Chirp-Evoked VEMPs: A Test-Retest Reliability Study.

OBJECTIVES: To determine the test-retest reliability of cervical and ocular vestibular-evoked myogenic potentials (c&oVEMP) evoked by 500 Hz narrowband (NB) CE-Chirp and broadband (BB) CE-Chirp stimuli. DESIGN: Twenty healthy participants (10 female) were tested twice on the same day to determine the within-session reliability and 1 week later to determine the between-session reliability. The latency, amplitude, and asymmetry ratio of c&oVEMPs elicited by 95 dB nHL air-conducted (AC) 500 Hz NB CE-Chirp and BB CE-Chirp were recorded bilaterally. RESULTS: A moderate to good between-session reliability with intraclass correlation coefficient (ICC) values ranging from 0.52 to 0.82 was observed for cVEMP latency, amplitude, and asymmetry ratio evoked by 500 Hz NB CE-Chirp, as well as for the BB CE-Chirp cVEMP amplitude (ICC of 0.70 and 0.84). In contrast, an overall poor reliability ICC values between 0.30 and 0.42 for cVEMP latency and asymmetry ratio were observed for BB CE-Chirp. For the oVEMP, overall poor between-session reliability for all response parameters evoked by the 500 Hz NB CE-Chirp and the BB CE-Chirp was observed. CONCLUSIONS: The 500 Hz NB CE-Chirp was more reliable than the BB CE-Chirp in terms of cVEMP latency, amplitude, and asymmetry ratio. Further investigation using the standard electrode montage is necessary to assess the test-retest reliability of the chirp-evoked oVEMP.

Cervical and ocular vestibular evoked myogenic potential: A comparison of narrowband chirp, broadband chirp, tone burst and click stimulation.

OBJECTIVES: To compare the response rate and response parameters of cervical and ocular vestibular evoked myogenic potentials (c&oVEMP) elicited by narrowband (NB) and broadband (BB) CE-Chirp, with the more classical tone burst (TB) and click VEMPs. DESIGN: The response rate, latency, amplitude and asymmetry ratio of c&oVEMPs elicited by 95 dB nHL air conducted (AC) 500 Hz NB CE-chirp, BB CE-chirp, 500 Hz TB and click stimuli were recorded bilaterally. STUDY SAMPLE: 20 male and 38 female participants (19-39 years). RESULTS: For the cVEMP, the highest response rate was found for NB chirp (100%), followed by TB (91%), BB chirp (87%) and finally click (85%). A similar order was seen for oVEMP with percentages of 100%; 57%, 57%, and 43%. The 500 Hz NB CE-Chirp elicited significantly shorter cVEMP P1 and N1 latencies and significantly larger c&oVEMP amplitudes compared to all other stimuli. BB CE-Chirp elicited significantly shorter c&oVEMP P1 and N1 latencies with smaller amplitudes compared to TB. Asymmetry ratios were not statistically significant for all comparisons. CONCLUSION: The 500 Hz NB CE-chirp provides the highest response rates, shorter latencies and larger amplitudes, and therefore seem a promising stimulus for reliably measuring c&oVEMPs in clinical practice.

cVEMPs: a systematic review and meta-analysis.

OBJECTIVE: A systematic literature review and meta-analysis was performed to determine the effect of stimulus type, SCM muscle activation method, transducer type, and method to control SCM muscle EMG level on response parameter values for 0.1-ms click-evoked and 500-Hz tone burst cVEMPs. A description of normative response values was attempted. DESIGN: An electronic systematic literature review was performed to obtain normative cVEMP response data. Subsequently a meta-analysis was conducted to determine significant effects on cVEMP response parameters and to obtain norms. STUDY SAMPLE: Scopus was used to identify reports containing normative data. Reports were selected based on inclusion and exclusion criteria determined beforehand. Weighted means were calculated and compared to identify significant effects and normative data. RESULTS: Sixty-six reports were included in the systematic review. Stimulus type, SCM muscle activation method, transducer type, and method to control SCM muscle EMG level had significant effects on all response parameters. CONCLUSIONS: Optimal stimulus and recording parameters suggested by previous research are confirmed by the current systematic review and meta-analysis and are suggested for clinical use. Response parameter values are influenced by variations in stimulus and recording parameters and normative response values are suggested as guideline for cVEMP interpretation.

Computerized Rotational Head Impulse Test: Age-Dependent Normative Data.

PURPOSE: The objective of this study was to determine the normative vestibulo-ocular reflex gain output values of the computerized rotational head impulse test (crHIT) with stationary visual targets (earth bound) in healthy participants in each decade age band of life: 10-19, 20-29, 30-39, 40-49, 50-59, 60-69, and 70+ years. METHOD: Seventy-seven community-dwelling participants (10-85 years of age) with normal lateral semicircular canal (SCC) functioning and no symptoms or history of vestibular dysfunction were recruited through convenience sampling and assessed with the crHIT using stationary targets. These participants were assessed using two standard protocols in a randomized order. RESULTS: Results from 77 participants (M age = 46 years; 43 women, 34 men) were analyzed. Pearson's correlation coefficient and simple linear regression indicated a statistically significant relationship between crHIT gain output and age (p > .05) for right gain, 1030°/s2, and left gain, 1005°/s2. Although a statistically significant relationship was found, the slope was minor, demonstrating that the clinical effect of age on crHIT gain output was insignificant. Furthermore, no statistically significant relationship exists between crHIT gain output and gender (p > .05). Age-dependent normative data were calculated using the 2.5th and 97.5th confidence interval (CI) percentile method. The responses of angular vestibulo-ocular reflex (aVOR) gain values for crHIT are expected to occur within the range for lower limit reference interval (RI) of 0.85-0.9 and upper limit RI of 1.11-1.18 for 1030°/s2 and lower limit RI of 0.86-0.92 and upper limit RI of 1.13-1.16 for 1005°/s2. It can be expected that 90% CI of the population with normal lateral SCC functioning will have aVOR gain values that fall within this range. CONCLUSION: Despite a statistically significant relationship that exists with aVOR gain output and age, the changes are minor, declining by 0.0088 units per 10 years, justifying the same normative data for all decade age bands.

Auditory and otological manifestations in adults with HIV/AIDS.

OBJECTIVES: This study describes the prevalence and nature of auditory and otological manifestations in adults with HIV/AIDS through clinical examinations and self-reported symptoms across stages of disease progression. DESIGN: Descriptive cross-sectional group design. STUDY SAMPLE: Two hundred HIV positive adult patients (56.5% male; 43.5% female; mean age: 37.99 ± 6.66 years) attending the Infectious Disease Clinic of a tertiary referral hospital in Pretoria, South Africa were included. Patients were interviewed, medical files were reviewed, and clinical examinations, including otoscopy, tympanometry, pure-tone audiometry, and distortion product otoacoustic emissions, were conducted. A matched HIV negative control group was used to compare hearing loss prevalence. RESULTS: Tinnitus (26%), vertigo (25%) hearing loss (27.5%), otalgia (19%), and ear canal pruritis (38%) were prevalent self-reported symptoms. Abnormalities in otoscopy, tympanometry, and otoacoustic emissions were evident in 55%, 41%, and 44% of patients respectively. Pure-tone average (PTA) hearing loss > 25 dBHL was evident in 14% of patients and 39% for hearing loss > 15 dBHL (PTA). Significant differences across average thresholds in the HIV positive and HIV negative control group was present. An increase in self reported vertigo, self reported hearing loss, OAE abnormalities, and hearing loss (PTA > 15 dBHL and PTA > 25 dBHL) was seen with disease progression but was not statistically significant. A significant increase (p <.05) in sensorineural hearing loss was however evident with disease progression. CONCLUSIONS: Auditory and otological symptoms are more common in patients with HIV with a general increase of symptoms, especially sensorineural hearing loss, towards advanced stages of disease progression.

On the Power of Additional and Complex Chromosomal Aberrations in CML.

Unregulated proliferation of mainly myeloid bone marrow cells and genetic changes in the hematopoietic stem cell system are important features in Chronic Myeloid Leukemia (CML). In clinical diagnosis of CML, classical banding techniques, fluorescence in situ hybridization (FISH) probing for the Philadelphia chromosome (Ph) or polymerase chain reaction amplifying the fusion products of the BCR-ABL fusion are state of the art techniques. Nevertheless, the genome of CML patients harbors many more cytogenetic changes. These might be hidden in subpopulations due to clonal events or involved in extremely complex aberrations. To identify these additional changes, several cytogenetic and molecular genetic techniques could be applied. Nevertheless, it has been proposed that identifying these aberrations is time consuming and costly and since they cannot be converted into a benefit for the patients, the necessity to perform these investigations has been questioned. In the times where highly specialized medicine is advancing into several areas of cancer, this attitude needs to be reassessed. Therefore, we looked at the usefulness of a combination of different techniques to unravel the genetic changes in CML patients and to identify new chromosomal aberrations, which potentially can be correlated to different stages of the disease and the strength of therapy resistance. We are convinced that the combination of these techniques could be extremely useful in unraveling even the most complex karyotypes and in dissecting different clones contributing to the disease. We propose that by doing so, this would improve CML diagnostic and prognostic findings, especially with regard to CML resistance mechanisms and new therapeutic strategies.

Ototoxicity monitoring in South African cancer facilities: A national survey.

BACKGROUND: National information regarding ototoxicity monitoring practices are limited for patients undergoing chemotherapy in South Africa. OBJECTIVES: To determine (1) the national status of ototoxicity monitoring implemented in private and public cancer facilities, (2) the knowledge and ototoxicity monitoring approaches implemented, and (3) reported challenges. METHOD: A descriptive quantitative survey was conducted in public and private oncology units and audiology referral clinics. Private (60%) and public (43%) oncology units that provide platinum-based chemotherapy in South Africa and audiology referral units (54%) were: (1) surveyed telephonically to determine if ototoxicity monitoring takes place; and (2) a self-administered survey was sent to qualifying oncology units and audiology referral clinics. RESULTS: All public oncology units reported that ototoxicity monitoring only occurs on referral and is not standard practice. All private oncology units indicated that monitoring is on a patient self-referral basis when symptoms occur. Poor awareness of ototoxicity monitoring best practice guidelines was reported by all oncology units and 14% of audiology referral clinics. Audiology referral clinics reported adequate knowledge of ototoxicity protocols although they are not widely used with only 43% following best practice guidelines. The most prominent challenges reported by participants was referral system (67% oncology units; 57% audiology referral clinics), environmental noise (83% oncology units; 86% audiology referral clinics) and the compromised status of cancer patients (67% oncology units; 57% audiology referral clinics). CONCLUSION: Ototoxicity monitoring is not routinely implemented across oncology units in South Africa. Multidisciplinary teamwork and a simplified national ototoxicity monitoring protocol may improve hearing outcomes for patients.

Changes in vestibular and cochlear function following platinum-based chemotherapy: A preliminary report.

OBJECTIVES: This study investigated the changes in vestibular and cochlear function in patients receiving platinum-based chemotherapy. METHODS: A longitudinal study of 32 participants (10-70 years) receiving chemotherapy participated in the study. Baseline and exit vestibular and hearing assessments that included video head impulse (VHIT) testing, cervical and ocular vestibular evoked myogenic potentials (VEMP), dynamic visual acuity (DVA) and pure-tone audiometry were performed at the patient's treatment venue. RESULTS: Half (50%) of the participants showed cochleotoxicity from baseline to exit testing, with left ears significantly more affected than right ears. There was no consistent relationship between hearing loss and vestibular dysfunction. DVA yielded normal results at baseline and exit testing in all participants. VEMP responses were absent in 28.1% of participants at baseline, reflecting the challenges of using VEMP for monitoring. VEMP and VHIT results showed a statistically significant (p < 0.05) decline in results from baseline to exit testing; however, participants did not report symptoms related to vestibular dysfunction. VHIT also showed left ears significantly (p < 0.05) more affected than right ears. CONCLUSION: VHIT proved to be a valuable measure of changes in vestibular function secondary to ototoxicity. Future investigations should determine vestibulotoxicity criteria and optimal protocols for vestibulotoxicity monitoring at the patient's treatment venue.

Auditory, video head impulse test and vestibular evoked myogenic potentials findings in adults with human immunodeficiency virus.

OBJECTIVES: Even though there is an association between hearing loss and human immunodeficiency virus (HIV), particularly in low- and middle-income countries, further research is needed to investigate the nature of such hearing loss. Likewise, despite documented vestibular alterations in people with HIV, the true occurrence, presentation, and nature of these manifestations are yet to be established. Advances in technology for vestibular testing has allowed for objective site-of-lesion tests such as the video head impulse test (vHIT), cervical vestibular evoked myogenic potentials (cVEMPs) and ocular vestibular evoked myogenic potential (oVEMPs). The current study aimed to compare and describe auditory, vHIT, cVEMPs and oVEMPs findings in adults with and without HIV. METHODS: The current study included an HIV positive group (n = 30) and an HIV negative group (n = 30) who underwent an auditory assessment (tympanometry and pure tone audiometry) and objective vestibular assessments. RESULTS: The occurrence of hearing loss was 53.3% in the HIV positive group compared to 33.3% in the HIV negative group. A higher occurrence of vestibular involvement was documented in the HIV positive group (73.3%) compared to 13.3% in the HIV negative group. CONCLUSION: Auditory assessment and objective measures of vestibular end-organ function (vHIT and VEMPs) can be useful to detect sub-clinical alterations. The equipment is mobile and can be performed in any health care setting such as infectious disease clinics for surveillance and monitoring purposes.

Monitoring Hearing in an Infectious Disease Clinic with mHealth Technologies.

BACKGROUND: Decentralized detection and monitoring of hearing loss can be supported by new mobile health technologies using automated testing that can be facilitated by minimally trained persons. These may prove particularly useful in an infectious disease (ID) clinic setting where the risk of hearing loss is high. PURPOSE: To evaluate the clinical utility of mobile and automated audiometry hearing health technology in an ID clinic setting. RESEARCH DESIGN: Smartphone-automated pure-tone audiometry (PTA) (hearTest™) and speech-in-noise testing (SA English digits-in-noise [DIN] test) were compared with manual audiometry (2, 4, and 8 kHz). Smartphone-automated PTA and the DIN test were repeated to determine the test-retest reliability. STUDY SAMPLE: Two hundred subjects (73% female and 27% male) were enrolled. Fifty participants were retested with the smartphone applications. Participants ranged from an age of 18 to 55 years with a mean age of 44.4 (8.7 standard deviation). DATA ANALYSIS: Threshold comparisons were made between smartphone audiometry testing and manual audiometry. Smartphone-automated PTA, manual audiometry, and test-retest measures were compared (Wilcoxon signed ranked test). Spearman rank correlation test was used to determine the relationship between the smartphone applications and manual audiometry, as well as for test-retest reliability. RESULTS: Within all participants, 88.2% of thresholds corresponded within 10 dB or less between smartphone audiometry and manual audiometry. There was a significant difference (p < 0.05) between the right ear at 4 and 8 kHz and in the left ear at 2 and 4 kHz between smartphone and manual audiometry, respectively. No significant difference was noted (p < 0.05) between test and retest measures of smartphone technology. CONCLUSIONS: Smartphone audiometry with calibrated headphones provides reliable results in an ID clinic setting and can be used as a baseline and monitoring tool at ID clinics.

A novel breast cancer cell line initially established from pleural effusion: evolution towards a more aggressive phenotype.

Many human breast cancer cell lines have been in culture for several years, serving as model systems for studying aspects of breast cancer biology. Molecular alterations might occur in these cells during cultivation, and it remains unknown to which extent findings in these cell lines can be related to human disease. Hereby, we describe the establishment of a breast cancer cell line, MW1, from malignant pleural effusion. We compare expression patterns of several molecular markers in breast biopsy tissue, in cultivated tumor cells derived from pleural effusion reflecting the metastatic state, and in late passages of a lineage derived from the pleural culture. Our data show that expression of estrogen and progesterone receptors was lost in the cultivated tumor cells derived from pleural effusion as shown by immunohistochemical staining. Cytokeratin expression patterns remained luminal. During cultivation, the growth rate of MW1 cells increased dramatically and the morphology underwent alterations. As shown by Western blotting, E-cadherin expression remained unchanged whereas P-cadherin expression had increased after 4 years of cultivation of the cell line. Integrin beta4 expression was low in early passages of the pleural effusion whereas the cell line exhibited high expression levels of beta4. HGF receptor (c-Met), EGF receptor, VEGF and VEGF receptor-2 (KDR) expression was detectable by semiquantitative RT-PCR and remained unchanged during cultivation. In contrast, VEGF receptor-1 (flt-1) expression showed lower expression after 4 years of cultivation. The cell line migrated towards HGF, but not towards VEGF. This study provides exemplary insight into the molecular metamorphosis tumor cells undergo in vivo or in vitro on their way from the primary tumor via an equivalent of the metastatic state and during the development of a clonal cell line.

'Standard' versus 'nose reference' electrode placement for measuring oVEMPs with air-conducted sound: Test-retest reliability and preliminary patient results.

OBJECTIVES: This study compared two electrode placements ('standard' versus 'nose reference' placement) for measuring oVEMPs, elicited by air-conducted 500Hz tone bursts. The test-retest reliability of both positions was evaluated and additionally both electrode placements were applied on a group of vestibular patients. METHODS: Eighteen healthy volunteers (range of 20-25years) participated in the first part and were retested after one week for evaluation of the test-retest reliability. Eleven patients (range of 41-74years) with a variety of vestibular pathologies were tested once. RESULTS: In the normal group, the nose reference electrode placement resulted in significantly larger peak-to-peak amplitudes (p<0.001), shorter n10 (p=0.001) and p15 (p<0.001) latencies and smaller 95% prediction intervals for the Inter-Ocular Ratio (IOR) ([-68, 68] for the standard position versus [-32, 32] for the nose reference position). Furthermore, an excellent amplitude and IOR test-retest reliability was observed with the nose reference configuration, as shown by the intraclass correlation coefficient (ICC), the coefficient of variation of the method error (CVME) and the minimal detectable differences (MDD). In the patient group, the same significant amplitude difference was found. Moreover, three patients presented with absent oVEMPs when recorded with the standard placement, whereas the nose reference placement could evoke a detectable oVEMP response. CONCLUSIONS: This study demonstrated that a nose reference electrode position results in larger oVEMP amplitudes and achieves a better reliability for the most important clinical parameters (amplitude and IOR). Our patient data substantiate the possible clinical benefit of this position, but further systematic patient verification is required. SIGNIFICANCE: The nose reference electrode position facilitates the detection of generally very small oVEMP responses and shows a high test-retest reliability, showing promising potential for future use in the vestibular clinic.

A Cross-sectional Survey and Cross-sectional Clinical Trial to Determine the Prevalence and Management of Eye Movement Disorders and Vestibular Dysfunction in Post-Stroke Patients in the Sub-Acute Phase: Protocol.

INTRODUCTION: Visual impairment, specifically eye movement disorders and vestibular dysfunction may have a negative influence on the functional recovery in post-stroke patients. This type of sensory dysfunction may further be associated with poor functional outcome in patients' post-stroke. METHODS: In phase 1, a cross-sectional survey (n = 100) will be conducted to determine the prevalence of eye movement disorders and vestibular dysfunction in patients who sustained a stroke. A cross-sectional clinical trial (n = 60) will be conducted during phase 2 of the study to determine the effect of the combination of vestibular rehabilitation therapy (VRT) and visual scanning exercises (VSE) (experimental group) integrated with task-specific activities compared with the effect of task-specific activities as an intervention (control group) on patients who present with eye movement impairment and central vestibular dysfunction post-stroke. An audiologist will assess (a) visual acuity (static and dynamic), (b) nystagmus, (c) saccadic eye movements, (d) smooth pursuit eye movements, (e) vestibulo-ocular reflex, and (f) saccular, utricular, and vestibular nerve function. An independent physiotherapist will assess (1) cognitive function, (2) residual oculomotor visual performance, (3) visual-perceptual system, (4) functional balance, (5) gait, (6) functional ability, (7) presence of anxiety and/or depression, and (8) level of participation in physical activity. ETHICS AND DISSEMINATION: Ethics approval has been obtained from the Ethics Committee of the Faculty of Health Sciences at the University of Pretoria (UP) (374/2015). The study will be submitted as fulfillment for the PhD degree at UP. Dissemination will include submission to peer-reviewed professional journals and presentation at congresses. Training of rehabilitation team members on the integration of VSE and VRT into task-specific activities in rehabilitation will be done if the outcome of the experimental group's functional performance is clinically and statistically significantly better than the control group on the Barthel Index. TRIAL REGISTRATION: Pan African Clinical Trials Registry (PACTR201509001223262).

Computer aided analysis of additional chromosome aberrations in Philadelphia chromosome positive acute lymphoblastic leukaemia using a simplified computer readable cytogenetic notation.

BACKGROUND: The analysis of complex cytogenetic databases of distinct leukaemia entities may help to detect rare recurring chromosome aberrations, minimal common regions of gains and losses, and also hot spots of genomic rearrangements. The patterns of the karyotype alterations may provide insights into the genetic pathways of disease progression. RESULTS: We developed a simplified computer readable cytogenetic notation (SCCN) by which chromosome findings are normalised at a resolution of 400 bands. Lost or gained chromosomes or chromosome segments are specified in detail, and ranges of chromosome breakpoint assignments are recorded. Software modules were written to summarise the recorded chromosome changes with regard to the respective chromosome involvement. To assess the degree of karyotype alterations the ploidy levels and numbers of numerical and structural changes were recorded separately, and summarised in a complex karyotype aberration score (CKAS). The SCCN and CKAS were used to analyse the extend and the spectrum of additional chromosome aberrations in 94 patients with Philadelphia chromosome positive (Ph-positive) acute lymphoblastic leukemia (ALL) and secondary chromosome anomalies. Dosage changes of chromosomal material represented 92.1% of all additional events. Recurring regions of chromosome losses were identified. Structural rearrangements affecting (peri)centromeric chromosome regions were recorded in 24.6% of the cases. CONCLUSIONS: SCCN and CKAS provide unifying elements between karyotypes and computer processable data formats. They proved to be useful in the investigation of additional chromosome aberrations in Ph-positive ALL, and may represent a step towards full automation of the analysis of large and complex karyotype databases.

Vestibular involvement in adults with HIV/AIDS.

OBJECTIVE: HIV/AIDS is responsible for widespread clinical manifestations involving the head, and neck. The prevalence and nature of vestibular involvement is still largely unknown. This study, aimed to describe and compare the occurrence and nature of vestibular involvement among a group of, adults infected with HIV compared to a control group. It also aimed to compare the vestibular function, of symptomatic and asymptomatic HIV positive adults who receive antiretroviral (ARV) therapies to, subjects not receiving ARV. METHODS: A cross-sectional study was conducted on 53 adults (29 male, 24 female, aged 23-49 years, mean=38.5, SD=4.4) infected with HIV, compared to a control group of 38 HIV negative adults (18, male, 20 female, aged 20-49 years, mean=36.9, SD=8.2). A structured interview probed the subjective, perception of vestibular symptoms. Medical records were reviewed for CD4+ cell counts and the use of, ARV medication. An otologic assessment and a comprehensive vestibular assessment (bedside, assessments, vestibular evoked myogenic potentials, ocular motor and positional tests and bithermal, caloric irrigation) were conducted. RESULTS: Vestibular involvement occurred in 79.2% of subjects with HIV in all categories of disease, progression, compared to 18.4% in those without HIV. Vestibular involvement increased from 18.9% in CDC category 1 to 30.2% in category 2. Vestibular involvement was 30.1% in category 3. There were, vestibular involvement in 35.9% of symptomatic HIV positive subjects, and 41.5% in asymptomatic, HIV positive subjects. There was no significant difference in the occurrence of vestibular involvement, in subjects receiving ARV therapies compared to those not receiving ARV therapies (p=.914; chi-square, test). The odds ratio indicates that individuals with HIV have a 16.61 times higher risk of developing, vestibular involvement during their lifetime of living with the disease and that it may occur despite, being asymptomatic. CONCLUSION: Vestibular involvement was significantly more common in subjects with HIV. Primary health care providers could screen HIV positive patients to ascertain if there are symptoms of vestibular involvement. If there are any, then they may consider further vestibular assessments and subsequent vestibular rehabilitation therapy.

CD10- pre-B acute lymphoblastic leukemia (ALL) is a distinct high-risk subgroup of adult ALL associated with a high frequency of MLL aberrations: results of the German Multicenter Trials for Adult ALL (GMALL).

Immunophenotyping disclosed CD10 negativity in 70 of 2408 cases of B-lineage acute lymphoblastic leukemia (ALL), although other criteria followed classification of pre-B ALL (eg, cytoplasmic immunoglobulin positivity). These blasts showed high myeloid antigen expression (60% CD65 positivity) and reacted with antibody 7.1 in 95% of the cases. MLL-AF4 fusion transcripts or an 11q23/MLL rearrangement or both were evident in 46 of 56 samples (82%). Although 83% of the patients achieved complete remission, the remission duration remained remarkably low: 141 days for MLL rearrangement-positive and 245 days for MLL rearrangement-negative CD10(-) pre-B ALL. Thus, the overall survival probability 3 years after diagnosis was 0.34 +/- 0.20 SE in MLL-rearrangement-negative versus 0.12 +/- 0.06 SE in MLL rearrangement-positive CD10- pre-B ALL. Our data identify CD10- cytoplasmic immunoglobulin-positive pre-B ALL as a rare (2.2%) but distinct immuno-subtype of adult ALL that is characterized by a high MLL rearrangement rate and a worse outcome.

CaT1 knock-down strategies fail to affect CRAC channels in mucosal-type mast cells.

CaT1, the calcium transport protein 1 encoded by TRPV6, is able to generate a Ca(2+) conductance similar but not identical to the classical CRAC current in mucosal-type mast cells. Here we show that CaT1-derived Ca(2+) entry into HEK293 cells is effectively inhibited either by expression of various dominant negative N-terminal fragments of CaT1 (N(334)-CaT1, N(198)-CaT1 and N(154)-CaT1) or by antisense suppression. By contrast, the endogenous CRAC current of the mast cells was unaffected by CaT1 antisense and siRNA knockdown but markedly suppressed by two (N(334)-CaT1, N(198)-CaT1) of the dominant negative N-CaT1 fragments. Inhibition of CRAC current was not an unspecific, toxic effect, as inward rectifier K(+) and MagNuM currents of the mast cells were not significantly affected by these N-CaT1 fragments. The shortest N(154)-CaT1 fragment inhibited CaT1-derived currents in mast cells, but failed to inhibit CRAC currents. Thus, the structural requirements of rCaT N-terminal fragments for inhibition of rCaT1 and CRAC channels are different. These results together with the lack of CaT1 antisense and siRNA effects on currents render it unlikely that CaT1 is a component of native CRAC channels in mast cells. The data further demonstrate a novel strategy for CRAC current inhibition by an N-terminal structure of CaT1.