstrated efficient gene transfer with the OAV vector into mice immunized with hAd vectors and vice versa. We also confirm that the immune response to a transgene product can prevent its functional expression following sequential application of a vector. Our results suggest a possible solution to endemic humoral immunity against currently used hAd vectors and should therefore have an impact on the design of improved gene therapy protocols utilizing adenovirus vectors.
Adenoviruses, Human↗
Ex vivo breast cancer cell purging by adenovirus-mediated cytosine deaminase gene transfer and short-term incubation with 5-fluorocytosine completely prevents tumor growth after transplantation.
Peripheral blood progenitor harvests of breast cancer patients are contaminated with tumor cells, suggesting a potential role for these cells in the relapse after high-dose chemotherapy. Whereas physical purging methods do not eliminate contaminating tumor cells completely, pharmacological purging, although highly efficient, is hampered by a strong nonspecific toxicity toward hematopoietic progenitor cells. Taking advantage of the high efficiency of adenovirus-mediated gene transfer to epithelial cells, we selectively loaded breast cancer cells in vitro with a cytotoxic drug by gene transfer of the prodrug-converting enzyme cytosine deaminase (AdCMV.CD) and 5-fluorocytosine (5-FC). Despite the low dose of vector administered, limited exposure to 5-FC, and transplantation only of viable tumor cells into SCID mice, all animals that received cells treated in vitro with AdCMV.CD plus 5-FC were completely free of tumor development. These data show that the selective loading of tumor cells with AdCMV.CD/5-FC might be useful for purging of autografts.
Adenoviridae↗
Allergic reactions after systemic administration of glucocorticosteroid therapy.
OBJECTIVE: To describe patients who developed allergic reactions (ie, erythema on their face and body, itching, flushing, drop in blood pressure, respiratory distress, and cold sweats) immediately after intravenous injection of prednisolone hemisuccinate (SoluDecortin H, E Merck, Darmstadt, Germany). SETTING: Academic medical center. RESULTS: Three of 4 patients had a positive reaction to an intracutaneous test with prednisolone hemisuccinate (SoluDecortin H) but no reaction to the additive sodium succinate. The results of the prick test were negative for all patients. Although no specific IgE antibodies were detected in the serum of these patients, allergic reaction was noted in 3 cases, since standardized techniques to detect antibodies in the serum for hydrocortisone acetate (ie, prednisolone) are lacking. One female patient had a cross-reaction to prednisolone and dexamethasone (Fortecortin, E Merck, Darmstadt, Germany). A renewed application of prednisolone hemisuccinate was well tolerated by all patients when histamine1 and histamine2 receptors were blocked with the use of cimetidine hydrochloride, 200 mg twice per day (1-0-1 ampules, Tagamet, SmithKline Beecham Pharmaceuticals, Philadelphia, Pa) and dimethindene maleate, 4 mg twice per day (1-0-1 ampules, Fenistil, Novartis, Munich, Germany); calcium was given for membrane stabilization. CONCLUSIONS: Allergic reactions to glucocorticoid therapy are only occasionally mentioned in the literature. These reactions appear more often when glucocorticoids are applied topically and may lead to dangerous complications in patients if administered systemically. Therefore, when allergic reactions result from glucocorticoid therapy, (immediate-type reactions should be suspect), consider corticosteroid allergy as a differential diagnosis.
Adult↗
A carbon-13 nuclear magnetic resonance spectroscopic study of inter-proton pair order parameters: a new approach to study order and dynamics in phospholipid membrane systems.
We report a simple new nuclear magnetic resonance (NMR) spectroscopic method to investigate order and dynamics in phospholipids in which inter-proton pair order parameters are derived by using high resolution 13C cross-polarization/magic angle spinning (CP/MAS) NMR combined with 1H dipolar echo preparation. The resulting two-dimensional NMR spectra permit determination of the motionally averaged interpair second moment for protons attached to each resolved 13C site, from which the corresponding interpair order parameters can be deducted. A spin-lock mixing pulse before cross-polarization enables the detection of spin diffusion amongst the different regions of the lipid molecules. The method was applied to a variety of model membrane systems, including 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC)/sterol and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC)/sterol model membranes. The results agree well with previous studies using specifically deuterium labeled or predeuterated phospholipid molecules. It was also found that efficient spin diffusion takes place within the phospholipid acyl chains, and between the glycerol backbone and choline headgroup of these molecules. The experiment was also applied to biosynthetically 13C-labeled ergosterol incorporated into phosphatidylcholine bilayers. These results indicate highly restricted motions of both the sterol nucleus and the aliphatic side chain, and efficient spin exchange between these structurally dissimilar regions of the sterol molecule. Finally, studies were carried out in the lamellar liquid crystalline (L alpha) and inverted hexagonal (HII) phases of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE). These results indicated that phosphatidylethanolamine lamellar phases are more ordered than the equivalent phases of phosphatidylcholines. In the HII (inverted hexagonal) phase, despite the increased translational freedom, there is highly constrained packing of the lipid molecules, particularly in the acyl chain region.
Biophysical Phenomena↗
The effect of prednisolone and non-steroidal anti-inflammatory agents on the normal and noise-damaged guinea pig inner ear.
The effect of anti-inflammatory agents, such as the synthetic glucocorticoid prednisolone, diclofenac sodium, and histamine H1-receptor antagonist, was studied in unexposed and noise-exposed (broad-band noise, bandwidth 1-12 kHz, 106 dB SPL, 30 min) guinea pigs. The results were compared with the results obtained from no treatment and with isotonic saline (placebo) therapy. The cochlear blood flow (CoBF) and the partial oxygen pressure in the perilymph (PL-pO2) were continuously and simultaneously recorded over a period of 210 min. In addition, cochlear microphonics (CMs), compound action potentials of the auditory nerve (CAPs), and auditory brain stem responses (ABRs) were registered. Noise-induced hearing loss paralleled a decrease of PL-pO2. Both were found to occur before evidence of reduced CoBF. PL-pO2 and CoBF progressively declined post-exposure, while CMs, CAPs, and ABRs did not further deteriorate nor showed signs of recovery up to 180 min after cessation of noise. Treatment started 60 min post-exposure, or after 90 min without manipulation and was then further studied for 120 min. In the unexposed animals, diclofenac sodium and prednisolone induced a significant decline of PL-pO2, while CoBF, CMs, CAPs, and ABRs revealed no change. Isotonic saline did not influence the measured parameters. After infusion of the histamine H1-receptor antagonist, a significant decrease of CoBF together with blood pressure and CMs was observed, while PL-pO2, CAPs, and ABRs showed no change. In the noise-exposed animals, diclofenac sodium induced partial restoration of CM and CAP amplitudes and full restoration of ABRs. Following a high dose of prednisolone (25 mg), partial restoration of CMs and full restoration of CAPs and ABRs were registered. This effect was significantly less pronounced following a low dose of prednisolone (2.5 mg). Restoration of CMs, CAPs, and ABRs was immediate (i.e. 50 min after infusion) and remained stable for another 60 min until the end of the recording period. The histamine H1-receptor antagonist and isotonic saline did not influence CMs, CAPs, and ABRs. None of the applied drugs resulted in relief of progressive noise-induced cochlear hypoxia and post-traumatic ischemia. These findings indicate direct cellular effects of prednisolone and diclofenac sodium in the cochlea taking into account no blood flow and oxygenation. The possible mechanisms involved are discussed.
Acoustic Stimulation↗