Clarion 1.2 standard electrode array with partial space-filling positioner: radiological and histological evaluation in human temporal bones

The purpose of this study was to evaluate whether use of a positioner for situating the Clarion 1.29 standard electrode array in close proximity to the modiolus, causes damage to fine intra-cochlear structures, and to provide a comparison with results obtained for insertions of the array performed without a positioner. The study was performed in seven freshly frozen human temporal bones. Electrode location and intra-cochlear trauma was analysed using cross-sectional imaging and histological analysis. Insertion of the Clarion array did not reveal major trauma. The devices inserted with the positioner showed a consistently closer location of the electron array towards the modiolus, however, insertion resulted in significant displacement of both the electrode array and the positioner resulting in severe destruction of the basilar membrane and osseous spiral lamina along the length of the basal and middle turns. The devices inserted with the positioner resulted in major trauma to the basilar membrane and osseous spiral lamina. Therefore, systematic safety studies in larger samples of human temporal bones should be performed and the results carefully evaluated before implantation can be recommended unreservedly.     

A season of aseptic meningitis in Germany: epidemiologic,clinical and diagnostic aspects

OBJECTIVE: We assessed epidemiologic, clinical and laboratory features of aseptic meningitis during one season of multiserotype enteroviral meningitis in East Germany in 70 consecutive patients with aseptic meningitis admitted to the Children's University Hospital Leipzig. RESULTS: Patients, age 1 to 16 years, typically presented with headache, emesis and fever, whereas signs of meningeal irritation were only moderately expressed in one-half of the patients. The median number of leukocytes in the CSF was 151 cells/mm(3) (range, 2 to 1,820) with a high percentage of polymorphonuclear cells (PMNs). Initial blood counts showed mild leukocytosis and pronounced PMN predominance (78.9 +/- 1.3%). The percentage of PMNs in the peripheral blood decreased in favor of mononuclear cells after 3 days to a pattern more compatible with viral infection as opposed to that suggestive for bacteria in the beginning. Mean cerebrospinal fluid values of protein, glucose and lactate and the C-reactive protein were mildly elevated or normal. Nonpolio enteroviruses were detected in 30 of 70 patients. Subsequent serotyping revealed echovirus type 13 (13 patients), type 6 (2), type 30 (1) and coxsackie B virus type 5 (2). There were no differences in demographic or clinical data between enterovirus positive and negative patients. CONCLUSIONS: Even though individual laboratory values do not solely allow discrimination between viral and bacterial meningitis, the combined epidemiologic, clinical and laboratory data facilitate the diagnosis of aseptic meningitis in most cases. Viral diagnostics, identifying echovirus type 13 that thus far has not been associated with epidemics of meningitis, adds important epidemiologic information.     

Protein-mediated transbilayer movement of lipids in eukaryotes and prokaryotes: the relevance of ABC transporters

Lipid distribution across cellular membranes is regulated by specific membrane proteins controlling transbilayer movement of lipids. Flippases facilitate flip-flop of lipids and allow them to equilibrate between the two membrane leaflets independent of ATP. Distinct P-Type-ATPases transport specific lipids unidirectionally across the membrane at the expense of ATP. A group of ATP-dependent lipid transporters, the ATP-binding cassette (ABC) transporter family, was identified in studies originally related to multidrug resistance (MDR) in cancer cells. Meanwhile, lipid transport activity has been shown for full and half size ABC proteins in eukaryotic and prokaryotic cells. This activity may not only modify the organisation of lipids in membranes, but could also be of significant consequence for cell homeostasis. The various types of lipid movement mediating proteins and their cellular localisation in eukaryotes and prokaryotes are reviewed.     

Inhaled corticosteroids plus long-acting beta2-agonists as a combined therapy in asthma

Inhaled corticosteroids (ICS) are the mainstay of asthma treatment. Since 1994, when the first trial showed an equivalent effect of doubling the ICS dose or adding salmeterol, it has repeatedly been shown that the combinations of beclomethasone dipropionate and salmeterol, budesonide and formoterol, or fluticasone propionate and salmeterol have at least the same efficacy as doubling the dose of the ICS in adults, though a conclusive trial in asthmatic children is still lacking. The addition of a long-acting beta(2)-agonist (LABA) to ICS appears more efficacious than adding a short-acting beta(2)-agonist or an antileukotriene, even though available data are sparse. Concurrent (two inhalers) and combination (same inhaler) modes of administration are equivalent from the clinical point of view, as is also true regarding administration via metered dose inhaler or dry powder inhaler. Using a single inhaler might eventually have a positive effect on treatment compliance, but there are no confirmatory data yet. Despite some clues regarding a presumed agonist effect of ICS and LABAs, there are still more doubts than certainties. Even though there are still unanswered questions, the data available strongly suggest that the fixed combination of ICS and LABAs using the same inhaler is an efficacious, safe and practical approach for those asthmatic patients who are not well controlled with low doses of ICS alone.     

Pharmacoeconomics of obesity management in childhood and adolescence

The level of fatness of a child at which morbidity acutely increases is operationally determined by calculating the body mass index (BMI). An increased risk of death from cardiovascular disease in adults has been found in subjects whose BMI had been > 75(th) percentile as adolescents. Childhood obesity seems to substantially increase the risk of subsequent morbidity whether or not obesity persists into adulthood. Among the most common sequelae of primary childhood obesity are hypertension, dyslipidaemia, back pain and psychosocial problems. Environmental/exogenous factors largely contribute to the development of body fatness early in life. Therapeutic strategies include psychological and family therapy, lifestyle/behaviour modification and nutrition education. The role of regular exercise and exercise programmes is emphasised. Surgical procedures and drugs used in adult obesity are not generally recommended in children and adolescents. Appetite suppressants and thermogenic drugs have not been approved for use in children. Digestive inhibitors such as lipase inhibitors and fat substitutes have been used in children and adolescents in off-label use and in only a few clinical studies. As obesity is the most common chronic disorder in the industrialised societies, its impact on individual lives, as well as on health economics, has to be recognised more widely. One should aim to increase public awareness of the ever increasing health burden and economic dimension of the childhood obesity epidemic that is present around the globe.     

Aminoguanidine downregulates expression of cytokine-induced Fas and inducible nitric oxide synthase but not cytokine-enhanced surface antigens of rat islet cells

Autoimmune beta-cell destruction occurs directly by cell-mediated cytotoxicity or indirectly by cytokines released from infiltrating lymphocytes. Cytokines (IL-1beta/IFN-gamma) modify or induce expression of MHC antigens and ICAM-1 on beta-cells which can lead to an improved binding of T-lymphocytes to beta-cells and finally to an enhanced cell-mediated cytotoxicity. Cytokines also induce Fas-expression and inducible nitric oxide synthase (iNOS) causing generation of nitric oxide (NO) which is toxic for beta-cells. The iNOS inhibitor aminoguanidine (AG) delays diabetes onset, but does not reduce diabetes incidence. We wanted to know whether AG inhibits cytokine-induced expression of Fas, MHC antigens and ICAM-1 on beta-cells of LEW.1W and BB/OK rat islets after culture with IL-1beta/IFN-gamma. NO was completely inhibited by 5.0 mmol/L AG while 0.5 mmol/L had no inhibitory effect. AG downregulated Fas-expression on the surface of beta-cells. Cytokine-induced/enhanced expression of MHC class-II and ICAM-1 was not affected by any AG concentration. AG syngergistically increased cytokine-induced enhancement of MHC class-I antigen density. AG possibly blocks the indirect pathway of beta-cell damage in vivo due to inhibition of Fas and iNOS and improves direct cell-mediated cytotoxicity due to drastic increased MHC class-I expression. Inhibition of only one pathway of beta-cell destruction is not sufficient to prevent diabetes.     

On the analysis of viral load endpoints in HIV vaccine trials

First generation HIV vaccines are not likely to provide complete protection from HIV-1 infection. Therefore, it is important to assess a vaccine's effect on disease progression and infectiousness of infected vaccinees in an efficacy trial; however, direct assessment of such vaccine effects is not feasible within current trial designs. Viral load in HIV-infected individuals correlates with infectiousness and disease progression in a natural history setting, and thus is a reasonable candidate for a surrogate outcome in vaccine efficacy trials. We consider comparisons of viral load of infected vaccinees to that of infected trial participants in the control group. Dramatic differences in viral loads between these groups would suggest a vaccine effect on disease progression. However, modest differences, even if statistically significant, could be consistent with an imperfect vaccine effect on susceptibility to infection and not an effect on disease progression, that is, a selection effect of the vaccine. Thus, the usual statistical tests for no difference between groups do not test the biologically and clinically relevant hypothesis. We propose a model for the possible selective effects of a vaccine and develop several test statistics for assessing a direct effect of the vaccine on viral load given this selection model. Finite sample properties of these tests are evaluated using computer simulations.     

Evaluation of mammographic and clinical follow-up after 755 stereotactic vacuum-assisted breast biopsies

PURPOSE: Stereotactic vacuum-assisted breast biopsy (VB) is a new method that promises high accuracy and reliability. In order to avoid surgery in cases with benign histology the examination must be quality assured and the accuracy should be well established. We present follow-up data of 755 VBs with benign results. METHODS: In all, 984 of 1268 consecutive VBs proved histopathologically benign (lobular carcinoma in situ and atypical ductal hyperplasia not included). Follow-up data are available for 755 of 984 (77%) lesions and constitute the basis of this evaluation. Follow-up mammograms were performed of 728 lesions at 6 to 67 months (mean 24, median 17.8) after VB. RESULTS: Seven technically unsuccessful cases underwent immediate rebiopsy; 3 unsuccessful cases were diagnosed otherwise. No false negative occurred among the 752 followed-up, eventually successful VBs. On follow-up mammography 444 of 728 (61%) benign lesions proved radiologically completely removed, 284 (39%) partially. In 6 cases (0.8%) a surgical biopsy was performed again during the follow-up time confirming the benign result. No scar was seen in 96%, a slight scar in 3.8%, and a small stellate scar with possible diagnostic interference in 0.3%. CONCLUSIONS: A benign diagnosis of quality assured VB is very reliable and leads to no or minimal scarring.     

beta1-integrin mediates asbestos-induced phosphorylation of AKT and ERK1/2 in a rat pleural mesothelial cell line

Integrin-mediated signalling has been implicated in asbestos-induced carcinogenesis. In studies here, we examined signal transduction events associated with integrin-directed cell reactions triggered by crocidolite asbestos in the pleural mesothelial cell line 4/4 RM-4. Crocidolite fibres induced a significant time- and dose-dependent activation of the extracellular-signal-regulated kinases ERK1 and ERK2. ERK activation was specifically inhibited by integrin-blocking agents, that are integrin-binding peptides containing the sequence arginine-glycine-aspartic acid (RGD), and monoclonal antibodies against the integrin beta1-chain. Integrin-dependent activation of ERK1/2 in response to asbestos appeared to be independent of focal adhesion kinase pp125FAK (FAK) since FAK autophosphorylation remained unaffected in crocidolite-exposed mesothelial cells. Instead, we observed striking similarities in the kinetics of asbestos-induced ERK1/2 responses and phosphorylation of protein kinase B (AKT) at serine 473, a possible target residue for integrin-linked kinase. As with ERK activation, asbestos-induced AKT stimulation was significantly blocked by both the RGD-peptide and the beta1-integrin antibodies. These studies are the first to establish that in mesothelial cells ERK1/2 and AKT are simultaneously phosphorylated upon asbestos exposure in a beta1-integrin-dependent manner.