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survival: evidence for isotype switching within the myeloma clone Persistent preswitch clonotypic myeloma cells correlate with decreased http://bloodjournal.hematologylibrary.org/content/98/9/2791.full.html Updated information and services can be found at: (4217 articles) Neoplasia Articles on similar topics can be found in the following Blood collections http://bloodjournal.hematologylibrary.org/site/misc/rights.xhtml#repub_requests

Chlamydiae are obligate intracellular bacteria residing exclusively in host cell vesicles termed inclusions. We have investigated the effects of deferoxamine mesylate (DAM)-induced iron deficiency on the growth of Chlamydia pneumoniae and Chlamydia trachomatis serovar L2. In epithelial cells subjected to iron starvation and infected with either C. pneumoniae or C. trachomatis L2, small inclusions were formed, and the infectivity of chlamydial progeny was impaired. Moreover, for C. trachomatis L2, we observed a delay in homotypic fusion of inclusions. The inhibitory effects of DAM were reversed by adding exogenous iron-saturated transferrin, which restored the production of infectious chlamydiae. Electron microscopy examination of iron-deprived specimens revealed that the small inclusions contained reduced numbers of C. pneumoniae that were mostly reticulate bodies. We have previously reported specific accumulation of transferrin receptors (TfRs) around C. pneumoniae inclusions within cells grown under normal conditions. Using confocal and electron microscopy, we show here a remarkable increase in the amount of TfRs surrounding the inclusions in iron-starved cultures. It has been shown that iron is an essential factor in the growth and survival of C. trachomatis. Here, we postulate that, for C. pneumoniae also, iron is an indispensable element and that Chlamydia may use iron transport pathways of the host by attracting TfR to the phagosome.

The aim of this review is to focus the attention of clinicians and basic researchers on the association between psycho-social stress and tinnitus. Although tinnitus is an auditory symptom, its onset and progression often associates with emotional strain. Recent epidemiological studies have provided evidence for a direct relationship between the emotional status of subjects and tinnitus. In addition, studies of function, morphology, and gene and protein expression in the auditory system of animals exposed to stress support the notion that the emotional status can influence the auditory system. The data provided by clinical and basic research with use of animal stress models offers valuable clues for an improvement in diagnosis and more effective treatment of tinnitus.

The obligate intracellular pathogen Chlamydophila pneumoniae (Chlamydia pneumoniae) initiates infections in humans via the mucosal epithelia of the respiratory tract. Here, we report that epithelial cells infected with C. pneumoniae are resistant to apoptosis induced by treatment with drugs or by death receptor ligation. The induction of protection from apoptosis depended on the infection conditions since only cells containing large inclusions were protected. The underlying mechanism of infection-induced apoptosis resistance probably involves mitochondria, the major integrators of apoptotic signaling. In the infected cells, mitochondria did not respond to apoptotic stimuli by the release of apoptogenic factors required for the activation of caspases. Consequently, active caspase-3 was absent in infected cells. Our data suggest a direct modulation of apoptotic pathways in epithelial cells by C. pneumoniae.

Tinnitus disturbs lives and negatively affects the quality of life of about 2% of the adult world population. Research has shown that the main cause of tinnitus is hearing loss. To analyze a possible association of the degree of hearing loss with the severity of tinnitus, we have performed a retrospective study using admission data on 531 patients suffering from chronic tinnitus. We have found that 83% of our tinnitus patients had a high frequency hearing loss corresponding to a noise-induced hearing loss (NIHL). There was a significant correlation between the mean hearing loss and the tinnitus loudness (p < 0.0001). Interestingly, patients suffering from decompensated chronic tinnitus had a greater degree of hearing loss than the patients with compensated form of tinnitus. In addition, we demonstrate that the degree of hearing loss positively correlates with the two subscales ("intrusiveness" and "auditory perceptional difficulties") of the Tinnitus Questionnaire. Our retrospective study provides indirect evidence supporting the hypothesis that the degree of noise-induced hearing loss influences the severity of tinnitus.

The obligate intracellular human pathogenic bacterium Chlamydia trachomatis has evolved multiple mechanisms to circumvent the host immune system. Infected cells exhibit a profound resistance to the induction of apoptosis and downregulate the expression of major histocompatibility complex class I and class II molecules to evade the cytotoxic effect of effector immune cells. Here we demonstrate the down-regulation of tumor necrosis factor receptor 1 (TNFR1) on the surface of infected cells. Interestingly, other members of the TNFR family such as TNFR2 and CD95 (Fas/Apo-1) were not modulated during infection, suggesting a selective mechanism underlying surface reduction of TNFR1. The observed effect was not due to reduced expression since the overall amount of TNFR1 protein was increased in infected cells. TNFR1 accumulated at the chlamydial inclusion and was shed by the infected cell into the culture supernatant. Receptor shedding depended on the infection-induced activation of the MEK-ERK pathway and the metalloproteinase TACE (TNF␣ converting enzyme). Our results point to a new function of TNFR1 modulation by C. trachomatis in controlling inflammatory signals during infection.

Background: Heat shock protein 70 (HSP70) protects inner ear cells from damage and death induced by e.g. heat or toxins. Benzoquinone ansamycin antibiotic geldanamycin (GA) was demonstrated to induce the expression of HSP70 in various animal cell types. The aim of our study was to investigate whether GA induces HSP70 in the organ of Corti (OC), which contains the auditory sensory cells, and whether GA can protect these cells from toxicity caused by a common aminoglycoside antibiotic gentamicin.

Hearing loss can be induced by a variety of factors including hypoxia and inflammation. Here, we investigated in vitro the effect of hypoxia on the expression of proinflammatory cytokines in the explanted cochlear tissues. Using RT-PCR, we determined the expression of genes encoding IL-1beta, IL-6 and TNF in the organ of Corti (OC), modiolus (MOD) and stria vascularis together with spiral ligament (SV+SL). In addition, using ELISA, we determined the concentration of IL-1beta and IL-6 in the supernatants of explant cultures. We found that the dissection, explanting and consecutive 24-h normoxic culture results in highly increased expression of IL-1beta and IL-6, as compared to the freshly isolated tissues. TNFalpha was upregulated only in the MOD. Interestingly, 24h of hypoxia decreased the number of mRNA encoding IL-1beta and IL-6 and increased the number of mRNA encoding TNFalpha in the SV+SL as compared to normoxia. The concentration of IL-6 measured in the explant tissue culture supernatants was significantly lower in hypoxic than in the normoxic cultures. Our results show that tissue dissection and explanting as well as hypoxia can influence the expression and secretion of proinflammatory cytokines. This implies the presence of tissue-specific regulatory pathways between hypoxia and inflammation in the inner ear.

Salicylate has been shown to protect animals and people from the gentamicin-induced hearing loss. The objective of our study was to determine if salicylate is otoprotective in vitro. In this fashion, we wanted to validate the use of explant culture system for future studies on the ototoxicity prevention. In addition, we wanted to find out if salicylate protects from the ototoxicity of other aminoglycosides. As a model, we used the membranous cochlear tissues containing the organ of Corti, spiral limbus and spiral ganglion neurons dissected from the cochleas of p3-p5 Wistar pups. The explants were divided into apical, medial and basal parts and cultured in presence or absence of 100μM gentamicin, 100μM neomycin and 5mM salicylate. Following the tissue fixation and staining with phalloidin-TRITC, the number of inner and outer hair cells (IHCs, OHCs) was scored under the fluorescent microscope. Presence of 5mM salicylate in explants cultures exposed to 100μM gentamicin significantly reduced the loss of IHCs and OHCs, as compared to explants exposed to gentamicin alone. In contrast, neomycin-induced auditory hair cell loss remained unaffected by the presence of salicylate. Our results corroborate earlier in vivo findings and validate the use of cochlear explants for future studies on ototoxicity and its prevention. Moreover, the inability of salicylate to prevent neomycin-induced ototoxicity implies possible differences between the mechanisms of auditory hair cell loss induced by gentamicin and neomycin.

To determine the effect of cochlear implantation (CI) on health-related quality of life (HRQoL), tinnitus, and psychological comorbidity in patients with severe to profound postlingual hearing loss and to analyze the relationship between these parameters.

Multiple myeloma (MM) is characterized by a plasma cell infiltrate of the bone marrow (BM). However, late-stage monotypic B cells have been detected in the blood. This work analyzes the effects of clinical treatment on late stage CD19+ B cells present in 752 blood samples from 152 MM patients. MM patients have 2 to 8 times as many circulating CD19+ cells as do normal donors. Analysis of the Ig heavy chain (IgH) gene rearrangements using polymerase chain reaction indicates that the CD19+ population includes cells sharing the same clonotypic CDR3 region as is detected in the BM plasma cells, for patients analyzed during chemotherapy or in relapse. They are also monotypic as defined by their cytoplasmic or surface expression of Ig kappa or lambda light chain. The light chain restriction is the same as that of the BM plasma cells. Individual patients observed over 1- to 2-year periods exhibit considerable variation in the number of B cells present in blood; this number does not correlat...

Ischemia can contribute to the inner ear pathology and hearing loss. To determine the susceptibility of inner and outer hair cells (IHCs/OHCs) to ischemic and post-ischemic period, we used organotypic cultures of the organ of Corti isolated from P3 rats as an in vitro model of inner ear ischemia (oxygen-glucose deprivation, OGD). We identified the hair cells (HCs) by phalloidin staining. The cells with damaged cellular membrane integrity were identified by propidium iodide (PI)-exclusion assay. The cells with fragmented chromosomal DNA were detected by TUNEL assay. Organotypic cultures were subjected to a mild (3 h duration) or severe (4 h duration) OGD, followed by a recovery period of 21 h and 20 h, respectively. Mild OGD induced a loss of 10-20% HCs, whereas severe OGD induced loss of 35% HCs. We confirmed that OHCs are less vulnerable to OGD than IHCs. Of all missing OHCs, 80-90% was lost during the OGD period and 10-20% during the recovery period. In contrast, the loss of IHCs ...

A young girl with Goldenhar syndrome and bilateral, unbalanced, fluctuating and progressive hearing loss successfully employed an FM system during classroom activities. Teacher and student questionnaires revealed overall satisfaction with the FM system, as well as a significant progress in the academic performance. Schoolchildren with mild hearing loss often reject the use of conventional hearing aids during school hours, when acoustic inadequacies and social stigma eclipse any perceived benefit. FM systems such as EduLink TM are a viable alternative in those situations and, in some instances, may predispose reluctant patients to accept a more conventional hearing solution.

Presbycusis or age-related hearing loss (ARHL) is a ubiquitous health problem. It is estimated that it will affect up to 1.5 billion people by 2025. In addition, tinnitus occurs in a large majority of cases with presbycusis. Glutamate metabotropic receptor 7 () and-acetyltransferase 2 () are some of the genetic markers for presbycusis.To explore patterns of hearing loss and the role ofandas possible markers of presbycusis and tinnitus in a Portuguese population sample.Tonal and speech audiometry, tinnitus assessment, clinical interview, and DNA samples were obtained from patients aged from 55 to 75 with or without tinnitus.analysis was performed by qPCR. Genotyping of single nucleotide polymorphisms (SNPs) inwas performed by PCR amplification followed by Sanger sequencing or by qPCR.We screened samples from 78 individuals (33 men and 45 women). T allele atgene was the most observed (60.3% T/T and 33.3% A/T). Individuals with a T/T genotype have a higher risk for ARHL and 33% lower r...

Objective. To investigate the participation of clonotypic MM B cells in the IL-6 network in patients with multiple myeloma. Methods. CD19 ϩ B cells from 45 patients with multiple myeloma and from 18 healthy donors were sorted and their expression of IL-6, IL-6 receptor (CD126) characterized by flow cytometry, in situ RT-PCR, and ELISA measurement of IL-6 and soluble IL-6R. Expression of CD31 was detected by flow cytometry. Results. Interleukin-6 (IL-6) is a pleiotropic cytokine often overexpressed in multiple myeloma (MM). IL-6 induces growth and inhibits apoptosis of MM plasma cells, and upregulates the activity of osteoclasts. MM plasma cells, the most mature component of the MM clone, secrete IL-6 and induce IL-6 production from other cell types. However, the MM clone also includes circulating clonotypic B lymphocytes. Using ELISA and in situ RT-PCR we demonstrate here that, unlike the healthy control B cells, MM B cells express IL-6 mRNA and secrete IL-6 protein. In vitro, MM B cells were the major producers of IL-6 in peripheral blood mononuclear cells. On average, 50% of MM B cells express the IL-6 receptor (IL-6R, CD126), suggestive of autocrine stimulation. They also express CD31, potentially facilitating their paracrine interactions with osteoclast precursors. Conclusion. Secretion of IL-6 by circulating clonotypic B cells in MM may contribute to the autocrine and paracrine cytokine networks that maintain the malignant clone and are responsible for disruption of normal bone metabolism in this incurable disease.

Ischemia can contribute to the inner ear pathology and hearing loss. To determine the susceptibility of inner and outer hair cells (IHCs/OHCs) to ischemic and post-ischemic period, we used organotypic cultures of the organ of Corti isolated from P3 rats as an in vitro model of inner ear ischemia (oxygen glucose deprivation, OGD). We identified the hair cells (HCs) by phalloidin staining. The cells with damaged cellular membrane integrity were identified by propidium iodide (PI)-exclusion assay. The cells with fragmented chromosomal DNA were detected by TUNEL assay. Organotypic cultures were subjected to a mild (3 h duration) or severe (4 h duration) OGD, followed by a recovery period of 21 h and 20 h, respectively. Mild OGD induced a loss of 10-20 % HCs whereas severe OGD induced loss of 35 % HCs. We confirmed that OHCs are less vulnerable to OGD than IHCs. Of all missing OHCs, 80-90 % was lost during the OGD period and 10-20 % during the recovery period. In contrast, the loss of IHCs was equal during both experimental periods. The OGD period was mainly associated with PI-positive nuclei. TUNEL-positive nuclei were a minor fraction during the OGD period and increased during the recovery period, indicating the progression of DNA fragmentation. Our results implicate a differential susceptibility of IHCs and OHCs during and after ischemia-like insult, which may be of therapeutic consequence.

Objective: The primary cause of subjective tinnitus is a dysfunction of the auditory system; however, the degree of distress tinnitus causes depends largely on the psychological status of the patient. Our goal was to attempt to associate the grade of tinnitus-related distress with the psychological distress, physical, or psychological discomfort patients experienced, as well as potentially relevant social parameters, through a simultaneous analysis of these factors. Methods: We determined the level of tinnitus-related distress in 531 tinnitus patients using the German version of the tinnitus questionnaire (TQ). In addition, we used the Perceived Stress Questionnaire (PSQ); General Depression Scale Allgemeine Depression Skala (ADS), Berlin Mood Questionnaire (BSF); somatic symptoms inventory (BI), and SF-8 health survey as well as general information collected through a medical history. Results: The TQ score significantly correlated with a score obtained using PSQ, ADS, BSF, BI, and SF-8 alongside psychosocial factors such as age, gender, and marital status. The level of hearing loss and the auditory properties of the specific tinnitus combined with perceived stress and the degree of depressive mood and somatic discomfort of a patient were identified as medium-strong predictors of chronic tinnitus. Social factors such as gender, age, or marital status also had an impact on the degree of tinnitus distress. The results that were obtained were implemented in a specific cortical distress network model. Conclusions: Using a large representative sample of patients with chronic tinnitus permitted a simultaneous statistical measurement of psychometric and audiological parameters in predicting tinnitus distress. We demonstrate that single factors can be distinguished in a manner that explains their causative association and influence on the induction of tinnitus-related distress.