In the ischemic or hypoxic heart, an impairment of electrical cell-to-cell coupling and a dephosphorylation of the connexins that comprise the gap junction channel were observed. However, it remains to be elucidated whether the dephosphorylation of the connexin during hypoxia is due to alterations in the ionic strength of Ca(2+) or H(+), and how the activation of protein kinase A (PKA) affects the hypoxia-induced abnormal function of the gap junction.The effects of hypoxia, intracellular Ca(2+) overload and intracellular acidosis on the PKA-mediated phosphorylation of connexin 43 (Cx43) were examined in relation to the function of the cardiac gap junction.Hearts isolated from adult, male guinea pigs were used. The intercellular electrical cell-to-cell coupling was evaluated by the longitudinal internal resistance and the conduction velocity observed in in vitro experiments using isolated muscle strip preparations. The phosphorylation of Cx43 was evaluated by an immunoblot (Western blot). The localization of immunoreactive Cx43 at the intercalated disk was detected using confocal laser scan microscopy.Cyclic AMP or the activation of PKA promotes the intercellular electrical coupling that accompanies an augmentation of the PKA-mediated phosphorylation of Cx43. Electrical cell-to-cell decoupling and reduction of the PKA-mediated phosphorylation of Cx43 were dependent on the progression of hypoxia. These results agree with those observed in the progression of intracellular Ca(2+) overload or intracellular acidosis. Cyclic AMP or the activation of PKA alleviated the electrical cellular decoupling and the hypoxia-, intracellular Ca(2+) overload- and intracellular acidosis-induced deteriorated expression of Cx43. These ameliorative effects of cyclic AMP on the function of the gap junction and on the expression of Cx43 weakened as the hypoxia progressed, and as the intracellular ionic strength of Ca(2+) and H(+) increased.In cardiac ventricular muscle cells, cyclic AMP or the activation of PKA promotes electrical cell-to-cell coupling through the gap junction due to an augmentation of the PKA-mediated phosphorylation of Cx43 in the early stage of hypoxia, as well as in normoxia. The suppression of PKA-mediated phosphorylation of Cx43 during hypoxia may be caused by an increase in the intracellular ionic strength of Ca(2+) and H(+). Thus, the activation of cyclic AMP-dependent PKA may have an antiarrhythmic effect in the early stage of hypoxia.
The use of positron emission tomography (PET) imaging in progressive multifocal leukoencephalopathy (PML) has rarely been reported. We herein report a set of PET images in a 63-year-old patient with PML. In PML lesions, the uptake of 18F-fluorodeoxyglucose, 11C-methionine, 11C-flumazenil, and [methyl-11C]4′-thiothymidine was decreased, increased, decreased, and unchanged, respectively. These results suggest that glucose metabolism decreased, protein synthesis increased, neuronal integrity decreased, and the DNA synthesis and cellular proliferation of host cells were not activated in PML lesions. These results may reflect very little infiltration by inflammatory cells and active infection with JC virus in this case.
The cerebellum plays important roles in motor coordination and learning. However, motor learning has not been quantitatively evaluated clinically. It thus remains unclear how motor learning is influenced by cerebellar diseases or aging, and is related with incoordination. Here, we present a new application for testing human cerebellum-dependent motor learning using prism adaptation. In our paradigm, the participant wearing prism-equipped goggles touches their index finger to the target presented on a touchscreen in every trial. The whole test consisted of three consecutive sessions: (1) 50 trials with normal vision (BASELINE), (2) 100 trials wearing the prism that shifts the visual field 25° rightward (PRISM), and (3) 50 trials without the prism (REMOVAL). In healthy subjects, the prism-induced finger-touch error, i.e., the distance between touch and target positions, was decreased gradually by motor learning through repetition of trials. We found that such motor learning could be quantified using the "adaptability index (AI)", which was calculated by multiplying each probability of [acquisition in the last 10 trials of PRISM], [retention in the initial five trials of REMOVAL], and [extinction in the last 10 trials of REMOVAL]. The AI of cerebellar patients less than 70 years old (mean, 0.227; n = 62) was lower than that of age-matched healthy subjects (0.867, n = 21; p < 0.0001). While AI did not correlate with the magnitude of dysmetria in ataxic patients, it declined in parallel with disease progression, suggesting a close correlation between the impaired cerebellar motor leaning and the dysmetria. Furthermore, AI decreased with aging in the healthy subjects over 70 years old compared with that in the healthy subjects less than 70 years old. We suggest that our paradigm of prism adaptation may allow us to quantitatively assess cerebellar motor learning in both normal and diseased conditions.
