MYC antagonizes the differentiation induced by imatinib in chronic myeloid leukemia cells through downregulation of p27(KIP1.).

Chronic myeloid leukemia (CML) progresses from a chronic to a blastic phase where the leukemic cells are proliferative and undifferentiated. The CML is nowadays successfully treated with BCR-ABL kinase inhibitors as imatinib and dasatinib. In the CML-derived K562 cell line, low concentrations of imatinib induce proliferative arrest and erythroid differentiation. We found that imatinib upregulated the cell cycle inhibitor p27(KIP1) (p27) in a time- and -concentration dependent manner, and that the extent of imatinib-mediated differentiation was severely decreased in cells with depleted p27. MYC (c-Myc) is a transcription factor frequently deregulated in human cancer. MYC is overexpressed in untreated CML and is associated to poor response to imatinib. Using K562 sublines with conditional MYC expression (induced by Zn(2+) or activated by 4-hydroxy-tamoxifen) we show that MYC prevented the erythroid differentiation induced by imatinib and dasatinib. The differentiation inhibition is not due to increased proliferation of MYC-expressing clones or enhanced apoptosis of differentiated cells. As p27 overexpression is reported to induce erythroid differentiation in K562, we explored the effect of MYC on imatinib-dependent induction of p27. We show that MYC abrogated the imatinib-induced upregulation of p27 concomitantly with the differentiation inhibition, suggesting that MYC inhibits differentiation by antagonizing the imatinib-mediated upregulation of p27. This effect occurs mainly by p27 protein destabilization. This was in part due to MYC-dependent induction of SKP2, a component of the ubiquitin ligase complex that targets p27 for degradation. The results suggest that, although MYC deregulation does not directly confer resistance to imatinib, it might be a factor that contributes to progression of CML through the inhibition of differentiation.

Hearing loss and vestibular function correlation in Menière's disease patients.

OBJECTIVES: To analyse the correlation between vestibular dysfunction and hearing level of patients diagnosed with Menière's disease. METHODS: Retrospective study on the correlation between hearing level and unilateral weakness in 100 Menière's disease patients. In order assess the effect of disease severity in such correlation, the study group included 50 patients who subsequently were treated with oral medication and 50 who later received intratympanic gentamicin to control their symptoms. Audiogram and caloric tests were performed before beginning both of the treatments. Patients were classified according to the AAO-HNS guidelines. Handicap was assessed with the Functional Level of the AAO-HNS and the Dizziness Handicap Inventory. RESULTS: No correlation was found between pure tone average and canal paresis neither when patients were analysed as a whole nor when correlation was controlled for the treatment installed afterwards. Nevertheless, when they were grouped by hearing loss AAO-HNS stages, we found a greater canal paresis in those with a higher hearing loss (groups 3 and 4). CONCLUSION: No correlation was found between hearing loss and canal paresis of patients diagnosed with Menière's disease. However patients with a higher amount of hearing damage have a tendency to abnormal caloric results.

Disability in patients with Menière's disease following the use of two different treatment modalities: betahistine and intratympanic gentamicin.

OBJECTIVE: The objective of this study was to assess the level of residual disability and handicap in patients with Menière's disease (MD) that were free of new vertigo spells 2 years after having been administered treatment with either oral medication or with intratympanic gentamcin. SETTING: University hospital. Tertiary medical center. MATERIAL AND METHOD: 40 patients with MD were included in this study, of which 20 were treated with oral medication (betahistine) and 20 with intratympanic gentamicin; intratympanic gentamicin was for patients considered failures for the oral medication treatment. All of them are free of new vertigo in the 16-24 month period after beginning the treatment. They were matched by age and disease duration. Disability and handicap were assessed with conventional questionnaires at the time of inclusion and 2 years after beginning oral medication or ended the intratympanic gentamicin treatment. According to the treatment two groups were created: oral medication treatment and intratympanic gentamicin treatment. RESULTS: The amount of disability before treatment was higher in patients treated with intratympanic gentamicin than in those under oral medication; However, after treatment when no more vertigo spells takes place, this disability is significantly reduced and becomes similar for both groups of patients. In patients treated with oral medication the items reflecting the intensity of vertigo spell, the impact of vertigo in daily activities, the perception of quality of life and level of somatization do not show a significant reduction. CONCLUSION: The number or frequency of vertigo spells are very relevant for the process of disability and handicap of patients with MD when that is low or when oral medication is sufficient to eliminate vertigo spells. However when that number is high and the only possibility to arrest those vertigo spells is the use of intratympanic gentamicin, fear of vertigo must be considered as an associated problem for the patient.

The subjective visual vertical in benign paroxysmal positional vertigo. A preliminary study.

In Benign Paroxysmal Positional Vertigo (BPPV), the existence of otoconial debris in the cupula or canal explains most of the symptoms and signs characteristic of this common inner ear disorder. We have studied the ability of patients with BPPV to correctly determine the subjective visual vertical, as this is a good test to evaluate utricular function. Only 1 of 10 patients with BPPV displayed a clearly abnormal response, and there was no correlation between the side of the lesion and the perceived tilt. This might imply that the limited damage induced by the dislodged otoconia does not disrupt utricular function or that the saccule is the source of the problem.