Noninvasive finding of local repolarization changes in the heart using dipole models and simplified torso geometry

Two inverse methods using dipole models for noninvasive assessment of local repolarization changes were investigated and compared in the simulation study. Lesions with changed repolarization were modeled by shortening of the action potential durations in ventricular regions typically influenced by occlusion of coronary arteries. Corresponding body surface potentials were computed using a multiple dipole model of the cardiac generator and an inhomogeneous torso model. Position of each lesion was then estimated by an inverse solution to a single dipole and to a group of five neighbouring dipoles. For both methods the lesion localization error was evaluated and its dependence on the lesion size and the noise in input data was studied. When no noise was present in the input data, the use of the inverse method to a group of dipoles instead of a single dipole resulted in an unsubstantial reduction of the mean localization error of small lesions from 0.6 to 0.5 cm. For medium and especially for large lesions the mean localization errors decreased significantly from 1.1 to 0.6 cm and from 2.3 to 1.0 cm, respectively. The inverse solution to a group of five dipoles was more sensitive to noise. However, for large lesions it still gave better results than the solution to a single dipole if the signal to noise ratio was higher than 30 dB.     

Molecular dissection of Meis1 reveals 2 domains required for leukemia induction and a key role for Hoxa gene activation

The Hoxa9 and Meis1 genes represent important oncogenic collaborators activated in a significant proportion of human leukemias with genetic alterations in the MLL gene. In this study, we show that the transforming property of Meis1 is modulated by 3 conserved domains, namely the Pbx interaction motif (PIM), the homeodomain, and the C-terminal region recently described to possess transactivating properties. Meis1 and Pbx1 interaction domain-swapping mutants are dysfunctional separately, but restore the full oncogenic activity of Meis1 when cotransduced in primary cells engineered to overexpress Hoxa9, thus implying a modular nature for PIM in Meis1-accelerated transformation. Moreover, we show that the transactivating domain of VP16 can restore, and even enhance, the oncogenic potential of the Meis1 mutant lacking the C-terminal 49 amino acids. In contrast to Meis1, the fusion VP16-Meis1 is spontaneously oncogenic, and all leukemias harbor genetic activation of endogenous Hoxa9 and/or Hoxa7, suggesting that Hoxa gene activation represents a key event required for the oncogenic activity of VP16-Meis1.     

Auditory function in presbycusis: peripheral vs. central changes

The hearing abilities of a group of 30 elderly (67-93 yr of age) subjects were compared with those of a group of 30 young (19-27 yr of age) normal hearing volunteers with the aim of characterizing the changes in the peripheral and central parts of the auditory system. In elderly subjects the pure-tone thresholds were typically represented by a gradually sloping curve with a significantly greater decline in men than in women at frequencies of 3 and 4 kHz. In spite of pure tone threshold elevation in the elderly, the difference limen for intensity at 1 and 3 kHz were not significantly smaller than in the young subjects. The incidence and levels of spontaneous, transient and distortion product otoacoustic emissions were low, which would suggest the involvement of outer hair cell pathology. Also, contralateral suppression was less marked in elderly than in young subjects. Speech audiometry in the elderly revealed serious difficulties in understanding speech. Deteriorated temporal resolution, as demonstrated by increased gap detection thresholds, correlated significantly with increased speech recognition thresholds. The results support the view that presbycusis represents a combination of deteriorated function of the auditory periphery with deteriorated function of the central auditory system.